WO2024078555A1 - Pyrimidopyridine compound, and pharmaceutical composition and use thereof - Google Patents

Pyrimidopyridine compound, and pharmaceutical composition and use thereof Download PDF

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WO2024078555A1
WO2024078555A1 PCT/CN2023/124140 CN2023124140W WO2024078555A1 WO 2024078555 A1 WO2024078555 A1 WO 2024078555A1 CN 2023124140 W CN2023124140 W CN 2023124140W WO 2024078555 A1 WO2024078555 A1 WO 2024078555A1
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alkyl
butyl
membered
compound
independently
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PCT/CN2023/124140
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French (fr)
Chinese (zh)
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谢洪明
刘海望
罗国林
冯锡晖
张英俊
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广东东阳光药业股份有限公司
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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • 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
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention belongs to the field of medicine. Specifically, the present invention relates to a pyrimidopyridine compound as a KRAS G12D inhibitor, a pharmaceutical composition thereof, and the use of such compound and pharmaceutical composition thereof in the preparation of drugs for preventing or treating KRAS G12D-related diseases.
  • the RAS gene is one of the most commonly mutated genes in cancer (20%-25%).
  • the currently known members of the RAS gene family include KRAS, NRAS and HRAS, among which KRAS mutation is the most common, accounting for about 85%.
  • the mutation rate of KRAS in pancreatic ductal adenocarcinoma (PDAC) is the highest, reaching 97%, followed by colorectal cancer, multiple myeloma and lung cancer, which are 52%, 42% and 32% respectively.
  • PDAC pancreatic ductal adenocarcinoma
  • the most common way for the KRAS gene to mutate is point mutation, and common mutation forms include KRAS G12D mutation (41%), KRAS G12V (28%) and KRAS G12C (14%) mutations.
  • KRAS can be transiently activated by upstream growth factors or tyrosine kinases (such as EGFR).
  • the activated KRAS can activate downstream pathways, including the PI3K-AKT-mTOR signaling pathway that controls cell generation, and the RAS-RAF-MEK-ERK signaling pathway that controls cell proliferation. This also lays a biological foundation for the combination of many targets.
  • KRAS G12C small molecule inhibitors Nature, 2013, 503, 548-551
  • KRAS G12D small molecule inhibitors
  • other mutation types such as KRAS G12D and KRAS G12V have a higher proportion in pancreatic cancer. Therefore, inhibiting KRAS G12D mutations to treat pancreatic cancer is a potentially effective means.
  • Mirati has published a series of KRAS G12D inhibitors in patent application WO20211041671, which show specificity for KRAS G12D mutants and have anti-pancreatic cancer activity.
  • the present invention provides a compound, or a pharmaceutical composition thereof, which can be used as an inhibitor of KRAS, especially as a KRAS 12D inhibitor.
  • the present invention further relates to the use of the compound or the pharmaceutical composition thereof for preparing a medicament for treating a disease and/or condition, especially cancer, by inhibiting KRAS activity.
  • the compounds of the present invention can effectively bind to KRAS G12D-GTP and inhibit the phosphorylation of ERK downstream of KRAS G12D.
  • the present invention provides a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I),
  • Q is O or S
  • Ring A is a C 3-6 carbocyclyl, a C 7-12 carbocyclyl, a 3-6 membered heterocyclyl, a 7-12 membered heterocyclyl, a C 6-12 aryl or a 5-12 membered heteroaryl;
  • Ring B is C 6-12 aryl or 5-12 membered heteroaryl
  • R3 is -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl or C1-4 haloalkyl;
  • Y is a bond, O or S
  • L is a C 1-6 alkylene group
  • R 6 , R 7 , R 6b , R 7b , R 6d , R 7d , R 6e and R 7e are each independently -H, -D or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C( ⁇ O)H, -C( ⁇ O)OH, -NR 6g R 7g , C 1-6 alkoxy, C 6-12 aryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
  • R 6a , R 6c , R 6g and R 7g are each independently -H, -D or C 1-6 alkyl;
  • n are each independently 0, 1, 2, 3, 4, 5, 6 or 7.
  • Ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, octahydropentalenyl, bicyclo[3.1.0]cyclohexyl, 2,3-dihydro-1H-indenyl, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, piperidinyl, phenyl, pyridinyl, pyrrolyl, imidazolyl, pyrimidinyl, or benzofuranyl.
  • R 6a , R 6g and R 7g are each independently -H, -D or C 1-4 alkyl.
  • R 6a , R 6g and R 7g are each independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • Ring B is one of the following substructures
  • Each R 6c is independently -H, -D or C 1-4 alkyl
  • R 6b , R 7b and the N atom to which they are attached form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted by 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl.
  • substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered hetero
  • Each R 6c is independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
  • R 6b , R 7b together with the N atom to which they are attached form pyrrolidine, piperazine, piperidine, morpholine, oxazolidine or imidazolidine, wherein the pyrrolidine, piperazine, piperidine, morpholine, oxazolidine and imidazolidine are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy, ethoxy, isopropoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, tri
  • R 4 is -H, -D, C 1-4 alkyl, 3-6 membered heterocyclyl, 7-10 membered heterocyclyl, -L-pyrrolidinyl, -L-morpholinyl, -L-oxetanyl, -L-oxetanyl, -L-tetrahydrofuranyl, -L-octahydroindolizinyl, -L-cyclopropyl, -L-cyclopentyl, -L-octahydropentalenyl, -L-octahydro-1H-indenyl, -L-decalinyl, -L-pyridinyl, -L-pyrazolyl, -L-phenyl, -L-NR 6 R 7 , -NR 6 R 7 , -L-NHC( ⁇ NH)NH 2 or -LC( ⁇ O)NR 6 R 7 , wherein the C 1-4
  • L is a C 1-4 alkylene group
  • R 6d , R 7d , R 6e and R 7e are each independently -H, -D or C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C( ⁇ O)H, -C( ⁇ O)OH, -NR 6g R 7g , C 1-4 alkoxy, C 6-10 aryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
  • substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C
  • R 4 is -H, -D, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, -CH 2 -pyrrolidinyl, -CH 2 -morpholinyl, -(CH 2 ) 2 -morpholinyl, -CH 2 -oxetanyl, -CH 2 -oxirane, -CH 2 -tetrahydrofuranyl, -CH 2 -octahydroindolizinyl, -CH 2 -cyclopropyl, -CH 2 -cyclopentyl, -CH 2 -octahydropentalenyl, -CH 2 -octahydro-1H- indenyl, -CH2 -decalinyl, -CH2 -pyridinyl, -( CH
  • R4 is 4-(6-oxo)-1, 4-oxo-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-pyrrolidino-1, 4-pyrrolidino-1, 4-pyrrolidino-1, 4-pyrrolidino-1, 4-pyrrolidino-1, 4 -pyrrolidino- 1 , 4-pyrrolidino- 1 , 4-pyrrolidino- 1 , 4-pyrrolidino- 1 , 4-pyrrolidino- 1 , 4-pyrrolidino- 1 , 4-pyrrolidino- 1 , 4-pyrrolidino- 1 , 4-
  • the invention is substituted with a substituent selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy,
  • the compound described in the present invention has a compound represented by formula (I-1), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-1),
  • R 2a , R 2b and R 2c each have the same definition as described for R 2 in any one of claims 1 to 10.
  • the present invention provides a pharmaceutical composition comprising the compound of the present invention.
  • the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable adjuvant.
  • the adjuvants described in the present invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof.
  • the pharmaceutical composition can be in liquid, solid, semisolid, gel or spray form.
  • the present invention provides the use of the pharmaceutical composition described in the present invention in the preparation of drugs for preventing, treating or alleviating KRas G12D-related diseases.
  • the KRas G12D-related disease described in the present invention is cancer.
  • the cancer described herein is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, colon cancer, small intestine cancer, pancreatic cancer, uterine cancer, gastric cancer, esophageal cancer, prostate cancer, ovarian cancer, breast cancer, leukemia, melanoma, lymphoma or neuroendocrine cancer. tumor.
  • the present invention also provides a method for preventing or treating KRas G12D-related diseases, which comprises administering a therapeutically effective amount of the compound described in the present invention or a pharmaceutical composition thereof to a patient.
  • the present invention relates to methods for preparing, isolating and purifying the compounds of formula (I) or (I-1).
  • the salts are pharmaceutically acceptable salts.
  • pharmaceutically acceptable includes that the substance or composition must be suitable chemically and toxicologically with respect to the other ingredients that make up the formulation and with the mammal to be treated.
  • the salts of the compounds of the present invention also include intermediates used in the preparation or purification of the compounds of formula (I) or (I-1) or salts of separated enantiomers of the compounds of formula (I) or (I-1), but they are not necessarily pharmaceutically acceptable salts.
  • subject refers to an animal. Typically, the animal is a mammal. Subjects, for example, also refer to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
  • primates e.g., humans, male or female
  • the subject is a primate. In other embodiments, the subject is a human.
  • patient used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, “patient” refers to humans.
  • Stereoisomers refer to compounds with the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like. Unless otherwise indicated, all stereoisomers or mixtures of stereoisomers of the structural formula described in the present invention are within the scope of the present invention. In addition, unless otherwise indicated, the structural formula of the compounds described in the present invention includes one or more enriched isotopes of different atoms.
  • Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and/or fractional crystallization.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversions via reorganization of some of the bonding electrons.
  • keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-keto tautomerism.
  • a specific example of phenol-keto tautomerism is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • the compounds of the present invention may be independently optionally substituted with one or more substituents, such as the general formula compounds above, or as specific examples in the embodiments, subclasses, and classes of compounds encompassed by the present invention.
  • substituents such as the general formula compounds above, or as specific examples in the embodiments, subclasses, and classes of compounds encompassed by the present invention.
  • substituents such as the general formula compounds above, or as specific examples in the embodiments, subclasses, and classes of compounds encompassed by the present invention.
  • substituents such as the general formula compounds above, or as specific examples in the embodiments, subclasses, and classes of compounds encompassed by the present invention.
  • C 1-6 alkyl specifically refers to the independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl.
  • linking substituents are described.
  • the Markush variable listed for that group should be understood as a linking group.
  • the Markush group definition for that variable lists “alkyl” or “aryl”, it should be understood that the "alkyl” or “aryl” represents an alkylene group or an arylene group, respectively, that is connected.
  • alkyl refers to a saturated straight or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein.
  • the alkyl group contains 1-6 carbon atoms, represented by C 1-6 alkyl; in another embodiment, the alkyl group contains 1-4 carbon atoms, represented by C 1-4 alkyl; in another embodiment, the alkyl group contains 1-3 carbon atoms, represented by C 1-3 alkyl.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 ),
  • alkylene refers to a saturated divalent hydrocarbon group derived from a saturated straight or branched hydrocarbon by removing two hydrogen atoms.
  • the alkylene group contains 1-6 carbon atoms, represented by C 1-6 alkylene; in other embodiments, the alkylene group contains 1-4 carbon atoms, represented by C 1-4 alkylene; in other embodiments, the alkylene group contains 1-3 carbon atoms, represented by C 1-3 alkylene; in other embodiments, the alkylene group contains 1-2 carbon atoms, represented by C 1-2 alkylene.
  • alkylene groups include, but are not limited to, methylene (i.e., -CH 2 -), ethylene (i.e., -CH 2 CH 2 -), isopropylene (i.e., -CH(CH 3 )CH 2 -), and the like.
  • alkenyl refers to a straight or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., one carbon-carbon sp2 double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including “cis” and “trans” orientations, or "E” and “Z” orientations.
  • the alkenyl group contains 2 to 6 carbon atoms, represented by C2-6 alkenyl; in another embodiment, the alkenyl group contains 2 to 4 carbon atoms, represented by C2-4 alkenyl.
  • alkynyl refers to a straight or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents described herein.
  • the alkynyl group contains 2 to 6 carbon atoms, represented by C2-6 alkynyl; in another embodiment, the alkynyl group contains 2 to 4 carbon atoms, represented by C2-4 alkynyl.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl ( -CH2C ⁇ CH ), 1-propynyl (-C ⁇ C- CH3 ), and the like.
  • cyanoalkyl refers to an alkyl group substituted by one or more cyano groups, wherein cyano and alkyl groups have the definitions as described herein.
  • cyanoalkyl refers to an alkyl group substituted by one cyano group.
  • cyanoalkyl is a C 1-6 cyanoalkyl, i.e., a C 1-6 alkyl group substituted by one or more cyano groups.
  • C 1-6 cyanoalkyl is a C 1-6 alkyl group substituted by one cyano group.
  • cyanoalkyl is a C 1-4 cyanoalkyl, i.e., a C 1-4 alkyl group substituted by one or more cyano groups.
  • cyanoalkyl include, but are not limited to, -CH 2 CN, -CH 2 CH 2 CH 2 CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH(CN)CH 2 CH 2 CN, -CH 2 CH(CN)CH 2 CH(CH 3 )CN, and the like.
  • hydroxyalkyl refers to an alkyl group substituted by one or more hydroxyl groups, wherein alkyl and hydroxyl groups have the definitions as described herein. In some embodiments, hydroxyalkyl refers to an alkyl group substituted by 1, 2, 3 or 4 hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted by one or two hydroxyl groups. In some embodiments, hydroxyalkyl refers to a C 1-6 hydroxyalkyl group, i.e., a C 1-6 alkyl group substituted by one or more hydroxyl groups, preferably, a C 1-6 hydroxyalkyl group refers to an alkyl group substituted by one hydroxyl group.
  • hydroxyalkyl refers to a C 1-4 hydroxyalkyl group. In some embodiments, hydroxyalkyl refers to a C 1-3 hydroxyalkyl group. Examples of hydroxyalkyl groups include, but are not limited to, -CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH(OH)CH 2 CH 2 OH, -CH 2 CH(OH)CH 2 CH( CH 3 ) OH, and the like.
  • haloalkyl means that an alkyl group is substituted with one or more halogen atoms, wherein alkyl and halogen have the definitions as described herein.
  • the haloalkyl is C 1-6 haloalkyl, which means that the C 1-6 alkyl group is substituted with one or more halogen atoms; in other embodiments, the haloalkyl is C 1-4 haloalkyl, which means that the C 1-4 alkyl group is substituted with one or more halogen atoms; in other embodiments, the haloalkyl is C 1-3 haloalkyl, which means that the C 1-3 alkyl group is substituted with one or more halogen atoms.
  • Such embodiments include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and the like.
  • haloalkenyl means an alkenyl group substituted with one or more halogen atoms, wherein alkenyl has the definition as described herein.
  • the haloalkenyl is a C2-6 haloalkenyl, which means a C2-6 alkenyl group substituted with one or more halogen atoms; in other embodiments, the haloalkenyl is a C2-4 haloalkenyl, which means a C2-4 alkenyl group substituted with one or more halogen atoms.
  • haloalkynyl means that an alkynyl group is substituted with one or more halogen atoms, wherein alkynyl has the definition as described herein.
  • the haloalkynyl is a C 2-6 haloalkynyl, which means that a C 2-6 alkynyl group is substituted with one or more halogen atoms; in other embodiments, the haloalkynyl is a C 2-4 haloalkynyl, which means that a C 2-4 alkynyl group is substituted with one or more halogen atoms.
  • Such examples include, but are not limited to, 2-chloroethynyl (-C ⁇ CCl), 1-chloropropargyl (-CHClC ⁇ CH), 3-chloropropynyl (-C ⁇ C-CH 2 Cl), and the like.
  • hydroxyalkynyl means an alkynyl group substituted with one or more hydroxyl groups, wherein hydroxyl and alkynyl are defined as described herein.
  • the hydroxyalkynyl group is a C 2-6 hydroxyalkynyl group, which means that the C 2-6 alkynyl group is substituted with one or more hydroxyl groups; in other embodiments, the hydroxyalkynyl group is a C 2-4 hydroxyalkynyl group, which means that the C 2-4 alkynyl group is substituted with one or more hydroxyl groups.
  • Such examples include, but are not limited to, 3-hydroxypropynyl (-C ⁇ C-CH 2 OH), 4-hydroxybutynyl (-C ⁇ C-(CH 2 ) 2 OH), and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group, wherein alkoxy and alkyl have the definitions described herein.
  • alkoxyalkyl refers to C 1-6 alkoxy C 1-6 alkyl; in other embodiments, alkoxyalkyl refers to C 1-4 alkoxy C 1-4 alkyl; in other embodiments, alkoxyalkyl refers to C 1-4 alkoxy C 1-3 alkyl; in some embodiments, alkoxyalkyl refers to C 1-3 alkoxy C 1-3 alkyl.
  • alkoxy groups include, but are not limited to, methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, methoxyethyl, methoxy-n-propyl, methoxy-isopropyl, ethoxyethyl, ethoxy-n-propyl, ethoxy-isopropyl, n-propoxyethyl, isopropoxyethyl, n-propoxy-n-propyl, n-propoxy-isopropyl, isopropoxy-n-propyl, isopropoxy-isopropyl, and the like.
  • carboxyalkyl refers to an alkyl group substituted by one or more carboxyl groups, wherein the carboxyl group and the alkyl group are specifically defined as described herein.
  • the carboxyalkyl group is a C 1-6 carboxyalkyl group, which refers to a C 1-6 alkyl group substituted by one or more carboxyl groups; in other embodiments, the carboxyalkyl group is a C 1-4 carboxyalkyl group, which refers to a C 1-4 alkyl group substituted by one or more carboxyl groups; in other embodiments, the carboxyalkyl group is a C 1-3 carboxyalkyl group, which refers to a C 1-3 alkyl group substituted by one or more carboxyl groups.
  • carboxyalkyl groups include, but are not limited to, carboxymethyl (-CH 2 COOH), 2-carboxyethyl (-(CH 2 ) 2 COOH), 3-carboxypropyl (-(CH 2 ) 3 COOH), and the like.
  • aminoalkyl refers to an alkyl group substituted by one or more amino groups, wherein alkyl and amino groups have the meanings as described herein.
  • the aminoalkyl group is a C 1-6 aminoalkyl group, which refers to a C 1-6 alkyl group substituted by one or more amino groups; in other embodiments, the aminoalkyl group is a C 1-4 aminoalkyl group, which refers to a C 1-4 alkyl group substituted by one or more amino groups; in other embodiments, the aminoalkyl group is a C 1-3 aminoalkyl group, which refers to a C 1-3 alkyl group substituted by one or more amino groups.
  • aminoalkyl groups include, but are not limited to, aminomethyl (-CH 2 NH 2 ), 2-aminoethyl (-(CH 2 ) 2 NH 2 ), 1-aminoethyl (-CH(NH 2 )CH 3 ), 1,2-diaminoethyl (-CH(NH 2 )CH 2 NH 2 ), and 3-aminopropyl (-(CH 2 ) 3 NH 2 ).
  • alkylamino refers to an amino group substituted by one or two alkyl groups, including “N-alkylamino” and “N,N-dialkylamino", wherein the alkyl and amino groups have the meanings as described in the present invention.
  • alkylamino refers to a C 1-6 alkyl Amino is an alkylamino group containing 1 to 6 carbon atoms; in other embodiments, alkylamino represents C 1-4 alkylamino, which is an alkylamino group containing 1 to 4 carbon atoms; alkylamino represents C 1-3 alkylamino, which is an alkylamino group containing 1 to 3 carbon atoms.
  • Suitable alkylamino groups can be monoalkylamino or dialkylamino groups, such as, but not limited to, N-methylamino (-NHCH 3 ), N-ethylamino (-NHCH 2 CH 3 ), N,N-dimethylamino (-N(CH 3 ) 2 ), N,N-diethylamino (-N(CH 2 CH 3 ) 2 ), and the like.
  • mercaptoalkyl refers to an alkyl group substituted by one or more mercapto groups, wherein the alkyl group has the meaning as described herein.
  • mercaptoalkyl refers to C 1-6 mercaptoalkyl, which is a C 1-6 alkyl group substituted by one or more mercapto groups; preferably, C 1-6 mercaptoalkyl is a C 1-6 alkyl group substituted by one mercapto group.
  • mercaptoalkyl refers to C 1-4 mercaptoalkyl.
  • mercaptoalkyl refers to C 1-3 mercaptoalkyl.
  • mercaptoalkyl examples include, but are not limited to, mercaptomethyl (-CH 2 SH), 2-mercaptoethyl (-(CH 2 ) 2 SH), 3-mercaptopropyl (-(CH 2 ) 3 SH), 2,3-dimercaptopropyl (-CH 2 CH(SH)CH 2 (SH)), and the like.
  • alkoxy means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms, representing a C 1-6 alkoxy group; in another embodiment, the alkoxy group contains 1-4 carbon atoms, representing a C 1-4 alkoxy group; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms, representing a C 1-3 alkoxy group.
  • the alkoxy group may be optionally substituted with one or more substituents as described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3 ), ethoxy (EtO, -OCH2CH3 ) , 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3 ), 2-propoxy (i-PrO, i - propoxy , -OCH( CH3 ) 2 ), 1 -butoxy ( n-BuO, n-butoxy , -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy , -OCH2CH ( CH3 ) 2 ), 2 -butoxy (s-BuO, s-butoxy, -OCH( CH3 ) CH2CH3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC( CH3 ) 3 ), 1-pentoxy (n-pentoxy, -OCH 2 CH 2 CH 2 CH 3 ), 1-
  • haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein alkoxy and halogen have the same meanings as those defined herein.
  • haloalkoxy refers to a haloalkoxy group containing 1 to 6 carbon atoms, i.e., C 1-6 haloalkoxy; in other embodiments, haloalkoxy refers to a haloalkoxy group containing 1 to 4 carbon atoms, i.e., C 1-4 haloalkoxy; in other embodiments, haloalkoxy refers to a haloalkoxy group containing 1 to 3 carbon atoms, i.e., C 1-3 haloalkoxy. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy (-OCF 3 ), monofluoromethoxy (-OCH 2 F), 2-fluoroethoxy (-OCH 2 CH 2 F), and the
  • the carbocyclyl contains 3-6 ring carbon atoms, represented by C3-6 carbocyclyl; in other embodiments, the carbocyclyl is a saturated ring containing 3-6 ring carbon atoms, represented by C3-6 cycloalkyl; in other embodiments, the C3-6 cycloalkyl is a saturated monocyclic ring.
  • the carbocyclyl contains 7-12 ring carbon atoms, represented by C7-12 carbocyclyl; in other embodiments, the carbocyclyl is a saturated ring containing 7-12 ring carbon atoms, represented by C7-12 cycloalkyl.
  • carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, octahydro-1H-indenyl, octahydropentalenyl, etc.
  • the cycloalkyl contains 3-10 ring carbon atoms, i.e., C3-10 cycloalkyl; in another embodiment, the cycloalkyl contains 3-6 ring carbon atoms, i.e., C3-6 cycloalkyl; in another embodiment, the cycloalkyl contains 3-5 ring carbon atoms, i.e., C3-5 cycloalkyl.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydro-1H-indenyl, octahydrocyclopentyl, cyclopentyl, cyclohexyl, cyclopent ... Dienyl, etc.
  • heterocycle or “heterocyclyl” means a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms; wherein the heterocycle or heterocyclyl is non-aromatic and does not contain any aromatic rings.
  • the heterocycle represents a monovalent heterocyclyl.
  • the sulfur atom of the ring may be optionally oxidized to S-oxide.
  • the heterocycle or heterocyclyl consists of 3-10 atoms, represented by a 3-10-membered heterocycle or a 3-10-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 3-9 atoms, represented by a 3-9-membered heterocycle or a 3-9-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 5-9 atoms, represented by a 5-9-membered heterocycle or a 5-9-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 3-6 atoms, represented by a 3-6-membered heterocycle or a 3-6-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 5-6 atoms, represented by a 5-6-membered heterocycle or a 5-6-membere
  • heterocycle examples include, but are not limited to, oxirane, aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiazolidine, pyrazolidine, pyrazoline, oxazolidine, imidazolidine, piperidine, piperazine, morpholine, 3,8-diazabicyclo[3.2.1]octane, 3,6-diazabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.2]octane.
  • the heterocyclic group includes, but is not limited to, oxirane, aziridine, azetidine, oxetane, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophene, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, etc.
  • aryl refers to a monovalent, monocyclic, bicyclic and tricyclic carbon ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring consisting of 3-7 atoms.
  • the aryl contains 6-12 ring atoms, represented by C 6-12 aryl or 6-12 membered aryl.
  • the aryl contains 6-10 ring atoms, represented by C 6-10 aryl or 6-10 membered aryl. Examples of aryl groups can include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl and anthracene.
  • heteroaryl or “heteroaromatic ring” refers to a monovalent monocyclic, bicyclic or tricyclic ring system containing 5-14 ring atoms, or 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the heteroaryl group is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the heteroaryl group.
  • heteroaryl group may be attached to the rest of the molecule (e.g., the main structure in the general formula) through any reasonable position (which may be C or N).
  • heteroaryl can be used interchangeably with the term “heteroaromatic ring” or “heteroaromatic compound”.
  • heteroaryl is a heteroaryl containing 5-12 ring atoms, represented by a 5-12 membered heteroaryl; in other embodiments, heteroaryl is a heteroaryl containing 5-10 ring atoms, represented by a 5-10 membered heteroaryl; in other embodiments, heteroaryl is a heteroaryl containing 5-6 ring atoms, represented by a 5-6 membered heteroaryl.
  • heteroaryl examples include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, benzopyridinyl, benzimidazolyl, benzopyrrolyl, benzopyrazolyl, benzopyrrolidinyl, and the like.
  • alkylthio means an alkyl group attached to the rest of the molecule through a sulfur atom, wherein alkyl has the definition as described herein.
  • alkylthio is C 1-6 alkylthio, meaning an alkylthio containing 1 to 6 carbon atoms; in other embodiments, alkylthio is C 1-4 alkylthio, meaning an alkylthio containing 1 to 4 carbon atoms; in other embodiments, alkylthio is C 1-3 alkylthio, meaning an alkylthio containing 1 to 3 carbon atoms.
  • alkylthio include, but are not limited to, methylthio (-SCH 3 ), ethylthio (-SCH 2 CH 3 ), and the like.
  • haloalkylthio refers to an alkylthio group substituted by one or more halogen atoms, wherein the alkylthio group has the definition as described herein.
  • the haloalkylthio group is a C 1-6 haloalkylthio group, which refers to a C 1-6 alkylthio group substituted by one or more halogen atoms;
  • haloalkylthio is C 1-4 haloalkylthio, which means C 1-4 alkylthio substituted by one or more halogens; in other embodiments, haloalkylthio is C 1-3 haloalkylthio, which means C 1-3 alkylthio substituted by one or more halogens.
  • haloalkylthio includes, but is not limited to, trifluoromethylthio (-SCF 3 ), 2,2,2-trifluoroethylthio (-SCH 2 CF 3 ), monofluoromethylthio (-SCH 2 F), and the like.
  • arylalkyl refers to an alkyl group substituted with an aryl group, wherein aryl and alkyl have the definitions described herein.
  • arylalkyl is C 6-10 arylC 1-6 alkyl or (6-10 membered aryl)-C 1-6 alkyl; in other embodiments, arylalkyl is C 6-10 arylC 1-4 alkyl or (6-10 membered aryl)-C 1-4 alkyl; in other embodiments, arylalkyl is C 6-10 arylC 1-3 alkyl or (6-10 membered aryl)-C 1-3 alkyl; in other embodiments, arylalkyl is phenylC 1-6 alkyl; in other embodiments, arylalkyl is phenylC 1-4 alkyl; in other embodiments, arylalkyl is phenylC 1-3 alkyl. Examples of arylalkyl include, but are not limited to,
  • heteroarylalkyl refers to an alkyl group substituted with a heteroaryl group, wherein heteroaryl and alkyl are as defined herein.
  • heteroarylalkyl is (5-12 membered heteroaryl)-C 1-6 alkyl; in other embodiments, heteroarylalkyl is 5-12 membered heteroarylC 1-4 alkyl; in other embodiments, heteroarylalkyl is (5-12 membered heteroaryl)-C 1-3 alkyl; in other embodiments, heteroarylalkyl is (5-6 membered heteroaryl)-C 1-6 alkyl; in other embodiments, heteroarylalkyl is (5-6 membered heteroaryl)-C 1-4 alkyl; in other embodiments, heteroarylalkyl is (5-6 membered heteroaryl)-C 1-3 alkyl.
  • heteroarylalkyl include, but are not limited to, pyrimidinylmethyl, pyridinylmethyl, pyridinyle
  • heterocyclylalkyl refers to an alkyl group substituted with a heterocyclyl group, wherein heterocyclyl and alkyl are as specifically defined herein.
  • heterocyclylalkyl is (3-6 membered heterocyclyl)C 1-6 alkyl; in other embodiments, heterocyclylalkyl is (3-6 membered heterocyclyl)-C 1-4 alkyl; in other embodiments, heterocyclylalkyl is (3-6 membered heterocyclyl)-C 1-4 alkyl; in other embodiments, heterocyclylalkyl is (3-6 membered heterocyclyl)-C 1-3 alkyl.
  • heterocyclylalkyl include, but are not limited to, piperidinylmethyl, piperidinylethyl, pyrrolidinylmethyl, and the like.
  • cycloalkylalkyl refers to an alkyl group substituted with a cycloalkyl group.
  • the cycloalkylalkyl group is a C 3-6cycloalkylC 1-6alkyl group; in other embodiments, the cycloalkylalkyl group is a C 3-6cycloalkylC 1-4alkyl group; in other embodiments, the cycloalkylalkyl group is a C 3-6cycloalkylC 1-3alkyl group.
  • Examples of cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, and the like.
  • halogen means F (fluorine), Cl (chlorine), Br (bromine) or I (iodine).
  • cyano means -CN or -C ⁇ N.
  • mercapto refers to -SH.
  • hydroxy refers to -OH.
  • amino refers to -NH2 .
  • j-k atoms or "j-k-membered” means that the cyclic group is composed of j-k ring atoms, and the ring atoms include carbon atoms and/or heteroatoms such as O, N, S, P, etc.; j and k are each independently any non-zero natural number, and k>j; "j-k” includes j, k and any natural number in between.
  • “consisting of 3-8 atoms” or “3-8 members”, “consisting of 3-6 atoms” or “3-6 members”, “consisting of 5-10 atoms” or “5-10 members”, or “consisting of 5-6 atoms” or “5-6 members” means that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7 or 8), 3-6 (i.e., 3, 4, 5 or 6), 5-10 (i.e., 5, 6, 7, 8, 9 or 10) or 5-6 (i.e., 5 or 6) ring atoms, and the ring atoms include carbon atoms and/or heteroatoms such as O, N, S, P, etc.
  • the ring system formed by substituent (R) q connected to the central ring by a bond represents that q substituents R can be substituted at any substitutable position or any reasonable position on the ring.
  • formula a represents that the naphthalene ring can be substituted by n R 2 , and when n is greater than 1, each R 2 can be independently selected from the same or different substituent groups.
  • prodrug used in the present invention refers to a compound that is converted into a compound represented by formula (I) or (I-1) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues.
  • the prodrug compound of the present invention can be an ester.
  • the esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug.
  • Other prodrug forms include phosphate esters, such as these phosphate ester compounds obtained by phosphorylation of the hydroxyl group on the parent.
  • Metal refers to a product obtained by the metabolism of a specific compound or salt thereof in vivo.
  • the metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc.
  • the present invention includes metabolites of compounds, including metabolites produced by contacting the compounds of the present invention with mammals for a period of time.
  • the "pharmaceutically acceptable salt” used in the present invention refers to the organic salt and inorganic salt of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts.
  • the present invention also contemplates quaternary ammonium salts formed by any compound containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium and amine cations which counter-form counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 - C8 sulfonates and aromatic sulfonates.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or a mixture thereof.
  • hydrate refers to an association in which the solvent molecule is water.
  • the term "hydrate” may be used.
  • one molecule of the compound of the present invention may be combined with one water molecule, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be combined with more than one water molecule, such as a dihydrate; in yet another embodiment, one molecule of the compound of the present invention may be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the non-hydrated form of the compound.
  • the term “treating" any disease or condition refers to ameliorating the disease or condition (i.e., slowing or preventing or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, “treating” refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.
  • prevent refers to a reduction in the risk of acquiring a disease or disorder (i.e., halting the development of at least one clinical symptom of a disease in a subject who may be exposed or predisposed to the disease but does not yet experience or display symptoms of the disease).
  • terapéuticaally effective amount refers to an amount of a compound that, when administered to a subject to treat a disease, is sufficient to be effective in treating the disease.”
  • Therapeutically effective amount may vary with the compound, the disease and its severity, and the condition, age, weight, sex, etc. of the subject to be treated.
  • stereochemistry of any particular chiral atom when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated within the present invention and are included as compounds disclosed herein. When stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of the structure are thus unambiguous and defined.
  • Nitrogen oxides of the compounds of the invention are also included within the scope of the invention.
  • Nitrogen oxides of the compounds of the invention can be prepared by oxidation of the corresponding nitrogen-containing basic substance using a conventional oxidizing agent (e.g., hydrogen peroxide) at elevated temperatures in the presence of an acid such as acetic acid, or by reaction with a peracid in a suitable solvent, such as peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.
  • a conventional oxidizing agent e.g., hydrogen peroxide
  • the compound represented by formula (I) or (I-1) may exist in the form of a salt.
  • any structural formula provided by the present invention is also intended to represent the form of these compounds that are not enriched with isotopes and the form of isotopes that are enriched with isotopes.
  • Isotopically enriched compounds have the structure that the general formula provided by the present invention describes, except that one or more atoms are replaced by atoms with selected atomic weight or mass number.
  • Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the present invention provides a compound, or a pharmaceutical composition thereof, which can be used as an inhibitor of KRAS, in particular as a KRAS 12D inhibitor.
  • the present invention further relates to the use of the compound or the pharmaceutical composition thereof for preparing a medicament for treating a disease and/or condition by inhibiting KRAS activity by the compound.
  • the excellent properties of certain parameters of the compounds of the present invention can promote the reduction of side effects, the expansion of therapeutic index or the improvement of tolerance.
  • the compounds of the present invention have better intracellular inhibitory activity and better in vivo performance in rats and dogs. Better pharmacokinetic properties such as reduced exposure.
  • the present invention provides a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I),
  • Q is O or S
  • Ring A is a C 3-6 carbocyclyl, a C 7-12 carbocyclyl, a 3-6 membered heterocyclyl, a 7-12 membered heterocyclyl, a C 6-12 aryl or a 5-12 membered heteroaryl;
  • Ring B is C 6-12 aryl or 5-12 membered heteroaryl
  • R3 is -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl or C1-4 haloalkyl;
  • Y is a bond, O or S
  • the -L-(3-10 membered heterocyclyl) is substituted with a substituent selected from the group consisting of -D, -OH
  • L is a C 1-6 alkylene group
  • R 6 , R 7 , R 6b , R 7b , R 6d , R 7d , R 6e and R 7e are each independently -H, -D or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C( ⁇ O)H, -C( ⁇ O)OH, -NR 6g R 7g , C 1-6 alkoxy, C 6-12 aryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
  • R 6a , R 6c , R 6g and R 7g are each independently -H, -D or C 1-6 alkyl;
  • n are each independently 0, 1, 2, 3, 4, 5, 6 or 7.
  • Ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, octahydropentalenyl, bicyclo[3.1.0]cyclohexyl, 2,3-dihydro-1H-indenyl, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, piperidinyl, phenyl, pyridinyl, pyrrolyl, imidazolyl, pyrimidinyl, or benzofuranyl.
  • R6 , R7 and the N atom to which they are attached form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2 , C1-4 alkyl, C1-4 alkylamino, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C1-4 alkoxy, C1-4 cyanoalkyl, C1-4 hydroxyalkyl, C1-4 haloalkoxy and C1-4 haloalkyl.
  • substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2 , C1-4 alkyl, C1-4 alkylamino, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C1-4 alkoxy, C1-4
  • R 6a , R 6g and R 7g are each independently -H, -D or C 1-4 alkyl.
  • R 6a , R 6g and R 7g are each independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • Ring B is one of the following substructures
  • each R 6c is independently -H, -D, or C 1-4 alkyl.
  • R 6b , R 7b and the N atom to which they are attached form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy, C 1-4 cyanoalkyl , C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl.
  • substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered
  • each R 6c is independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.
  • R 4 is -H, -D, C 1-4 alkyl, 3-6 membered heterocyclyl, 7-10 membered heterocyclyl, -L-pyrrolidinyl, -L-morpholinyl, -L-oxetanyl, -L-oxetanyl, -L-tetrahydrofuranyl, -L-octahydroindolizinyl, -L-cyclopropyl, -L-cyclopentyl, -L-octahydropentalenyl, -L-octahydro-1H-indenyl, -L-decahydronaphthyl, -L-pyridyl, -L-pyrazolyl, -L-phenyl, -L-NR 6 R 7 , -NR 6 R 7 , -L-NHC( ⁇ NH)NH 2 or -LC( ⁇ O)NR 6 R 7 , where
  • L is C 1-4 alkylene.
  • R 6d , R 7d and the N atom to which they are attached form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy, C 1-4 cyanoalkyl , C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl.
  • substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered
  • the group is preferably substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C1-4 alkyl , C1-4 alkylamino, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C1-4 alkoxy, C1-4 cyanoalkyl, C1-4 hydroxyalkyl, C1-4 haloalkoxy and C1-4 haloalkyl.
  • R 4 is -H, -D, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, -CH 2 -pyrrolidinyl, -CH 2 -morpholinyl, -(CH 2 ) 2 -morpholinyl, -CH 2 -oxetanyl, -CH 2 -oxiranyl, -CH 2 -tetrahydrofuranyl, -CH 2 -octahydroindolizinyl, -CH 2 -cyclopropyl, -CH 2 -cyclopentyl, -CH 2 -octahydropentalenyl, -CH 2 -octahydro-1H-indenyl, -CH 2 -decalinyl, -CH 2 -pyridinyl , -
  • R 6d , R 7d , R 6e and R 7e are each as defined in the present invention.
  • R4 is
  • R4 is
  • R 6d , R 7d and the N atom to which they are attached are taken together to form azetidine, pyrrolidine, piperazine, piperidine, morpholinyl, oxazolidine or imidazolidine, wherein each of the azetidine, pyrrolidine, piperazine, piperidine, morpholinyl, oxazolidine and imidazolidine is independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy, ethoxy,
  • the compound described in the present invention has a compound represented by formula (I-1), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-1),
  • R 2a , R 2b and R 2c each have the same definition as described for R 2 in the present invention.
  • R 2a , R 2b and R 2c are each independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH 2 C( ⁇ O)NR 6b R 7b , -C( ⁇ O)R 6c , -C( ⁇ O)OR 6c , -C( ⁇ O)NR 6b R 7b , -NR 6b C( ⁇ O)R 7b , -NR 6b R 7b , C 1-6 alkyl, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 hydroxyalkynyl, C 1-6 alkoxy, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, C 1-6 haloalkoxy, C 1-6 C1-6 alky
  • R 2a , R 2b and R 2c are each independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH 2 C( ⁇ O)NR 6b R 7b , -C( ⁇ O)R 6c , -C( ⁇ O)OR 6c , -C( ⁇ O)NR 6b R 7b , -NR 6b C( ⁇ O)R 7b , -NR 6b R 7b , C 1-4 alkyl, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 hydroxyalkynyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 2-4 haloalkenyl, C 2-4 haloalkynyl, C 1-4 haloalkoxy, C 1-4 C 1-4 alkyl, C
  • the compound described in the present invention has a compound represented by formula (I-2), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-2),
  • the compound described in the present invention is a compound of the following structure, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure,
  • the present invention provides a pharmaceutical composition comprising the compound of the present invention.
  • the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable adjuvant.
  • the adjuvants described in the present invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof.
  • the pharmaceutical composition can be in liquid, solid, semisolid, gel or spray form.
  • the present invention provides the use of the pharmaceutical composition described in the present invention in the preparation of drugs for preventing, treating or alleviating KRas G12D-related diseases.
  • the KRas G12D-related disease described in the present invention is cancer.
  • the compounds of the present invention or their pharmaceutical compositions can be effectively used to prevent, treat or alleviate the symptoms of cancer in patients, including, but not limited to: cardiac cancer: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; lung cancer: bronchial cancer (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), non-small cell lung cancer, small cell lung cancer, alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma hamartoma, mesothelioma; Gastrointestinal cancers: Esophageal (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lympho
  • the cancer described herein is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, colon cancer, small intestine cancer, pancreatic cancer, uterine cancer, gastric cancer, esophageal cancer, prostate cancer, ovarian cancer, breast cancer, leukemia, melanoma, lymphoma or neuroma.
  • the present invention also provides a method for preventing or treating KRas G12D-related diseases, which comprises administering a therapeutically effective amount of the compound described in the present invention or a pharmaceutical composition thereof to a patient.
  • the present invention relates to methods for preparing, isolating and purifying compounds of formula (I), (I-1) or (I-2).
  • the salts are pharmaceutically acceptable salts.
  • pharmaceutically acceptable includes that the substance or composition must be suitable chemically and toxicologically with respect to the other ingredients that make up the formulation and with the mammal to be treated.
  • the salts of the compounds of the present invention also include intermediates used to prepare or purify the compounds represented by formula (I), (I-1) or (I-2) or salts of separated enantiomers of the compounds represented by formula (I), (I-1) or (I-2), but are not necessarily pharmaceutically acceptable salts.
  • the pharmaceutical composition of the present invention is characterized by comprising a compound represented by formula (I), (I-1) or (I-2), a compound listed in the present invention, or
  • the amount of the compound in the pharmaceutical composition of the present invention is effective to treat or alleviate KRAS G12D-mediated diseases in patients.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be directly or indirectly administered according to the needs of the patient, the compounds described in other aspects of the present invention, their metabolites or their residues.
  • the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable adjuvant, which, as used in the present invention, includes any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a specific target dosage form.
  • a pharmaceutically acceptable adjuvant includes any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc.
  • Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose sodium cellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa
  • active ingredient is usually mixed with excipient, diluted by excipient or encapsulated in such carrier in the form of capsule, pouch, paper or other container, for example.
  • excipient can be solid, semisolid or liquid material, which is used as carrier, carrier or medium of active ingredient.
  • Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter, etc.
  • the composition can be tablets, pills, powders, lozenges, capsules, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid form or in liquid medium), for example, ointments containing up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions and aseptically packaged powders.
  • the composition is formulated for oral administration.
  • the composition is formulated into tablets or capsules.
  • the compounds or pharmaceutical compositions of the present invention can be administered in the form of oral dosage forms, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, and all dosage forms used are well known to those of ordinary skill in the pharmaceutical field. They can be administered alone, but will generally be administered together with a pharmaceutical carrier selected based on the selected mode of administration and standard pharmaceutical practice.
  • oral dosage forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, and all dosage forms used are well known to
  • the compounds or pharmaceutical compositions of the invention can be administered in intranasal form via topical use of a suitable intranasal vehicle, or via the use of an intranasal Patches are administered transdermally.
  • the dosage is administered continuously rather than intermittently throughout the duration of administration.
  • the compounds or pharmaceutical compositions of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine.
  • the compounds of the invention or pharmaceutical compositions are also coupled with soluble polymers, which serve as targeted drug carriers.
  • soluble polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide-polylysine substituted with palmitoyl residues.
  • the compounds of the invention can be coupled with a class of biodegradable polymers for controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly- ⁇ -caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic blocking copolymers of hydrogels.
  • biodegradable polymers for controlled drug release for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly- ⁇ -caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic blocking copolymers of hydrogels.
  • the dosage regimen of the compounds or pharmaceutical compositions of the present invention will vary with known factors, such as the pharmacokinetic characteristics of the specific agent and its mode and route of administration; the race, age, sex, health status, medical condition and weight of the recipient; the nature and extent of the symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's renal and liver function, and the desired effect.
  • a physician or veterinarian can make a decision and prescribe an effective amount of the drug to prevent, offset or stop the development of cancer.
  • the dosage of each active ingredient used is between about 0.001 and 1000 mg/kg body weight per day, preferably, between about 0.01 and 100 mg/kg body weight.
  • the compound of the present invention can be administered once a day, or can be administered twice, three times or four times a day.
  • Each unit dose of a dosage form (pharmaceutical composition) suitable for administration may contain about 1 mg to about 100 mg of active ingredient.
  • the weight of the active ingredient will generally account for about 0.5-95% of the total weight of the composition.
  • the compounds and compositions described herein can be administered alone or in combination with other compounds or other therapeutic agents.
  • the compounds or compositions of the present invention can be administered simultaneously or sequentially with other therapeutic agents by the same or different routes of administration.
  • the compounds of the present invention can be included in a single formulation or in a separate formulation with other therapeutic agents.
  • the amount of each component in a typical daily dose and typical dosage form may be reduced relative to the usual dose when administered alone, taking into account the additive or synergistic effects of the therapeutic agents when administered in combination.
  • the compounds or pharmaceutically acceptable salts or hydrates thereof or pharmaceutical compositions thereof involved in the present invention can be effectively used to prevent, treat or alleviate KRAS-mediated diseases, especially KRAS G12D-mediated diseases, especially cancer, in patients.
  • the compounds of the present invention or their pharmaceutical compositions can be effectively used to prevent, treat or alleviate the symptoms of cancer in patients, including, but not limited to: cardiac cancer: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; lung cancer: bronchial cancer (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), non-small cell lung cancer, small cell lung cancer, alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma hamartoma Cancers of the gastrointestinal tract: esophageal (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcino
  • the compounds of the present invention or their pharmaceutical compositions can be effectively used to prevent, treat or alleviate cancer symptoms in patients including non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, colon cancer, small intestine cancer, pancreatic cancer, uterine cancer, gastric cancer, esophageal cancer, prostate cancer, ovarian cancer, breast cancer, leukemia, melanoma, lymphoma or neuroma.
  • the present invention will further illustrate the technical scheme of the present invention with the following examples.
  • the following examples are only used to illustrate the specific implementation method of the present invention so that those skilled in the art can understand the present invention, but are not used to limit the scope of protection of the present invention.
  • the technical means or methods not specifically described are conventional technical means or methods in the art.
  • Room temperature in the embodiments means 15°C–30°C; in some embodiments, room temperature is 20°C–30°C.
  • Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, etc. None of them were further purified when used.
  • Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by drying under reflux with sodium metal.
  • Anhydrous dichloromethane and chloroform were obtained by drying under reflux with calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.
  • reaction bottles were plugged with appropriate rubber stoppers, and substrates were injected via syringe. All glassware was dried.
  • the chromatographic column used was a silica gel column, and the silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.
  • the low-resolution mass spectrometry (MS) data were measured using an Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 microns, 6 min, flow rate 0.6 mL/min.
  • Mobile phase 5%-95% (CH 3 CN containing 0.1% formic acid) in (H 2 O containing 0.1% formic acid), electrospray ionization (ESI), at 210 nm/254 nm, with UV detection.
  • Compound (IA) can be synthesized by referring to the method of Synthesis Scheme 1.
  • R 1 , R 2 , R 3 , R 5 , ring A, m and n have the same definitions as those described in the present invention
  • Hal is a halogen, preferably Cl or Br
  • Ra is a C 1-4 alkyl, preferably a methyl or ethyl group
  • q is a natural number of 1-6, preferably 1 or 2
  • the 3-10 membered heterocyclic group has the same definitions as those described in the present invention, and may be optionally substituted by the substituents described in the present invention.
  • Compound (IA-01) reacts with compound (IA-02) under appropriate conditions (such as in the presence of cesium carbonate, t-BuBrettPhos G3 Pd and t-BuBrettPhos) to obtain compound (IA-0); compound (IA-0) is deprotected from the amino group under acidic conditions to obtain compound (IA-1); compound (IA-1) is reacted with NIS or I2 under appropriate acidic conditions (such as periodic acid or p-toluenesulfonic acid) and in a suitable solvent (such as ethanol or acetonitrile) to obtain compound (IA-2); compound (IA-2) is reacted with CO and alcohol R a under the action of a palladium catalyst (such as Pd(PPh 3 ) 2 Cl 2 ) and appropriate conditions (such as the action of a base TEA); OH (such as ethanol or methanol) to obtain compound (IA-3); compound (IA-3) reacts with 2,2,2-
  • Compound (IB) can be synthesized by referring to the method of Synthesis Scheme 2.
  • R 1 , R 2 , R 3 , R 5 , Ring A and m have the definitions described in the present invention
  • n1 is a natural number of 1-6
  • q is a natural number of 1-6, preferably 1 or 2
  • 3-10 membered heterocyclic group has the definitions described in the present invention, and can be optionally substituted by the substituents described in the present invention.
  • Compound (IA-10) is reacted with compound (IB-1) in the presence of a suitable catalyst (such as XPhos Pd G2) to obtain compound (IB-2); compound (IB-2) is reacted under acidic conditions (such as HCl) to obtain compound (IB).
  • a suitable catalyst such as XPhos Pd G2
  • compound (IB-2) is reacted under acidic conditions (such as HCl) to obtain compound (IB).
  • Compound (IC) can be synthesized by referring to the method of Synthesis Scheme 3.
  • R 1 , R 2 , R 3 , R 5 , Ring A and m are as defined in the present invention;
  • n2 is a natural number of 1-5;
  • q is a natural number of 1-6, preferably 1 or 2;
  • 3-10 membered heterocyclic group is as defined in the present invention, and can be optionally substituted by a substituent as described in the present invention.
  • Compound (IA-10) reacts with compound (IC-1) under the action of a suitable catalyst (such as XPhos Pd G2 or XPhos Pd G3) to obtain compound (IC-2); compound (IC-2) reacts under acidic conditions (such as HCl) to obtain compound (IC-3) or an acid addition salt of compound (IC-3); compound (IC-3) or an acid addition salt of compound (IC-3) removes the TIPS group under suitable conditions (such as CsF in DMF solvent) to obtain compound (IC).
  • a suitable catalyst such as XPhos Pd G2 or XPhos Pd G3
  • compound M1-2 (2.40 g, 7.14 mmol), Pd 2 (dba) 3 (0.13 g, 0.14 mmol), XantPhos (0.21 g, 0.36 mmol), tert-butyl carbamate (1.00 g, 8.57 mmol) and cesium carbonate (5.82 g, 17.85 mmol) were added, and the atmosphere was replaced with nitrogen three times.
  • Anhydrous 1,4-dioxane (40 mL) was added, and the atmosphere was replaced with nitrogen three times. The temperature was raised to 80°C and stirred for reaction for 2 h.
  • compound 1-8 (256 mg, 0.48 mmol), 1,4-dioxane (5 mL), ((2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizine-7a-yl)methanol (110 mg, 0.72 mmol) and DIPEA (0.24 mL, 1.44 mmol) were added, the temperature was raised to 90 ° C and stirred for 24 h, the stirring was stopped, the mixture was concentrated, ethyl acetate (40 mL) was added, and saturated ammonium chloride solution (20 mL) and saturated sodium chloride solution (20 mL) were used in sequence.
  • Example 6 The synthesis of Example 6 was performed with reference to Example 2, and cyclopentanol was used instead of 3-fluorocyclobutane-1-ol to obtain 47 mg of yellow solid compound 6, LC-MS (ESI, pos.ion) m/z: 685.6 [M+H] + ; HRMS (ESI): 685.3156 [M+H] + .
  • Example 9 The synthesis of Example 9 was performed by referring to Example 2, and 3-hydroxycyclopentanone was used instead of 3-fluorocyclobutane-1-ol to obtain 21 mg of yellow solid compound 9, LC-MS (ESI, pos.ion) m/z: 699.5 [M+H] + ; HRMS (ESI): 699.2935 [M+H] + .
  • Example 10 The synthesis of Example 10 was performed by referring to Example 2, and 1-methylcyclopentanol was used instead of 3-fluorocyclobutane-1-ol to obtain 32 mg of yellow solid compound 10.
  • Example 11 The synthesis of Example 11 was carried out with reference to Example 2, and bicyclo[3.1.0]hexan-3-ol was substituted for 3-fluorocyclobutane-1-ol to obtain 45 mg of yellow solid compound 11, LC-MS (ESI, pos.ion) m/z: 697.5 [M+H] + ; HRMS (ESI): 697.3124 [M+H] + .
  • Example 12 The synthesis of Example 12 was carried out in accordance with Example 2, with 2-indanol replacing 3-fluorocyclobutane-1-ol, and finally 30 mg of yellow solid compound 12 was obtained, LC-MS (ESI, pos.ion) m/z: 733.5 [M+H] + ; HRMS (ESI): 733.3136 [M+H] + .
  • Example 13 The synthesis of Example 13 was carried out in accordance with Example 2, with cyclohexanol replacing 3-fluorocyclobutane-1-ol, and finally 40 mg of yellow solid compound 13 was obtained, LC-MS (ESI, pos.ion) m/z: 699.5 [M+H] + ; HRMS (ESI): 699.3246 [M+H] + .
  • Example 14 The synthesis of Example 14 was carried out in accordance with Example 2, with phenol replacing 3-fluorocyclobutane-1-ol, and finally 20 mg of yellow solid compound 14 was obtained, LC-MS (ESI, pos.ion) m/z: 693.0 [M+H] + ; HRMS (ESI): 693.2788 [M+H] + .
  • Example 15 The synthesis of Example 15 was carried out in accordance with Example 2, with 3-hydroxypyridine replacing 3-fluorocyclobutane-1-ol, and finally 10 mg of yellow solid compound 15 was obtained, LC-MS (ESI, pos.ion) m/z: 694.2 [M+H] + ; HRMS (ESI): 694.2732 [M+H] + .
  • Example 19 Referring to Example 16, tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzo[b]thiophene-2-yl)carbamate was used to replace 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for synthesis, and finally 12 mg of yellow solid compound 19 was obtained, LC-MS (ESI, pos.ion) m/z: 713.4 [M+H] + ; HRMS (ESI): 713.2424 [M+H] + .
  • Example 20 Referring to the steps in Example 16, 2-(tert-butoxycarbonylamino)-7-fluoro-1,3-benzothiazol-4-yl]boric acid was used instead of 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane to synthesize, and finally 15 mg of yellow solid compound 20 was obtained, LC-MS (ESI, pos.ion) m/z: 689.2 [M+H] + ; HRMS (ESI): 689.2468 [M+H] + .
  • compound 1-8 200 mg, 0.37 mmol
  • 1,4-dioxane 4 mL
  • (hexahydro-1H-pyrrolidine-7a-yl)methanol 78 mg, 0.55 mmol
  • DIPEA 0.18 mL, 1.11 mmol
  • Example 22 The synthesis of Example 22 was performed with reference to Example 21, and N-methyl-L-prolinol was used instead of (hexahydro-1H-pyrroline-7a-yl)methanol to obtain 18 mg of yellow solid compound 22.
  • Example 23 The synthesis of Example 23 was performed with reference to Example 21, and N-methyl-D-prolinol was used instead of (hexahydro-1H-pyrroline-7a-yl)methanol to obtain 10 mg of yellow solid compound 23.
  • Example 24 The synthesis of Example 24 was performed with reference to Example 21, and (hexahydro-1H-pyrrolidine-7a-yl)methanol was substituted with ⁇ 1-[(dimethylamino)methyl]cyclopropyl ⁇ methanol to obtain 9 mg of yellow solid compound 23.
  • Example 25 [1-(morpholin-4-ylmethyl)cyclopropyl]methanol was substituted for (hexahydro-1H-pyrrolidine-7a-yl)methanol to obtain 16 mg of yellow solid compound 25, LC-MS (ESI, pos.ion) m/z: 719.5 [M+H] + ; HRMS (ESI): 719.2985 [M+H] + .
  • Example 26 The synthesis of Example 26 was performed with reference to Example 21, and (2,6-dimethyltetrahydro-1H-pyrroline-7a(5H)-yl)methanol was substituted for (hexahydro-1H-pyrroline-7a-yl)methanol to obtain 8 mg of yellow solid compound 26.
  • AGS cells were revived using 1640 medium containing 10% fetal bovine serum;
  • Relative signal value (signal value of the channel corresponding to the target protein/signal value of the channel corresponding to the internal reference protein) ⁇ 10000
  • the compounds of the present invention can effectively bind to KRAS G12D-GTP, inhibiting the binding of KRAS to cRAF and SOS1 proteins.
  • the compounds of the present invention can effectively inhibit pERK downstream of KRAS.
  • the inventors conducted a pharmacokinetic evaluation of the compound of the present invention in rats.
  • the animal information is shown in Table 3.
  • the compound of the present invention was diluted with 5% DMSO + 30% PEG400 + 65% saline, 10% DMSO + 10% Kolliphor HS15 +
  • the animals were administered with 80% Saline, 10% DMSO + 89% (25% SBE-B-CD) + (2% HCl), 20% PEG400 + 80% sterile water for injection or 10% DMA + 10% HS15 + 30% PEG400 + 50% sterile aqueous solution for injection.
  • the animals were fasted for 12 hours before administration and had free access to water.
  • the rats were administered a dose of 1 mg/kg.
  • blood was collected venously at the following time points (blood volume of about 0.15 mL): 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hours (rats).
  • EDTA-K 2 was added to the blood collection tube as an anticoagulant in advance.
  • the blood samples were centrifuged at 12,000 rpm for 2 minutes, and the plasma was collected and stored at -20°C or -70°C.

Abstract

The present invention relates to the field of drugs, and specifically, the present invention relates to a pyrimidopyridine compound, and a pharmaceutical composition and use thereof. Specifically, the present invention relates to a compound of formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I). The compound and the pharmaceutical composition thereof, involved in the present invention, as a KRAS G12D inhibitor can be used for preparing drugs for preventing or treating KRAS G12D related diseases, and particularly can be used for preparing drugs for preventing or treating cancers.

Description

一种嘧啶并吡啶化合物、其药物组合物及其用途A pyrimidopyridine compound, its pharmaceutical composition and its use 技术领域Technical Field
本发明属于药物领域，具体地，本发明涉及一种作为KRAS G12D抑制剂的嘧啶并吡啶化合物、其药物组合物，以及该类化合物和其药物组合物在制备用于预防或治疗KRAS G12D相关疾病药物中的用途。The present invention belongs to the field of medicine. Specifically, the present invention relates to a pyrimidopyridine compound as a KRAS G12D inhibitor, a pharmaceutical composition thereof, and the use of such compound and pharmaceutical composition thereof in the preparation of drugs for preventing or treating KRAS G12D-related diseases.
背景技术Background technique
RAS基因是癌症中最常见的突变基因之一(20％-25％)，RAS基因家族目前已知的成员包括KRAS，NRAS和HRAS，其中KRAS突变最为常见，大约占85％。KRAS在胰腺导管腺癌(pancreatic ductal adenocarcinoma，PDAC)中的突变率最高，达97％，其次为结直肠癌、多发性骨髓瘤和肺癌，分别为52％、42％和32％。KRAS基因突变的最常见方式是点突变，常见的突变形式有KRAS G12D突变(41％)、KRAS G12V(28％)和KRAS G12C(14％)突变。RAS基因突变常与癌症的不良预后相关，KRAS可被上游的生长因子或酪氨酸激酶(如EGFR)短暂活化，活化后的KRAS可以激活下游通路，常见的有控制细胞生成的PI3K-AKT-mTOR信号通路，以及控制细胞增殖的RAS-RAF-MEK-ERK信号通路，这也给众多靶点联用奠定了生物学基础。The RAS gene is one of the most commonly mutated genes in cancer (20%-25%). The currently known members of the RAS gene family include KRAS, NRAS and HRAS, among which KRAS mutation is the most common, accounting for about 85%. The mutation rate of KRAS in pancreatic ductal adenocarcinoma (PDAC) is the highest, reaching 97%, followed by colorectal cancer, multiple myeloma and lung cancer, which are 52%, 42% and 32% respectively. The most common way for the KRAS gene to mutate is point mutation, and common mutation forms include KRAS G12D mutation (41%), KRAS G12V (28%) and KRAS G12C (14%) mutations. RAS gene mutations are often associated with poor prognosis in cancer. KRAS can be transiently activated by upstream growth factors or tyrosine kinases (such as EGFR). The activated KRAS can activate downstream pathways, including the PI3K-AKT-mTOR signaling pathway that controls cell generation, and the RAS-RAF-MEK-ERK signaling pathway that controls cell proliferation. This also lays a biological foundation for the combination of many targets.
近年来，人们利用KRAS G12C突变体的变构位点进行药物研发取得了一定的进展，例如，2013年，有研究小组报道了KRAS G12C小分子抑制剂的发现(Nature,2013,503,548-551)；但人们对KRAS G12D的研究较少。而相对于KRAS G12C突变，在胰腺癌中，KRAS G12D和KRAS G12V等其它突变类型的比例更高。因此，通过抑制KRAS G12D突变来治疗胰腺癌是潜在的有效手段。目前，Mirati公司在专利申请WO20211041671中公布了一系列的KRAS G12D抑制剂，它们表现出对KRAS G12D突变体的特异性，且具有抗胰腺癌的活性。In recent years, people have made some progress in drug development using the allosteric sites of KRAS G12C mutants. For example, in 2013, a research team reported the discovery of KRAS G12C small molecule inhibitors (Nature, 2013, 503, 548-551); but people have done less research on KRAS G12D. Compared with KRAS G12C mutations, other mutation types such as KRAS G12D and KRAS G12V have a higher proportion in pancreatic cancer. Therefore, inhibiting KRAS G12D mutations to treat pancreatic cancer is a potentially effective means. Currently, Mirati has published a series of KRAS G12D inhibitors in patent application WO20211041671, which show specificity for KRAS G12D mutants and have anti-pancreatic cancer activity.
因此，开发靶向抑制KRAS G12D突变的化合物应对KRAS G12D相关疾病具有很强的吸引力和迫切的需求。Therefore, the development of compounds that target and inhibit KRAS G12D mutations is very attractive and urgent to treat KRAS G12D-related diseases.
发明内容Summary of the invention
本发明提供一种化合物，或其药物组合物，它们可作为KRAS的抑制剂，尤其作为KRAS 12D抑制剂。本发明进一步涉及所述化合物或其药物组合物用于制备药物的用途，该药物通过抑制KRAS活性来治疗疾病和/或病症，尤其是癌症。The present invention provides a compound, or a pharmaceutical composition thereof, which can be used as an inhibitor of KRAS, especially as a KRAS 12D inhibitor. The present invention further relates to the use of the compound or the pharmaceutical composition thereof for preparing a medicament for treating a disease and/or condition, especially cancer, by inhibiting KRAS activity.
本发明化合物作为一类非共价KRAS G12D特异性抑制剂，能够有效地与KRAS G12D-GTP结合，抑制KRAS G12D下游ERK的磷酸化。As a type of non-covalent KRAS G12D specific inhibitor, the compounds of the present invention can effectively bind to KRAS G12D-GTP and inhibit the phosphorylation of ERK downstream of KRAS G12D.
一方面，本发明提供式(I)所示的化合物，或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
In one aspect, the present invention provides a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I),
其中，in,
Q为O或S；Q is O or S;
环A为C3-6碳环基、C7-12碳环基、3-6元杂环基、7-12元杂环基、C6-12芳基或5-12元杂芳基；Ring A is a C 3-6 carbocyclyl, a C 7-12 carbocyclyl, a 3-6 membered heterocyclyl, a 7-12 membered heterocyclyl, a C 6-12 aryl or a 5-12 membered heteroaryl;
各R1独立地为-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、-NO2、-C(＝O)R6a、-C(＝O)OR6a、-C(＝O)NR6R7、-NR6C(＝O)R7、-NR6R7、-NR6S(＝O)2R7、氧代、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氰基烷基、C1-6羟基烷基、C1-6卤代烷基、C2-6卤代烯基、C2-6卤代炔基、C1-6烷氧基C1-6烷基、C1-6羧基烷基、C1-6氨基烷基、C1-6巯基烷基、C1-6烷氧基、C3-6环烷基、3-6元杂环基、C6-12芳基或5-12元杂芳基；each R 1 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -NO 2 , -C(=O)R 6a , -C(=O)OR 6a , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -NR 6 R 7 , -NR 6 S(=O) 2 R 7 , oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 carboxyalkyl, C 1-6 aminoalkyl, C 1-6 mercaptoalkyl, C 1-6 alkoxy, C 1-6 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;
环B为C6-12芳基或5-12元杂芳基；Ring B is C 6-12 aryl or 5-12 membered heteroaryl;
各R2独立地为-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、-CH2C(＝O)NR6bR7b、-C(＝O)R6c、-C(＝O)OR6c、-C(＝O)NR6bR7b、-NR6bC(＝O)R7b、-NR6bR7b、C1-6烷基、C1-6烷硫基、C2-6烯基、C2-6炔基、C2-6羟基炔基、C1-6烷氧基、C1-6氰基烷基、C1-6羟基烷基、C1-6卤代烷基、C2-6卤代烯基、C2-6卤代炔基、C1-6卤代烷氧基、C1-6卤代烷硫基、6-12元芳基、5-12元杂芳基、C3-6环烷基或3-6元杂环基，其中所述的C1-6烷基、C1-6烷硫基、C2-6烯基、C2-6炔基、C2-6羟基炔基、C1-6烷氧基、C1-6氰基烷基、C1-6羟基烷基、C2-6卤代烷基、C2-6卤代烯基、C2-6卤代炔基、C1-6卤代烷氧基、C1-6卤代烷硫基、6-12元芳基、5-12元杂芳基、C3-6环烷基和3-6元杂环基各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、-C(＝O)H、-C(＝O)OH、C1-6烷基、C1-6烷氧基、C3-6环烷基和3-6元杂环基的取代基所取代；each R2 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C (=O ) NR6bR7b , -C (=O) R6c , -C(=O)OR6c, -C(=O)NR6bR7b, -NR6bC(=O)R7b, -NR6bR7b , C1-6alkyl , C1-6alkylthio , C2-6alkenyl , C2-6alkynyl , C2-6hydroxyalkynyl , C1-6alkoxy, C1-6cyanoalkyl , C1-6hydroxyalkyl , C1-6haloalkyl , C2-6haloalkenyl , C2-6haloalkynyl , C1-6haloalkoxy , C1-6 C1-6 alkylthio, C2-6 alkenyl, C2-6 alkynyl, C2-6 hydroxyalkynyl, C1-6 alkoxy, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C2-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, C1-6 haloalkoxy, C1-6 haloalkylthio, 6-12 membered aryl, 5-12 membered heteroaryl, C3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the C1-6 alkyl, C1-6 alkylthio , C2-6 alkenyl, C2-6 alkynyl, C2-6 hydroxyalkynyl, C1-6 alkoxy, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C2-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, C1-6 haloalkoxy, C1-6 haloalkylthio, 6-12 membered aryl, 5-12 membered heteroaryl, C3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted by 1, 2, 3 or 4 members selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2 , -C(=O)H, -C(=O)OH, C substituted by a C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, and 3-6 membered heterocyclic group;
R3为-H、-D、-OH、-SH、-F、-Cl、-Br、-I、-CN、甲基、乙基、正丙基、异丙基、正丁基或C1-4卤代烷基； R3 is -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl or C1-4 haloalkyl;
Y为键、O或S；Y is a bond, O or S;
R4为-H、-D、C1-6烷基、3-10元杂环基、-L-(3-10元杂环基)、-L-C3-10环烷基、-L-(5-12元杂芳基)、-L-(C6-10芳基)、-L-NR6R7、-NR6R7、-L-NHC(＝NH)NH2或-L-C(＝O)NR6R7，其中所述的C1-6烷基、3-10元杂环基、-L-(3-10元杂环基)、-L-C3-10环烷基、-L-(5-12元杂芳基)和-L-(C6-10芳基)各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NR6dR7d、-C(＝O)NR6dR7d、-CH2NR6dR7d、-CH2OC(＝O)NR6dR7d、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C6-10芳基C1-6烷基、(5-12元杂芳基)-C1-6烷基、 (3-6元杂环基)-C1-6烷基、C3-6环烷基C1-6烷基、C3-6环烷基和3-6元杂环基的取代基所取代，或，所述的-L-(3-10元杂环基)中的3-10元杂环基上的任意位置任意个数的环碳原子上的两个氢原子被取代，其中所述取代基中的C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C6-10芳基C1-6烷基、(5-12元杂芳基)-C1-6烷基、(3-6元杂环基)-C1-6烷基、C3-6环烷基C1-6烷基、C3-6环烷基和3-6元杂环基各自独立任选地被1、2、3或4个选自-D、-F、-Cl、-Br、-I、-OH、-CN、NR6eR7e、-C(＝O)C1-6烷基和C1-6烷基的取代基所取代； R4 is -H, -D, C1-6 alkyl, 3-10 membered heterocyclyl, -L-(3-10 membered heterocyclyl), -LC3-10 cycloalkyl, -L-(5-12 membered heteroaryl), -L-( C6-10 aryl), -L- NR6R7 , -NR6R7 , -L -NHC(=NH) NH2 or -LC(=O) NR6R7 , wherein the C1-6 alkyl, 3-10 membered heterocyclyl, -L-(3-10 membered heterocyclyl), -LC3-10 cycloalkyl, -L-(5-12 membered heteroaryl) and -L-( C6-10 aryl) are each independently optionally substituted by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN , -NR6dR7d , -C(=O) NR6dR7d , -CH 2 NR 6d R 7d , -CH 2 OC(＝O)NR 6d R 7d , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 arylC 1-6 alkyl, (5-12 membered heteroaryl)-C 1-6 alkyl, (3-6 membered heterocyclyl)-C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl substituents, or, the two hydrogen atoms on any number of ring carbon atoms at any position on the 3-10 membered heterocyclyl in the -L-(3-10 membered heterocyclyl) are replaced by substituted, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 arylC 1-6 alkyl, (5-12 membered heteroaryl)-C 1-6 alkyl, (3-6 membered heterocyclyl)-C 1-6 alkyl, C 3-6 cycloalkylC 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl in the substituent are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -F, -Cl, -Br, -I, -OH, -CN, NR 6e R 7e , -C(＝O)C 1-6 alkyl and C 1-6 alkyl;
L为C1-6亚烷基；L is a C 1-6 alkylene group;
为至少含有两个环N原子的5-12元杂环； is a 5-12 membered heterocyclic ring containing at least two ring N atoms;
R5为-H、-D、-OH、-SH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OR6a、-C(＝O)NR6R7、C1-6烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基或5-6元杂芳基；R 5 is -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OR 6a , -C(=O)NR 6 R 7 , C 1-6 alkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or 5-6 membered heteroaryl;
R6、R7、R6b、R7b、R6d、R7d、R6e和R7e各自独立地为-H、-D或C1-6烷基，其中所述的C1-6烷基任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、C1-6烷氧基、C6-12芳基、C3-6环烷基和3-6元杂环基的取代基所取代；R 6 , R 7 , R 6b , R 7b , R 6d , R 7d , R 6e and R 7e are each independently -H, -D or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(═O)H, -C(═O)OH, -NR 6g R 7g , C 1-6 alkoxy, C 6-12 aryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
或R6和R7、或R6b和R7b、或R6d和R7d、或R6e和R7e，分别和与之相连的N原子一起形成4-6元杂环，其中所述的4-6元杂环任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、C1-6烷基、C1-6烷氨基、C3-6环烷基、3-6元杂环基、C1-6烷氧基、C1-6氰基烷基、C1-6羟基烷基、C1-6卤代烷氧基和C1-6卤代烷基的取代基所取代；or R 6 and R 7 , or R 6b and R 7b , or R 6d and R 7d , or R 6e and R 7e , together with the N atom to which they are attached, form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 1-6 alkoxy, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy and C 1-6 haloalkyl;
R6a、R6c、R6g和R7g各自独立地为-H、-D或C1-6烷基；R 6a , R 6c , R 6g and R 7g are each independently -H, -D or C 1-6 alkyl;
m和n各自独立地为0、1、2、3、4、5、6或7。m and n are each independently 0, 1, 2, 3, 4, 5, 6 or 7.
在一些实施方案中，环A为环丙基、环丁基、环戊基、环己基、环戊烯基、八氢并环戊二烯基、双环[3.1.0]环己基、2,3-二氢-1H-茚基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、四氢吡喃基、吗啉基、哌嗪基、哌啶基、苯基、吡啶基、吡咯基、咪唑基、嘧啶基或苯并呋喃基。In some embodiments, Ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, octahydropentalenyl, bicyclo[3.1.0]cyclohexyl, 2,3-dihydro-1H-indenyl, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, piperidinyl, phenyl, pyridinyl, pyrrolyl, imidazolyl, pyrimidinyl, or benzofuranyl.
在一些实施方案中，各R1独立地为-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、-NO2、-C(＝O)R6a、-C(＝O)OR6a、-C(＝O)NR6R7、-NR6C(＝O)R7、-NR6R7、-NR6S(＝O)2R7、氧代、C1-4烷基、C2-4烯基、C2-4炔基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷基、C2-4卤代烯基、C2-4卤代炔基、C1-4烷氧基C1-4烷基、C1-4羧基烷基、C1-4氨基烷基、C1-4巯基烷基、C1-4烷氧基、C3-6环烷基、3-6元杂环基、C6-12芳基或5-12元杂芳基；In some embodiments, each R 1 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -NO 2 , -C(=O)R 6a , -C(=O)OR 6a , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -NR 6 R 7 , -NR 6 S(=O) 2 R 7 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 2-4 haloalkenyl, C 2-4 haloalkynyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 carboxyalkyl, C 1-4 aminoalkyl, C 1-4 mercaptoalkyl, C 1-4 alkoxy, C 1-4 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;
R6和R7各自独立地为-H、-D或C1-4烷基，其中所述的C1-4烷基任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、C1-4烷氧基、6-10元芳基、C3-6环烷基和3-6元 杂环基的取代基所取代； R6 and R7 are each independently -H, -D or C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR6gR7g , C1-4 alkoxy, 6-10 membered aryl, C3-6 cycloalkyl and 3-6 membered substituted by a substituent of a heterocyclic group;
或R6、R7和与之相连的N原子一起形成4-6元杂环，其中所述的4-6元杂环任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、C1-4烷基、C1-4烷氨基、C3-6环烷基、3-6元杂环基、C1-4烷氧基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷氧基和C1-4卤代烷基的取代基所取代；or R 6 , R 7 and the N atom to which they are attached together form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted by 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl;
R6a、R6g和R7g各自独立地为-H、-D或C1-4烷基。R 6a , R 6g and R 7g are each independently -H, -D or C 1-4 alkyl.
在一些实施方案中，R1为-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、-NO2、-C(＝O)R6a、-C(＝O)OR6a、-C(＝O)NR6R7、-NR6C(＝O)R7、-NR6R7、-NR6S(＝O)2R7、氧代、-CH3、-CH2CH3、-(CH2)2CH3、-(CH2)3CH3、-C(CH3)3、-CH(CH3)2、-CH＝CH2、-CH＝CHCH3、-CH2CH＝CH2、-CHFCH＝CH2、-CH＝CHF、-CH＝CHCl、-CH＝CHCH2F、-CH＝CHCH3、-C≡CH、-C≡CCH3、-CH2C≡CH、-C≡CCH2F、-CH2CN、-(CH2)2CN、-(CH2)3CN、-CH2OH、-(CH2)2OH、-(CH2)3OH、-CH(OH)CH3、-CF3、-CHF2、-CH2F、-(CH2)2F、-(CH2)2Cl、-CH2CF3、-CH2OCH3、-(CH2)2OCH3、-(CH2)2OCH2CH3、-CH2OCH2CH3、-CH2C(＝O)OH、-(CH2)2C(＝O)OH、-(CH2)3C(＝O)OH、-CH2NH2、-(CH2)2NH2、-CH2SH、-(CH2)2SH、-OCH3、-OCH2CH3、-O(CH2)2CH3、-OCH2CH(CH3)2、-OCH(CH3)2、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氧杂环丁基、四氢呋喃基、吡咯烷基、苯基、吡啶基、嘧啶基、吡唑基或咪唑基；In some embodiments, R 1 is -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -NO 2 , -C(=O)R 6a , -C(=O)OR 6a , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -NR 6 R 7 , -NR 6 S(=O) 2 R 7 , oxo, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -C(CH 3 ) 3 , -CH(CH 3 ) 2 , -CH=CH 2 , -CH=CHCH 3 , -CH 2 CH=CH 2 , -CHFCH=CH 2 , -CH=CHF , -CH=CHCl , -CH=CHCH 2 F , -CH=CHCH 3 , -C≡CH, -C≡CCH 3 , -CH 2 C≡CH, -C≡CCH 2 F, -CH 2 CN, -(CH 2 ) 2 CN, -(CH 2 ) 3 CN, -CH 2 OH, -(CH 2 ) 2 OH, -(CH 2 ) 3 OH, -CH(OH)CH 3 , -CF 3 , -CHF 2 , -CH 2 F, -(CH 2 ) 2 F, -(CH 2 ) 2 Cl, -CH 2 CF 3 , -CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , -(CH 2 ) 2 OCH 2 CH 3 , -CH 2 OCH 2 CH 3 , -CH 2 C(═O)OH, -(CH 2 ) 2 C(═O)OH, -(CH 2 ) 3 C(=O)OH, -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -CH 2 SH, -(CH 2 ) 2 SH, -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH 2 CH(CH 3 ) 2 , -OCH(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazolyl or imidazolyl;
R6和R7各自独立地为-H、-D、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基各自任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、甲氧基、乙氧基、正丙氧基、异丙氧基、异丁氧基、环丙基、环丁基、环戊基、环己基、苯基、环氧乙烷基、氧杂环丁基、氮杂环丁基和吡咯烷基的取代基所取代； R6 and R7 are each independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl are each optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR6gR7g , methoxy, ethoxy, n-propoxy, isopropoxy , isobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxiranyl, oxetanyl, azetidinyl and pyrrolidinyl;
或R6、R7和与之相连的N原子一起形成吡咯烷、哌嗪、哌啶、吗啉、恶唑烷或咪唑烷，其中所述的吡咯烷、哌嗪、哌啶、吗啉、恶唑烷和咪唑烷各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氨基、二甲氨基、乙氨基、环丙基、环戊基、吡咯烷基、甲氧基、乙氧基、异丙氧基、氰基甲基、羟基甲基、羟基乙基、三氟甲氧基、一氟甲基、二氟甲基、三氟甲基和1,2-二氯乙基的取代基所取代；or R 6 , R 7 and the N atom to which they are attached together form pyrrolidine, piperazine, piperidine, morpholine, oxazolidine or imidazolidine, wherein the pyrrolidine, piperazine, piperidine, morpholine, oxazolidine and imidazolidine are each independently and optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy, ethoxy, isopropoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl and 1,2-dichloroethyl;
R6a、R6g和R7g各自独立地为-H、-D、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。R 6a , R 6g and R 7g are each independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
在一些实施方案中，环B为以下其中子结构之一，

In some embodiments, Ring B is one of the following substructures,

在一些实施方案中，各R2独立地为-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、-CH2C(＝O)NR6bR7b、-C(＝O)R6c、-C(＝O)OR6c、-C(＝O)NR6bR7b、-NR6bC(＝O)R7b、-NR6bR7b、C1-4烷基、C1-4烷硫基、C2-4烯基、C2-4炔基、C2-4羟基炔基、C1-4烷氧基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷基、C2-4卤代烯基、C2-4卤代炔基、C1-4卤代烷氧基、C1-4卤代烷硫基、6-12元芳基、5-12元杂芳基、C3-6环烷基或3-6元杂环基，其中所述的C1-4烷基、C1-4烷硫基、C2-4烯基、C2-4炔基、C2-4羟基炔基、C1-4烷氧基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷基、C2-4卤代烯基、C2-4卤代炔基、C1-4卤代烷氧基、C1-4卤代烷硫基、C6-10芳基、5-10元杂芳基、C3-6环烷基和3-6元杂环基各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、-C(＝O)H、-C(＝O)OH、C1-4烷基、C1-4烷氧基、C3-6环烷基和3-6元杂环基的取代基所取代；In some embodiments, each R 2 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH 2 C(=O)NR 6b R 7b , -C(=O)R 6c , -C(=O)OR 6c , -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b R 7b , C 1-4 alkyl, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 hydroxyalkynyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 2-4 haloalkenyl, C 2-4 haloalkynyl, C 1-4 haloalkoxy, C 1-4 C 1-4 alkyl, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 hydroxyalkynyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 2-4 haloalkenyl, C 2-4 haloalkynyl, C 1-4 haloalkoxy, C 1-4 haloalkylthio, C 6-10 aryl, 5-10 membered heteroaryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted by 1, 2 , 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , -C(=O)H, -C(=O)OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocyclic substituents;
各R6c独立地为-H、-D或C1-4烷基；Each R 6c is independently -H, -D or C 1-4 alkyl;
R6b和R7b各自独立地为-H、-D或C1-4烷基，其中所述的C1-4烷基任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、C1-4烷氧基、C6-10芳基、C3-6环烷基和3-6元杂环基的取代基所取代；R 6b and R 7b are each independently -H, -D or C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted by 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g , C 1-4 alkoxy, C 6-10 aryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
或R6b、R7b和与之相连的N原子一起形成4-6元杂环，其中所述的4-6元杂环任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、C1-4烷基、C1-4烷氨基、C3-6环烷基、3-6元杂环基、C1-4烷氧基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷氧基和C1-4卤代烷基的取代基所取代。Or R 6b , R 7b and the N atom to which they are attached form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted by 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl.
在一些实施方案中，各R2独立地为-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、-CH2C(＝O)NR6bR7b、-C(＝O)R6c、-C(＝O)OR6c、-C(＝O)NR6bR7b、-NR6bC(＝O)R7b、-NR6bR7b、-CH3、-CH2CH3、-(CH2)2CH3、-(CH2)3CH3、-C(CH3)3、-CH(CH3)2、-SCH3、-SCH2CH3、-CH＝CH2、-CH＝CHCH3、-CH2CH＝CH2、-C≡CH、-C≡CCH3、-CH2C≡CH、-C≡CCH2OH、-C≡C(CH2)2OH、-OCH3、-OCH2CH3、-O(CH2)2CH3、-CH2CN、-(CH2)2CN、-(CH2)3CN、-CH2OH、-(CH2)2OH、-(CH2)3OH、-CH(OH)CH3、-(CH2)2F、-CH2CHF2、-CF3、-CH2CF3、-CHF2、-CH2F、-(CH2)2Cl、-CH＝CHF、-CH＝CHCl、-CH＝CHCH2F、-C≡CCH2F、-C≡C(CH2)2F、-C≡CF、-OCF3、-OCHF2、-OCH2CHF2、-OCH2CF3、-OCHClCHCl2、-OCH2CH2F、-SCF3、-SCH2CF3、-SCH2CHF2、苯基、萘基、吡啶基、嘧啶基、环丙基、环丁基、环戊基、环己基、吡咯烷基、恶唑烷基、四氢呋喃基、哌啶基或哌嗪基，其中所述的-CH3、-CH2CH3、-(CH2)2CH3、-(CH2)3CH3、-C(CH3)3、-CH(CH3)2、-SCH3、-SCH2CH3、-CH＝CH2、-CH＝CHCH3、-CH2CH＝CH2、-C≡CH、-C≡CCH3、-CH2C≡CH、-C≡CCH2OH、-C≡C(CH2)2OH、-OCH3、-OCH2CH3、 -O(CH2)2CH3、-CH2CN、-(CH2)2CN、-(CH2)3CN、-CH2OH、-(CH2)2OH、-(CH2)3OH、-CH(OH)CH3、-(CH2)2F、-CH2CHF2、-CH2CF3、-CHF2、-CH2F、-(CH2)2Cl、-CH＝CHF、-CH＝CHCl、-CH＝CHCH2F、-C≡CCH2F、-C≡C(CH2)2F、-OCHF2、-OCH2CHF2、-OCH2CF3、-OCHClCHCl2、-OCH2CH2F、-SCH2CF3、-SCH2CHF2、苯基、萘基、吡啶基、嘧啶基、环丙基、环丁基、环戊基、环己基、吡咯烷基、恶唑烷基、四氢呋喃基、哌啶基和哌嗪基各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、-C(＝O)H、-C(＝O)OH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、吡咯烷基、恶唑烷基、四氢呋喃基、哌啶基和哌嗪基的取代基所取代；In some embodiments, each R 2 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH 2 C(=O)NR 6b R 7b , -C(=O)R 6c , -C(=O)OR 6c , -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b R 7b , -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -C(CH 3 ) 3 , -CH(CH 3 ) 2 , -SCH 3 , -SCH 2 CH 3 , -CH=CH 2 , -CH=CHCH 3 , -CH 2 CH=CH 2 , -C≡CH , -C≡CCH 3 , -CH 2 C≡CH, -C≡CCH 2 OH, -C≡C(CH 2 ) 2 OH, -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -CH 2 CN, -(CH 2 ) 2 CN, -(CH 2 ) 3 CN, -CH 2 OH, -(CH 2 ) 2 OH, -(CH 2 ) 3 OH, -CH(OH)CH 3 , -(CH 2 ) 2 F, -CH 2 CHF 2 , -CF 3 , -CH 2 CF 3 , -CHF 2 , -CH 2 F, -(CH 2 ) 2 Cl, -CH＝CHF, -CH＝CHCl, -CH＝CHCH 2 F, -C≡CCH 2 F, -C≡C(CH 2 ) 2 F, -C≡CF , -OCF3 , -OCHF2 , -OCH2CHF2 , -OCH2CF3 , -OCHClCHCl2 , -OCH2CH2F, -SCF3, -SCH2CF3, -SCH2CHF2 , phenyl, naphthyl, pyridyl , pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl , piperidinyl or piperazinyl, wherein -CH3 , -CH2CH3 , -(CH2)2CH3, -(CH2)3CH3 , -C ( CH3 ) 3 , -CH( CH3 ) 2 , -SCH3 , -SCH2CH3 , -CH = CH2 , -CH= CHCH3 , -CH2 CH＝CH 2 , -C≡CH, -C≡CCH 3 , -CH 2 C≡CH, -C≡CCH 2 OH, -C≡C(CH 2 ) 2 OH, -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -CH 2 CN, -(CH 2 ) 2 CN, -(CH 2 ) 3 CN, -CH 2 OH, -(CH 2 ) 2 OH, -(CH 2 ) 3 OH, -CH(OH)CH 3 , -(CH 2 ) 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CHF 2 , -CH 2 F, -(CH 2 ) 2 Cl, -CH＝CHF, -CH＝CHCl, -CH＝CHCH 2 F, -C≡CCH 2 F, -C≡C(CH 2 ) 2 F, -OCHF 2 , -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCHClCHCl 2 , -OCH 2 CH 2 F, -SCH 2 CF 3 , -SCH 2 CHF2 , phenyl, naphthyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl and piperazinyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2 , -C(=O)H, -C(=O)OH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl and piperazinyl;
各R6c独立地为-H、-D、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；Each R 6c is independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
R6b和R7b各自独立地为-H、-D、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基各自任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、甲氧基、乙氧基、正丙氧基、异丙氧基、异丁氧基、苯基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氧杂环丁基、氮杂环丁基和吡咯烷基的取代基所取代；R 6b and R 7b are each independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl are each optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g , methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, azetidinyl and pyrrolidinyl;
或R6b、R7b和与之相连的N原子一起形成吡咯烷、哌嗪、哌啶、吗啉、恶唑烷或咪唑烷，其中所述的吡咯烷、哌嗪、哌啶、吗啉、恶唑烷和咪唑烷各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氨基、二甲氨基、乙氨基、环丙基、环戊基、吡咯烷基、甲氧基、乙氧基、异丙氧基、氰基甲基、羟基甲基、羟基乙基、三氟甲氧基、一氟甲基、二氟甲基、三氟甲基和1,2-二氯乙基的取代基所取代。or R 6b , R 7b together with the N atom to which they are attached form pyrrolidine, piperazine, piperidine, morpholine, oxazolidine or imidazolidine, wherein the pyrrolidine, piperazine, piperidine, morpholine, oxazolidine and imidazolidine are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy, ethoxy, isopropoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl and 1,2-dichloroethyl.
在一些实施方案中，R4为-H、-D、C1-4烷基、3-6元杂环基、7-10元杂环基、 -L-吡咯烷基、-L-吗啉基、-L-氧杂环丁基、-L-氧杂环丙基、-L-四氢呋喃基、-L-八氢吲哚嗪基、-L-环丙基、-L-环戊基、-L-八氢并环戊二烯基、-L-八氢-1H-茚基、-L-十氢萘基、-L-吡啶基、-L-吡唑基、-L-苯基、-L-NR6R7、-NR6R7、-L-NHC(＝NH)NH2或-L-C(＝O)NR6R7，其中所述的C1-4烷基、3-6元杂环基、7-10元杂环基、 -L-吡咯烷基、-L-吗啉基、-L-氧杂环丁基、-L-氧杂环丙 基、-L-四氢呋喃基、-L-八氢吲哚嗪基、-L-环丙基、-L-环戊基、-L-八氢并环戊二烯基、-L-八氢-1H-茚基、-L-十氢萘基、-L-吡啶基、-L-吡唑基和-L-苯基各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NR6dR7d、-C(＝O)NR6dR7d、-CH2NR6dR7d、-CH2OC(＝O)NR6dR7d、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基、苯基C1-4烷基、5-6元杂芳基C1-4烷基、(3-6元杂环基)-C1-4烷基、C3-6环烷基C1-4烷基、C3-6环烷基和3-6元杂环基的取代基所取代，或，所述的中的 中的中的中的 中的各自任意位置任意个数的环碳原子上的两个氢原子被取代，其中所述取代基中的C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基、苯基C1-4烷基、5-6元杂芳基C1-4烷基、(3-6元杂环基)-C1-4烷基、C3-6环烷基C1-4烷基、C3-6环烷基和3-6元杂环基各自独立任选地被1、2、3或4个选自-D、-F、-Cl、-Br、-I、-OH、-CN、NR6eR7e、-C(＝O)C1-4烷基和C1-4烷基的取代基所取代；In some embodiments, R 4 is -H, -D, C 1-4 alkyl, 3-6 membered heterocyclyl, 7-10 membered heterocyclyl, -L-pyrrolidinyl, -L-morpholinyl, -L-oxetanyl, -L-oxetanyl, -L-tetrahydrofuranyl, -L-octahydroindolizinyl, -L-cyclopropyl, -L-cyclopentyl, -L-octahydropentalenyl, -L-octahydro-1H-indenyl, -L-decalinyl, -L-pyridinyl, -L-pyrazolyl, -L-phenyl, -L-NR 6 R 7 , -NR 6 R 7 , -L-NHC(═NH)NH 2 or -LC(═O)NR 6 R 7 , wherein the C 1-4 alkyl, 3-6 membered heterocyclyl, 7-10 membered heterocyclyl, -L-pyrrolidinyl, -L-morpholinyl, -L-oxetanyl, -L-oxacyclopropyl The following are examples of the present invention: -L-butyl, -L-tetrahydrofuranyl, -L-octahydroindolizinyl, -L-cyclopropyl, -L-cyclopentyl, -L-octahydropentalenyl, -L-octahydro-1H-indenyl, -L-decalinyl, -L-pyridinyl, -L-pyrazolyl and -L-phenyl, each of which is independently optionally substituted by 1, 2, 3 or 4 groups selected from -D , -OH , -F, -Cl, -Br, -I, -CN, -NR6dR7d , -C ( =O) NR6dR7d , -CH2NR6dR7d , -CH2OC (=O)NR6dR7d, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, phenylC1-4 alkyl, 5-6 membered heteroarylC1-4 C 1-4 alkyl, (3-6 membered heterocyclic group)-C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic group, or middle middle middle middle middle Two hydrogen atoms on any number of ring carbon atoms at any position are substituted, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl C 1-4 alkyl, 5-6 membered heteroaryl C 1-4 alkyl, (3-6 membered heterocyclyl)-C 1-4 alkyl, C 3-6 cycloalkyl C 1-4 alkyl , C 3-6 cycloalkyl and 3-6 membered heterocyclyl in the substituent are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -F, -Cl, -Br, -I, -OH, -CN, NR 6e R 7e , -C(＝O)C 1-4 alkyl and C 1-4 alkyl;
L为C1-4亚烷基；L is a C 1-4 alkylene group;
R6d、R7d、R6e和R7e各自独立地为-H、-D或C1-4烷基，其中所述的C1-4烷基任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、C1-4烷氧基、C6-10芳基、C3-6环烷基和3-6元杂环基的取代基所取代；R 6d , R 7d , R 6e and R 7e are each independently -H, -D or C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(═O)H, -C(═O)OH, -NR 6g R 7g , C 1-4 alkoxy, C 6-10 aryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
或R6d和R7d、或R6e和R7e，分别和与之相连的N原子一起形成4-6元杂环，其中所述的4-6元杂环任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、C1-4烷基、C1-4烷氨基、C3-6环烷基、3-6元杂环基、C1-4烷氧基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷氧基和C1-4卤代烷基的取代基所取代。Or R 6d and R 7d , or R 6e and R 7e , respectively, together with the N atom to which they are connected, form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted by 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl.
在一些实施方案中，R4为-H、-D、-CH3、-CH2CH3、-(CH2)2CH3、哌啶基、哌嗪基、吡咯烷基、咪唑烷基、 -CH2-吡咯烷基、-CH2-吗啉基、-(CH2)2-吗啉基、-CH2-氧杂环丁基、-CH2-氧杂环丙基、-CH2-四氢呋喃基、-CH2-八氢吲哚嗪基、-CH2-环丙基、-CH2-环戊基、-CH2-八氢并环戊二烯基、-CH2-八氢-1H- 茚基、-CH2-十氢萘基、-CH2-吡啶基、-(CH2)2-吡啶基、-CH2-吡唑基、-(CH2)2-吡唑基、-CH2-苯基、-CH2-NR6R7、-(CH2)2-NR6R7、-CH(CH3)CH2NR6R7、-NR6R7、-CH2-NHC(＝NH)NH2或-CH2-C(＝O)NR6R7，其中所述的-CH3、-CH2CH3、-(CH2)2CH3、哌啶基、哌嗪基、吡咯烷基、咪唑烷基、 -CH2-吡咯烷基、-CH2-吗啉基、-(CH2)2-吗啉基、-CH2-氧杂环丁基、-CH2-氧杂环丙基、-CH2-四氢呋喃基、-CH2-八氢吲哚嗪基、-CH2-环丙基、-CH2-环戊基、-CH2-八氢并环戊二烯基、-CH2-八氢-1H-茚基、-CH2-十氢萘基、-CH2-吡啶基、-(CH2)2-吡啶基、-CH2-吡唑基、-(CH2)2-吡唑基和-CH2-苯基各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NR6dR7d、-C(＝O)NR6dR7d、-CH2NR6dR7d、-CH2OC(＝O)NR6dR7d、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、异丙氧基、-CHF2、-CF3、-OCF3、苯基甲基、吡啶基甲基、吡唑基甲基、吗啉基甲基、吡咯烷基甲基、哌嗪基甲基、氮杂环丁烷基甲基、哌啶基甲基、环丙基甲基、环戊基甲基、环己基甲基、环戊基、环己基、吗啉基、哌啶基、吡咯烷基、哌嗪基和氮杂环丁烷基的取代基所取代，其中所述取代基中的甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、异丙氧基、-CHF2、苯基甲基、吡啶基甲基、吡唑基甲基、吗啉基甲基、吡咯烷基甲基、哌嗪基甲基、氮杂环丁烷基甲基、哌啶基甲基、环丙基甲基、环戊基甲基、环己基甲基、环戊基、环己基、吗啉基、哌啶基、吡咯烷基、哌嗪基和氮杂环丁烷基各自独立任选地被1、2、3或4个选自-D、-F、-Cl、-Br、-I、-OH、-CN、-NH2、-NHCH3、-N(CH3)2、-NHCH2CH3、-C(＝O)CH3、-C(＝O)CH2CH3、甲基、乙基、正丙基和异丙基的取代基所取代，或，R4为 In some embodiments, R 4 is -H, -D, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, -CH 2 -pyrrolidinyl, -CH 2 -morpholinyl, -(CH 2 ) 2 -morpholinyl, -CH 2 -oxetanyl, -CH 2 -oxirane, -CH 2 -tetrahydrofuranyl, -CH 2 -octahydroindolizinyl, -CH 2 -cyclopropyl, -CH 2 -cyclopentyl, -CH 2 -octahydropentalenyl, -CH 2 -octahydro-1H- indenyl, -CH2 -decalinyl, -CH2 -pyridinyl, -( CH2 ) 2 -pyridinyl, -CH2 -pyrazolyl, -( CH2 ) 2 -pyrazolyl, -CH2 -phenyl, -CH2 - NR6R7 , -( CH2 ) 2 - NR6R7 , -CH( CH3 ) CH2NR6R7 , -NR6R7 , -CH2 - NHC (=NH) NH2 or -CH2 -C(=O) NR6R7 , wherein -CH3 , -CH2CH3 , -( CH2 )2CH3 , piperidinyl , piperazinyl , pyrrolidinyl, imidazolidinyl, -CH2 -pyrrolidinyl, -CH2 -morpholinyl, -( CH2 ) 2 -morpholinyl, -CH2 - oxetanyl, -CH2-oxiranepropyl, -CH2-tetrahydrofuranyl, -CH2-octahydroindolizinyl, -CH2 -cyclopropyl, -CH2 -cyclopentyl, -CH2 -octahydropentalenyl, -CH2 -octahydro-1H-indenyl, -CH2 -decalinyl, -CH2 -pyridinyl, -( CH2 ) 2 -pyridinyl, -CH2 -pyrazolyl, -( CH2 ) 2 -pyrazolyl and -CH2 -phenyl are each independently optionally substituted by 1, 2 , 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN , -NR6dR7d , -C(=O) NR6dR7d , -CH 2 NR 6d R 7d , -CH 2 OC(＝O)NR 6d R 7d , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, isopropyloxy, -CHF 2 , -CF 3 , -OCF 3 , phenylmethyl, pyridylmethyl, pyrazolylmethyl, morpholinylmethyl, pyrrolidinylmethyl, piperazinylmethyl, azetidinylmethyl, piperidinylmethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl and azetidinyl substituents, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, isopropyloxy, -CHF 2 , -CF 3 , -OCF 3 , phenylmethyl, pyridylmethyl, pyrazolylmethyl, morpholinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl and azetidinyl substituents are substituted. wherein R4 is 4-(6-oxo)-1, 4-oxo-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-pyrrolidino-1, 4-pyrrolidino-1, 4-pyrrolidino-1, 4-pyrrolidino-1, 4 -pyrrolidino- 1 , 4-pyrrolidino- 1 , 4-pyrrolidino- 1 , 4 -pyrrolidino- 1 , 4-pyrrolidino- 1 , 4-pyrrolidino- 1 , 4-pyrrolidino-1, 4-pyrrolidino-1, 4-pyrrolidino- 1 , 4-pyrrolidino-1, 4-pyrrolidino- 1 , 4-pyrrolidino-1
R6d和R7d各自独立地为-H、-D、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基各自任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、甲氧基、乙氧基、正丙氧基、异丙氧基、异丁氧基、苯基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氧杂环丁基、氮杂环丁基和吡咯烷基的取代基所取代；R 6d and R 7d are each independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl are each optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g , methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, azetidinyl and pyrrolidinyl;
或R6d、R7d和与之相连的N原子一起形成氮杂环丁烷、吡咯烷、哌嗪、哌啶、吗啉、恶唑烷或咪唑烷，其中所述的氮杂环丁烷、吡咯烷、哌嗪、哌啶、吗啉、恶唑烷和咪唑烷各自独立任选地被1、2、3或4个 选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氨基、二甲氨基、乙氨基、环丙基、环戊基、吡咯烷基、甲氧基、乙氧基、异丙氧基、氰基甲基、羟基甲基、羟基乙基、三氟甲氧基、一氟甲基、二氟甲基、三氟甲基和1,2-二氯乙基的取代基所取代。or R 6d , R 7d and the N atom to which they are attached together form azetidine, pyrrolidine, piperazine, piperidine, morpholine, oxazolidine or imidazolidine, wherein the azetidine, pyrrolidine, piperazine, piperidine, morpholine, oxazolidine and imidazolidine are each independently and optionally substituted by 1, 2, 3 or 4 The invention is substituted with a substituent selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy, ethoxy, isopropoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl and 1,2-dichloroethyl.
在一些实施方案中，为其中以下子结构之一，
In some embodiments, is one of the following substructures,
R5为-H、-D、-OH、-SH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-C(＝O)OCH3、-C(＝O)NH2、-CH3、-CH2CH3、C3-4烷基、-CH2OH、-(CH2)2OH、-CH2CN、-(CH2)2CN、-CF3、-CHF2、-CH2F、-OCF3、-OCH3或-OCH2CH3。 R5 is -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O) OH, -C(=O)OCH3, -C(=O)NH2, -CH3, -CH2CH3, C3-4 alkyl , -CH2OH , - ( CH2 ) 2OH , -CH2CN, -( CH2 ) 2CN , -CF3 , -CHF2 , -CH2F , -OCF3 , -OCH3 , or -OCH2CH3 .
在一些实施方案中，本发明所述的化合物具有式(I-1)所示的化合物，或式(I-1)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
In some embodiments, the compound described in the present invention has a compound represented by formula (I-1), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-1),
其中，m、n、R1、R3、Y、Q、R4、R5和环A各自具有如本发明所述的定义；wherein m, n, R 1 , R 3 , Y, Q, R 4 , R 5 and ring A each have the meanings as described in the present invention;
R2a、R2b和R2c各自具有如权利要求1-10任意一项中R2所述相同的定义。R 2a , R 2b and R 2c each have the same definition as described for R 2 in any one of claims 1 to 10.
另一方面，本发明提供一种药物组合物，其包含本发明所述的化合物。In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention.
在一些实施方案中，本发明所述的药物组合物进一步包含药学上可接受的辅剂。In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable adjuvant.
在一些实施方案中，本发明所述的辅剂包括但不限于，载体，赋形剂，稀释剂，溶媒，或它们的组合。在一些实施方案中，药物组合物可以是液体，固体，半固体，凝胶或喷雾剂型。In some embodiments, the adjuvants described in the present invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof. In some embodiments, the pharmaceutical composition can be in liquid, solid, semisolid, gel or spray form.
另一方面，本发明提供本发明所述的药物组合物在制备用于预防、治疗或减轻KRas G12D相关疾病的药物中的用途。On the other hand, the present invention provides the use of the pharmaceutical composition described in the present invention in the preparation of drugs for preventing, treating or alleviating KRas G12D-related diseases.
在一些实施方案中，本发明所述的KRas G12D相关疾病为癌症。In some embodiments, the KRas G12D-related disease described in the present invention is cancer.
在一些实施方案中，本发明所述癌症为非小细胞肺癌、小细胞肺癌、结直肠癌、直肠癌、结肠癌、小肠癌、胰腺癌、子宫癌、胃癌、食道癌、前列腺癌、卵巢癌、乳腺癌、白血病、黑色素瘤、淋巴瘤或神经 瘤。In some embodiments, the cancer described herein is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, colon cancer, small intestine cancer, pancreatic cancer, uterine cancer, gastric cancer, esophageal cancer, prostate cancer, ovarian cancer, breast cancer, leukemia, melanoma, lymphoma or neuroendocrine cancer. tumor.
另一方面，本发明还提供了预防或治疗KRas G12D相关疾病的方法，所述方法包括向患者施用治疗有效量的本发明所述的化合物或其药物组合物。On the other hand, the present invention also provides a method for preventing or treating KRas G12D-related diseases, which comprises administering a therapeutically effective amount of the compound described in the present invention or a pharmaceutical composition thereof to a patient.
另一方面，本发明涉及式(I)或(I-1)化合物的制备、分离和纯化的方法。In another aspect, the present invention relates to methods for preparing, isolating and purifying the compounds of formula (I) or (I-1).
除非其他方面表明，本发明的化合物所有的立体异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，盐和药学上可接受的前药都属于本发明的范围。Unless otherwise indicated, all stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are within the scope of the invention.
具体地说，盐是药学上可接受的盐。术语“药学上可接受的”包括物质或组合物必须是适合化学或毒理学，与组成制剂的其他组分和用于治疗的哺乳动物有关。In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemically and toxicologically with respect to the other ingredients that make up the formulation and with the mammal to be treated.
本发明的化合物的盐还包括用于制备或纯化式(I)或(I-1)所示化合物的中间体或式(I)或(I-1)所示化合物分离的对映异构体的盐，但不一定是药学上可接受的盐。The salts of the compounds of the present invention also include intermediates used in the preparation or purification of the compounds of formula (I) or (I-1) or salts of separated enantiomers of the compounds of formula (I) or (I-1), but they are not necessarily pharmaceutically acceptable salts.
前面所述内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他的方面的内容将在下面作更加具体完整的描述。The foregoing description only summarizes certain aspects of the present invention, but is not limited to these aspects. These aspects and other aspects will be described in more detail and complete below.
本发明的详细说明书Detailed description of the present invention
定义和一般术语Definitions and general terms
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。It should be further appreciated that certain features of the invention, which for clarity are described in the context of multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.
本发明所使用的术语“受试对象”是指动物。典型地所述动物是哺乳动物。受试对象，例如也指灵长类动物(例如人类，男性或女性)、牛、绵羊、山羊、马、犬、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中，所述受试对象是灵长类动物。在其他实施方案中，所述受试对象是人。The term "subject" as used in the present invention refers to an animal. Typically, the animal is a mammal. Subjects, for example, also refer to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
本发明所使用的术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中，“患者”是指人。The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反异构体)、阻转异构体，等等。除非其他方面表明，本发明所描述的结构式的所有立体异构体或立体异构体的混合物都属于本发明的范围。另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。"Stereoisomers" refer to compounds with the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like. Unless otherwise indicated, all stereoisomers or mixtures of stereoisomers of the structural formula described in the present invention are within the scope of the present invention. In addition, unless otherwise indicated, the structural formula of the compounds described in the present invention includes one or more enriched isotopes of different atoms.
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical  Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。The stereochemical definitions and conventions used in this invention generally follow those in SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and/or fractional crystallization.
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerizations and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
像本发明所描述的，本发明的化合物可以独立任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“独立任选地被……取代”或“任选地被……取代”这两个术语与“取代或非取代”这个术语可以交换使用。一般而言，术语“取代”表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个任选的取代基团可以在基团各个可取代的位置进行取代。当所给出的结构式中不止一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。As described herein, the compounds of the present invention may be independently optionally substituted with one or more substituents, such as the general formula compounds above, or as specific examples in the embodiments, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the terms "independently optionally substituted" or "optionally substituted" are used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted the same or differently at each position.
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。In addition, it should be noted that, unless explicitly stated otherwise, the description methods used in the present invention, "each... is independently" and "... are each independently" and "... are independently" can be interchanged and should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C1-6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent secondary combination of the individual members of these group types and ranges. For example, the term "C 1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl.
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is connected.
术语“烷基”表示含有1至20个碳原子，饱和的直链或支链一价烃基基团，其中，所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。在一实施方案中，烷基基团含有1-6个碳原子，表示为C1-6烷基；在又一实施方案中，烷基基团含有1-4个碳原子，表示为C1-4烷基；还在一实施方案中，烷基基团含有1-3个碳原子，表示为C1-3烷基。烷基基团的实例包含，但并不限于，甲基(Me、-CH3)，乙基(Et、-CH2CH3)，正丙基(n-Pr、-CH2CH2CH3)，异丙基(i-Pr、-CH(CH3)2)，正丁基(n-Bu、-CH2CH2CH2CH3)，异丁基(i-Bu、-CH2CH(CH3)2)，仲丁基(s-Bu、-CH(CH3)CH2CH3)，叔丁基(t-Bu、-C(CH3)3)，正戊基(-CH2CH2CH2CH2CH3)，2-戊基(-CH(CH3)CH2CH2CH3)，3-戊基(-CH(CH2CH3)2)，2-甲基-2-丁基(-C(CH3)2CH2CH3)，3-甲基-2-丁基(-CH(CH3)CH(CH3)2)，3-甲基-1-丁基(-CH2CH2CH(CH3)2)，2-甲基-1- 丁基(-CH2CH(CH3)CH2CH3)，正己基(-CH2CH2CH2CH2CH2CH3)，2-己基(-CH(CH3)CH2CH2CH2CH3)，3-己基(-CH(CH2CH3)(CH2CH2CH3))，2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)，3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)，4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)，3-甲基-3-戊基(-C(CH3)(CH2CH3)2)，2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)，2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)，3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3)，正庚基，正辛基，等等。The term "alkyl" refers to a saturated straight or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. In one embodiment, the alkyl group contains 1-6 carbon atoms, represented by C 1-6 alkyl; in another embodiment, the alkyl group contains 1-4 carbon atoms, represented by C 1-4 alkyl; in another embodiment, the alkyl group contains 1-3 carbon atoms, represented by C 1-3 alkyl. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl butyl (—CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (—CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (—CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (—CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (—C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (—CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (—CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (—C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (—CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl(-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl(-CH(CH 3 )C(CH 3 ) 3 ), n-heptyl, n-octyl, and the like.
术语“亚烷基”表示从饱和的直链或支链烃中去掉两个氢原子所得到的饱和的二价烃基基团。在一些实施方案中，亚烷基基团含有1-6个碳原子，表示为C1-6亚烷基；在另一些实施方案中，亚烷基基团含有1-4个碳原子，表示为C1-4亚烷基；在另一些实施方案中，亚烷基基团含有1-3个碳原子，表示为C1-3亚烷基；在另一些实施方案中，亚烷基基团含有1-2个碳原子，表示为C1-2亚烷基。亚烷基基团的实例包括但不限于：亚甲基(即-CH2-)、亚乙基(即-CH2CH2-)、亚异丙基(即-CH(CH3)CH2-)，等等。The term "alkylene" refers to a saturated divalent hydrocarbon group derived from a saturated straight or branched hydrocarbon by removing two hydrogen atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms, represented by C 1-6 alkylene; in other embodiments, the alkylene group contains 1-4 carbon atoms, represented by C 1-4 alkylene; in other embodiments, the alkylene group contains 1-3 carbon atoms, represented by C 1-3 alkylene; in other embodiments, the alkylene group contains 1-2 carbon atoms, represented by C 1-2 alkylene. Examples of alkylene groups include, but are not limited to, methylene (i.e., -CH 2 -), ethylene (i.e., -CH 2 CH 2 -), isopropylene (i.e., -CH(CH 3 )CH 2 -), and the like.
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp2双键，其中，所述烯基基团可以任选地被一个或多个本发明所描述的取代基所取代，其包括“cis”和“trans”的定位，或者“E”和“Z”的定位。在一实施方案中，烯基基团包含2-6个碳原子，表示为C2-6烯基；在又一实施方案中，烯基基团包含2-4个碳原子，表示为C2-4烯基。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH2)、烯丙基(-CH2CH＝CH2)、1-丙烯基(即，丙烯基，-CH＝CH-CH3)，等等。The term "alkenyl" refers to a straight or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., one carbon-carbon sp2 double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including "cis" and "trans" orientations, or "E" and "Z" orientations. In one embodiment, the alkenyl group contains 2 to 6 carbon atoms, represented by C2-6 alkenyl; in another embodiment, the alkenyl group contains 2 to 4 carbon atoms, represented by C2-4 alkenyl. Examples of alkenyl groups include, but are not limited to, vinyl (-CH= CH2 ), allyl ( -CH2CH = CH2 ), 1-propenyl (i.e., propenyl, -CH=CH- CH3 ), and the like.
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键，其中，所述炔基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，炔基基团包含2-6个碳原子，表示为C2-6炔基；在又一实施方案中，炔基基团包含2-4个碳原子，表示为C2-4炔基。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH2C≡CH)、1-丙炔基(-C≡C-CH3)等等。The term "alkynyl" refers to a straight or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents described herein. In one embodiment, the alkynyl group contains 2 to 6 carbon atoms, represented by C2-6 alkynyl; in another embodiment, the alkynyl group contains 2 to 4 carbon atoms, represented by C2-4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl ( -CH2C≡CH ), 1-propynyl (-C≡C- CH3 ), and the like.
术语“氰基烷基”表示被一个或多个氰基取代的烷基，其中氰基和烷基基团具有如本发明所述的定义。在一些实施方案中，“氰基烷基”表示被一个氰基取代的烷基。在一些实施方案中，“氰基烷基”为C1-6氰基烷基，即被一个或多个氰基取代的C1-6烷基。在一些优选的实施方案中，C1-6氰基烷基为被一个氰基取代的C1-6烷基。在另一些实施方案中，“氰基烷基”为C1-4氰基烷基，即被一个或多个氰基取代的C1-4烷基。氰基烷基的实例包括但不限于，-CH2CN、-CH2CH2CH2CH2CN、-CH2CH2CN、-CH2CH(CN)CH2CH2CN、-CH2CH(CN)CH2CH(CH3)CN，等。The term "cyanoalkyl" refers to an alkyl group substituted by one or more cyano groups, wherein cyano and alkyl groups have the definitions as described herein. In some embodiments, "cyanoalkyl" refers to an alkyl group substituted by one cyano group. In some embodiments, "cyanoalkyl" is a C 1-6 cyanoalkyl, i.e., a C 1-6 alkyl group substituted by one or more cyano groups. In some preferred embodiments, C 1-6 cyanoalkyl is a C 1-6 alkyl group substituted by one cyano group. In other embodiments, "cyanoalkyl" is a C 1-4 cyanoalkyl, i.e., a C 1-4 alkyl group substituted by one or more cyano groups. Examples of cyanoalkyl include, but are not limited to, -CH 2 CN, -CH 2 CH 2 CH 2 CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH(CN)CH 2 CH 2 CN, -CH 2 CH(CN)CH 2 CH(CH 3 )CN, and the like.
术语“羟基烷基”表示被一个或多个羟基取代的烷基，其中烷基和羟基基团具有如本发明所述的定义。在一些实施方案中，羟基烷基表示被1、2、3或4个羟基取代的烷基。在一些实施方案中，羟基烷基表示被一个或两个羟基取代的烷基。在一些实施方案中，羟基烷基表示C1-6羟基烷基，即C1-6烷基被一个或多个羟基取代，优选地，C1-6羟基烷基表示C1-6烷基被一个羟基取代的烷基。在一些实施方案中，羟基烷基表示C1-4羟基烷基。在一些实施方案中，羟基烷基表示C1-3羟基烷基。羟基烷基的实例包括但不限于，-CH2OH、-CH2CH2CH2CH2OH、-CH2CH2OH、-CH2CH(OH)CH2CH2OH、-CH2CH(OH)CH2CH(CH3)OH，等。The term "hydroxyalkyl" refers to an alkyl group substituted by one or more hydroxyl groups, wherein alkyl and hydroxyl groups have the definitions as described herein. In some embodiments, hydroxyalkyl refers to an alkyl group substituted by 1, 2, 3 or 4 hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted by one or two hydroxyl groups. In some embodiments, hydroxyalkyl refers to a C 1-6 hydroxyalkyl group, i.e., a C 1-6 alkyl group substituted by one or more hydroxyl groups, preferably, a C 1-6 hydroxyalkyl group refers to an alkyl group substituted by one hydroxyl group. In some embodiments, hydroxyalkyl refers to a C 1-4 hydroxyalkyl group. In some embodiments, hydroxyalkyl refers to a C 1-3 hydroxyalkyl group. Examples of hydroxyalkyl groups include, but are not limited to, -CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH(OH)CH 2 CH 2 OH, -CH 2 CH(OH)CH 2 CH( CH 3 ) OH, and the like.
术语“卤代烷基”表示烷基基团被一个或多个卤素原子所取代，其中烷基和卤素具有如本发明所述的定义。在一些实施方案中，卤代烷基为C1-6卤代烷基，表示C1-6烷基基团被一个或多个卤素原子所取代；在另一些实施方案中，卤代烷基为C1-4卤代烷基，表示C1-4烷基基团被一个或多个卤素原子所取代；在另一些实施方案中，卤代烷基为C1-3卤代烷基，表示C1-3烷基基团被一个或多个卤素原子所取代。这样的实 例包含，但并不限于，单氟甲基、二氟甲基、三氟甲基、1-氟乙基、2-氟乙基、1,2-二氟乙基、1,1-二氟乙基、2,2-二氟乙基、单氯甲基、二氯甲基、三氯甲基、2-氯乙基、1-氯乙基、1,2-二氯乙基、1,1-二氯乙基、2,2-二氯乙基、1,1-二溴乙基，等等。The term "haloalkyl" means that an alkyl group is substituted with one or more halogen atoms, wherein alkyl and halogen have the definitions as described herein. In some embodiments, the haloalkyl is C 1-6 haloalkyl, which means that the C 1-6 alkyl group is substituted with one or more halogen atoms; in other embodiments, the haloalkyl is C 1-4 haloalkyl, which means that the C 1-4 alkyl group is substituted with one or more halogen atoms; in other embodiments, the haloalkyl is C 1-3 haloalkyl, which means that the C 1-3 alkyl group is substituted with one or more halogen atoms. Such embodiments are Examples include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and the like.
术语“卤代烯基”表示烯基基团被一个或多个卤素原子所取代，其中烯基具有如本发明所述的定义。在一些实施方案中，卤代烯基为C2-6卤代烯基，表示C2-6烯基基团被一个或多个卤素原子所取代；在另一些实施方案中，卤代烯基为C2-4卤代烯基，表示C2-4烯基基团被一个或多个卤素原子所取代。这样的实例包含，但并不限于，1-氯乙烯基(-CCl＝CH2)、2-氟乙烯基(-CH＝CHF)、1-氟烯丙基(-CHFCH＝CH2)、3-氟丙烯基(即，-CH＝CH-CH2F)、3,3-二氟丙烯基(即，-CH＝CH-CHF2)。The term "haloalkenyl" means an alkenyl group substituted with one or more halogen atoms, wherein alkenyl has the definition as described herein. In some embodiments, the haloalkenyl is a C2-6 haloalkenyl, which means a C2-6 alkenyl group substituted with one or more halogen atoms; in other embodiments, the haloalkenyl is a C2-4 haloalkenyl, which means a C2-4 alkenyl group substituted with one or more halogen atoms. Such examples include, but are not limited to, 1-chlorovinyl (-CCl= CH2 ), 2-fluorovinyl (-CH=CHF), 1-fluoroallyl (-CHFCH= CH2 ), 3-fluoropropenyl (i.e., -CH=CH- CH2F ), 3,3-difluoropropenyl (i.e., -CH=CH- CHF2 ).
术语“卤代炔基”表示炔基基团被一个或多个卤素原子所取代，其中炔基具有如本发明所述的定义。在一些实施方案中，卤代炔基为C2-6卤代炔基，表示C2-6炔基基团被一个或多个卤素原子所取代；在另一些实施方案中，卤代炔基为C2-4卤代炔基，表示C2-4炔基基团被一个或多个卤素原子所取代。这样的实例包含，但并不限于，2-氯乙炔基(-C≡CCl)、1-氯炔丙基(-CHClC≡CH)、3-氯丙炔基(-C≡C-CH2Cl)，等等。The term "haloalkynyl" means that an alkynyl group is substituted with one or more halogen atoms, wherein alkynyl has the definition as described herein. In some embodiments, the haloalkynyl is a C 2-6 haloalkynyl, which means that a C 2-6 alkynyl group is substituted with one or more halogen atoms; in other embodiments, the haloalkynyl is a C 2-4 haloalkynyl, which means that a C 2-4 alkynyl group is substituted with one or more halogen atoms. Such examples include, but are not limited to, 2-chloroethynyl (-C≡CCl), 1-chloropropargyl (-CHClC≡CH), 3-chloropropynyl (-C≡C-CH 2 Cl), and the like.
术语“羟基炔基”表示炔基基团被一个或多个羟基所取代，其中羟基和炔基具有如本发明所述的定义。在一些实施方案中，羟基炔基为C2-6羟基炔基，表示C2-6炔基基团被一个或多个羟基所取代；在另一些实施方案中，羟基炔基为C2-4羟基炔基，表示C2-4炔基基团被一个或多个羟基所取代。这样的实例包含，但并不限于，3-羟基丙炔基(-C≡C-CH2OH)、4-羟基丁炔基(-C≡C-(CH2)2OH)，等。The term "hydroxyalkynyl" means an alkynyl group substituted with one or more hydroxyl groups, wherein hydroxyl and alkynyl are defined as described herein. In some embodiments, the hydroxyalkynyl group is a C 2-6 hydroxyalkynyl group, which means that the C 2-6 alkynyl group is substituted with one or more hydroxyl groups; in other embodiments, the hydroxyalkynyl group is a C 2-4 hydroxyalkynyl group, which means that the C 2-4 alkynyl group is substituted with one or more hydroxyl groups. Such examples include, but are not limited to, 3-hydroxypropynyl (-C≡C-CH 2 OH), 4-hydroxybutynyl (-C≡C-(CH 2 ) 2 OH), and the like.
术语“烷氧基烷基”表示被一个烷氧基取代的烷基，其中，烷氧基和烷基具有如本发明所述的定义。在一些实施方案中，烷氧基烷基表示C1-6烷氧基C1-6烷基；在另一些实施方案中，烷氧基烷基表示C1-4烷氧基C1-4烷基；在另一些实施方案中，烷氧基烷基表示C1-4烷氧基C1-3烷基；在一些实施方案中，烷氧基烷基表示C1-3烷氧基C1-3烷基。烷氧基的实例包括但不限于，甲氧基甲基、乙氧基甲基、正丙氧基甲基、异丙氧基甲基、甲氧基乙基、甲氧基正丙基、甲氧基异丙基、乙氧基乙基、乙氧基正丙基、乙氧基异丙基、正丙氧基乙基、异丙氧基乙基、正丙氧基正丙基、正丙氧基异丙基、异丙氧基正丙基、异丙氧基异丙基，等。The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group, wherein alkoxy and alkyl have the definitions described herein. In some embodiments, alkoxyalkyl refers to C 1-6 alkoxy C 1-6 alkyl; in other embodiments, alkoxyalkyl refers to C 1-4 alkoxy C 1-4 alkyl; in other embodiments, alkoxyalkyl refers to C 1-4 alkoxy C 1-3 alkyl; in some embodiments, alkoxyalkyl refers to C 1-3 alkoxy C 1-3 alkyl. Examples of alkoxy groups include, but are not limited to, methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, methoxyethyl, methoxy-n-propyl, methoxy-isopropyl, ethoxyethyl, ethoxy-n-propyl, ethoxy-isopropyl, n-propoxyethyl, isopropoxyethyl, n-propoxy-n-propyl, n-propoxy-isopropyl, isopropoxy-n-propyl, isopropoxy-isopropyl, and the like.
术语“羧基烷基”表示被一个或多个羧基取代的烷基，其中羧基和烷基基团具体如本发明所述的定义。在一些实施方案中，羧基烷基为C1-6羧基烷基，表示被一个或多个羧基取代的C1-6烷基；在另一些实施方案中，羧基烷基为C1-4羧基烷基，表示被一个或多个羧基取代的C1-4烷基；在另一些实施方案中，羧基烷基为C1-3羧基烷基，表示被一个或多个羧基取代的C1-3烷基。羧基烷基的实例包括但不限于，羧基甲基(-CH2COOH)、2-羧基乙基(-(CH2)2COOH)、3-羧基丙基(-(CH2)3COOH)，等。The term "carboxyalkyl" refers to an alkyl group substituted by one or more carboxyl groups, wherein the carboxyl group and the alkyl group are specifically defined as described herein. In some embodiments, the carboxyalkyl group is a C 1-6 carboxyalkyl group, which refers to a C 1-6 alkyl group substituted by one or more carboxyl groups; in other embodiments, the carboxyalkyl group is a C 1-4 carboxyalkyl group, which refers to a C 1-4 alkyl group substituted by one or more carboxyl groups; in other embodiments, the carboxyalkyl group is a C 1-3 carboxyalkyl group, which refers to a C 1-3 alkyl group substituted by one or more carboxyl groups. Examples of carboxyalkyl groups include, but are not limited to, carboxymethyl (-CH 2 COOH), 2-carboxyethyl (-(CH 2 ) 2 COOH), 3-carboxypropyl (-(CH 2 ) 3 COOH), and the like.
术语“氨基烷基”表示被一个或多个氨基取代的烷基，其中烷基和氨基基团具有如本发明所述的含义。在一些实施方案中，氨基烷基为C1-6氨基烷基，表示被一个或多个氨基取代的C1-6烷基；在另一些实施方案中，氨基烷基为C1-4氨基烷基，表示被一个或多个氨基取代的C1-4烷基；在另一些实施方案中，氨基烷基为C1-3氨基烷基，表示被一个或多个氨基取代的C1-3烷基。氨基烷基的实例包括但不限于，氨基甲基(-CH2NH2)、2-氨基乙基(-(CH2)2NH2)、1-氨基乙基(-CH(NH2)CH3)、1,2-二氨基乙基(-CH(NH2)CH2NH2)、3-氨基丙基(-(CH2)3NH2)。The term "aminoalkyl" refers to an alkyl group substituted by one or more amino groups, wherein alkyl and amino groups have the meanings as described herein. In some embodiments, the aminoalkyl group is a C 1-6 aminoalkyl group, which refers to a C 1-6 alkyl group substituted by one or more amino groups; in other embodiments, the aminoalkyl group is a C 1-4 aminoalkyl group, which refers to a C 1-4 alkyl group substituted by one or more amino groups; in other embodiments, the aminoalkyl group is a C 1-3 aminoalkyl group, which refers to a C 1-3 alkyl group substituted by one or more amino groups. Examples of aminoalkyl groups include, but are not limited to, aminomethyl (-CH 2 NH 2 ), 2-aminoethyl (-(CH 2 ) 2 NH 2 ), 1-aminoethyl (-CH(NH 2 )CH 3 ), 1,2-diaminoethyl (-CH(NH 2 )CH 2 NH 2 ), and 3-aminopropyl (-(CH 2 ) 3 NH 2 ).
术语“烷氨基”或“烷基氨基”表示被一个或两个烷基基团取代的氨基，包括“N-烷基氨基”和“N,N-二烷基氨基”，其中烷基和氨基基团具有如本发明所述的含义。在一些实施方案中，烷氨基表示C1-6烷基 氨基，为含有1-6个碳原子的烷基氨基；在另一些实施方案中，烷氨基表示C1-4烷基氨基，为含有1-4个碳原子的烷基氨基；烷氨基表示C1-3烷基氨基，为含有1-3个碳原子的烷基氨基。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基，这样的实例包括，但并不限于、N-甲氨基(-NHCH3)、N-乙氨基(-NHCH2CH3)、N,N-二甲氨基(-N(CH3)2)、N,N-二乙氨基(-N(CH2CH3)2)，等。The term "alkylamino" or "alkylamino" refers to an amino group substituted by one or two alkyl groups, including "N-alkylamino" and "N,N-dialkylamino", wherein the alkyl and amino groups have the meanings as described in the present invention. In some embodiments, alkylamino refers to a C 1-6 alkyl Amino is an alkylamino group containing 1 to 6 carbon atoms; in other embodiments, alkylamino represents C 1-4 alkylamino, which is an alkylamino group containing 1 to 4 carbon atoms; alkylamino represents C 1-3 alkylamino, which is an alkylamino group containing 1 to 3 carbon atoms. Suitable alkylamino groups can be monoalkylamino or dialkylamino groups, such as, but not limited to, N-methylamino (-NHCH 3 ), N-ethylamino (-NHCH 2 CH 3 ), N,N-dimethylamino (-N(CH 3 ) 2 ), N,N-diethylamino (-N(CH 2 CH 3 ) 2 ), and the like.
术语“巯基烷基”表示被一个或多个巯基取代的烷基，其中烷基基团具有如本发明所述的含义。在一些实施方案中，巯基烷基表示C1-6巯基烷基，为被一个或多个巯基取代的C1-6烷基；优选地，C1-6巯基烷基为被一个巯基取代的C1-6烷基。在另一些实施方案中，巯基烷基表示C1-4巯基烷基。在另一些实施方案中，巯基烷基表示C1-3巯基烷基。巯基烷基的实例包括，但不限于，巯基甲基(-CH2SH)、2-巯基乙基(-(CH2)2SH)、3-巯基丙基(-(CH2)3SH)、2,3-二巯基丙基(-CH2CH(SH)CH2(SH))，等。The term "mercaptoalkyl" refers to an alkyl group substituted by one or more mercapto groups, wherein the alkyl group has the meaning as described herein. In some embodiments, mercaptoalkyl refers to C 1-6 mercaptoalkyl, which is a C 1-6 alkyl group substituted by one or more mercapto groups; preferably, C 1-6 mercaptoalkyl is a C 1-6 alkyl group substituted by one mercapto group. In other embodiments, mercaptoalkyl refers to C 1-4 mercaptoalkyl. In other embodiments, mercaptoalkyl refers to C 1-3 mercaptoalkyl. Examples of mercaptoalkyl include, but are not limited to, mercaptomethyl (-CH 2 SH), 2-mercaptoethyl (-(CH 2 ) 2 SH), 3-mercaptopropyl (-(CH 2 ) 3 SH), 2,3-dimercaptopropyl (-CH 2 CH(SH)CH 2 (SH)), and the like.
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一实施方案中，烷氧基基团含有1-6个碳原子，表示C1-6烷氧基；在另一实施方案中，烷氧基基团含有1-4个碳原子，表示C1-4烷氧基；在又一实施方案中，烷氧基基团含有1-3个碳原子，表示C1-3烷氧基。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH3)，乙氧基(EtO、-OCH2CH3)，1-丙氧基(n-PrO、n-丙氧基、-OCH2CH2CH3)，2-丙氧基(i-PrO、i-丙氧基、-OCH(CH3)2)，1-丁氧基(n-BuO、n-丁氧基、-OCH2CH2CH2CH3)，2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH2CH(CH3)2)，2-丁氧基(s-BuO、s-丁氧基、-OCH(CH3)CH2CH3)，2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH3)3)，1-戊氧基(n-戊氧基、-OCH2CH2CH2CH2CH3)，2-戊氧基(-OCH(CH3)CH2CH2CH3)，3-戊氧基(-OCH(CH2CH3)2)，2-甲基-2-丁氧基(-OC(CH3)2CH2CH3)，3-甲基-2-丁氧基(-OCH(CH3)CH(CH3)2)，3-甲基-l-丁氧基(-OCH2CH2CH(CH3)2)，2-甲基-l-丁氧基(-OCH2CH(CH3)CH2CH3)，等等。The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms, representing a C 1-6 alkoxy group; in another embodiment, the alkoxy group contains 1-4 carbon atoms, representing a C 1-4 alkoxy group; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms, representing a C 1-3 alkoxy group. The alkoxy group may be optionally substituted with one or more substituents as described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3 ), ethoxy (EtO, -OCH2CH3 ) , 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3 ), 2-propoxy (i-PrO, i - propoxy , -OCH( CH3 ) 2 ), 1 -butoxy ( n-BuO, n-butoxy , -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy , -OCH2CH ( CH3 ) 2 ), 2 -butoxy (s-BuO, s-butoxy, -OCH( CH3 ) CH2CH3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC( CH3 ) 3 ), 1-pentoxy (n-pentoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-pentyloxy (-OCH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyloxy (-OCH(CH 2 CH 3 ) 2 ), 2-methyl-2-butoxy (-OC(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butoxy (-OCH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butoxy (-OCH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butoxy (-OCH 2 CH(CH 3 )CH 2 CH 3 ), and the like.
术语“卤代烷氧基”表示被一个或多个卤素取代的烷氧基，其中烷氧基和卤素具有如本发明所的定义。在一些实施方案中，卤代烷氧基表示含有1-6个碳原子的卤代烷氧基，即C1-6卤代烷氧基；在另一些实施方案中，卤代烷氧基表示含有1-4个碳原子的卤代烷氧基，即C1-4卤代烷氧基；在另一些实施方案中，卤代烷氧基表示含有1-3个碳原子的卤代烷氧基，即C1-3卤代烷氧基。卤代烷氧基的实例包括，但不限于，三氟甲氧基(-OCF3)、一氟甲氧基(-OCH2F)、2-氟乙氧基(-OCH2CH2F)，等。The term "haloalkoxy" refers to an alkoxy group substituted by one or more halogens, wherein alkoxy and halogen have the same meanings as those defined herein. In some embodiments, haloalkoxy refers to a haloalkoxy group containing 1 to 6 carbon atoms, i.e., C 1-6 haloalkoxy; in other embodiments, haloalkoxy refers to a haloalkoxy group containing 1 to 4 carbon atoms, i.e., C 1-4 haloalkoxy; in other embodiments, haloalkoxy refers to a haloalkoxy group containing 1 to 3 carbon atoms, i.e., C 1-3 haloalkoxy. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy (-OCF 3 ), monofluoromethoxy (-OCH 2 F), 2-fluoroethoxy (-OCH 2 CH 2 F), and the like.
术语“碳环”或“碳环基”表示包含3-12个环原子的，饱和或部分不饱和的单环、双环或三环碳环体系，碳环中-CH2-基团可以任选地被-C(＝O)-(或-(CO)-)替代。在一实施方案中，碳环基包含3-6个环碳原子，表示为C3-6碳环基；在另一些实施方案中，碳环基为包含3-6个环碳原子的饱和环，表示为C3-6环烷基；在另一些实施方案中，所述C3-6环烷基为饱和单环。在一实施方案中，碳环基包含7-12个环碳原子，表示为C7-12碳环基；在另一些实施方案中，碳环基为包含7-12个环碳原子的饱和环，表示为C7-12环烷基。碳环基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、八氢-1H-茚基、八氢并环戊二烯基，等。碳环中-CH2-基团可被-C(＝O)-替代的实例包括但不限于：环戊酮、环丁酮，等。The term "carbocycle" or "carbocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic carbon ring system containing 3-12 ring atoms, in which the -CH2- group may be optionally replaced by -C(=O)- (or -(CO)-). In one embodiment, the carbocyclyl contains 3-6 ring carbon atoms, represented by C3-6 carbocyclyl; in other embodiments, the carbocyclyl is a saturated ring containing 3-6 ring carbon atoms, represented by C3-6 cycloalkyl; in other embodiments, the C3-6 cycloalkyl is a saturated monocyclic ring. In one embodiment, the carbocyclyl contains 7-12 ring carbon atoms, represented by C7-12 carbocyclyl; in other embodiments, the carbocyclyl is a saturated ring containing 7-12 ring carbon atoms, represented by C7-12 cycloalkyl. Examples of carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, octahydro-1H-indenyl, octahydropentalenyl, etc. Examples of carbocyclic rings in which -CH2- groups may be replaced by -C(=O)- include, but are not limited to, cyclopentanone, cyclobutanone, etc.
术语“环烷基”表示3-12个碳原子的单价的饱和单环或双环碳环体系，碳环中-CH2-基团可以任选地被-C(＝O)-(或-(CO)-)替代。在一实施方案中，环烷基包含3-10个环碳原子，即C3-10环烷基；在另一实施方案中，环烷基包含3-6个环碳原子，即C3-6环烷基；在另一实施方案中，环烷基包含3-5个环碳原子，即C3-5环烷基。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、八氢-1H-茚基、八氢并环戊 二烯基，等。碳环中-CH2-基团可被-C(＝O)-替代的实例包括但不限于：环戊酮、环丁酮，等。The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic carbon ring system of 3-12 carbon atoms, in which the -CH2- group may be optionally replaced by -C(=O)- (or -(CO)-). In one embodiment, the cycloalkyl contains 3-10 ring carbon atoms, i.e., C3-10 cycloalkyl; in another embodiment, the cycloalkyl contains 3-6 ring carbon atoms, i.e., C3-6 cycloalkyl; in another embodiment, the cycloalkyl contains 3-5 ring carbon atoms, i.e., C3-5 cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydro-1H-indenyl, octahydrocyclopentyl, cyclopentyl, cyclohexyl, cyclopent ... Dienyl, etc. Examples of the carbon ring in which the -CH 2 - group may be replaced by -C(=O)- include, but are not limited to, cyclopentanone, cyclobutanone, and the like.
术语“杂环”或“杂环基”表示包含3-12个环原子的，饱和或部分不饱和的单环、双环或三环体系，其中至少一个环原子选自氮、硫和氧原子；其中，所述杂环或杂环基是非芳香性的，且不包含任何芳香环。当杂环通过一个连接位点与分子其他部分相连时，杂环表示为一价的杂环基。除非另外说明，杂环基可以是碳基或氮基，且-CH2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化物。在一些实施方案中，所述杂环或杂环基由3-10个原子组成，表示为3-10元杂环或3-10元杂环基；在另一些实施方案中，所述杂环或杂环基由3-9个原子组成，表示为3-9元杂环或3-9元杂环基；在另一些实施方案中，所述杂环或杂环基由5-9个原子组成，表示为5-9元杂环或5-9元杂环基；在另一些实施方案中，所述杂环或杂环基由3-6个原子组成，表示为3-6元杂环或3-6元杂环基；在另一些实施方案中，所述杂环或杂环基由5-6个原子组成，表示为5-6元杂环或5-6元杂环基。所述杂环的实例包括但不限于，环氧乙烷、氮杂环丙烷、氮杂环丁烷、氧杂环丁烷、吡咯烷、四氢呋喃、四氢噻吩、噻唑烷、吡唑烷、吡唑啉、噁唑烷、咪唑烷、哌啶、哌嗪、吗啉、3,8-二氮杂双环[3.2.1]辛烷、3,6-二氮杂双环[3.1.1]庚烷、2,5-二氮杂双环[2.2.2]辛烷。所述杂环基包括但不限于，环氧乙烷基、氮杂环丙烷基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、四氢噻吩基、噻唑烷基、吡唑烷基、吡唑啉基、噁唑烷基、咪唑烷基、哌啶基、哌嗪基或吗啉基等。The term "heterocycle" or "heterocyclyl" means a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms; wherein the heterocycle or heterocyclyl is non-aromatic and does not contain any aromatic rings. When the heterocycle is attached to the rest of the molecule via one attachment point, the heterocycle represents a monovalent heterocyclyl. Unless otherwise specified, the heterocyclyl may be carbonyl or nitrogenyl, and the -CH2- group may be optionally replaced by -C(=O)-. The sulfur atom of the ring may be optionally oxidized to S-oxide. The nitrogen atom of the ring may be optionally oxidized to N-oxide. In some embodiments, the heterocycle or heterocyclyl consists of 3-10 atoms, represented by a 3-10-membered heterocycle or a 3-10-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 3-9 atoms, represented by a 3-9-membered heterocycle or a 3-9-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 5-9 atoms, represented by a 5-9-membered heterocycle or a 5-9-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 3-6 atoms, represented by a 3-6-membered heterocycle or a 3-6-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 5-6 atoms, represented by a 5-6-membered heterocycle or a 5-6-membered heterocyclyl. Examples of the heterocycle include, but are not limited to, oxirane, aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiazolidine, pyrazolidine, pyrazoline, oxazolidine, imidazolidine, piperidine, piperazine, morpholine, 3,8-diazabicyclo[3.2.1]octane, 3,6-diazabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.2]octane. The heterocyclic group includes, but is not limited to, oxirane, aziridine, azetidine, oxetane, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophene, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, etc.
术语“芳基”表示一价的含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子组成的环。在一些实施方案中，芳基含有6-12个环原子，表示为C6-12芳基或6-12元芳基。在一些实施方案中，芳基含有6-10个环原子，表示为C6-10芳基或6-10元芳基。芳基基团的实例可以包括苯基、萘基、1,2,3,4-四氢萘基和蒽。The term "aryl" refers to a monovalent, monocyclic, bicyclic and tricyclic carbon ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring consisting of 3-7 atoms. In some embodiments, the aryl contains 6-12 ring atoms, represented by C 6-12 aryl or 6-12 membered aryl. In some embodiments, the aryl contains 6-10 ring atoms, represented by C 6-10 aryl or 6-10 membered aryl. Examples of aryl groups can include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl and anthracene.
术语“杂芳基”或“杂芳环”表示含有5-14个环原子，或5-12个环原子，或5-10个环原子，或5-6个环原子的，单价的单环、双环或三环体系，其中至少一个环是芳香族的，且至少一个环包含一个或多个选自氮、氧、硫的环杂原子。杂芳基基团通常，但不必须地通过杂芳基基团的芳香性环与母体分子连接。当杂芳基基团中存在-CH2-基团时，所述的-CH2-基团可以任选地被-C(＝O)-替代。除非另外说明，所述的杂芳基基团可以通过任何合理的位点(可以为C或者N)连接到分子其余部分(例如通式中的主体结构)上。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。在一些实施方案中，杂芳基为含有5-12个环原子的杂芳基，表示为5-12元杂芳基；在另一些实施方案中，杂芳基为含有5-10个环原子的杂芳基，表示为5-10元杂芳基；在另一些实施方案中，杂芳基为含有5-6个环原子的杂芳基，表示为5-6元杂芳基。杂芳基的实例包括，但并不限于，呋喃基、咪唑基、异噁唑基、噁唑基、吡咯基、吡唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻吩基、噻唑基、三氮唑基、四氮唑基、苯并吡啶基、苯并咪唑基、苯并吡咯基、苯并吡唑基、苯并吡咯烷基，等。The term "heteroaryl" or "heteroaromatic ring" refers to a monovalent monocyclic, bicyclic or tricyclic ring system containing 5-14 ring atoms, or 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. The heteroaryl group is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the heteroaryl group. When a -CH 2 - group is present in the heteroaryl group, the -CH 2 - group may be optionally replaced by -C(=O)-. Unless otherwise specified, the heteroaryl group may be attached to the rest of the molecule (e.g., the main structure in the general formula) through any reasonable position (which may be C or N). The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is a heteroaryl containing 5-12 ring atoms, represented by a 5-12 membered heteroaryl; in other embodiments, heteroaryl is a heteroaryl containing 5-10 ring atoms, represented by a 5-10 membered heteroaryl; in other embodiments, heteroaryl is a heteroaryl containing 5-6 ring atoms, represented by a 5-6 membered heteroaryl. Examples of heteroaryl include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, benzopyridinyl, benzimidazolyl, benzopyrrolyl, benzopyrazolyl, benzopyrrolidinyl, and the like.
术语“烷硫基”表示烷基基团通过硫原子与分子其他部分相连，其中烷基具有如本发明所述的定义。在一些实施方案中，烷硫基为C1-6烷硫基，表示含有1-6个碳原子的烷硫基；在另一些实施方案中，烷硫基为C1-4烷硫基，表示含有1-4个碳原子的烷硫基；在在另一些实施方案中，烷硫基为C1-3烷硫基，表示含有1-3个碳原子的烷硫基。烷硫基的实例包括，但不限于，甲硫基(-SCH3)、乙硫基(-SCH2CH3)，等。The term "alkylthio" means an alkyl group attached to the rest of the molecule through a sulfur atom, wherein alkyl has the definition as described herein. In some embodiments, alkylthio is C 1-6 alkylthio, meaning an alkylthio containing 1 to 6 carbon atoms; in other embodiments, alkylthio is C 1-4 alkylthio, meaning an alkylthio containing 1 to 4 carbon atoms; in other embodiments, alkylthio is C 1-3 alkylthio, meaning an alkylthio containing 1 to 3 carbon atoms. Examples of alkylthio include, but are not limited to, methylthio (-SCH 3 ), ethylthio (-SCH 2 CH 3 ), and the like.
术语“卤代烷硫基”表示被一个或多个卤素原子取代的烷硫基基团，其中烷硫基基团具有如本发明所述的定义。在一些实施方案中，卤代烷硫基为C1-6卤代烷硫基，表示被一个或多个卤素取代的C1-6烷硫基； 在另一些实施方案中，卤代烷硫基为C1-4卤代烷硫基，表示被一个或多个卤素取代的C1-4烷硫基；在另一些实施方案中，卤代烷硫基为C1-3卤代烷硫基，表示被一个或多个卤素取代的C1-3烷硫基。卤代烷硫基的定义包括，但不限于，三氟甲硫基(-SCF3)、2,2,2-三氟乙硫基(-SCH2CF3)、单氟甲硫基(-SCH2F)，等。The term "haloalkylthio" refers to an alkylthio group substituted by one or more halogen atoms, wherein the alkylthio group has the definition as described herein. In some embodiments, the haloalkylthio group is a C 1-6 haloalkylthio group, which refers to a C 1-6 alkylthio group substituted by one or more halogen atoms; In other embodiments, haloalkylthio is C 1-4 haloalkylthio, which means C 1-4 alkylthio substituted by one or more halogens; in other embodiments, haloalkylthio is C 1-3 haloalkylthio, which means C 1-3 alkylthio substituted by one or more halogens. The definition of haloalkylthio includes, but is not limited to, trifluoromethylthio (-SCF 3 ), 2,2,2-trifluoroethylthio (-SCH 2 CF 3 ), monofluoromethylthio (-SCH 2 F), and the like.
术语“芳基烷基”表示被一个芳基取代的烷基，其中芳基和烷基具有如本发明所述的定义。在一些实施芳案中，芳基烷基为C6-10芳基C1-6烷基或(6-10元芳基)-C1-6烷基；在另一些实施方案中，芳基烷基为C6-10芳基C1-4烷基或(6-10元芳基)-C1-4烷基；在另一些实施方案中，芳基烷基为C6-10芳基C1-3烷基或(6-10元芳基)-C1-3烷基；在另一些实施方案中，芳基烷基为苯基C1-6烷基；在另一些实施方案中，芳基烷基为苯基C1-4烷基；在另一些实施方案中，芳基烷基为苯基C1-3烷基。芳基烷基的实例包括，但不限于苯基甲基、苯基乙基、苯并吡咯烷基甲基、萘基甲基，等。The term "arylalkyl" refers to an alkyl group substituted with an aryl group, wherein aryl and alkyl have the definitions described herein. In some embodiments, arylalkyl is C 6-10 arylC 1-6 alkyl or (6-10 membered aryl)-C 1-6 alkyl; in other embodiments, arylalkyl is C 6-10 arylC 1-4 alkyl or (6-10 membered aryl)-C 1-4 alkyl; in other embodiments, arylalkyl is C 6-10 arylC 1-3 alkyl or (6-10 membered aryl)-C 1-3 alkyl; in other embodiments, arylalkyl is phenylC 1-6 alkyl; in other embodiments, arylalkyl is phenylC 1-4 alkyl; in other embodiments, arylalkyl is phenylC 1-3 alkyl. Examples of arylalkyl include, but are not limited to, phenylmethyl, phenylethyl, benzopyrrolidinylmethyl, naphthylmethyl, and the like.
术语“杂芳基烷基”表示被被一个杂芳基取代的烷基，其中杂芳基和烷基具有如本发明所述的定义。在一些实施芳案中，杂芳基烷基为(5-12元杂芳基)-C1-6烷基；在另一些实施方案中，杂芳基烷基为5-12元杂芳基C1-4烷基；在另一些实施方案中，杂芳基烷基为(5-12元杂芳基)-C1-3烷基；在另一些实施方案中，杂芳基烷基为(5-6元杂芳基)-C1-6烷基；在另一些实施方案中，杂芳基烷基为(5-6元杂芳基)-C1-4烷基；在另一些实施方案中，杂芳基烷基为(5-6元杂芳基)-C1-3烷基。杂芳基烷基的实例包括，但不限于，嘧啶基甲基、吡啶基甲基、吡啶基乙基、吡唑基甲基，等。The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, wherein heteroaryl and alkyl are as defined herein. In some embodiments, heteroarylalkyl is (5-12 membered heteroaryl)-C 1-6 alkyl; in other embodiments, heteroarylalkyl is 5-12 membered heteroarylC 1-4 alkyl; in other embodiments, heteroarylalkyl is (5-12 membered heteroaryl)-C 1-3 alkyl; in other embodiments, heteroarylalkyl is (5-6 membered heteroaryl)-C 1-6 alkyl; in other embodiments, heteroarylalkyl is (5-6 membered heteroaryl)-C 1-4 alkyl; in other embodiments, heteroarylalkyl is (5-6 membered heteroaryl)-C 1-3 alkyl. Examples of heteroarylalkyl include, but are not limited to, pyrimidinylmethyl, pyridinylmethyl, pyridinylethyl, pyrazolylmethyl, and the like.
术语“杂环基烷基”表示被一个杂环基取代的烷基，其中杂环基和烷基具体如本发明所述的定义。在一些实施方案中，杂环基烷基为(3-6元杂环基)C1-6烷基；在另一些实施方案中，杂环基烷基为(3-6元杂环基)-C1-4烷基；在另一些实施方案中，杂环基烷基为(3-6元杂环基)-C1-4烷基；在另一些实施方案中，杂环基烷基为(3-6元杂环基)-C1-3烷基。杂环基烷基的实例包括，但不限于，哌啶基甲基、哌啶基乙基、吡咯烷基甲基，等。The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein heterocyclyl and alkyl are as specifically defined herein. In some embodiments, heterocyclylalkyl is (3-6 membered heterocyclyl)C 1-6 alkyl; in other embodiments, heterocyclylalkyl is (3-6 membered heterocyclyl)-C 1-4 alkyl; in other embodiments, heterocyclylalkyl is (3-6 membered heterocyclyl)-C 1-4 alkyl; in other embodiments, heterocyclylalkyl is (3-6 membered heterocyclyl)-C 1-3 alkyl. Examples of heterocyclylalkyl include, but are not limited to, piperidinylmethyl, piperidinylethyl, pyrrolidinylmethyl, and the like.
术语“环烷基烷基”表示被一个环烷基取代的烷基。在一些实施方案中，环烷基烷基为C3-6环烷基C1-6烷基；在另一些实施方案中，环烷基烷基为C3-6环烷基C1-4烷基；在另一些实施方案中，环烷基烷基为C3-6环烷基C1-3烷基。环烷基烷基的实例包括但不限于：环丙基甲基、环戊基甲基、环己基甲基、环己基乙基，等。The term "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group. In some embodiments, the cycloalkylalkyl group is a C 3-6cycloalkylC 1-6alkyl group; in other embodiments, the cycloalkylalkyl group is a C 3-6cycloalkylC 1-4alkyl group; in other embodiments, the cycloalkylalkyl group is a C 3-6cycloalkylC 1-3alkyl group. Examples of cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, and the like.
本发明中描述的“3-10元杂环基上的任意位置任意个数的环碳原子的两个氢原子被取代”，其中“任意位置”表示3-10元杂环基上的任何位置，“任意个数”表示所述的“环碳原子的两个氢原子被取代”中的环碳原子的个数可以是一个或多个，包括但不限于：1、2或3个。In the present invention, "two hydrogen atoms of any number of ring carbon atoms at any position on the 3-10 membered heterocyclic group are "replaced", wherein "any position" means any position on the 3-10 membered heterocyclic group, and "any number" means that "two hydrogen atoms of the ring carbon atom are replaced" The number of ring carbon atoms in the "substituted" may be one or more, including but not limited to: 1, 2 or 3.
术语“卤素”表示F(氟)、Cl(氯)、Br(溴)或I(碘)。The term "halogen" means F (fluorine), Cl (chlorine), Br (bromine) or I (iodine).
术语“氧代”表示＝O。The term "oxo" means =0.
术语“氰基”表示-CN或-C≡N。The term "cyano" means -CN or -C≡N.
术语“巯基”表示-SH。The term "mercapto" refers to -SH.
术语“羟基”表示-OH。The term "hydroxy" refers to -OH.
术语“羧基”表示-C(＝O)OH。 The term "carboxy" refers to -C(=O)OH.
术语“氨基”表示-NH2。The term "amino" refers to -NH2 .
术语“j-k个原子组成的”或“j-k元的”表示所述环状基团由j-k个环原子所组成，所述的环原子包括碳原子和/或O、N、S、P等杂原子；所述j和k各自独立地为任意非零的自然数，且k>j；所述“j-k”包括j、k和两者之间的任意自然数。例如，“3-8个原子组成的”或“3-8元的”、“3-6个原子组成的”或“3-6元的”、“5-10个原子组成的”或“5-10元的”，或“5-6个原子组成的”或“5-6元的”，表示所述环状基团由3-8(即，3、4、5、6、7或8)、3-6(即，3、4、5或6)、5-10(即，5、6、7、8、9或10)或5-6(即，5或6)个环原子所组成，所述的环原子包括碳原子和/或O、N、S、P等杂原子。The term "composed of j-k atoms" or "j-k-membered" means that the cyclic group is composed of j-k ring atoms, and the ring atoms include carbon atoms and/or heteroatoms such as O, N, S, P, etc.; j and k are each independently any non-zero natural number, and k>j; "j-k" includes j, k and any natural number in between. For example, “consisting of 3-8 atoms” or “3-8 members”, “consisting of 3-6 atoms” or “3-6 members”, “consisting of 5-10 atoms” or “5-10 members”, or “consisting of 5-6 atoms” or “5-6 members” means that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7 or 8), 3-6 (i.e., 3, 4, 5 or 6), 5-10 (i.e., 5, 6, 7, 8, 9 or 10) or 5-6 (i.e., 5 or 6) ring atoms, and the ring atoms include carbon atoms and/or heteroatoms such as O, N, S, P, etc.
如本发明所描述，取代基(R)q由一个键连接到中心的环上形成的环体系代表q个取代基R可以在所在的环上任何可取代的位置或任何合理的位置进行取代。例如，式a代表萘环可被n个R2取代，当n大于1时，各R2可独立地选自相同或不同的取代基团。
As described in the present invention, the ring system formed by substituent (R) q connected to the central ring by a bond represents that q substituents R can be substituted at any substitutable position or any reasonable position on the ring. For example, formula a represents that the naphthalene ring can be substituted by n R 2 , and when n is greater than 1, each R 2 can be independently selected from the same or different substituent groups.
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)或(I-1)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。The term "prodrug" used in the present invention refers to a compound that is converted into a compound represented by formula (I) or (I-1) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, the esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds obtained by phosphorylation of the hydroxyl group on the parent.
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化、还原、水解、酰氨化、脱酰氨作用、酯化、脱脂作用、酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。"Metabolite" refers to a product obtained by the metabolism of a specific compound or salt thereof in vivo. The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting the compounds of the present invention with mammals for a period of time.
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、高氯酸盐，和有机酸盐如乙酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物、氢氧化物、羧化物、硫酸化物、磷酸化物、硝酸化物、C1-C8磺酸化物和芳香磺酸化物。The "pharmaceutically acceptable salt" used in the present invention refers to the organic salt and inorganic salt of the compound of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts. The present invention also contemplates quaternary ammonium salts formed by any compound containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium and amine cations which counter-form counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 - C8 sulfonates and aromatic sulfonates.
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于、水、异丙醇、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸、乙醇胺或其混合物。术 语“水合物”是指溶剂分子是水所形成的缔合物。The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or a mixture thereof. The term "hydrate" refers to an association in which the solvent molecule is water.
当所述溶剂为水时，可以使用术语“水合物”。在一实施方案中，一个本发明化合物分子可以与一个水分子相结合，比如一水合物；在另一实施方案中，一个本发明化合物分子可以与多于一个的水分子相结合，比如二水合物；在又一实施方案中，一个本发明化合物分子可以与少于一个的水分子相结合，比如半水合物。应注意，本发明所述的水合物保留有非水合形式的所述化合物的生物有效性。When the solvent is water, the term "hydrate" may be used. In one embodiment, one molecule of the compound of the present invention may be combined with one water molecule, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be combined with more than one water molecule, such as a dihydrate; in yet another embodiment, one molecule of the compound of the present invention may be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the non-hydrated form of the compound.
如本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or preventing or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.
术语“防止”或“预防”指获病或障碍的风险的减少(即：使疾病的至少一种临床症状在主体内停止发展，该主体可能面对或预先倾向面对这种疾病，但还没有经历或表现出疾病的症状)。The terms "prevent" or "prevention" refer to a reduction in the risk of acquiring a disease or disorder (i.e., halting the development of at least one clinical symptom of a disease in a subject who may be exposed or predisposed to the disease but does not yet experience or display symptoms of the disease).
术语“治疗有效量”是指当给药于主体来治疗疾病时，化合物的分量足够对这种疾病的治疗起效。“治疗有效量”可以随着化合物，疾病和严重程度，以及有待治疗的主体的条件、年龄、体重、性别等而改变。The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a subject to treat a disease, is sufficient to be effective in treating the disease."Therapeutically effective amount" may vary with the compound, the disease and its severity, and the condition, age, weight, sex, etc. of the subject to be treated.
除非另作说明，本发明的化合物所有合适的同位素变化、立体异构体、互变异构体、溶剂化物、代谢产物、药学上可接受的盐和它的前药都包含在本发明范围内。Unless otherwise stated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts and prodrugs thereof of the compounds of the present invention are encompassed within the scope of the present invention.
在本发明公开的结构中，当任意特定的手性原子的立体化学未指明时，则该结构的所有立体异构体都考虑在本发明之内，并且作为本发明公开化合物包括在本发明中。当立体化学被表示特定构型的实楔形线(solid wedge)或虚线指明时，则该结构的立体异构体就此明确和定义。In structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated within the present invention and are included as compounds disclosed herein. When stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of the structure are thus unambiguous and defined.
本发明化合物的氮氧化物也包含在本发明的范围之内。可以通过在升温下使用常用氧化剂(例如过氧化氢)，在有例如乙酸的酸存在下，氧化相应的含氮碱性物质，或者通过在适合的溶剂中与过酸反应，例如在二氯甲烷、乙酸乙酯或乙酸甲酯中与过乙酸反应，或在氯仿或二氯甲烷中与3-氯过氧苯甲酸反应，制备本发明化合物的氮氧化物。Nitrogen oxides of the compounds of the invention are also included within the scope of the invention. Nitrogen oxides of the compounds of the invention can be prepared by oxidation of the corresponding nitrogen-containing basic substance using a conventional oxidizing agent (e.g., hydrogen peroxide) at elevated temperatures in the presence of an acid such as acetic acid, or by reaction with a peracid in a suitable solvent, such as peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.
式(I)或(I-1)所示化合物可以以盐的形式存在。The compound represented by formula (I) or (I-1) may exist in the form of a salt.
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构，除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟、氯和碘的同位素，如2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl和125I。Any structural formula provided by the present invention is also intended to represent the form of these compounds that are not enriched with isotopes and the form of isotopes that are enriched with isotopes. Isotopically enriched compounds have the structure that the general formula provided by the present invention describes, except that one or more atoms are replaced by atoms with selected atomic weight or mass number. Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
本发明化合物的描述Description of the compounds of the present invention
本发明提供一种化合物，或其药物组合物，其可作为KRAS的抑制剂，尤其作为KRAS 12D抑制剂。本发明进一步涉及所述化合物或其药物组合物用于制备药物的用途，该药物通过所述化合物抑制KRAS活性来治疗疾病和/或病症。The present invention provides a compound, or a pharmaceutical composition thereof, which can be used as an inhibitor of KRAS, in particular as a KRAS 12D inhibitor. The present invention further relates to the use of the compound or the pharmaceutical composition thereof for preparing a medicament for treating a disease and/or condition by inhibiting KRAS activity by the compound.
本发明化合物某些参数的优良特性，如半衰期、清除率、选择性、生物利用度、化学稳定性、代谢稳定性、膜的渗透性、溶解性等，能够促使副作用的降低、治疗指数的扩大或耐受性的改进等。另外，与现有技术化合物相比，本发明化合物具有更优的细胞内抑制活性、在大鼠和犬体内也具有更优 的暴露量等更优的药代动力学性质。The excellent properties of certain parameters of the compounds of the present invention, such as half-life, clearance rate, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, solubility, etc., can promote the reduction of side effects, the expansion of therapeutic index or the improvement of tolerance. In addition, compared with the prior art compounds, the compounds of the present invention have better intracellular inhibitory activity and better in vivo performance in rats and dogs. Better pharmacokinetic properties such as reduced exposure.
一方面，本发明提供式(I)所示的化合物，或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
In one aspect, the present invention provides a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I),
其中，in,
Q为O或S；Q is O or S;
环A为C3-6碳环基、C7-12碳环基、3-6元杂环基、7-12元杂环基、C6-12芳基或5-12元杂芳基；Ring A is a C 3-6 carbocyclyl, a C 7-12 carbocyclyl, a 3-6 membered heterocyclyl, a 7-12 membered heterocyclyl, a C 6-12 aryl or a 5-12 membered heteroaryl;
各R1独立地为-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、-NO2、-C(＝O)R6a、-C(＝O)OR6a、-C(＝O)NR6R7、-NR6C(＝O)R7、-NR6R7、-NR6S(＝O)2R7、氧代、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氰基烷基、C1-6羟基烷基、C1-6卤代烷基、C2-6卤代烯基、C2-6卤代炔基、C1-6烷氧基C1-6烷基、C1-6羧基烷基、C1-6氨基烷基、C1-6巯基烷基、C1-6烷氧基、C3-6环烷基、3-6元杂环基、C6-12芳基或5-12元杂芳基；each R 1 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -NO 2 , -C(=O)R 6a , -C(=O)OR 6a , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -NR 6 R 7 , -NR 6 S(=O) 2 R 7 , oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 carboxyalkyl, C 1-6 aminoalkyl, C 1-6 mercaptoalkyl, C 1-6 alkoxy, C 1-6 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;
环B为C6-12芳基或5-12元杂芳基；Ring B is C 6-12 aryl or 5-12 membered heteroaryl;
各R2独立地为-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、-CH2C(＝O)NR6bR7b、-C(＝O)R6c、-C(＝O)OR6c、-C(＝O)NR6bR7b、-NR6bC(＝O)R7b、-NR6bR7b、C1-6烷基、C1-6烷硫基、C2-6烯基、C2-6炔基、C2-6羟基炔基、C1-6烷氧基、C1-6氰基烷基、C1-6羟基烷基、C1-6卤代烷基、C2-6卤代烯基、C2-6卤代炔基、C1-6卤代烷氧基、C1-6卤代烷硫基、6-12元芳基、5-12元杂芳基、C3-6环烷基或3-6元杂环基，其中所述的C1-6烷基、C1-6烷硫基、C2-6烯基、C2-6炔基、C2-6羟基炔基、C1-6烷氧基、C1-6氰基烷基、C1-6羟基烷基、C1-6卤代烷基、C2-6卤代烯基、C2-6卤代炔基、C1-6卤代烷氧基、C1-6卤代烷硫基、6-12元芳基、5-12元杂芳基、C3-6环烷基和3-6元杂环基各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、-C(＝O)H、-C(＝O)OH、C1-6烷基、C1-6烷氧基、C3-6环烷基和3-6元杂环基的取代基所取代；each R2 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C (=O ) NR6bR7b , -C (=O) R6c , -C(=O)OR6c, -C(=O)NR6bR7b, -NR6bC(=O)R7b, -NR6bR7b , C1-6alkyl , C1-6alkylthio , C2-6alkenyl , C2-6alkynyl , C2-6hydroxyalkynyl , C1-6alkoxy, C1-6cyanoalkyl , C1-6hydroxyalkyl , C1-6haloalkyl , C2-6haloalkenyl , C2-6haloalkynyl , C1-6haloalkoxy , C1-6 C1-6 alkylthio, C2-6 alkenyl, C2-6 alkynyl, C2-6 hydroxyalkynyl, C1-6 alkoxy, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, C1-6 haloalkoxy, C1-6 haloalkylthio, 6-12 membered aryl, 5-12 membered heteroaryl, C3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the C1-6 alkyl, C1-6 alkylthio, C2-6 alkenyl, C2-6 alkynyl, C2-6 hydroxyalkynyl, C1-6 alkoxy , C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, C1-6 haloalkoxy, C1-6 haloalkylthio, 6-12 membered aryl, 5-12 membered heteroaryl, C3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2 , -C(=O)H, -C(=O)OH, C substituted by a C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, and 3-6 membered heterocyclic group;
R3为-H、-D、-OH、-SH、-F、-Cl、-Br、-I、-CN、甲基、乙基、正丙基、异丙基、正丁基或C1-4卤代烷基； R3 is -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl or C1-4 haloalkyl;
Y为键、O或S；Y is a bond, O or S;
R4为-H、-D、C1-6烷基、3-10元杂环基、-L-(3-10元杂环基)、-L-C3-10环烷基、-L-(5-12元杂芳基)、-L-(C6-10芳基)、-L-NR6R7、-NR6R7、-L-NHC(＝NH)NH2或-L-C(＝O)NR6R7，其中所述的C1-6烷基、3-10元杂环基、-L-(3-10元杂环基)、-L-C3-10环烷基、-L-(5-12元杂芳基)和-L-(C6-10芳基)各自独立任选地被1、2、3或4 个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NR6dR7d、-C(＝O)NR6dR7d、-CH2NR6dR7d、-CH2OC(＝O)NR6dR7d、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C6-10芳基C1-6烷基、(5-12元杂芳基)-C1-6烷基、(3-6元杂环基)-C1-6烷基、C3-6环烷基C1-6烷基、C3-6环烷基和3-6元杂环基的取代基所取代，或，所述的-L-(3-10元杂环基)中的3-10元杂环基上的任意位置任意个数的环碳原子上的两个氢原子被取代，其中所述取代基中的C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C6-10芳基C1-6烷基、(5-12元杂芳基)-C1-6烷基、(3-6元杂环基)-C1-6烷基、C3-6环烷基C1-6烷基、C3-6环烷基和3-6元杂环基独立任选地被1、2、3或4个选自-D、-F、-Cl、-Br、-I、-OH、-CN、NR6eR7e、-C(＝O)C1-6烷基和C1-6烷基的取代基所取代； R4 is -H, -D, C1-6 alkyl, 3-10 membered heterocyclyl, -L-(3-10 membered heterocyclyl), -LC3-10 cycloalkyl, -L-(5-12 membered heteroaryl), -L-( C6-10 aryl), -L- NR6R7 , -NR6R7 , -L -NHC(=NH) NH2 or -LC(=O) NR6R7 , wherein the C1-6 alkyl, 3-10 membered heterocyclyl, -L-(3-10 membered heterocyclyl), -LC3-10 cycloalkyl, -L-(5-12 membered heteroaryl) and -L-( C6-10 aryl) are each independently optionally substituted by 1, 2, 3 or 4 The -L-(3-10 membered heterocyclyl) is substituted with a substituent selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d , -C(═O)NR 6d R 7d , -CH 2 NR 6d R 7d , -CH 2 OC(═O)NR 6d R 7d , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 arylC 1-6 alkyl, (5-12 membered heteroaryl)-C 1-6 alkyl, (3-6 membered heterocyclyl)-C 1-6 alkyl, C 3-6 cycloalkylC 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; or, two hydrogen atoms on any number of ring carbon atoms at any position on the 3-10 membered heterocyclyl in the -L-( 3-10 membered heterocyclyl) are replaced with a substituent selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d , -C(═O)NR 6d R 7d , -CH 2 NR 6d R 7d , -CH 2 OC(═O)NR 6d R 7d substituted, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 arylC 1-6 alkyl, (5-12 membered heteroaryl)-C 1-6 alkyl, (3-6 membered heterocyclyl)-C 1-6 alkyl, C 3-6 cycloalkylC 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl in the substituent are independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -F, -Cl, -Br, -I, -OH, -CN, NR 6e R 7e , -C(＝O)C 1-6 alkyl and C 1-6 alkyl;
L为C1-6亚烷基；L is a C 1-6 alkylene group;
为至少含有两个环N原子的5-12元杂环； is a 5-12 membered heterocyclic ring containing at least two ring N atoms;
R5为-H、-D、-OH、-SH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OR6a、-C(＝O)NR6R7、C1-6烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基或5-6元杂芳基；R 5 is -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OR 6a , -C(=O)NR 6 R 7 , C 1-6 alkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or 5-6 membered heteroaryl;
R6、R7、R6b、R7b、R6d、R7d、R6e和R7e各自独立地为-H、-D或C1-6烷基，其中所述的C1-6烷基任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、C1-6烷氧基、C6-12芳基、C3-6环烷基和3-6元杂环基的取代基所取代；R 6 , R 7 , R 6b , R 7b , R 6d , R 7d , R 6e and R 7e are each independently -H, -D or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(═O)H, -C(═O)OH, -NR 6g R 7g , C 1-6 alkoxy, C 6-12 aryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
或R6和R7、或R6b和R7b、或R6d和R7d、或R6e和R7e，分别和与之相连的N原子一起形成4-6元杂环，其中所述的4-6元杂环任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、C1-6烷基、C1-6烷氨基、C3-6环烷基、3-6元杂环基、C1-6烷氧基、C1-6氰基烷基、C1-6羟基烷基、C1-6卤代烷氧基和C1-6卤代烷基的取代基所取代；or R 6 and R 7 , or R 6b and R 7b , or R 6d and R 7d , or R 6e and R 7e , together with the N atom to which they are attached, form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 1-6 alkoxy, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy and C 1-6 haloalkyl;
R6a、R6c、R6g和R7g各自独立地为-H、-D或C1-6烷基；R 6a , R 6c , R 6g and R 7g are each independently -H, -D or C 1-6 alkyl;
m和n各自独立地为0、1、2、3、4、5、6或7。m and n are each independently 0, 1, 2, 3, 4, 5, 6 or 7.
在一些实施方案中，环A为环丙基、环丁基、环戊基、环己基、环戊烯基、八氢并环戊二烯基、双环[3.1.0]环己基、2,3-二氢-1H-茚基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、四氢吡喃基、吗啉基、哌嗪基、哌啶基、苯基、吡啶基、吡咯基、咪唑基、嘧啶基或苯并呋喃基。In some embodiments, Ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, octahydropentalenyl, bicyclo[3.1.0]cyclohexyl, 2,3-dihydro-1H-indenyl, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, piperidinyl, phenyl, pyridinyl, pyrrolyl, imidazolyl, pyrimidinyl, or benzofuranyl.
在一些实施方案中，各R1独立地为-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、-NO2、-C(＝O)R6a、-C(＝O)OR6a、-C(＝O)NR6R7、-NR6C(＝O)R7、-NR6R7、-NR6S(＝O)2R7、氧代、C1-4烷基、C2-4烯基、C2-4炔基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷基、C2-4卤代烯基、C2-4卤代炔基、C1-4烷氧基C1-4烷基、C1-4羧基烷基、C1-4氨基烷基、C1-4巯基烷基、C1-4烷氧基、C3-6环烷基、3-6元杂环基、C6-12芳基或5-12元杂芳基，其中， R6、R7和R6a各自具有如本发明所述的定义。In some embodiments, each R 1 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -NO 2 , -C(=O)R 6a , -C(=O)OR 6a , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -NR 6 R 7 , -NR 6 S(=O) 2 R 7 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 2-4 haloalkenyl, C 2-4 haloalkynyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 carboxyalkyl, C 1-4 aminoalkyl, C 1-4 mercaptoalkyl, C 1-4 alkoxy, C 1-4 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, wherein R 6 , R 7 and R 6a each have the same meaning as defined in the present invention.
在一些实施方案中，R6和R7各自独立地为-H、-D或C1-4烷基，其中所述的C1-4烷基任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、C1-4烷氧基、6-10元芳基、C3-6环烷基和3-6元杂环基的取代基所取代，其中，R6g和R7g各自具有如本发明所述的定义。In some embodiments, R 6 and R 7 are each independently -H, -D or C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(＝O)H, -C(＝O)OH, -NR 6g R 7g , C 1-4 alkoxy, 6-10 membered aryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, wherein R 6g and R 7g each have the definition as described herein.
在一些实施方案中，R6、R7和与之相连的N原子一起形成4-6元杂环，其中所述的4-6元杂环任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、C1-4烷基、C1-4烷氨基、C3-6环烷基、3-6元杂环基、C1-4烷氧基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷氧基和C1-4卤代烷基的取代基所取代。In some embodiments, R6 , R7 and the N atom to which they are attached form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2 , C1-4 alkyl, C1-4 alkylamino, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C1-4 alkoxy, C1-4 cyanoalkyl, C1-4 hydroxyalkyl, C1-4 haloalkoxy and C1-4 haloalkyl.
在一些实施方案中，R6a、R6g和R7g各自独立地为-H、-D或C1-4烷基。In some embodiments, R 6a , R 6g and R 7g are each independently -H, -D or C 1-4 alkyl.
在一些实施方案中，R1为-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、-NO2、-C(＝O)R6a、-C(＝O)OR6a、-C(＝O)NR6R7、-NR6C(＝O)R7、-NR6R7、-NR6S(＝O)2R7、氧代、-CH3、-CH2CH3、-(CH2)2CH3、-(CH2)3CH3、-C(CH3)3、-CH(CH3)2、-CH＝CH2、-CH＝CHCH3、-CH2CH＝CH2、-CHFCH＝CH2、-CH＝CHF、-CH＝CHCl、-CH＝CHCH2F、-CH＝CHCH3、-C≡CH、-C≡CCH3、-CH2C≡CH、-C≡CCH2F、-CH2CN、-(CH2)2CN、-(CH2)3CN、-CH2OH、-(CH2)2OH、-(CH2)3OH、-CH(OH)CH3、-CF3、-CHF2、-CH2F、-(CH2)2F、-(CH2)2Cl、-CH2CF3、-CH2OCH3、-(CH2)2OCH3、-(CH2)2OCH2CH3、-CH2OCH2CH3、-CH2C(＝O)OH、-(CH2)2C(＝O)OH、-(CH2)3C(＝O)OH、-CH2NH2、-(CH2)2NH2、-CH2SH、-(CH2)2SH、-OCH3、-OCH2CH3、-O(CH2)2CH3、-OCH2CH(CH3)2、-OCH(CH3)2、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氧杂环丁基、四氢呋喃基、吡咯烷基、苯基、吡啶基、嘧啶基、吡唑基或咪唑基其中，R6、R7和R6a各自具有如本发明所述的定义。In some embodiments, R 1 is -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -NO 2 , -C(=O)R 6a , -C(=O)OR 6a , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -NR 6 R 7 , -NR 6 S(=O) 2 R 7 , oxo, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -C(CH 3 ) 3 , -CH(CH 3 ) 2 , -CH=CH 2 , -CH=CHCH 3 , -CH 2 CH=CH 2 , -CHFCH=CH 2 , -CH=CHF , -CH=CHCl , -CH=CHCH 2 F , -CH=CHCH 3 , -C≡CH, -C≡CCH 3 , -CH 2 C≡CH, -C≡CCH 2 F, -CH 2 CN, -(CH 2 ) 2 CN, -(CH 2 ) 3 CN, -CH 2 OH, -(CH 2 ) 2 OH, -(CH 2 ) 3 OH, -CH(OH)CH 3 , -CF 3 , -CHF 2 , -CH 2 F, -(CH 2 ) 2 F, -(CH 2 ) 2 Cl, -CH 2 CF 3 , -CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , -(CH 2 ) 2 OCH 2 CH 3 , -CH 2 OCH 2 CH 3 , -CH 2 C(═O)OH, -(CH 2 ) 2 C(═O)OH, -(CH 2 ) 3 C(＝O ) OH, -CH2NH2 , -( CH2 ) 2NH2 , -CH2SH, -( CH2 ) 2SH , -OCH3 , -OCH2CH3 , -O(CH2)2CH3, -OCH2CH(CH3)2 , -OCH ( CH3 ) 2 , cyclopropyl , cyclobutyl , cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazolyl or imidazolyl wherein R6 , R7 and R6a each have the meanings as described herein.
在一些实施方案中，R6和R7各自独立地为-H、-D、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基各自任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、甲氧基、乙氧基、正丙氧基、异丙氧基、异丁氧基、环丙基、环丁基、环戊基、环己基、苯基、环氧乙烷基、氧杂环丁基、氮杂环丁基和吡咯烷基的取代基所取代，其中，R6g和R7g各自具有如本发明所述的定义。In some embodiments, R 6 and R 7 are each independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl are each optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g , methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxiranyl, oxetanyl, azetidinyl and pyrrolidinyl, wherein R 6g and R 7g are each defined as described herein.
在一些实施方案中，R6、R7和与之相连的N原子一起形成吡咯烷、哌嗪、哌啶、吗啉基、恶唑烷或咪唑烷，其中所述的吡咯烷、哌嗪、哌啶、吗啉基、恶唑烷和咪唑烷各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氨基、二甲氨基、乙氨基、环丙基、环戊基、吡咯烷基、甲氧基、乙氧基、异丙氧基、氰基甲基、羟基甲基、羟基乙基、三氟甲氧基、一氟甲基、二氟甲基、三氟甲基或1,2-二氯乙基的取代基所取代。In some embodiments, R 6 , R 7 and the N atom to which they are attached together form pyrrolidine, piperazine, piperidine, morpholinyl, oxazolidine or imidazolidine, wherein the pyrrolidine, piperazine, piperidine, morpholinyl, oxazolidine and imidazolidine are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy, ethoxy, isopropoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl or 1,2-dichloroethyl.
在一些实施方案中，R6a、R6g和R7g各自独立地为-H、-D、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。In some embodiments, R 6a , R 6g and R 7g are each independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
在一些实施方案中，环B为以下其中子结构之一，
In some embodiments, Ring B is one of the following substructures,
在一些实施方案中，各R2独立地为-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、-CH2C(＝O)NR6bR7b、-C(＝O)R6c、-C(＝O)OR6c、-C(＝O)NR6bR7b、-NR6bC(＝O)R7b、-NR6bR7b、C1-4烷基、C1-4烷硫基、C2-4烯基、C2-4炔基、C2-4羟基炔基、C1-4烷氧基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷基、C2-4卤代烯基、C2-4卤代炔基、C1-4卤代烷氧基、C1-4卤代烷硫基、6-12元芳基、5-12元杂芳基、C3-6环烷基或3-6元杂环基，其中所述的C1-4烷基、C1-4烷硫基、C2-4烯基、C2-4炔基、C2-4羟基炔基、C1-4烷氧基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷基、C2-4卤代烯基、C2-4卤代炔基、C1-4卤代烷氧基、C1-4卤代烷硫基、C6-10芳基、5-10元杂芳基、C3-6环烷基和3-6元杂环基各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、-C(＝O)H、-C(＝O)OH、C1-4烷基、C1-4烷氧基、C3-6环烷基和3-6元杂环基的取代基所取代，其中R6b、R7b和R6c各自具有如本发明所述的定义。In some embodiments, each R 2 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH 2 C(=O)NR 6b R 7b , -C(=O)R 6c , -C(=O)OR 6c , -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b R 7b , C 1-4 alkyl, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 hydroxyalkynyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 2-4 haloalkenyl, C 2-4 haloalkynyl, C 1-4 haloalkoxy, C 1-4 C 1-4 alkyl, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 hydroxyalkynyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 2-4 haloalkenyl, C 2-4 haloalkynyl, C 1-4 haloalkoxy, C 1-4 haloalkylthio, C 6-10 aryl, 5-10 membered heteroaryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted by 1, 2 , 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , -C(=O)H, -C(=O)OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, wherein R 6b , R 7b and R 6c each have the meanings as described in the present invention.
在一些实施方案中，各R6c独立地为-H、-D或C1-4烷基。In some embodiments, each R 6c is independently -H, -D, or C 1-4 alkyl.
在一些实施方案中，R6b和R7b各自独立地为-H、-D或C1-4烷基，其中所述的C1-4烷基任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、C1-4烷氧基、C6-10芳基、C3-6环烷基和3-6元杂环基的取代基所取代，其中，R6g和R7g各自具有如本发明所述的定义。In some embodiments, R 6b and R 7b are each independently -H, -D or C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(＝O)H, -C(＝O)OH, -NR 6g R 7g , C 1-4 alkoxy, C 6-10 aryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, wherein R 6g and R 7g each have the definition as described herein.
在一些实施方案中，R6b、R7b和与之相连的N原子一起形成4-6元杂环，其中所述的4-6元杂环任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、C1-4烷基、C1-4烷氨基、C3-6环烷基、3-6元杂环基、C1-4烷氧基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷氧基和C1-4卤代烷基的取代基所取代。In some embodiments, R 6b , R 7b and the N atom to which they are attached form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy, C 1-4 cyanoalkyl , C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl.
在一些实施方案中，各R2独立地为-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、-CH2C(＝O)NR6bR7b、-C(＝O)R6c、-C(＝O)OR6c、-C(＝O)NR6bR7b、-NR6bC(＝O)R7b、-NR6bR7b、-CH3、-CH2CH3、-(CH2)2CH3、-(CH2)3CH3、-C(CH3)3、-CH(CH3)2、-SCH3、-SCH2CH3、-CH＝CH2、-CH＝CHCH3、-CH2CH＝CH2、-C≡CH、-C≡CCH3、-CH2C≡CH、-C≡CCH2OH、-C≡C(CH2)2OH、-OCH3、-OCH2CH3、-O(CH2)2CH3、-CH2CN、-(CH2)2CN、-(CH2)3CN、-CH2OH、-(CH2)2OH、-(CH2)3OH、-CH(OH)CH3、-(CH2)2F、-CH2CHF2、-CF3、-CH2CF3、-CHF2、-CH2F、-(CH2)2Cl、 -CH＝CHF、-CH＝CHCl、-CH＝CHCH2F、-C≡CCH2F、-C≡C(CH2)2F、-C≡CF、-OCF3、-OCHF2、-OCH2CHF2、-OCH2CF3、-OCHClCHCl2、-OCH2CH2F、-SCF3、-SCH2CF3、-SCH2CHF2、苯基、萘基、吡啶基、嘧啶基、环丙基、环丁基、环戊基、环己基、吡咯烷基、恶唑烷基、四氢呋喃基、哌啶基或哌嗪基，其中所述的-CH3、-CH2CH3、-(CH2)2CH3、-(CH2)3CH3、-C(CH3)3、-CH(CH3)2、-SCH3、-SCH2CH3、-CH＝CH2、-CH＝CHCH3、-CH2CH＝CH2、-C≡CH、-C≡CCH3、-CH2C≡CH、-C≡CCH2OH、-C≡C(CH2)2OH、-OCH3、-OCH2CH3、-O(CH2)2CH3、-CH2CN、-(CH2)2CN、-(CH2)3CN、-CH2OH、-(CH2)2OH、-(CH2)3OH、-CH(OH)CH3、-(CH2)2F、-CH2CHF2、-CH2CF3、-CHF2、-CH2F、-(CH2)2Cl、-CH＝CHF、-CH＝CHCl、-CH＝CHCH2F、-C≡CCH2F、-C≡C(CH2)2F、-OCHF2、-OCH2CHF2、-OCH2CF3、-OCHClCHCl2、-OCH2CH2F、-SCH2CF3、-SCH2CHF2、苯基、萘基、吡啶基、嘧啶基、环丙基、环丁基、环戊基、环己基、吡咯烷基、恶唑烷基、四氢呋喃基、哌啶基和哌嗪基独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、-C(＝O)H、-C(＝O)OH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、吡咯烷基、恶唑烷基、四氢呋喃基、哌啶基和哌嗪基的取代基所取代，其中，其中R6b、R7b和R6c各自具有如本发明所述的定义。In some embodiments, each R 2 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH 2 C(=O)NR 6b R 7b , -C(=O)R 6c , -C(=O)OR 6c , -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b R 7b , -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -C(CH 3 ) 3 , -CH(CH 3 ) 2 , -SCH 3 , -SCH 2 CH 3 , -CH=CH 2 , -CH=CHCH 3 , -CH 2 CH=CH 2 , -C≡CH , -C≡CCH 3 、-CH 2 C≡CH、-C≡CCH 2 OH、-C≡C(CH 2 ) 2 OH、-OCH 3 、-OCH 2 CH 3 、-O(CH 2 ) 2 CH 3 、-CH 2 CN、-(CH 2 ) 2 CN、-(CH 2 ) 3 CN、-CH 2 OH、-(CH 2 ) 2 OH、-(CH 2 ) 3 OH、-CH(OH)CH 3 、-(CH 2 ) 2 F、-CH 2 CHF 2 、-CF 3 、-CH 2 CF 3 、-CHF 2 、-CH 2 F、-(CH 2 ) 2 Cl、 -CH═CHF, -CH═CHCl, -CH═CHCH 2 F, -C≡CCH 2 F, -C≡C(CH 2 ) 2 F, -C≡CF, -OCF 3 , -OCHF 2 , -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCHClCHCl 2 , -OCH 2 CH 2 F, -SCF 3 , -SCH 2 CF 3 , -SCH 2 CHF 2 , phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl or piperazinyl, wherein -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -C(CH 3 ) 3 , -CH(CH 3 ) 2 、-SCH 3 、-SCH 2 CH 3 、-CH＝CH 2 、-CH＝CHCH 3 、-CH 2 CH＝CH 2 、-C≡CH 、-C≡CCH 3 、-CH 2 C≡CH 、-C≡CCH 2 OH、-C≡C(CH 2 ) 2 OH、-OCH 3 、-OCH 2 CH 3 、-O(CH 2 ) 2 CH 3 、-CH 2 CN、-(CH 2 ) 2 CN、-(CH 2 ) 3 CN、-CH 2 OH、-(CH 2 ) 2 OH、-(CH 2 ) 3 OH、-CH(OH)CH 3 、-(CH 2 ) 2 F、-CH 2 CHF 2 、-CH 2 CF 3 、-CHF 2 、-CH 2 F, -(CH 2 ) 2 Cl, -CH═CHF, -CH═CHCl, -CH═CHCH 2 F, -C≡CCH 2 F, -C≡C(CH 2 ) 2 F, -OCHF 2 , -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCHClCHCl 2 , -OCH 2 CH 2 F, -SCH 2 CF 3 , -SCH 2 CHF 2 , phenyl, naphthyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl and piperazinyl are independently optionally substituted by 1, 2, 3 or 4 radicals selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , -C(=O)H, -C(=O)OH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl and piperazinyl substituents, wherein R 6b , R 7b and R 6c each have the definition as described in the present invention.
在一些实施方案中，各R6c独立地为-H、-D、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。In some embodiments, each R 6c is independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.
在一些实施方案中，R6b和R7b各自独立地为-H、-D、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基各自任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、甲氧基、乙氧基、正丙氧基、异丙氧基、异丁氧基、苯基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氧杂环丁基、氮杂环丁基和吡咯烷基的取代基所取代，其中，R6g和R7g各自具有如本发明所述的定义。In some embodiments, R 6b and R 7b are each independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl are each optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g , methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, azetidinyl and pyrrolidinyl, wherein R 6g and R 7g each have the definition as described herein.
在一些实施方案中，R6b、R7b和与之相连的N原子一起形成吡咯烷、哌嗪、哌啶、吗啉、恶唑烷或咪唑烷，其中所述的吡咯烷、哌嗪、哌啶、吗啉、恶唑烷和咪唑烷各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氨基、二甲氨基、乙氨基、环丙基、环戊基、吡咯烷基、甲氧基、乙氧基、异丙氧基、氰基甲基、羟基甲基、羟基乙基、三氟甲氧基、一氟甲基、二氟甲基、三氟甲基和1,2-二氯乙基的取代基所取代。In some embodiments, R 6b , R 7b and the N atom to which they are attached together form pyrrolidine, piperazine, piperidine, morpholine, oxazolidine or imidazolidine, wherein the pyrrolidine, piperazine, piperidine, morpholine, oxazolidine and imidazolidine are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy, ethoxy, isopropoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl and 1,2-dichloroethyl.
在一些实施方案中，R4为-H、-D、C1-4烷基、3-6元杂环基、7-10元杂环基、 -L-吡咯烷基、-L-吗啉基、-L-氧杂环丁基、-L-氧杂环丙基、-L-四氢呋喃基、-L-八氢吲哚嗪基、-L-环丙基、-L-环戊基、-L-八氢并环戊二烯基、 -L-八氢-1H-茚基、-L-十氢萘基、-L-吡啶基、-L-吡唑基、-L-苯基、-L-NR6R7、-NR6R7、-L-NHC(＝NH)NH2或-L-C(＝O)NR6R7，其中所述的C1-4烷基、3-6元杂环基、7-10元杂环基、 -L-吡咯烷基、-L-吗啉基、-L-氧杂环丁基、-L-氧杂环丙基、-L-四氢呋喃基、-L-八氢吲哚嗪基、-L-环丙基、-L-环戊基、-L-八氢并环戊二烯基、-L-八氢-1H-茚基、-L-十氢萘基、-L-吡啶基、-L-吡唑基和-L-苯基各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NR6dR7d、-C(＝O)NR6dR7d、-CH2NR6dR7d、-CH2OC(＝O)NR6dR7d、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基、苯基C1-4烷基、5-6元杂芳基C1-4烷基、(3-6元杂环基)-C1-4烷基、C3-6环烷基C1-4烷基、C3-6环烷基和3-6元杂环基的取代基所取代，或，所述的中的 中的中的中的 中的各自任意位置任意个数的环碳原子上的两个氢原子被取代，其中所述取代基中的C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基、苯基C1-4烷基、5-6元杂芳基C1-4烷基、(3-6元杂环基)-C1-4烷基、C3-6环烷基C1-4烷基、C3-6环烷基和3-6元杂环基各自独立任选地被1、2、3或4个选自-D、-F、-Cl、-Br、-I、-OH、-CN、NR6eR7e、-C(＝O)C1-4烷基和C1-4烷基的取代基所取代，其中，L、R6d、R7d、R6e和R7e各自具有如本发明所述的定义。In some embodiments, R 4 is -H, -D, C 1-4 alkyl, 3-6 membered heterocyclyl, 7-10 membered heterocyclyl, -L-pyrrolidinyl, -L-morpholinyl, -L-oxetanyl, -L-oxetanyl, -L-tetrahydrofuranyl, -L-octahydroindolizinyl, -L-cyclopropyl, -L-cyclopentyl, -L-octahydropentalenyl, -L-octahydro-1H-indenyl, -L-decahydronaphthyl, -L-pyridyl, -L-pyrazolyl, -L-phenyl, -L-NR 6 R 7 , -NR 6 R 7 , -L-NHC(═NH)NH 2 or -LC(═O)NR 6 R 7 , wherein the C 1-4 alkyl, 3-6 membered heterocyclyl, 7-10 membered heterocyclyl, -L-pyrrolidinyl, -L-morpholinyl, -L-oxetanyl, -L-oxetanyl, -L-tetrahydrofuranyl, -L-octahydroindolizinyl, -L-cyclopropyl, -L-cyclopentyl, -L-octahydropentalenyl, -L-octahydro-1H-indenyl, -L-decalinyl, -L-pyridinyl, -L-pyrazolyl and -L-phenyl are each independently optionally substituted by 1, 2, 3 or 4 groups selected from -D, -OH, -F , -Cl , -Br, -I , -CN, -NR6dR7d , -C(=O) NR6dR7d, -CH2NR6dR7d, -CH2OC(=O)NR6dR7d , C1-4alkyl , C1-4alkoxy , C1-4haloalkyl , C1-4haloalkoxy , phenylC1-4 C 1-4 alkyl, 5-6 membered heteroaryl C 1-4 alkyl, (3-6 membered heterocyclic)-C 1-4 alkyl, C 3-6 cycloalkyl C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic substituents, or, middle middle middle middle middle Two hydrogen atoms on any number of ring carbon atoms at any position are Substituted, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl C 1-4 alkyl, 5-6 membered heteroaryl C 1-4 alkyl, (3-6 membered heterocyclyl)-C 1-4 alkyl, C 3-6 cycloalkyl C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl in the substituent are each independently optionally substituted with 1, 2 , 3 or 4 substituents selected from -D, -F, -Cl, -Br, -I, -OH, -CN, NR 6e R 7e , -C(＝O)C 1-4 alkyl and C 1-4 alkyl, wherein L, R 6d , R 7d , R 6e and R 7e each have the definition as described in the present invention.
在一些实施方案中，L为C1-4亚烷基。In some embodiments, L is C 1-4 alkylene.
在一些实施方案中，R6d、R7d、R6e和R7e各自独立地为-H、-D或C1-4烷基，其中所述的C1-4烷基任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、C1-4烷氧基、C6-10芳基、C3-6环烷基和3-6元杂环基的取代基所取代。In some embodiments, R 6d , R 7d , R 6e and R 7e are each independently -H, -D or C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(＝O)H, -C(＝O)OH, -NR 6g R 7g , C 1-4 alkoxy, C 6-10 aryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl.
在一些实施方案中，R6d、R7d和与之相连的N原子一起形成4-6元杂环，其中所述的4-6元杂环任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、C1-4烷基、C1-4烷氨基、C3-6环烷基、3-6元杂环基、C1-4烷氧基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷氧基和C1-4卤代烷基的取代基所取代。In some embodiments, R 6d , R 7d and the N atom to which they are attached form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy, C 1-4 cyanoalkyl , C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl.
在一些实施方案中，R6e、R7e和与之相连的N原子一起形成4-6元杂环，其中所述的4-6元杂环任选 地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、C1-4烷基、C1-4烷氨基、C3-6环烷基、3-6元杂环基、C1-4烷氧基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷氧基和C1-4卤代烷基的取代基所取代。In some embodiments, R 6e , R 7e and the N atom to which they are attached together form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally The group is preferably substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C1-4 alkyl , C1-4 alkylamino, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C1-4 alkoxy, C1-4 cyanoalkyl, C1-4 hydroxyalkyl, C1-4 haloalkoxy and C1-4 haloalkyl.
在一些实施方案中，R4为-H、-D、-CH3、-CH2CH3、-(CH2)2CH3、哌啶基、哌嗪基、吡咯烷基、咪唑烷基、 -CH2-吡咯烷基、-CH2-吗啉基、-(CH2)2-吗啉基、-CH2-氧杂环丁基、-CH2-氧杂环丙基、-CH2-四氢呋喃基、-CH2-八氢吲哚嗪基、-CH2-环丙基、-CH2-环戊基、-CH2-八氢并环戊二烯基、-CH2-八氢-1H-茚基、-CH2-十氢萘基、-CH2-吡啶基、-(CH2)2-吡啶基、-CH2-吡唑基、-(CH2)2-吡唑基、-CH2-苯基、-CH2-NR6R7、-(CH2)2-NR6R7、-CH(CH3)CH2NR6R7、-NR6R7、-CH2-NHC(＝NH)NH2或-CH2-C(＝O)NR6R7，其中所述的-CH3、-CH2CH3、-(CH2)2CH3、哌啶基、哌嗪基、吡咯烷基、咪唑烷基、 -CH2-吡咯烷基、-CH2-吗啉基、-(CH2)2-吗啉基、-CH2-氧杂环丁基、-CH2-氧杂环丙基、-CH2-四氢呋喃基、-CH2-八氢吲哚嗪基、-CH2-环丙基、-CH2-环戊基、-CH2-八氢并环戊二烯基、-CH2-八氢-1H-茚基、-CH2-十氢萘基、-CH2-吡啶基、-(CH2)2-吡啶基、-CH2-吡唑基、-(CH2)2-吡唑基和-CH2-苯基各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NR6dR7d、-C(＝O)NR6dR7d、-CH2NR6dR7d、-CH2OC(＝O)NR6dR7d、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、异丙氧基、-CHF2、-CF3、-OCF3、苯基甲基、吡啶基甲基、吡唑基甲基、吗啉基甲基、吡咯烷基甲基、哌嗪基甲基、氮杂环丁烷基甲基、哌啶基甲基、环丙基甲基、环戊基甲基、环己基甲基、环戊基、环己基、吗啉基、哌啶基、吡咯烷基、哌嗪基和氮杂环丁烷基的取代基所取代，其中所述取代基中的甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、异丙氧基、-CHF2、苯基甲基、吡啶基甲基、吡唑基甲基、吗啉基甲基、吡咯烷基甲基、哌嗪基甲基、氮杂环丁烷基甲基、哌啶基甲基、环丙基甲基、环戊基甲基、环己基甲基、环戊基、环己基、吗啉基、哌啶基、吡咯烷基、哌嗪基和氮杂环丁烷基各自独立任选地被1、2、3或4个选自-D、-F、-Cl、-Br、-I、-OH、-CN、-NH2、-NHCH3、-N(CH3)2、-NHCH2CH3、-C(＝O)CH3、-C(＝O)CH2CH3、甲基、乙基、正丙基和异 丙基的取代基所取代，或，R4为 In some embodiments, R 4 is -H, -D, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, -CH 2 -pyrrolidinyl, -CH 2 -morpholinyl, -(CH 2 ) 2 -morpholinyl, -CH 2 -oxetanyl, -CH 2 -oxiranyl, -CH 2 -tetrahydrofuranyl, -CH 2 -octahydroindolizinyl, -CH 2 -cyclopropyl, -CH 2 -cyclopentyl, -CH 2 -octahydropentalenyl, -CH 2 -octahydro-1H-indenyl, -CH 2 -decalinyl, -CH 2 -pyridinyl , -(CH 2 ) 2 -pyridinyl, -CH 2 -pyrazolyl, -(CH 2 ) 2 -pyrazolyl, -CH 2 -phenyl, -CH 2 -NR 6 R 7 , -(CH 2 ) 2 -NR 6 R 7 , -CH ( CH 3 )CH 2 NR 6 R 7 , -NR 6 R 7 , -CH 2 -NHC(=NH)NH 2 or -CH 2 -C(=O)NR 6 R 7 , wherein the -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, -CH2 -pyrrolidinyl, -CH2 -morpholinyl, -( CH2 ) 2 -morpholinyl, -CH2 - oxetanyl, -CH2-oxiranepropyl, -CH2-tetrahydrofuranyl, -CH2-octahydroindolizinyl, -CH2 -cyclopropyl, -CH2 -cyclopentyl, -CH2 -octahydropentalenyl, -CH2 -octahydro-1H-indenyl, -CH2 -decalinyl, -CH2 -pyridinyl, -( CH2 ) 2 -pyridinyl, -CH2 -pyrazolyl, -( CH2 ) 2 -pyrazolyl and -CH2 -phenyl are each independently optionally substituted by 1, 2 , 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN , -NR6dR7d , -C(=O) NR6dR7d , -CH 2 NR 6d R 7d , -CH 2 OC(＝O)NR 6d R 7d , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, isopropyloxy, -CHF 2 , -CF 3 , -OCF 3 , phenylmethyl, pyridylmethyl, pyrazolylmethyl, morpholinylmethyl, pyrrolidinylmethyl, piperazinylmethyl, azetidinylmethyl, piperidinylmethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl and azetidinyl substituents, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, isopropyloxy, -CHF 2 , -CF 3 , -OCF 3 , phenylmethyl, pyridylmethyl, pyrazolylmethyl, morpholinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl and azetidinyl substituents are substituted. wherein the alkyl, phenyl, pyridinylmethyl, pyrazolylmethyl, morpholinylmethyl, pyrrolidinylmethyl, piperazinylmethyl, azetidinylmethyl, piperidinylmethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl and azetidinyl are each independently optionally substituted by 1, 2, 3 or 4 groups selected from -D, -F, -Cl, -Br, -I, -OH, -CN, -NH2 , -NHCH3 , -N( CH3 ) 2 , -NHCH2CH3 , -C (=O) CH3 , -C(=O) CH2CH3 , methyl, ethyl, n-propyl and iso- propyl group, or R4 is
其中，R6d、R7d、R6e和R7e各自具有如本发明所述的定义。wherein R 6d , R 7d , R 6e and R 7e are each as defined in the present invention.
在一些实施方案中，R4为 In some embodiments, R4 is
在一些实施方案中，R4为 In some embodiments, R4 is
在一些实施方案中，R6d和R7d各自独立地为-H、-D、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基各自任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、甲氧基、乙氧基、正丙氧基、异丙氧基、异丁氧基、苯基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氧杂环丁基、氮杂环丁基和吡咯烷基的取代基所取代；其中，R6g和R7g各自具有如本发明所述的定义。In some embodiments, R 6d and R 7d are each independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl are each optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g , methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, azetidinyl and pyrrolidinyl; wherein R 6g and R 7g each have the definition as described herein.
在一些实施方案中，R6d、R7d和与之相连的N原子一起形成氮杂环丁烷、吡咯烷、哌嗪、哌啶、吗啉基、恶唑烷或咪唑烷，其中所述的氮杂环丁烷、吡咯烷、哌嗪、哌啶、吗啉基、恶唑烷和咪唑烷各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氨基、二甲氨基、乙氨基、环丙基、环戊基、吡咯烷基、甲氧基、乙氧基、异丙氧基、氰基甲基、羟基甲基、羟基乙基、三氟甲氧基、一氟甲基、二氟甲基、三氟甲基或1,2-二氯乙基的取代基所取代。In some embodiments, R 6d , R 7d and the N atom to which they are attached are taken together to form azetidine, pyrrolidine, piperazine, piperidine, morpholinyl, oxazolidine or imidazolidine, wherein each of the azetidine, pyrrolidine, piperazine, piperidine, morpholinyl, oxazolidine and imidazolidine is independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy, ethoxy, isopropoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl or 1,2-dichloroethyl.
在一些实施方案中，为其中以下子结构之一，
In some embodiments, is one of the following substructures,
在一些实施方案中，R5为-H、-D、-OH、-SH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OCH3、-C(＝O)NH2、-CH3、-CH2CH3、C3-4烷基、-CH2OH、-(CH2)2OH、-CH2CN、-(CH2)2CN、-CF3、-CHF2、-CH2F、-OCF3、 -OCH3或-OCH2CH3。In some embodiments, R 5 is -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OCH 3 , -C(=O)NH 2 , -CH 3 , -CH 2 CH 3 , C 3-4 alkyl, -CH 2 OH, -(CH 2 ) 2 OH, -CH 2 CN, -(CH 2 ) 2 CN, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCH3 or -OCH2CH3 .
在一些实施方案中，本发明所述的化合物具有式(I-1)所示的化合物，或式(I-1)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
In some embodiments, the compound described in the present invention has a compound represented by formula (I-1), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-1),
其中，m、n、R1、R3、Y、R4、R5和环A各自具有如本发明所述的定义；wherein m, n, R 1 , R 3 , Y, R 4 , R 5 and ring A each have the meanings as described in the present invention;
R2a、R2b和R2c各自具有如本发明中R2所述相同的定义。R 2a , R 2b and R 2c each have the same definition as described for R 2 in the present invention.
在一些实施方案中，R2a、R2b和R2c各自独立地为-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、-CH2C(＝O)NR6bR7b、-C(＝O)R6c、-C(＝O)OR6c、-C(＝O)NR6bR7b、-NR6bC(＝O)R7b、-NR6bR7b、C1-6烷基、C1-6烷硫基、C2-6烯基、C2-6炔基、C2-6羟基炔基、C1-6烷氧基、C1-6氰基烷基、C1-6羟基烷基、C1-6卤代烷基、C2-6卤代烯基、C2-6卤代炔基、C1-6卤代烷氧基、C1-6卤代烷硫基、6-12元芳基、5-12元杂芳基、C3-6环烷基或3-6元杂环基，其中所述的C1-6烷基、C1-6烷硫基、C2-6烯基、C2-6炔基、C2-6羟基炔基、C1-6烷氧基、C1-6氰基烷基、C1-6羟基烷基、C1-6卤代烷基、C2-6卤代烯基、C2-6卤代炔基、C1-6卤代烷氧基、C1-6卤代烷硫基、6-12元芳基、5-12元杂芳基、C3-6环烷基和3-6元杂环基各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、-C(＝O)H、-C(＝O)OH、C1-6烷基、C1-6烷氧基、C3-6环烷基和3-6元杂环基的取代基所取代，其中，R6b、R7b和R6c各自具有如本发明所述的定义。In some embodiments, R 2a , R 2b and R 2c are each independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH 2 C(═O)NR 6b R 7b , -C(═O)R 6c , -C(═O)OR 6c , -C(═O)NR 6b R 7b , -NR 6b C(═O)R 7b , -NR 6b R 7b , C 1-6 alkyl, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 hydroxyalkynyl, C 1-6 alkoxy, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, C 1-6 haloalkoxy, C 1-6 C1-6 alkylthio, C2-6 alkenyl, C2-6 alkynyl, C2-6 hydroxyalkynyl, C1-6 alkoxy, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, C1-6 haloalkoxy, C1-6 haloalkylthio, 6-12 membered aryl, 5-12 membered heteroaryl, C3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the C1-6 alkyl, C1-6 alkylthio, C2-6 alkenyl, C2-6 alkynyl, C2-6 hydroxyalkynyl, C1-6 alkoxy , C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, C1-6 haloalkoxy, C1-6 haloalkylthio, 6-12 membered aryl, 5-12 membered heteroaryl, C3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted by 1, 2, 3 or 4 members selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2 , -C(=O)H, -C(=O)OH, C The present invention is substituted by a substituent selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocyclic group, wherein R 6b , R 7b and R 6c are each as defined in the present invention.
在一些实施方案中，R2a、R2b和R2c各自独立地为-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、-CH2C(＝O)NR6bR7b、-C(＝O)R6c、-C(＝O)OR6c、-C(＝O)NR6bR7b、-NR6bC(＝O)R7b、-NR6bR7b、C1-4烷基、C1-4烷硫基、C2-4烯基、C2-4炔基、C2-4羟基炔基、C1-4烷氧基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷基、C2-4卤代烯基、C2-4卤代炔基、C1-4卤代烷氧基、C1-4卤代烷硫基、6-12元芳基、5-12元杂芳基、C3-6环烷基或3-6元杂环基，其中所述的C1-4烷基、C1-4烷硫基、C2-4烯基、C2-4炔基、C2-4羟基炔基、C1-4烷氧基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷基、C2-4卤代烯基、C2-4卤代炔基、C1-4卤代烷氧基、C1-4卤代烷硫基、C6-10芳基、5-10元杂芳基、C3-6环烷基和3-6元杂环基各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、-C(＝O)H、-C(＝O)OH、C1-4烷基、C1-4烷氧基、C3-6环烷基和3-6元杂环基的取代基所取代，其中，R6b、R7b和R6c各自具有如本发明所述的定义。In some embodiments, R 2a , R 2b and R 2c are each independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH 2 C(═O)NR 6b R 7b , -C(═O)R 6c , -C(═O)OR 6c , -C(═O)NR 6b R 7b , -NR 6b C(═O)R 7b , -NR 6b R 7b , C 1-4 alkyl, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 hydroxyalkynyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 2-4 haloalkenyl, C 2-4 haloalkynyl, C 1-4 haloalkoxy, C 1-4 C 1-4 alkyl, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 hydroxyalkynyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 2-4 haloalkenyl, C 2-4 haloalkynyl, C 1-4 haloalkoxy, C 1-4 haloalkylthio, C 6-10 aryl, 5-10 membered heteroaryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted by 1, 2 , 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , -C(=O)H, -C(=O)OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocyclic group, wherein R 6b , R 7b and R 6c each have the definition as described in the present invention.
在一些实施方案中，R2a,R2b和R2c各自独立地-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、CH2C(＝O)NR6bR7b、-C(＝O)R6c、-C(＝O)OR6c、-C(＝O)NR6bR7b、-NR6bC(＝O)R7b、-NR6bR7b、-CH3、-CH2CH3、-(CH2)2CH3、-(CH2)3CH3、 -C(CH3)3、-CH(CH3)2、-SCH3、-SCH2CH3、-CH＝CH2、-CH＝CHCH3、-CH2CH＝CH2、-C≡CH、-C≡CCH3、-CH2C≡CH、-C≡CCH2OH、-C≡C(CH2)2OH、-OCH3、-OCH2CH3、-O(CH2)2CH3、-CH2CN、-(CH2)2CN、-(CH2)3CN、-CH2OH、-(CH2)2OH、-(CH2)3OH、-CH(OH)CH3、-(CH2)2F、-CH2CHF2、-CF3、-CH2CF3、-CHF2、-CH2F、-(CH2)2Cl、-CH＝CHF、-CH＝CHCl、-CH＝CHCH2F、-C≡CCH2F、-C≡C(CH2)2F、-C≡CF、-OCF3、-OCHF2、-OCH2CHF2、-OCH2CF3、-OCHClCHCl2、-OCH2CH2F、-SCF3、-SCH2CF3、-SCH2CHF2、苯基、萘基、吡啶基、嘧啶基、环丙基、环丁基、环戊基、环己基、吡咯烷基、恶唑烷基、四氢呋喃基、哌啶基或哌嗪基，其中所述的-CH3、-CH2CH3、-(CH2)2CH3、-(CH2)3CH3、-C(CH3)3、-CH(CH3)2、-SCH3、-SCH2CH3、-CH＝CH2、-CH＝CHCH3、-CH2CH＝CH2、-C≡CH、-C≡CCH3、-CH2C≡CH、-C≡CCH2OH、-C≡C(CH2)2OH、-OCH3、-OCH2CH3、-O(CH2)2CH3、-CH2CN、-(CH2)2CN、-(CH2)3CN、-CH2OH、-(CH2)2OH、-(CH2)3OH、-CH(OH)CH3、-(CH2)2F、-CH2CHF2、-CH2CF3、-CHF2、-CH2F、-(CH2)2Cl、-CH＝CHF、-CH＝CHCl、-CH＝CHCH2F、-C≡CCH2F、-C≡C(CH2)2F、-OCHF2、-OCH2CHF2、-OCH2CF3、-OCHClCHCl2、-OCH2CH2F、-SCH2CF3、-SCH2CHF2、苯基、萘基、吡啶基、嘧啶基、环丙基、环丁基、环戊基、环己基、吡咯烷基、恶唑烷基、四氢呋喃基、哌啶基和哌嗪基各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、-C(＝O)H、-C(＝O)OH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、吡咯烷基、恶唑烷基、四氢呋喃基、哌啶基和哌嗪基的取代基所取代，其中，R6b、R7b和R6c各自具有如本发明所述的定义。In some embodiments, R 2a , R 2b and R 2c are each independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, CH 2 C(═O)NR 6b R 7b , -C(═O)R 6c , -C(═O)OR 6c , -C(═O)NR 6b R 7b , -NR 6b C(═O)R 7b , -NR 6b R 7b , -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -C(CH 3 ) 3 , -CH(CH 3 ) 2 , -SCH 3 , -SCH 2 CH 3 , -CH＝CH 2 , -CH＝CHCH 3 , -CH 2 CH＝CH 2 , -C≡CH, -C≡CCH 3 , -CH 2 C≡CH, -C≡CCH 2 OH, -C≡C(CH 2 ) 2 OH, -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -CH 2 CN, -(CH 2 ) 2 CN, -(CH 2 ) 3 CN, -CH 2 OH, -(CH 2 ) 2 OH, -(CH 2 ) 3 OH, -CH(OH)CH 3 , -(CH 2 ) 2 F, -CH 2 CHF 2 , -CF 3 , -CH2CF3 , -CHF2, -CH2F, -(CH2)2Cl , -CH = CHF , -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -C≡C(CH2) 2F , -C≡CF , -OCF3, -OCHF2 , -OCH2CHF2 , -OCH2CF3 , -OCHClCHCl2 , -OCH2CH2F , -SCF3, -SCH2CF3 , -SCH2CHF2 , phenyl, naphthyl , pyridyl , pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl or piperazinyl, wherein said -CH3 , -CH2CH3 , -( CH2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -C(CH 3 ) 3 , -CH(CH 3 ) 2 , -SCH 3 , -SCH 2 CH 3 , -CH＝CH 2 , -CH＝CHCH 3 , -CH 2 CH＝CH 2 , -C≡CH, -C≡CCH 3 , -CH 2 C≡CH, -C≡CCH 2 OH, -C≡C(CH 2 ) 2 OH, -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -CH 2 CN, -(CH 2 ) 2 CN, -(CH 2 ) 3 CN, -CH 2 OH, -(CH 2 ) 2 OH, -(CH 2 ) 3 OH, -CH(OH)CH 3 , -(CH 2 ) 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CHF 2 , -CH 2 F, -(CH 2 ) 2 Cl, -CH＝CHF, -CH＝CHCl, -CH＝CHCH 2 F, -C≡CCH 2 F, -C≡C(CH 2 ) 2 F, -OCHF 2 , -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCHClCHCl 2 , -OCH 2 CH 2 F, -SCH 2 CF 3 , -SCH 2 CHF 2 R 6b , R 7b , R 6c , phenyl, naphthyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl and piperazinyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , -C(═O)H, -C(═O)OH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl and piperazinyl, wherein R 6b , R 7b and R 6c each have the definition as described herein.
在一些实施方案中，本发明所述的化合物具有式(I-2)所示的化合物，或式(I-2)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
In some embodiments, the compound described in the present invention has a compound represented by formula (I-2), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-2),
其中，m、n、R1、R2a、R2b、R2c、R3、R5和环A各自具有如本发明所述的定义。wherein m, n, R 1 , R 2a , R 2b , R 2c , R 3 , R 5 and ring A are each as defined in the present invention.
在一些实施方案中，本发明所述的化合物为其中以下结构的化合物，或所述结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，

In some embodiments, the compound described in the present invention is a compound of the following structure, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure,

另一方面，本发明提供一种药物组合物，其包含本发明所述的化合物。In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention.
在一些实施方案中，本发明所述的药物组合物进一步包含药学上可接受的辅剂。In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable adjuvant.
在一些实施方案中，本发明所述的辅剂包括但不限于，载体，赋形剂，稀释剂，溶媒，或它们的组合。在一些实施方案中，药物组合物可以是液体，固体，半固体，凝胶或喷雾剂型。In some embodiments, the adjuvants described in the present invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof. In some embodiments, the pharmaceutical composition can be in liquid, solid, semisolid, gel or spray form.
另一方面，本发明提供本发明所述的药物组合物在制备用于预防、治疗或减轻KRas G12D相关疾病的药物中的用途。On the other hand, the present invention provides the use of the pharmaceutical composition described in the present invention in the preparation of drugs for preventing, treating or alleviating KRas G12D-related diseases.
在一些实施方案中，本发明所述的KRas G12D相关疾病为癌症。In some embodiments, the KRas G12D-related disease described in the present invention is cancer.
在一些实施方案中，本发明化合物或其药物组合物能有效用于预防、治疗或减轻患者癌症的病症包括，但不限于：心脏部位癌症：肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤)、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤和畸胎瘤；肺部癌症：支气管癌(鳞状细胞、未分化小细胞、未分化大细胞、腺癌)、非小细胞肺癌、小细胞肺癌、肺泡(细支气管)癌、支气管腺瘤、肉瘤、淋巴瘤、软骨瘤错构瘤、间皮瘤； 胃肠道癌症：食道(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)癌、胃(癌、淋巴瘤、平滑肌肉瘤)癌、胰腺(导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤、vipoma)癌、小肠(腺癌、淋巴瘤、类癌瘤、卡波西肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤)癌、结肠(腺癌、管状腺瘤、绒毛状腺瘤、错构瘤、平滑肌瘤)癌、结直肠癌；泌尿生殖道癌症：肾(腺癌、肾母细胞瘤(肾母细胞瘤)、淋巴瘤、白血病)癌、膀胱和尿道癌症(鳞状细胞癌、移行细胞癌、腺癌)、前列腺(腺癌、肉瘤)癌、睾丸(精原细胞瘤、畸胎瘤、胚胎癌、畸胎癌、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样肿瘤、脂肪瘤)癌；肝脏部位癌症：肝癌(肝细胞癌)、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤、血管瘤；胆道部位癌症：胆囊癌、壶腹癌、胆管癌；骨癌：成骨肉瘤(osteosarcoma)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤文氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)，多发性骨髓瘤，恶性巨细胞瘤脊索瘤，osteochronfroma(骨软骨外生骨瘤)，良性软骨瘤、软骨母细胞瘤、软骨粘液纤维瘤、骨样骨瘤和巨细胞瘤；神经系统癌症：神经瘤、颅骨(骨瘤、血管瘤、肉芽肿、黄瘤、畸形骨炎)、脑膜部位癌症(脑膜瘤、脑膜肉瘤、胶质瘤病)、脑部位癌症(星形细胞瘤、成神经管细胞瘤、胶质瘤、室管膜瘤、生殖细胞瘤(松果体瘤)、多形性胶质母细胞瘤、少突胶质细胞瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤)、脊髓神经纤维瘤、脑膜瘤、神经胶质瘤、肉瘤)；妇科癌症：子宫(子宫内膜癌(浆液性囊腺癌，粘液性囊腺癌，未分类)癌)、颗粒鞘细胞瘤、间质细胞瘤、无性细胞瘤、恶性畸胎瘤)、外阴(鳞状细胞癌、上皮内癌、腺癌)癌、纤维肉瘤、黑色素瘤)、阴道癌(透明细胞癌、鳞状细胞癌、葡萄样肉瘤(胚胎横纹肌肉瘤)、输卵管(癌)、卵巢癌、乳腺癌；血液学癌症：白血病(髓性白血病(急性和慢性)、急性淋巴细胞白血病、慢性淋巴细胞白血病、骨髓增殖性白血病)疾病、多发性骨髓瘤、骨髓增生异常综合征)、霍奇金病、非霍奇金淋巴瘤(恶性淋巴瘤)；皮肤癌症：黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、痣发育不良痣、脂肪瘤、血管瘤、皮肤纤维瘤，瘢痕疙瘩，牛皮癣；和肾上腺部位癌症：神经母细胞瘤。In some embodiments, the compounds of the present invention or their pharmaceutical compositions can be effectively used to prevent, treat or alleviate the symptoms of cancer in patients, including, but not limited to: cardiac cancer: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; lung cancer: bronchial cancer (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), non-small cell lung cancer, small cell lung cancer, alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma hamartoma, mesothelioma; Gastrointestinal cancers: Esophageal (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma) cancer, stomach (carcinoma, lymphoma, leiomyosarcoma) cancer, pancreatic (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma) cancer, small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) cancer, colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) cancer, colorectal cancer; genitourinary tract cancers: kidney (adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia) cancer, bladder and urethra cancers (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma) cancer, testicular cancer Cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, mesenchymal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver cancer: liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct cancer: gallbladder cancer, ampullary carcinoma, bile duct cancer; bone cancer: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyx fibroma Nervous system cancers: neuroma, skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningeal cancers (meningioma, meningeal sarcoma, glioma), brain cancers (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); Gynecological cancers: uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified) cancer), granulosa cell tumor, interstitial cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma Cancers of the vagina: clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma), ovarian, breast; Hematologic cancers: leukemias (myeloid leukemias (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative leukemia) diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin cancers: melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland cancers: neuroblastoma.
在一些实施方案中，本发明所述癌症为非小细胞肺癌、小细胞肺癌、结直肠癌、直肠癌、结肠癌、小肠癌、胰腺癌、子宫癌、胃癌、食道癌、前列腺癌、卵巢癌、乳腺癌、白血病、黑色素瘤、淋巴瘤或神经瘤。In some embodiments, the cancer described herein is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, colon cancer, small intestine cancer, pancreatic cancer, uterine cancer, gastric cancer, esophageal cancer, prostate cancer, ovarian cancer, breast cancer, leukemia, melanoma, lymphoma or neuroma.
另一方面，本发明还提供了预防或治疗KRas G12D相关疾病的方法，所述方法包括向患者施用治疗有效量的本发明所述的化合物或其药物组合物。On the other hand, the present invention also provides a method for preventing or treating KRas G12D-related diseases, which comprises administering a therapeutically effective amount of the compound described in the present invention or a pharmaceutical composition thereof to a patient.
另一方面，本发明涉及式(I)、(I-1)或(I-2)化合物的制备、分离和纯化的方法。In another aspect, the present invention relates to methods for preparing, isolating and purifying compounds of formula (I), (I-1) or (I-2).
除非其他方面表明，本发明的化合物所有的立体异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，盐和药学上可接受的前药都属于本发明的范围。Unless otherwise indicated, all stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are within the scope of the invention.
具体地说，盐是药学上可接受的盐。术语“药学上可接受的”包括物质或组合物必须是适合化学或毒理学，与组成制剂的其他组分和用于治疗的哺乳动物有关。In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemically and toxicologically with respect to the other ingredients that make up the formulation and with the mammal to be treated.
本发明的化合物的盐还包括用于制备或纯化式(I)、(I-1)或(I-2)所示化合物的中间体或式(I)、(I-1)或(I-2)所示化合物分离的对映异构体的盐，但不一定是药学上可接受的盐。The salts of the compounds of the present invention also include intermediates used to prepare or purify the compounds represented by formula (I), (I-1) or (I-2) or salts of separated enantiomers of the compounds represented by formula (I), (I-1) or (I-2), but are not necessarily pharmaceutically acceptable salts.
本发明化合物的药物组合物的制剂、给药和用途Preparation, administration and use of the pharmaceutical composition of the compound of the present invention
本发明的药物组合物的特点包括式(I)、(I-1)或(I-2)所示的化合物，本发明所列出的化合物，或实 施例的化合物，和药学上可接受的载体。本发明的药物组合物中化合物的量能有效地治疗或减轻患者KRAS G12D介导的疾病。The pharmaceutical composition of the present invention is characterized by comprising a compound represented by formula (I), (I-1) or (I-2), a compound listed in the present invention, or The amount of the compound in the pharmaceutical composition of the present invention is effective to treat or alleviate KRAS G12D-mediated diseases in patients.
本发明的化合物存在自由形态，或合适的、作为药学上可接受的衍生物。根据本发明，药学上可接受的衍生物包括，但并不限于，药学上可接受的前药，盐，酯，酯类的盐，或能直接或间接地根据患者的需要给药的其他任何加合物或衍生物，本发明其他方面所描述的化合物，其代谢产物或它的残留物。The compounds of the present invention exist in free form, or are suitable as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be directly or indirectly administered according to the needs of the patient, the compounds described in other aspects of the present invention, their metabolites or their residues.
像本发明所描述的，本发明药学上可接受的组合物进一步包含药学上可接受的辅剂，这些像本发明所应用的，包括任何溶剂，稀释剂，或其他液体赋形剂，分散剂或悬浮剂，表面活性剂，等渗剂，增稠剂，乳化剂，防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York,综合此处文献的内容，表明不同的辅剂可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的辅剂与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。As described in the present invention, the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable adjuvant, which, as used in the present invention, includes any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a specific target dosage form. As described in the following documents: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, Comprehensively the contents of the documents here, it is shown that different adjuvants can be applied to the preparation of the pharmaceutically acceptable composition and their known preparation methods. Except insofar as any conventional adjuvant is incompatible with the compounds of the present invention, for example by producing any undesirable biological effect or interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, their use is contemplated by the present invention.
可作为药学上可接受载体的物质包括，但并不限于，离子交换剂，铝，硬脂酸铝，卵磷脂，血清蛋白，如人血清蛋白，缓冲物质如磷酸盐，甘氨酸，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，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，胶体硅，三硅酸镁，聚乙烯吡咯烷酮，聚丙烯酸脂，蜡，聚乙烯-聚氧丙烯-阻断聚合体，羊毛脂，糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇，磷酸缓冲溶液，和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁，着色剂，释放剂，包衣衣料，甜味剂，调味剂和香料，防腐剂和抗氧化剂。Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose sodium cellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol, phosphate buffered solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and fragrances, preservatives and antioxidants.
在制备本发明提供的药物组合物时，通常将活性成分与赋形剂混合，通过赋形剂稀释或以例如胶囊、小袋、纸或其它容器的形式封装在这种运载体内。如果将赋形剂用作稀释剂，它可以是固体、半固体或液体材料，其用作活性成分的运载体、载体或介质。适宜的载体包括但不限于碳酸镁、硬脂酸镁、滑石粉、糖、乳糖、果胶、糊精、淀粉、明胶、西黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可脂等。因此，组合物可以是片剂、丸剂、粉末剂、锭剂、囊剂、扁胶囊、酏剂、混悬剂、乳剂、溶液剂、糖浆剂、气雾剂(固体形式或在液体介质中)、例如最多含有10重量％活性化合物的软膏剂、软和硬明胶胶囊、栓剂、无菌注射溶液以及无菌包装的粉末剂。在一个实施方式中，组合物被配制用于口服给药。在一个实施方式中，组合物被配制成片剂或胶囊剂。When preparing the pharmaceutical composition provided by the invention, active ingredient is usually mixed with excipient, diluted by excipient or encapsulated in such carrier in the form of capsule, pouch, paper or other container, for example. If excipient is used as diluent, it can be solid, semisolid or liquid material, which is used as carrier, carrier or medium of active ingredient. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter, etc. Therefore, the composition can be tablets, pills, powders, lozenges, capsules, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid form or in liquid medium), for example, ointments containing up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions and aseptically packaged powders. In one embodiment, the composition is formulated for oral administration. In one embodiment, the composition is formulated into tablets or capsules.
本发明化合物或药物组合物可以以口服剂的形式被施用，如片剂，胶囊(其中的每一个都包括持续释放或者定时释放的配方)，丸剂，粉剂，粒剂，酏剂，酊剂，悬浮剂，糖浆剂，和乳化剂。它们也可以以静脉内(大丸剂或者输液)，腹膜内，皮下或者肌肉内的形式施用，所有使用的剂量形式都是药学领域的普通技术人员所熟知的。它们可以单独施用，但一般将基于所选择的施用方式和标准的药学实践选择一种药学载体一起施用。The compounds or pharmaceutical compositions of the present invention can be administered in the form of oral dosage forms, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, and all dosage forms used are well known to those of ordinary skill in the pharmaceutical field. They can be administered alone, but will generally be administered together with a pharmaceutical carrier selected based on the selected mode of administration and standard pharmaceutical practice.
本发明的化合物或药物组合物可以经过合适的鼻内载体的局部使用以鼻内形式施用，或者通过使用经 皮药贴以经皮途径施用。当以经皮传递系统的形式施用时，在整个用药期间施用的剂量是连续的而不是间歇的。The compounds or pharmaceutical compositions of the invention can be administered in intranasal form via topical use of a suitable intranasal vehicle, or via the use of an intranasal Patches are administered transdermally. When administered as a transdermal delivery system, the dosage is administered continuously rather than intermittently throughout the duration of administration.
本发明化合物或药物组合物也可以以脂质体传递系统的形式施用，如小的单层的囊泡，大的单层的囊泡以及多层囊泡。脂质体可以通过不同的磷脂形成，如胆固醇，硬脂胺，或者磷脂酰胆碱。The compounds or pharmaceutical compositions of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine.
本发明化合物或药物组合物也与可溶性的聚合物偶联，该多聚物作为靶向的药物载剂。这样的多聚物包括聚乙烯吡咯烷酮，吡喃共聚物，聚羟基丙基甲基丙烯酸胺-酚，聚羟基乙基天冬酰胺酚，或者用棕榈酰残基取代的聚乙烯氧化物-聚赖氨酸。而且，本发明化合物可以与一类生物可降解的聚合物偶联，用于完成可控制的药物释放，例如，聚乳酸，聚羟基乙酸，聚乳酸和聚羟基乙酸的共聚物，聚ε己内酯，聚羟基丁酸，聚原酸酯，聚缩醛，聚二氢吡喃，聚氰基丙烯酸酯，和水凝胶的交联的或者两亲性的阻断共聚物。The compounds of the invention or pharmaceutical compositions are also coupled with soluble polymers, which serve as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Moreover, the compounds of the invention can be coupled with a class of biodegradable polymers for controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic blocking copolymers of hydrogels.
本发明化合物或药物组合物的给药方案将随已知的各种因素而不同，如特定试剂的药动学特征及其模式和施用途径；接受者的种族，年龄，性别，健康状况，医疗状况和体重；症状的性质和程度；并行的治疗的种类；治疗的频率；施药的途径，病人的肾和肝功能，和希望达到的效果。一个医师或者兽医可以作出决定并开出有效量的药物来预防、抵销或者阻止癌症的发展。The dosage regimen of the compounds or pharmaceutical compositions of the present invention will vary with known factors, such as the pharmacokinetic characteristics of the specific agent and its mode and route of administration; the race, age, sex, health status, medical condition and weight of the recipient; the nature and extent of the symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's renal and liver function, and the desired effect. A physician or veterinarian can make a decision and prescribe an effective amount of the drug to prevent, offset or stop the development of cancer.
根据一般的指导原则，为了达到指定的效果，所使用的每一种活性成分的剂量在日口服剂量的范围为大约0.001到1000mg/kg体重之间，优选地，在大约0.01到100mg/kg体重之间。。本发明化合物可以以每日一次来施用，或者可以以每日分两次，三次或者四次进行施用。According to general guidelines, in order to achieve the specified effect, the dosage of each active ingredient used is between about 0.001 and 1000 mg/kg body weight per day, preferably, between about 0.01 and 100 mg/kg body weight. The compound of the present invention can be administered once a day, or can be administered twice, three times or four times a day.
适于施用的剂型(药物组合物)的每一单位剂量，可以含有大约1mg到大约100mg的活性成分。在这些药物组合物中，活性成分的重量一般将占组合物的总重量的大约0.5-95％。Each unit dose of a dosage form (pharmaceutical composition) suitable for administration may contain about 1 mg to about 100 mg of active ingredient. In these pharmaceutical compositions, the weight of the active ingredient will generally account for about 0.5-95% of the total weight of the composition.
本文所述的化合物和组合物可单独施用或与其它化合物或其它治疗剂组合施用。本发明的化合物或组合物可通过相同或不同给药途径与其它治疗剂同时或相继施用。本发明的化合物可与其它治疗剂一起包含在单一制剂中或在单独的制剂中。The compounds and compositions described herein can be administered alone or in combination with other compounds or other therapeutic agents. The compounds or compositions of the present invention can be administered simultaneously or sequentially with other therapeutic agents by the same or different routes of administration. The compounds of the present invention can be included in a single formulation or in a separate formulation with other therapeutic agents.
当本发明化合物与其他治疗剂一起施用时，一般地，考虑到联合施用时治疗剂的附加的或者协同的效果，在典型的日剂量和典型的剂型中的每一个组分的量，相对于单独施用时的通常剂量，可以有所下降。When the compounds of the invention are administered with other therapeutic agents, generally the amount of each component in a typical daily dose and typical dosage form may be reduced relative to the usual dose when administered alone, taking into account the additive or synergistic effects of the therapeutic agents when administered in combination.
本发明涉及的化合物或者其药用盐或其水合物或其药物组合物能有效用于预防、治疗或减轻患者由KRAS介导的疾病，尤其是KRAS G12D介导的疾病，特别是癌症。The compounds or pharmaceutically acceptable salts or hydrates thereof or pharmaceutical compositions thereof involved in the present invention can be effectively used to prevent, treat or alleviate KRAS-mediated diseases, especially KRAS G12D-mediated diseases, especially cancer, in patients.
在一些实施方案中，本发明化合物或其药物组合物能有效用于预防、治疗或减轻患者癌症的病症包括，但不限于：心脏部位癌症：肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤)、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤和畸胎瘤；肺部癌症：支气管癌(鳞状细胞、未分化小细胞、未分化大细胞、腺癌)、非小细胞肺癌、小细胞肺癌、肺泡(细支气管)癌、支气管腺瘤、肉瘤、淋巴瘤、软骨瘤错构瘤、间皮瘤；胃肠道癌症：食道(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)癌、胃(癌、淋巴瘤、平滑肌肉瘤)癌、胰腺(导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤、vipoma)癌、小肠(腺癌、淋巴瘤、类癌瘤、卡波西肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤)癌、结肠(腺癌、管状腺瘤、绒毛状腺瘤、错构瘤、平滑肌瘤)癌、结直肠癌；泌尿生殖道癌症：肾(腺癌、肾母细胞瘤(肾母细胞瘤)、淋巴瘤、白血病)癌、膀胱和尿道癌症(鳞状细胞癌、移行细胞癌、腺癌)、前列腺(腺癌、肉瘤)癌、睾丸(精原细胞瘤、畸胎瘤、胚胎癌、畸胎癌、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样肿瘤、脂肪瘤)癌；肝脏部位癌症：肝癌(肝细胞癌)、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤、血管瘤；胆道部位癌症：胆囊癌、壶腹癌、胆管癌；骨癌：成骨肉瘤(osteosarcoma)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤文氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)，多发性骨髓瘤，恶性巨细胞瘤脊索瘤，osteochronfroma(骨软骨外生骨瘤)，良性软骨瘤、软骨母细胞瘤、软骨粘液纤维瘤、骨样骨瘤和巨细胞瘤；神经系统癌症：神经瘤、颅骨(骨瘤、血管瘤、肉芽肿、黄瘤、畸形骨炎)、脑膜部位癌症(脑 膜瘤、脑膜肉瘤、胶质瘤病)、脑部位癌症(星形细胞瘤、成神经管细胞瘤、胶质瘤、室管膜瘤、生殖细胞瘤(松果体瘤)、多形性胶质母细胞瘤、少突胶质细胞瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤)、脊髓神经纤维瘤、脑膜瘤、神经胶质瘤、肉瘤)；妇科癌症：子宫(子宫内膜癌(浆液性囊腺癌，粘液性囊腺癌，未分类)癌)、颗粒鞘细胞瘤、间质细胞瘤、无性细胞瘤、恶性畸胎瘤)、外阴(鳞状细胞癌、上皮内癌、腺癌)癌、纤维肉瘤、黑色素瘤)、阴道癌(透明细胞癌、鳞状细胞癌、葡萄样肉瘤(胚胎横纹肌肉瘤)、输卵管(癌)、卵巢癌、乳腺癌；血液学癌症：白血病(髓性白血病(急性和慢性)、急性淋巴细胞白血病、慢性淋巴细胞白血病、骨髓增殖性白血病)疾病、多发性骨髓瘤、骨髓增生异常综合征)、霍奇金病、非霍奇金淋巴瘤(恶性淋巴瘤)；皮肤癌症：黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、痣发育不良痣、脂肪瘤、血管瘤、皮肤纤维瘤，瘢痕疙瘩，牛皮癣；和肾上腺部位癌症：神经母细胞瘤。In some embodiments, the compounds of the present invention or their pharmaceutical compositions can be effectively used to prevent, treat or alleviate the symptoms of cancer in patients, including, but not limited to: cardiac cancer: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; lung cancer: bronchial cancer (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), non-small cell lung cancer, small cell lung cancer, alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma hamartoma Cancers of the gastrointestinal tract: esophageal (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreatic (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colorectal cancer; genitourinary tract cancer: kidney ( Adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia) cancer, bladder and urethra cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma) cancer, testicular (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma) cancer; liver cancer: liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct cancer: gallbladder cancer, ampullary cancer, bile duct cancer Bone cancer: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; Nervous system cancer: neuroma, skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningeal cancer (brain Meningioma, meningiosarcoma, glioma), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, neurothecoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); gynecological cancer: uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified) cancer), granulosa cell tumor, interstitial cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma) cancer, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma), ovarian cancer, breast cancer; hematological cancers: leukemias (myeloid leukemias (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative leukemia) diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin cancers: melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland cancers: neuroblastoma.
尤其，本发明化合物或其药物组合物能有效用于预防、治疗或减轻患者癌症的病症包括，非小细胞肺癌、小细胞肺癌、结直肠癌、直肠癌、结肠癌、小肠癌、胰腺癌、子宫癌、胃癌、食道癌、前列腺癌、卵巢癌、乳腺癌、白血病、黑色素瘤、淋巴瘤或神经瘤。In particular, the compounds of the present invention or their pharmaceutical compositions can be effectively used to prevent, treat or alleviate cancer symptoms in patients including non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, colon cancer, small intestine cancer, pancreatic cancer, uterine cancer, gastric cancer, esophageal cancer, prostate cancer, ovarian cancer, breast cancer, leukemia, melanoma, lymphoma or neuroma.
一般合成过程General synthesis process
为描述本发明，本发明将用下面实施例来进一步阐述本发明的技术方案。以下实施例仅应用于说明本发明的具体实施方法，以使本领域的技术人员能够理解本发明，但不用于限制本发明的保护范围。本发明的具体实施方法中，未做特别说明的技术手段或方法等为本领域的常规技术手段或方法等。To describe the present invention, the present invention will further illustrate the technical scheme of the present invention with the following examples. The following examples are only used to illustrate the specific implementation method of the present invention so that those skilled in the art can understand the present invention, but are not used to limit the scope of protection of the present invention. In the specific implementation method of the present invention, the technical means or methods not specifically described are conventional technical means or methods in the art.
除非有进一步的说明，其中取代基的定义如本发明所述。下面的反应方案和实施例用于进一步举例说明本发明的内容。Unless otherwise specified, the substituents are as defined herein. The following reaction schemes and examples are provided to further illustrate the present invention.
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the invention.
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度(℃)，实施例中的室温，表示15℃–30℃；在一些实施例中，室温为20℃–30℃。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，等。使用时都没有经过进一步纯化。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，天津市福晨化学试剂厂，武汉鑫华远科技发展有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂，等供应商购买得到。In the embodiments described below, all temperatures are set in degrees Celsius (°C) unless otherwise indicated. Room temperature in the embodiments means 15°C–30°C; in some embodiments, room temperature is 20°C–30°C. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, etc. None of them were further purified when used. General reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Plant, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant, etc.
无水四氢呋喃，二氧六环，甲苯，乙醚是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯，石油醚，正己烷，N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by drying under reflux with sodium metal. Anhydrous dichloromethane and chloroform were obtained by drying under reflux with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿均是经过干燥的。The following reactions were generally carried out under positive pressure of nitrogen or argon or with a drying tube over anhydrous solvent (unless otherwise indicated), reaction bottles were plugged with appropriate rubber stoppers, and substrates were injected via syringe. All glassware was dried.
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。The chromatographic column used was a silica gel column, and the silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.
1H NMR谱使用Bruker 400MHz或600MHz核磁共振谱仪记录。1H NMR谱以CDC13、DMSO-d6、CD3OD或丙酮-d6为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)、d(doublet，双峰)、t(triplet，三重峰)、q(quartet，四重峰)、m(multiplet，多重峰)、br(broadened，宽峰)、br s(broadened singlet，br.s,宽的单峰)、dd(doublet  of doublets，双二重峰)、dt(doublet of triplets，双三重峰)。偶合常数J，用赫兹(Hz)表示。 1 H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz NMR spectrometer. 1 H NMR spectra were recorded using CDCl 3 , DMSO-d 6 , CD 3 OD or acetone-d 6 as solvents (in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), br s (broadened singlet, br.s, broad singlet), dd (doublet), d ... The coupling constant J is expressed in Hertz (Hz).
低分辨率质谱(MS)数据的测定条件是：Agilent 6120四级杆HPLC-MS(色谱柱型号：Zorbax SB-C18,2.1x 30mm,3.5微米,6min,流速为0.6mL/min。流动相：5％-95％(含0.1％甲酸的CH3CN)在(含0.1％甲酸的H2O)中的比例，采用电喷雾电离(ESI)，在210nm/254nm下，用UV检测。The low-resolution mass spectrometry (MS) data were measured using an Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 microns, 6 min, flow rate 0.6 mL/min. Mobile phase: 5%-95% (CH 3 CN containing 0.1% formic acid) in (H 2 O containing 0.1% formic acid), electrospray ionization (ESI), at 210 nm/254 nm, with UV detection.
纯的化合物使用Agilent 1260 pre-HPLC或Calesep pump 250 pre-HPLC(色谱柱型号：NOVASEP 50/80mm DAC)，在210nm/254nm下，用UV检测。Pure compounds were analyzed using Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50/80mm DAC) at 210nm/254nm with UV detection.
下面简写词的使用贯穿本发明：
The following abbreviations are used throughout this invention:
合成方案1
Synthesis Scheme 1
化合物(IA)可参考合成方案1的方法合成得到。其中R1、R2、R3、R5、环A、m和n具有如本发明所述的定义；Hal为卤素，优选Cl或Br；Ra为C1-4烷基，优选甲基或乙基；q为1-6的自然数，优选1或2；3-10元杂环基具有如本发明所述的定义，可任选被本发明所述的取代基所取代。化合物(IA-01)与化合物(IA-02)在合适的条件下(如碳酸铯、t-BuBrettPhos G3 Pd和t-BuBrettPhos存在下)反应得到化合物(IA-0)；化合物(IA-0)在酸性条件下脱除氨基保护得到化合物(IA-1)；化合物(IA-1)在NIS或I2作用下在合适的酸性条件下(如高碘酸或对甲苯磺酸)和合适的溶剂(如乙醇或乙腈)中反应得到化合物(IA-2)；化合物(IA-2)在钯催化剂(如Pd(PPh3)2Cl2)作用下和合适的条件下(如碱TEA作用下)与CO和醇RaOH(如乙醇或甲醇)反应后得到化合物(IA-3)；化合物(IA-3)与2,2,2-三氯乙酰基异氰酸酯在合适溶剂(如四氢呋喃)中反应得到化合物(IA-4)；化合物(IA-4)在氨的甲醇溶液中反应得到化合物(IA-5)；化合物(IA-5)与POCl3在合适的条件下(如加热)反应得到化合物(IA-6)；化合物(IA-6)与化合物(IA-7)在合适条件(如DIPEA存在)下反应得到化合物(IA-8)；化合物(IA-8)与化合物(IA-9)在合适条件(如加热、在DIPEA作用下)下反应得到化合物(IA-10)；化合物(IA-10)与化合物(IA-11)在合适催化剂作用下(如XPhos Pd G2)反应得到化合物(IA-12)；化合物(IA-12)在酸性条件(如HCl)下反应得到化合物(IA)。 Compound (IA) can be synthesized by referring to the method of Synthesis Scheme 1. Wherein R 1 , R 2 , R 3 , R 5 , ring A, m and n have the same definitions as those described in the present invention; Hal is a halogen, preferably Cl or Br; Ra is a C 1-4 alkyl, preferably a methyl or ethyl group; q is a natural number of 1-6, preferably 1 or 2; and the 3-10 membered heterocyclic group has the same definitions as those described in the present invention, and may be optionally substituted by the substituents described in the present invention. Compound (IA-01) reacts with compound (IA-02) under appropriate conditions (such as in the presence of cesium carbonate, t-BuBrettPhos G3 Pd and t-BuBrettPhos) to obtain compound (IA-0); compound (IA-0) is deprotected from the amino group under acidic conditions to obtain compound (IA-1); compound (IA-1) is reacted with NIS or I2 under appropriate acidic conditions (such as periodic acid or p-toluenesulfonic acid) and in a suitable solvent (such as ethanol or acetonitrile) to obtain compound (IA-2); compound (IA-2) is reacted with CO and alcohol R a under the action of a palladium catalyst (such as Pd(PPh 3 ) 2 Cl 2 ) and appropriate conditions (such as the action of a base TEA); OH (such as ethanol or methanol) to obtain compound (IA-3); compound (IA-3) reacts with 2,2,2-trichloroacetyl isocyanate in a suitable solvent (such as tetrahydrofuran) to obtain compound (IA-4); compound (IA-4) reacts in a methanol solution of ammonia to obtain compound (IA-5); compound (IA-5) reacts with POCl 3 under suitable conditions (such as heating) to obtain compound (IA-6); compound (IA-6) reacts with compound (IA-7) under suitable conditions (such as the presence of DIPEA) to obtain compound (IA-8); compound (IA-8) reacts with compound (IA-9) under suitable conditions (such as heating, under the action of DIPEA) to obtain compound (IA-10); compound (IA-10) reacts with compound (IA-11) under the action of a suitable catalyst (such as XPhos Pd G2) to obtain compound (IA-12); compound (IA-12) reacts under acidic conditions (such as HCl) to obtain compound (IA).
合成方案2
Synthesis Scheme 2
化合物(IB)可参考合成方案2的方法合成得到。其中R1、R2、R3、R5、环A和m具有如本发明所述的定义；n1为1-6的自然数；q为1-6的自然数，优选1或2；3-10元杂环基具有如本发明所述的定义，可任选被本发明所述的取代基所取代。化合物(IA-10)与化合物(IB-1)在合适催化剂作用下(如XPhos Pd G2)反应得到化合物(IB-2)；化合物(IB-2)在酸性条件(如HCl)下反应得到化合物(IB)。Compound (IB) can be synthesized by referring to the method of Synthesis Scheme 2. Wherein R 1 , R 2 , R 3 , R 5 , Ring A and m have the definitions described in the present invention; n1 is a natural number of 1-6; q is a natural number of 1-6, preferably 1 or 2; 3-10 membered heterocyclic group has the definitions described in the present invention, and can be optionally substituted by the substituents described in the present invention. Compound (IA-10) is reacted with compound (IB-1) in the presence of a suitable catalyst (such as XPhos Pd G2) to obtain compound (IB-2); compound (IB-2) is reacted under acidic conditions (such as HCl) to obtain compound (IB).
合成方案3
Synthesis Scheme 3
化合物(IC)可参考合成方案3的方法合成得到。其中R1、R2、R3、R5、环A和m具有如本发明所述的定义；n2为1-5的自然数；q为1-6的自然数，优选1或2；3-10元杂环基具有如本发明所述的定义，可任选被本发明所述的取代基所取代。化合物(IA-10)与化合物(IC-1)在合适催化剂作用下(如XPhos Pd G2或XPhos Pd G3)反应得到化合物(IC-2)；化合物(IC-2)在酸性条件(如HCl)下反应得到化合物(IC-3)或化合物(IC-3)的酸加成盐；化合物(IC-3)或化合物(IC-3)的酸加成盐在合适的条件下(如CsF作用下，在DMF溶剂中)脱去TIPS基团得到化合物(IC)。Compound (IC) can be synthesized by referring to the method of Synthesis Scheme 3. Wherein R 1 , R 2 , R 3 , R 5 , Ring A and m are as defined in the present invention; n2 is a natural number of 1-5; q is a natural number of 1-6, preferably 1 or 2; 3-10 membered heterocyclic group is as defined in the present invention, and can be optionally substituted by a substituent as described in the present invention. Compound (IA-10) reacts with compound (IC-1) under the action of a suitable catalyst (such as XPhos Pd G2 or XPhos Pd G3) to obtain compound (IC-2); compound (IC-2) reacts under acidic conditions (such as HCl) to obtain compound (IC-3) or an acid addition salt of compound (IC-3); compound (IC-3) or an acid addition salt of compound (IC-3) removes the TIPS group under suitable conditions (such as CsF in DMF solvent) to obtain compound (IC).
以下结合实施例对本发明提供的化合物、药物组合物及其应用进行进一步说明。The compounds, pharmaceutical compositions and applications of the present invention are further described below in conjunction with the examples.
实施例Example
中间体化合物M1的合成

Synthesis of intermediate compound M1

步骤1：化合物M1-2的合成Step 1: Synthesis of compound M1-2
于100mL的三口瓶中，加入化合物M1-1(503.0mg,2.39mmol)，氮气置换3次，加入无水THF(3mL)，冷却至-78℃后缓慢滴加LDA的THF溶液(2.39mL,4.78mmol,2mol/L)，-78℃条件下搅拌45min，再滴加配制好的碘(1.22g,4.78mmol)的THF溶液(3mL)，-78℃搅拌0.5h。停止搅拌，加入饱和氯化铵溶液(10mL)淬灭反应，分液，用EA(20mL×3)萃取，依次用饱和硫代硫酸钠溶液(20mL)和饱和氯化钠溶液(40mL)洗涤有机相，无水硫酸钠干燥，浓缩旋干，得到740.0mg粗产物，收率为92.1％.1H NMR(400MHz,CDCl3):δ7.82(d,J＝3.5Hz,1H).In a 100 mL three-necked flask, compound M1-1 (503.0 mg, 2.39 mmol) was added, the atmosphere was replaced with nitrogen three times, anhydrous THF (3 mL) was added, and after cooling to -78 °C, a THF solution of LDA (2.39 mL, 4.78 mmol, 2 mol/L) was slowly added dropwise, and stirred at -78 °C for 45 min. Then, a THF solution (3 mL) of iodine (1.22 g, 4.78 mmol) was added dropwise, and stirred at -78 °C for 0.5 h. Stop stirring, add saturated ammonium chloride solution (10 mL) to quench the reaction, separate the layers, extract with EA (20 mL × 3), wash the organic phase with saturated sodium thiosulfate solution (20 mL) and saturated sodium chloride solution (40 mL) in sequence, dry over anhydrous sodium sulfate, concentrate and spin dry to obtain 740.0 mg of crude product, with a yield of 92.1%. 1 H NMR (400 MHz, CDCl 3 ): δ7.82 (d, J＝3.5 Hz, 1H).
步骤2：化合物M1的合成Step 2: Synthesis of Compound M1
于250mL的三口瓶中，加入化合物M1-2(2.40g,7.14mmol)、Pd2(dba)3(0.13g,0.14mmol)、XantPhos(0.21g,0.36mmol)、氨基甲酸叔丁酯(1.00g,8.57mmol)和碳酸铯(5.82g,17.85mmol)，氮气置换3次，加入无水1,4-二氧六环(40mL)，氮气置换3次，升温至80℃搅拌反应2h。停止反应，硅藻土过滤，浓缩，加水(20mL)稀释，用EA(50mL×3)萃取，合并有机相并用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，柱层析(PE/EA(v/v＝98/2)分离，得到1.68g黄色固体，收率为72.3％。LC-MS(ESI,neg.ion)m/z:323.0[M-H]-；1H NMR(400MHz,CDCl3):δ8.32(d,J＝4.7Hz,1H),6.98(s,1H),1.54(s,9H).In a 250 mL three-necked flask, compound M1-2 (2.40 g, 7.14 mmol), Pd 2 (dba) 3 (0.13 g, 0.14 mmol), XantPhos (0.21 g, 0.36 mmol), tert-butyl carbamate (1.00 g, 8.57 mmol) and cesium carbonate (5.82 g, 17.85 mmol) were added, and the atmosphere was replaced with nitrogen three times. Anhydrous 1,4-dioxane (40 mL) was added, and the atmosphere was replaced with nitrogen three times. The temperature was raised to 80°C and stirred for reaction for 2 h. The reaction was stopped, filtered through celite, concentrated, diluted with water (20 mL), extracted with EA (50 mL×3), the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE/EA (v/v=98/2) to obtain 1.68 g of yellow solid with a yield of 72.3%. LC-MS (ESI, neg.ion) m/z: 323.0 [MH] - ; 1 H NMR (400 MHz, CDCl 3 ): δ8.32 (d, J=4.7 Hz, 1H), 6.98 (s, 1H), 1.54 (s, 9H).
中间体化合物M2的合成
Synthesis of intermediate compound M2
步骤1：化合物M2-2的合成Step 1: Synthesis of compound M2-2
于250mL的三口瓶中，加入化合物M2-1(10g,61.35mmol)和Selectfluor(32.6g,92.03mmol)，氮气置换3次，加入甲醇(100mL)和水(20mL)，搅拌溶解，加热到60℃后搅拌14h，停止反应，减压浓缩 反应液，加入饱和氯化铵水溶液(50mL)淬灭反应，用乙酸乙酯萃取(100mL×3)，合并有机相，用水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析(PE/EA(v/v＝100/0-9/1)分离，得到4.5g白色固体，收率为41.2％。LC-MS(ESI,pos.ion)m/z:181.1[M+H]+.Compound M2-1 (10 g, 61.35 mmol) and Selectfluor (32.6 g, 92.03 mmol) were added to a 250 mL three-necked flask, and the atmosphere was replaced with nitrogen three times. Methanol (100 mL) and water (20 mL) were added, and the mixture was stirred to dissolve. The mixture was heated to 60 °C and stirred for 14 h, the reaction was stopped, and the mixture was concentrated under reduced pressure. The reaction solution was quenched by adding saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (100 mL×3), the organic phases were combined, washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (PE/EA (v/v=100/0-9/1) to obtain 4.5 g of white solid with a yield of 41.2%. LC-MS (ESI, pos.ion) m/z: 181.1 [M+H] + .
步骤2：化合物M2-3的合成Step 2: Synthesis of Compound M2-3
室温下于100mL单口瓶中加入M2-2(2.75g,15.19mmol)、NIS(4.10g,18.23mmol)、对甲苯磺酸一水合物(0.14g,0.76mmol)和ACN(10mL)，氮气保护70℃反应4h。停止反应，用30mL饱和碳酸钠(30mL)和饱和亚硫酸钠(30mL)淬灭，EA(30mL)萃取分液，无水硫酸钠干燥有机相，过滤，旋蒸干得4.9g红黑色固体M2-3，收率按照100％计算。LC-MS(ESI,pos.ion)m/z:306.8[M+H]+。M2-2 (2.75 g, 15.19 mmol), NIS (4.10 g, 18.23 mmol), p-toluenesulfonic acid monohydrate (0.14 g, 0.76 mmol) and ACN (10 mL) were added to a 100 mL single-mouth bottle at room temperature, and the mixture was reacted at 70 ° C for 4 h under nitrogen protection. The reaction was stopped, quenched with 30 mL of saturated sodium carbonate (30 mL) and saturated sodium sulfite (30 mL), extracted with EA (30 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 4.9 g of red-black solid M2-3, and the yield was calculated as 100%. LC-MS (ESI, pos.ion) m/z: 306.8 [M+H] + .
步骤3：化合物M2-4的合成Step 3: Synthesis of Compound M2-4
室温下往250mL高压釜中加入M2-3(4.66g,15.18mmol)、Pd(PPh3)2Cl2(1.07g,1.52mmol)、EtOH(20mL)和TEA(4.61g,45.54mmol)，氮气置换后，冲入3兆帕一氧化碳，80℃高压反应22h。停止反应，加入饱和氯化铵(30mL)淬灭，EA(100mL)萃取分液，柱层析(PE/EA(v/v＝19/1)分离，得到4g黄色固体M2-4。LC-MS(ESI,pos.ion)m/z:252.9[M+H]+。M2-3 (4.66 g, 15.18 mmol), Pd(PPh 3 ) 2 Cl 2 (1.07 g, 1.52 mmol), EtOH (20 mL) and TEA (4.61 g, 45.54 mmol) were added to a 250 mL autoclave at room temperature. After nitrogen replacement, 3 MPa of carbon monoxide was introduced and the reaction was carried out at 80°C for 22 h. The reaction was stopped and quenched by adding saturated ammonium chloride (30 mL). The mixture was extracted with EA (100 mL) and separated by column chromatography (PE/EA (v/v=19/1) to obtain 4 g of yellow solid M2-4. LC-MS (ESI, pos.ion) m/z: 252.9 [M+H] + .
步骤4：化合物M2-5的合成Step 4: Synthesis of Compound M2-5
室温下100mL单口瓶加入M2-4(4g,15.81mmol)、THF(30mL)和三氯乙酰基异氰酸酯(5.96g,31.62mmol)。室温反应1h，停止反应，直接旋蒸干，产率按100％计算，直接用于下一步。M2-4 (4 g, 15.81 mmol), THF (30 mL) and trichloroacetyl isocyanate (5.96 g, 31.62 mmol) were added to a 100 mL single-necked bottle at room temperature. The reaction was carried out at room temperature for 1 h, and then the reaction was stopped and the product was directly evaporated to dryness. The yield was calculated as 100%, and it was directly used in the next step.
步骤5：化合物M2-6的合成Step 5: Synthesis of Compound M2-6
室温下，100mL单口瓶加入M2-5(6.98g,15.81mmol)、氨甲醇溶液(22.59mL,158.1mmol，7M甲醇溶液)和甲醇(30mL)，室温反应14.5h，停止反应，旋蒸干，用MTBE(100mL)打浆1h，过滤得3.67g白色固体产物M2-6，收率为92.84％。LC-MS(ESI,pos.ion)m/z:249.9[M+H]+.At room temperature, M2-5 (6.98 g, 15.81 mmol), ammonia methanol solution (22.59 mL, 158.1 mmol, 7 M methanol solution) and methanol (30 mL) were added to a 100 mL single-mouth bottle, and the reaction was carried out at room temperature for 14.5 h. The reaction was stopped, evaporated to dryness, slurried with MTBE (100 mL) for 1 h, and filtered to obtain 3.67 g of white solid product M2-6, with a yield of 92.84%. LC-MS (ESI, pos.ion) m/z: 249.9 [M + H] + .
步骤6：化合物M2的合成Step 6: Synthesis of Compound M2
室温下，250mL单口瓶加入M2-6(3.67g,14.68mmol)、甲苯(40mL)、DIPEA(5.69g,44.04mmol)和POCl3(22.51g,146.8mmol)，105℃反应15h,停止反应，旋干，加入1,4-二氧六环(50mL)，滴加300mL碳酸钾水溶液(300mL，20％)，室温搅拌2h后，调pH至2～3后有棕色固体析出，抽滤得粘稠固体，滤液用EA(30mL)萃取，粘稠固体用EA(50mL)溶解，合并有机相，用饱和食盐水(30mL)洗一次，无水硫酸钠干燥，过滤，有机相旋蒸干得3.6g白色产物M2，收率为92.84％。LC-MS(ESI,pos.ion)m/z:268.2[M+H]+.At room temperature, M2-6 (3.67 g, 14.68 mmol), toluene (40 mL), DIPEA (5.69 g, 44.04 mmol) and POCl 3 (22.51 g, 146.8 mmol) were added to a 250 mL single-mouth bottle, and the reaction was continued at 105 ° C for 15 h. The reaction was stopped and the mixture was dried by rotation. 1,4-dioxane (50 mL) was added, and 300 mL of potassium carbonate aqueous solution (300 mL, 20%) was added dropwise. After stirring at room temperature for 2 h, the pH was adjusted to 2-3, and a brown solid was precipitated. The viscous solid was filtered to obtain a viscous solid. The filtrate was extracted with EA (30 mL), and the viscous solid was dissolved with EA (50 mL). The organic phases were combined, washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was evaporated to dryness to obtain 3.6 g of white product M2, with a yield of 92.84%. LC-MS (ESI, pos.ion) m/z: 268.2 [M + H] + .
实施例1：化合物1的合成

Example 1: Synthesis of Compound 1

步骤1：化合物1-1的合成Step 1: Synthesis of compound 1-1
于100mL的两口瓶中，加入化合物M1(3.00g,9.21mmol)、碳酸铯(6.00g,18.42mmol)、甲磺酸-2-(二叔丁基膦基)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯(2-氨基-1,1'-联苯-2-基)钯(II)(0.79g,0.92mmol)和t-BuBrettPhos(0.22g,0.46mmol)，氮气置换3次，加入3,3-二氟环丁醇(1.29g,11.97mmol)和甲苯(30mL)，氮气置换3次，40℃搅拌反应21h，停止搅拌，硅藻土过滤，浓缩，硅胶拌样，用PE/EA(v/v＝99.5/0.5)洗脱液进行柱层析纯化，得到525mg黄色油状物，收率为16％。LC-MS(ESI,neg.ion)m/z:351.1[M+H]-1H NMR(599MHz,CDCl3):δ7.50(d,J＝4.1Hz,1H),6.91(s,1H),5.09–4.99(m,1H),3.22–2.97(m,2H),2.74–2.60(m,2H),1.53(s,9H).Compound M1 (3.00 g, 9.21 mmol), cesium carbonate (6.00 g, 18.42 mmol), methanesulfonic acid-2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl(2-amino-1,1'-biphenyl-2-yl)palladium(II) (0.79 g, 0.92 mmol) and t-BuBrettP were added. hos (0.22 g, 0.46 mmol), replaced with nitrogen three times, added 3,3-difluorocyclobutanol (1.29 g, 11.97 mmol) and toluene (30 mL), replaced with nitrogen three times, stirred at 40 ° C for 21 h, stopped stirring, filtered with diatomaceous earth, concentrated, mixed with silica gel, and purified by column chromatography with PE/EA (v/v=99.5/0.5) eluent to obtain 525 mg of yellow oil with a yield of 16%. LC-MS (ESI, negative ion) m/z: 351.1 [M+H] -1 H NMR (599 MHz, CDCl 3 ): δ 7.50 (d, J=4.1 Hz, 1H), 6.91 (s, 1H), 5.09-4.99 (m, 1H), 3.22-2.97 (m, 2H), 2.74-2.60 (m, 2H), 1.53 (s, 9H).
步骤2：化合物1-2的合成Step 2: Synthesis of compound 1-2
于250mL的单口瓶中，加入化合物1-1(520mg,1.47mmol)和乙腈(10mL)，0℃条件下滴加氯化氢的1,4-二氧六环溶液(2.21mL,8.82mmol,4M)，滴加后升温至室温搅拌2h，停止搅拌，浓缩，加入EA(15mL)和饱和NaHCO3溶液(20mL)，用EA(15mL×2)萃取，合并有机相并用饱和氯化钠溶液(15mL)洗涤，无水硫酸钠干燥，浓缩，真空抽干，产率按照100％计算。LC-MS(ESI,pos.ion)m/z:253.3[M+H]+；1H NMR(599MHz,CDCl3):δ5.97(d,J＝5.1Hz,1H),5.10–4.95(m,1H),4.36(s,2H),3.15–3.00(m,2H),2.72–2.59(m,2H). In a 250 mL single-necked bottle, compound 1-1 (520 mg, 1.47 mmol) and acetonitrile (10 mL) were added, and a solution of hydrogen chloride in 1,4-dioxane (2.21 mL, 8.82 mmol, 4 M) was added dropwise at 0°C. After the addition, the temperature was raised to room temperature and stirred for 2 h. Stirring was stopped, and the mixture was concentrated. EA (15 mL) and saturated NaHCO 3 solution (20 mL) were added, and the mixture was extracted with EA (15 mL × 2). The organic phases were combined and washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, concentrated, and dried under vacuum. The yield was calculated as 100%. LC-MS (ESI, pos.ion) m/z: 253.3 [M+H] + ; 1 H NMR (599 MHz, CDCl 3 ): δ 5.97 (d, J=5.1 Hz, 1H), 5.10–4.95 (m, 1H), 4.36 (s, 2H), 3.15–3.00 (m, 2H), 2.72–2.59 (m, 2H).
步骤3：化合物1-3的合成Step 3: Synthesis of Compound 1-3
于250mL的单口瓶中，加入化合物1-2(372mg,1.47mmol)、NIS(0.4g,1.76mmol)、乙腈(10mL)和对甲苯磺酸一水合物(0.02g,0.1mmol)，升温至70℃搅拌反应1h。停止加热搅拌，浓缩，加入EA(30mL)，依次用饱和NaHCO3溶液(20mL)、饱和Na2SO3溶液(20mL)和饱和氯化钠溶液(15mL)洗涤有机相，无水硫酸钠干燥有机相，浓缩，抽真空，得到黄色固体，收率按100％计算。LC-MS(ESI,pos.ion)m/z:379.00[M+H]+；1H NMR(599MHz,CDCl3):δ5.11–5.01(m,1H),4.90(s,2H),3.21–3.03(m,2H),2.79–2.69(m,2H)In a 250 mL single-necked bottle, add compound 1-2 (372 mg, 1.47 mmol), NIS (0.4 g, 1.76 mmol), acetonitrile (10 mL) and p-toluenesulfonic acid monohydrate (0.02 g, 0.1 mmol), heat to 70 ° C and stir to react for 1 h. Stop heating and stirring, concentrate, add EA (30 mL), wash the organic phase with saturated NaHCO 3 solution (20 mL), saturated Na 2 SO 3 solution (20 mL) and saturated sodium chloride solution (15 mL) in sequence, dry the organic phase with anhydrous sodium sulfate, concentrate, and evacuate to obtain a yellow solid. The yield is calculated as 100%. LC-MS (ESI, pos.ion) m/z: 379.00 [M+H] + ; 1 H NMR (599 MHz, CDCl 3 ): δ 5.11–5.01 (m, 1H), 4.90 (s, 2H), 3.21–3.03 (m, 2H), 2.79–2.69 (m, 2H)
步骤4：化合物1-4的合成Step 4: Synthesis of Compound 1-4
于200mL的高压釜中加入化合物1-3(557mg,1.47mmol)、Pd(PPh3)2Cl2(0.21g,0.29mmol)、EtOH(15mL)和三乙胺(0.74mL,5.31mmol)，依次氮气置换、CO置换，往釜内充CO，使釜内气压为2MPa，置于87℃条件下搅拌反应12h。停止反应，冷却后硅藻土过滤，浓缩，柱层析(PE/EA(v/v)＝30/1)洗脱，得到328mg黄白色固体，收率为68％。LC-MS(ESI,pos.ion)m/z:325.1[M+H]+；1H NMR(599MHz,CDCl3):δ6.46(br s,2H),5.17–5.06(m,1H),4.34(q,J＝7.1Hz,2H),3.19–3.02(m,2H),2.78–2.61(m,2H),1.39(t,J＝7.1Hz,3H).Compound 1-3 (557 mg, 1.47 mmol), Pd(PPh 3 ) 2 Cl 2 (0.21 g, 0.29 mmol), EtOH (15 mL) and triethylamine (0.74 mL, 5.31 mmol) were added to a 200 mL autoclave, and the atmosphere was replaced with nitrogen and CO in sequence. CO was added to the autoclave to make the pressure in the autoclave 2 MPa, and the reaction was stirred at 87°C for 12 h. The reaction was stopped, cooled, filtered through diatomaceous earth, concentrated, and eluted by column chromatography (PE/EA (v/v) = 30/1) to obtain 328 mg of a yellow-white solid with a yield of 68%. LC-MS (ESI, pos.ion) m/z: 325.1 [M+H] + ; 1 H NMR (599 MHz, CDCl 3 ): δ 6.46 (br s, 2H), 5.17-5.06 (m, 1H), 4.34 (q, J=7.1 Hz, 2H), 3.19-3.02 (m, 2H), 2.78-2.61 (m, 2H), 1.39 (t, J=7.1 Hz, 3H).
步骤5：化合物1-5的合成Step 5: Synthesis of Compound 1-5
于50mL的单口瓶中，加入化合物1-4(325mg,1.00mmol)、无水THF(10mL)和2,2,2-三氯乙酰基异氰酸酯(0.18mL,1.5mmol)，室温搅拌反应0.5h，停止搅拌，浓缩，抽真空，得到黄色固体，收率按100％计算。In a 50 mL single-necked bottle, compound 1-4 (325 mg, 1.00 mmol), anhydrous THF (10 mL) and 2,2,2-trichloroacetyl isocyanate (0.18 mL, 1.5 mmol) were added, and the reaction was stirred at room temperature for 0.5 h. Stirring was stopped, and the mixture was concentrated and vacuumed to obtain a yellow solid. The yield was calculated as 100%.
步骤6：化合物1-6的合成Step 6: Synthesis of Compound 1-6
于50mL的单口瓶中，加入化合物1-5(515mg,1.0mmol)、甲醇(10mL)和氨的甲醇溶液(0.71mL,5mmol,7mol/L)，室温搅拌反应0.5h，停止搅拌，浓缩，用MTBE(10mL)打浆20min，过滤，抽真空，得到281mg白色固体，收率为87％。LC-MS(ESI,neg.ion):m/z:320.2[M-H]-.Compound 1-5 (515 mg, 1.0 mmol), methanol (10 mL) and ammonia methanol solution (0.71 mL, 5 mmol, 7 mol/L) were added to a 50 mL single-mouth bottle, stirred at room temperature for 0.5 h, stopped stirring, concentrated, slurried with MTBE (10 mL) for 20 min, filtered, and vacuumed to obtain 281 mg of white solid, with a yield of 87%. LC-MS (ESI, neg.ion): m/z: 320.2 [MH] - .
步骤7：化合物1-7的合成Step 7: Synthesis of Compound 1-7
于50mL的单口瓶中，加入化合物1-6(279mg,0.87mmol)、甲苯(5mL)，三氯氧磷(0.24mL,2.61mmol)和DIPEA(0.72mL,4.35mmol)，氮气保护，升温至90℃搅拌反应1h，停止搅拌，浓缩，收率按100％计算，直接投下一步反应。In a 50 mL single-necked bottle, compound 1-6 (279 mg, 0.87 mmol), toluene (5 mL), phosphorus oxychloride (0.24 mL, 2.61 mmol) and DIPEA (0.72 mL, 4.35 mmol) were added. Under nitrogen protection, the temperature was raised to 90 °C and stirred for reaction for 1 h. Stirring was stopped and the mixture was concentrated. The yield was calculated as 100% and the mixture was directly used for the next step.
步骤8：化合物1-8的合成Step 8: Synthesis of Compound 1-8
于50mL的单口瓶中，加入化合物1-7(311mg,0.87mmol)和DCM(6mL)，氮气置换三次，-40℃加入DIPEA(0.72mL,4.35mmol)和3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯(0.18g,0.87mmol)的DCM溶液(2mL)，搅拌反应0.5h，停止搅拌，反应液加入饱和氯化铵溶液(30mL)，分液，用DCM(15mL×2)萃取，合并有机相，无水硫酸钠干燥，浓缩，硅胶拌样，用PE/EA(v/v＝8/1)洗脱液进行柱层析纯化，得到256mg黄色固体，收率为55％。LC-MS(ESI,pos.ion)m/z:534.4[M+H]+.Compound 1-7 (311 mg, 0.87 mmol) and DCM (6 mL) were added to a 50 mL single-mouth bottle, and the atmosphere was replaced with nitrogen three times. DIPEA (0.72 mL, 4.35 mmol) and tert-butyl 3,8-diazacyclo[3.2.1]octane-8-carboxylate (0.18 g, 0.87 mmol) in DCM (2 mL) were added at -40°C, and the reaction was stirred for 0.5 h. Stirring was stopped, and saturated ammonium chloride solution (30 mL) was added to the reaction solution. The mixture was separated and extracted with DCM (15 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, mixed with silica gel, and purified by column chromatography with PE/EA (v/v=8/1) eluent to obtain 256 mg of a yellow solid with a yield of 55%. LC-MS (ESI, pos.ion) m/z: 534.4 [M+H] + .
步骤9：化合物1-9的合成Step 9: Synthesis of Compound 1-9
于100mL的单口瓶中，加入化合物1-8(256mg,0.48mmol)、1,4-二氧六环(5mL)、((2R,7aS)-2-氟-六氢-1H-吡咯利嗪-7a-基)甲醇(110mg,0.72mmol)和DIPEA(0.24mL,1.44mmol)，升温至90℃搅拌反应24h，停止搅拌，浓缩，加入乙酸乙酯(40mL)，依次用饱和氯化铵溶液(20mL)和饱和氯化钠溶液(20mL) 洗涤有机相，分液，有机相无水硫酸钠干燥，浓缩，用DCM/MeOH(v/v＝12/1)洗脱液进行柱层析纯化，得到的固体用MTBE(10mL)打浆，得到144mg黄色固体，收率为45％。LC-MS(ESI,pos.ion)m/z:657.7[M+H]+.In a 100 mL single-necked bottle, compound 1-8 (256 mg, 0.48 mmol), 1,4-dioxane (5 mL), ((2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizine-7a-yl)methanol (110 mg, 0.72 mmol) and DIPEA (0.24 mL, 1.44 mmol) were added, the temperature was raised to 90 ° C and stirred for 24 h, the stirring was stopped, the mixture was concentrated, ethyl acetate (40 mL) was added, and saturated ammonium chloride solution (20 mL) and saturated sodium chloride solution (20 mL) were used in sequence. The organic phase was washed, separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM/MeOH (v/v=12/1) as eluent. The obtained solid was slurried with MTBE (10 mL) to obtain 144 mg of yellow solid with a yield of 45%. LC-MS (ESI, pos.ion) m/z: 657.7 [M+H] + .
步骤10：化合物1-10的合成Step 10: Synthesis of Compound 1-10
于25mL的两口瓶中，加入化合物1-9(139mg,0.21mmol)、M3(160mg,0.32mmol,上海思阔化学科技有限公司)、无水磷酸钾(110mg,0.53mmol)和XPhos Pd G3(36mg,0.042mmol)，氮气置换3次，加入水(1mL)和THF(4.5mL)，氮气置换3次，25℃搅拌反应17h，停止搅拌，硅藻土过滤，滤液浓缩，浓缩物中依次加入DCM(15mL)和饱和氯化铵溶液(30mL)，分液，用DCM(20mL×2)萃取水相，合并有机相，无水硫酸钠干燥，浓缩，残留物用DCM/MeOH(v/v＝98/2)洗脱液进行柱层析纯化纯化，得到211mg褐色固体，收率为99％。LC-MS(ESI,pos.ion)m/z:1008.0[M+H]+.In a 25 mL two-necked bottle, compound 1-9 (139 mg, 0.21 mmol), M3 (160 mg, 0.32 mmol, Shanghai Siko Chemical Technology Co., Ltd.), anhydrous potassium phosphate (110 mg, 0.53 mmol) and XPhos Pd G3 (36 mg, 0.042 mmol) were added, and the atmosphere was replaced with nitrogen three times. Water (1 mL) and THF (4.5 mL) were added, and the atmosphere was replaced with nitrogen three times. The reaction was stirred at 25 ° C for 17 h, and the stirring was stopped. The filtrate was filtered through diatomaceous earth, and the filtrate was concentrated. DCM (15 mL) and saturated ammonium chloride solution (30 mL) were added to the concentrate in turn, and the liquids were separated. The aqueous phase was extracted with DCM (20 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography with DCM/MeOH (v/v=98/2) as the eluent to obtain 211 mg of a brown solid with a yield of 99%. LC-MS (ESI, pos.ion) m/z: 1008.0 [M+H] + .
步骤11：化合物1-11的合成Step 11: Synthesis of Compound 1-11
于25mL的单口瓶中，加入化合物1-10(200mg,0.20mmol)和二氯甲烷(4mL)，0℃滴加氯化氢的1,4-二氧六环溶液(1mL,4mmol,4M)，升温至室温搅拌反应1h，停止搅拌，浓缩，得到200mg黄色固体，收率按照100％计算。LC-MS(ESI,pos.ion)m/z:863.4[M+H]+.In a 25 mL single-mouth bottle, add compound 1-10 (200 mg, 0.20 mmol) and dichloromethane (4 mL), add hydrogen chloride 1,4-dioxane solution (1 mL, 4 mmol, 4 M) dropwise at 0°C, heat to room temperature and stir for 1 h, stop stirring, concentrate, and obtain 200 mg of yellow solid, the yield is calculated as 100%. LC-MS (ESI, pos.ion) m/z: 863.4 [M + H] + .
步骤12：化合物1的合成Step 12: Synthesis of Compound 1
于25mL的单口瓶中，加入化合物1-11(171mg,0.20mmol)、DMF(1mL)和氟化铯(460mg,3mmol)，氮气置换3次，室温搅拌反应14h，停止搅拌，反应液用反相柱H2O/MeCN(v/v＝0-46/54)洗脱液纯化，得到64mg黄色固体，收率为45％。LC-MS(ESI,pos.ion)m/z:707.2[M+H]+；HRMS(ESI):707.2785[M+H]+；1H NMR(400MHz,CDCl3):δ7.74–7.60(m,1H),7.36–7.21(m,2H),7.20–7.08(m,1H),5.41–4.95(m,2H),4.38–4.01(m,4H),3.80–3.72(m,1H),3.65–3.27(m,6H),3.05–2.87(m,4H),2.29–1.74(m,8H),1.63–1.35(m,4H).Compound 1-11 (171 mg, 0.20 mmol), DMF (1 mL) and cesium fluoride (460 mg, 3 mmol) were added to a 25 mL single-necked bottle. The atmosphere was replaced with nitrogen three times. The reaction was stirred at room temperature for 14 h. Stirring was stopped and the reaction solution was purified with a reverse phase column using H 2 O/MeCN (v/v=0-46/54) as eluent to obtain 64 mg of a yellow solid with a yield of 45%. LC-MS (ESI, pos.ion) m/z: 707.2 [M+H] + ; HRMS (ESI): 707.2785 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ): δ7.74–7.60 (m, 1H), 7.36–7.21 (m, 2H), 7.20–7.08 (m, 1H), 5.41–4.95 (m, 2H), 4.38–4.01 (m, 4H), 3.80–3.72 (m, 1H), 3.65–3.27 (m, 6H), 3.05–2.87 (m, 4H), 2.29–1.74 (m, 8H), 1.63–1.35 (m, 4H).
实施例2：化合物2的合成

Example 2: Synthesis of Compound 2

步骤1：化合物2-1的合成Step 1: Synthesis of compound 2-1
100mL双口瓶中加入NaH(0.75g,18.6mmol,含量60％)，氮气置换3次，0℃下加入THF(20mL)和3-氟环丁烷-1-醇(0.44g,4.84mmol)，室温搅拌1h，加入M2(2.0g,3.72mmol)与THF(20mL)的混合溶液，40℃反应18h，停止反应，用5％柠檬酸水溶液调pH至5～6，EA(40mL)萃取分液，有机相干燥旋干后，柱层析(DCM/MeOH(v/v)＝49/1)洗脱，得到0.96g黄白色固体，收率为40％。LC-MS(ESI,pos.ion)m/z:322.2[M+H]+.NaH (0.75 g, 18.6 mmol, 60% content) was added to a 100 mL double-necked flask, and the atmosphere was replaced with nitrogen three times. THF (20 mL) and 3-fluorocyclobutane-1-ol (0.44 g, 4.84 mmol) were added at 0°C, and the mixture was stirred at room temperature for 1 h. A mixed solution of M2 (2.0 g, 3.72 mmol) and THF (20 mL) was added, and the mixture was reacted at 40°C for 18 h. The reaction was stopped, and the pH was adjusted to 5-6 with 5% citric acid aqueous solution. The organic phase was extracted with EA (40 mL), and the organic phase was dried and spin-dried. Column chromatography (DCM/MeOH (v/v) = 49/1) was used for elution to obtain 0.96 g of yellow-white solid, with a yield of 40%. LC-MS (ESI, pos.ion) m/z: 322.2 [M+H] + .
步骤2：化合物2-2的合成Step 2: Synthesis of compound 2-2
室温下，100mL单口瓶加入2-1(0.96g,2.98mmol)、甲苯(20mL)、三氯氧磷(1.83g,11.92mmol)和DIPEA(1.54g,11.92mmol)，100℃反应1h，45℃旋蒸除去溶剂得黑色油状产物，按100％收率计算，直接下一步反应。At room temperature, 2-1 (0.96 g, 2.98 mmol), toluene (20 mL), phosphorus oxychloride (1.83 g, 11.92 mmol) and DIPEA (1.54 g, 11.92 mmol) were added to a 100 mL single-necked bottle, and the mixture was reacted at 100 °C for 1 h. The solvent was removed by rotary evaporation at 45 °C to obtain a black oily product, which was directly used for the next step with a yield of 100%.
步骤3：化合物2-3的合成Step 3: Synthesis of compound 2-3
室温下，100mL单口瓶加入2-2(1.01g,2.98mmol)、DCM(10mL)和DIPEA(1.54g,11.92mmol)，降温至-30℃，加入8-Boc-3,8-二氮杂双环[3.2.1]辛烷(0.64g,2.98mmol)，-30℃反应0.5h。加入饱和氯化铵(20mL)淬灭，DCM(10mL)萃取分液。旋干，柱层析(PE/EA(v/v)＝9/1)洗脱，得到0.63g黄色固体，收率为41％。LC-MS(ESI,pos.ion)m/z:516.4[M+H]+.At room temperature, 2-2 (1.01 g, 2.98 mmol), DCM (10 mL) and DIPEA (1.54 g, 11.92 mmol) were added to a 100 mL single-mouth bottle, cooled to -30 °C, 8-Boc-3,8-diazabicyclo[3.2.1]octane (0.64 g, 2.98 mmol) was added, and the reaction was carried out at -30 °C for 0.5 h. Saturated ammonium chloride (20 mL) was added to quench, and DCM (10 mL) was used to extract the liquid. The mixture was spin-dried and eluted by column chromatography (PE/EA (v/v) = 9/1) to obtain 0.63 g of a yellow solid with a yield of 41%. LC-MS (ESI, pos.ion) m/z: 516.4 [M+H] + .
步骤4：化合物2-4的合成Step 4: Synthesis of compound 2-4
室温下100mL单口瓶加入2-3(0.63g,1.22mmol)、(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基]甲醇(0.29g,1.83mmol)、1,4-二氧六环(6mL)和DIPEA(0.47g,3.66mmol)，氮气置换3次，100℃反应16h，加入20mL饱和氯化铵(20mL)淬灭，EA(30mL)萃取分液，有机相旋蒸干，柱层析(PE/EA(v/v)＝1/1)洗脱，得到296mg黄色固体2-4，收率为38％。LC-MS(ESI,pos.ion)m/z:639.5[M+H]+。At room temperature, 2-3 (0.63 g, 1.22 mmol), (2R, 8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (0.29 g, 1.83 mmol), 1,4-dioxane (6 mL) and DIPEA (0.47 g, 3.66 mmol) were added to a 100 mL single-mouth bottle, and nitrogen was replaced three times. The reaction was carried out at 100 ° C for 16 h, and 20 mL of saturated ammonium chloride (20 mL) was added to quench, and EA (30 mL) was extracted and separated. The organic phase was evaporated to dryness and eluted by column chromatography (PE/EA (v/v) = 1/1) to obtain 296 mg of yellow solid 2-4, with a yield of 38%. LC-MS (ESI, pos.ion) m/z: 639.5 [M+H] + .
步骤5：化合物2-5的合成 Step 5: Synthesis of Compound 2-5
于25mL的双口瓶中加入化合物2-4(296mg,0.46mmol)、M3(470mg,0.92mmol)、Xphos Pd G3(78mg,0.094mmol)、K3PO4·7H2O(548mg,1.61mmol)和THF/H2O(3mL/0.5mL)，氮气置换三次，35℃搅拌16h，停止反应，加入饱和氯化铵溶液(5mL)，用EA(10mL×2)萃取，有机相合并后用无水硫酸钠干燥，浓缩，用DCM/MeOH(v/v＝49/1)洗脱液柱层析纯化，得到335mg黄色固体化合物2-5，产率73％。LC-MS(ESI,pos.ion)m/z:495.5[M+2H]2+.Compound 2-4 (296 mg, 0.46 mmol), M3 (470 mg, 0.92 mmol), Xphos Pd G3 (78 mg, 0.094 mmol), K 3 PO 4 ·7H 2 O (548 mg, 1.61 mmol) and THF/H 2 O (3 mL/0.5 mL) were added to a 25 mL two-necked bottle, replaced with nitrogen three times, stirred at 35°C for 16 h, the reaction was stopped, saturated ammonium chloride solution (5 mL) was added, extracted with EA (10 mL×2), the organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with DCM/MeOH (v/v=49/1) eluent to obtain 335 mg of yellow solid compound 2-5 with a yield of 73%. LC-MS (ESI, pos.ion) m/z: 495.5 [M+2H] 2+ .
步骤6：化合物2-6的合成Step 6: Synthesis of Compound 2-6
室温下加入2-5(0.335g,0.34mmol)和ACN(7mL)，降温至0℃，加入TMSOTf(0.30g,1.36mmol)，0℃反应0.5h。停止反应，加入饱和碳酸氢钠(20mL)淬灭，EA(20mL)萃取分液，有机相旋蒸干得产物黄色固体186mg，收率65％，直接用于下一步。LC-MS(ESI,pos.ion)m/z:845.7[M+H]+.Add 2-5 (0.335 g, 0.34 mmol) and ACN (7 mL) at room temperature, cool to 0 ° C, add TMSOTf (0.30 g, 1.36 mmol), and react at 0 ° C for 0.5 h. Stop the reaction, add saturated sodium bicarbonate (20 mL) to quench, extract and separate with EA (20 mL), and evaporate the organic phase to dryness to obtain 186 mg of yellow solid product with a yield of 65%, which is directly used in the next step. LC-MS (ESI, pos.ion) m/z: 845.7 [M+H] + .
步骤7：化合物2的合成Step 7: Synthesis of Compound 2
于25mL的单口瓶中加入2-6(186mg,0.22mmol)、氟化铯(165mg,1.1mmol)和DMF(2mL)，氮气置换三次，室温搅拌5h，停止反应，加入水(50mL)，析出固体，过滤得到固体粗产物，粗产物用DCM/MeOH/TEA(v/v/v＝6/1/0.2)洗脱液薄层色谱制备板纯化，得到33mg黄色固体化合物2，产率22％，LC-MS(ESI,pos.ion)m/z:689.4[M+H]+；HRMS(ESI):689.2876[M+H]+。1H NMR(400MHz,CDCl3):δ7.71–7.57(m,1H),7.30–7.15(m,2H),7.13–6.98(m,1H),5.37–4.91(m,3H),4.35–3.97(m,4H),3.76–3.68(m,1H),3.62–3.24(m,6H),3.01–2.82(m,4H),2.26–1.70(m,8H),1.61–1.36(m,4H).2-6 (186 mg, 0.22 mmol), cesium fluoride (165 mg, 1.1 mmol) and DMF (2 mL) were added to a 25 mL single-necked bottle. The atmosphere was replaced with nitrogen three times and stirred at room temperature for 5 h. The reaction was stopped and water (50 mL) was added to precipitate a solid, which was filtered to obtain a solid crude product. The crude product was purified by TLC preparation using DCM/MeOH/TEA (v/v/v=6/1/0.2) as the eluent to obtain 33 mg of yellow solid compound 2 with a yield of 22%. LC-MS (ESI, pos.ion) m/z: 689.4 [M+H] + ; HRMS (ESI): 689.2876 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 7.71–7.57 (m, 1H), 7.30–7.15 (m, 2H), 7.13–6.98 (m, 1H), 5.37–4.91 (m, 3H), 4.35–3.97 (m, 4H), 3.76–3.68 (m, 1H), 3.62–3.24 (m, 6H), 3.01–2.82 (m, 4H), 2.26–1.70 (m, 8H), 1.61–1.36 (m, 4H).
实施例3：化合物3的合成

Example 3: Synthesis of Compound 3

步骤1：化合物3-1的合成Step 1: Synthesis of compound 3-1
100mL双口瓶中加入NaH(0.75g,18.6mmol,含量60％)，氮气置换3次，0℃下加入THF(20mL)和2,2,3,3-四氟环丁醇(0.697g,4.84mmol)，室温搅拌1h，加入M2(2.0g,3.72mmol)与THF(20mL)的混合溶液，40℃反应18h，停止反应，用5％柠檬酸水溶液调pH至5～6，EA(40mL)萃取分液，有机相干燥旋干后，柱层析(DCM/MeOH(v/v)＝49/1)洗脱，得到0.98g黄白色固体，收率为35％。LC-MS(ESI,pos.ion)m/z:376.2[M+H]+.NaH (0.75 g, 18.6 mmol, 60% content) was added to a 100 mL double-necked flask, and the atmosphere was replaced with nitrogen three times. THF (20 mL) and 2,2,3,3-tetrafluorocyclobutanol (0.697 g, 4.84 mmol) were added at 0°C, and the mixture was stirred at room temperature for 1 h. A mixed solution of M2 (2.0 g, 3.72 mmol) and THF (20 mL) was added, and the mixture was reacted at 40°C for 18 h. The reaction was stopped, and the pH was adjusted to 5-6 with 5% citric acid aqueous solution. The organic phase was extracted with EA (40 mL), and the organic phase was dried and eluted by column chromatography (DCM/MeOH (v/v) = 49/1) to obtain 0.98 g of yellow-white solid with a yield of 35%. LC-MS (ESI, pos.ion) m/z: 376.2 [M+H] + .
步骤2：化合物3-2的合成Step 2: Synthesis of compound 3-2
室温下，100mL单口瓶加入3-1(0.98g,2.6mmol)、甲苯(20mL)、三氯氧磷(1.6g,10.4mmol)和DIPEA(1.34g,10.4mmol)，100℃反应1h，45℃旋蒸除去溶剂得黑色油状产物，按100％收率计算，直接下一步反应。At room temperature, 3-1 (0.98 g, 2.6 mmol), toluene (20 mL), phosphorus oxychloride (1.6 g, 10.4 mmol) and DIPEA (1.34 g, 10.4 mmol) were added to a 100 mL single-necked bottle, and the reaction was carried out at 100 °C for 1 h. The solvent was removed by rotary evaporation at 45 °C to obtain a black oily product, which was directly used for the next step of reaction based on a 100% yield.
步骤3：化合物3-3的合成Step 3: Synthesis of compound 3-3
室温下，100mL单口瓶加入3-2(1.02g,2.6mmol)、DCM(10mL)和DIPEA(1.34g,10.4mmol)，降温至-30℃，加入8-Boc-3,8-二氮杂双环[3.2.1]辛烷(0.558g,2.6mmol)，-30℃反应0.5h。加入饱和氯化铵(20mL)淬灭，DCM(10mL)萃取分液。旋干，柱层析(PE/EA(v/v)＝9/1)洗脱，得到0.638g黄色固体，收率为43％。LC-MS(ESI,pos.ion)m/z:571.3[M+H]+。At room temperature, 3-2 (1.02 g, 2.6 mmol), DCM (10 mL) and DIPEA (1.34 g, 10.4 mmol) were added to a 100 mL single-mouth bottle, cooled to -30 °C, 8-Boc-3,8-diazabicyclo[3.2.1]octane (0.558 g, 2.6 mmol) was added, and the reaction was carried out at -30 °C for 0.5 h. Saturated ammonium chloride (20 mL) was added to quench the mixture, and the mixture was extracted with DCM (10 mL). The mixture was spin-dried and eluted by column chromatography (PE/EA (v/v) = 9/1) to obtain 0.638 g of a yellow solid with a yield of 43%. LC-MS (ESI, pos.ion) m/z: 571.3 [M+H] + .
步骤4：化合物3-4的合成Step 4: Synthesis of compound 3-4
室温下100mL单口瓶加入3-3(0.638g,1.12mmol)、(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基]甲醇(0.266g,1.68mmol)、1,4-二氧六环(6mL)和DIPEA(0.43g,3.36mmol)，氮气置换3次，100℃反应18h，加入20mL饱和氯化铵(20mL)淬灭，EA(30mL)萃取分液，有机相旋蒸干，柱层析(PE/EA(v/v)＝1/1)洗脱，得到372mg黄色固体3-4，收率为48％。LC-MS(ESI,pos.ion)m/z:694.3[M+H]+. At room temperature, 3-3 (0.638 g, 1.12 mmol), (2R, 8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (0.266 g, 1.68 mmol), 1,4-dioxane (6 mL) and DIPEA (0.43 g, 3.36 mmol) were added to a 100 mL single-mouth bottle. The nitrogen was replaced three times and the reaction was carried out at 100 ° C for 18 h. 20 mL of saturated ammonium chloride (20 mL) was added to quench the reaction. The organic phase was extracted and separated by rotary evaporation and column chromatography (PE/EA (v/v) = 1/1) was used for elution to obtain 372 mg of yellow solid 3-4 with a yield of 48%. LC-MS (ESI, pos.ion) m/z: 694.3 [M+H] + .
步骤5：化合物3-5的合成Step 5: Synthesis of compound 3-5
于25mL的双口瓶中加入化合物3-4(372mg,0.537mmol)、M3(548mg,1.07mmol)、Xphos Pd G3(91mg,0.11mmol)、K3PO4·7H2O(639mg,1.88mmol)和THF/H2O(3mL/0.5mL)，氮气置换三次，35℃搅拌18h，停止反应，加入饱和氯化铵溶液(5mL)，用EA(10mL×2)萃取，有机相合并后用无水硫酸钠干燥，浓缩，用DCM/MeOH(v/v＝49/1)洗脱液柱层析纯化，得到381mg黄色固体化合物3-5，产率68％。LC-MS(ESI,pos.ion)m/z:522.2[M+2H]2+.Compound 3-4 (372 mg, 0.537 mmol), M3 (548 mg, 1.07 mmol), Xphos Pd G3 (91 mg, 0.11 mmol), K 3 PO 4 ·7H 2 O (639 mg, 1.88 mmol) and THF/H 2 O (3 mL/0.5 mL) were added to a 25 mL two-necked bottle, replaced with nitrogen three times, stirred at 35°C for 18 h, the reaction was stopped, saturated ammonium chloride solution (5 mL) was added, extracted with EA (10 mL×2), the organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with DCM/MeOH (v/v=49/1) eluent to obtain 381 mg of yellow solid compound 3-5 with a yield of 68%. LC-MS (ESI, pos.ion) m/z: 522.2 [M+2H] 2+ .
步骤6：化合物3-6的合成Step 6: Synthesis of Compound 3-6
室温下加入3-5(381mg,0.365mmol)和ACN(7mL)，降温至0℃，加入TMSOTf(0.32g,1.46mmol)，0℃反应0.5h。停止反应，加入饱和碳酸氢钠(20mL)淬灭，EA(20mL)萃取分液，有机相旋蒸干得产物黄色固体230mg，收率70％，直接用于下一步。LC-MS(ESI,pos.ion)m/z:899.5[M+H]+.Add 3-5 (381 mg, 0.365 mmol) and ACN (7 mL) at room temperature, cool to 0 ° C, add TMSOTf (0.32 g, 1.46 mmol), and react at 0 ° C for 0.5 h. Stop the reaction, add saturated sodium bicarbonate (20 mL) to quench, extract with EA (20 mL), and evaporate the organic phase to dryness to obtain 230 mg of yellow solid product with a yield of 70%, which is directly used in the next step. LC-MS (ESI, pos.ion) m/z: 899.5 [M + H] + .
步骤7：化合物3的合成Step 7: Synthesis of compound 3
于25mL的单口瓶中加入3-6(230mg,0.256mmol)、氟化铯(192mg,1.28mmol)和DMF(2mL)，氮气置换三次，室温搅拌5h，停止反应，加入50mL水，析出固体，过滤得到固体粗产物，粗产物用DCM/MeOH/TEA(v/v/v＝6/1/0.2)洗脱液薄层色谱制备板纯化，得到47mg黄色固体化合物3，产率25％，LC-MS(ESI,pos.ion)m/z:743.4[M+H]+；HRMS(ESI):743.7046[M+H]+.1H NMR(400MHz,CDCl3):δ7.72–7.58(m,1H),7.32–6.96(m,3H),5.57–4.99(m,2H),4.45–4.90(m,5H),3.81–3.26(m,6H),3.11–2.81(m,4H),2.38–1.87(m,6H),1.75–1.44(m,4H).3-6 (230 mg, 0.256 mmol), cesium fluoride (192 mg, 1.28 mmol) and DMF (2 mL) were added to a 25 mL single-necked bottle, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at room temperature for 5 h, the reaction was stopped, 50 mL of water was added, a solid was precipitated, and a solid crude product was obtained by filtration. The crude product was purified by TLC preparation using DCM/MeOH/TEA (v/v/v=6/1/0.2) as the eluent to obtain 47 mg of yellow solid compound 3 with a yield of 25%. LC-MS (ESI, pos.ion) m/z: 743.4 [M+H] + ; HRMS (ESI): 743.7046 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ):δ7.72–7.58(m,1H),7.32–6.96(m,3H),5.57–4.99(m,2H),4.45–4.90(m,5H),3.81–3.26(m,6H),3.11–2.81(m,4H),2.38–1.87(m,6H),1.75–1.44(m,4H).
实施例4：化合物4的合成
Example 4: Synthesis of Compound 4
以1-氟-3-羟基环丁腈作为原料，参考实施例2或3的方法制备得到23mg黄色固体化合物4。LC-MS(ESI,pos.ion)m/z:714.4[M+H]+；HRMS(ESI):714.2835[M+H]+.Using 1-fluoro-3-hydroxycyclobutanecarbonitrile as the raw material, 23 mg of yellow solid compound 4 was prepared according to the method of Example 2 or 3. LC-MS (ESI, pos.ion) m/z: 714.4 [M+H] + ; HRMS (ESI): 714.2835 [M+H] + .
实施例5：化合物5的合成
Example 5: Synthesis of Compound 5
以1-氟-3-羟基环丁烷-1-甲酸甲酯作为原料，参考实施例2的方法制备得到15mg黄色固体化合物5。LC-MS(ESI,pos.ion)m/z:747.6[M+H]+；HRMS(ESI):747.2902[M+H]+. Using 1-fluoro-3-hydroxycyclobutane-1-carboxylic acid methyl ester as raw material, 15 mg of yellow solid compound 5 was prepared according to the method of Example 2. LC-MS (ESI, pos.ion) m/z: 747.6 [M+H] + ; HRMS (ESI): 747.2902 [M+H] + .
实施例6：化合物6的合成
Example 6: Synthesis of Compound 6
实施例6的合成参考实施例2，以环戊醇替代3-氟环丁烷-1-醇进行合成，最终得到47mg黄色固体化合物6，LC-MS(ESI,pos.ion)m/z:685.6[M+H]+；HRMS(ESI):685.3156[M+H]+.The synthesis of Example 6 was performed with reference to Example 2, and cyclopentanol was used instead of 3-fluorocyclobutane-1-ol to obtain 47 mg of yellow solid compound 6, LC-MS (ESI, pos.ion) m/z: 685.6 [M+H] + ; HRMS (ESI): 685.3156 [M+H] + .
实施例7：化合物7的合成
Example 7: Synthesis of Compound 7
以3-环戊烯-1-醇作为原料，参考实施例2的方法制备得到50mg黄色固体化合物7。LC-MS(ESI,pos.ion)m/z:683.3[M+H]+；HRMS(ESI):683.2974[M+H]+；1H NMR(400MHz,CD3OD)δ7.91–7.84(m,1H),7.38–7.31(m,2H),7.24(s,1H),5.87–5.79(m,2H),5.66–5.50(m,1H),4.65–4.46(m,3H),4.25–4.10(m,2H),4.00–3.78(m,5H),3.49–3.42(m,2H),2.88–2.62(m,6H),2.60–2.42(m,2H),2.39–2.15(m,4H),2.12–1.98(m,4H).19F NMR(376MHz,CD3OD)δ-111.88(1F),-151.17(1F),-174.01(1F).Using 3-cyclopenten-1-ol as the raw material, 50 mg of yellow solid compound 7 was prepared according to the method of Example 2. LC-MS (ESI, pos.ion) m/z: 683.3 [M+H] + ; HRMS (ESI): 683.2974 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ7.91–7.84 (m, 1H), 7.38–7.31 (m, 2H), 7.24 (s, 1H), 5.87–5.79 (m, 2H), 5.66–5.50 (m, 1H), 4.65–4.46 (m, 3H), 4.25–4.10 (m, 2H), 4.00–3.78 (m, 5H), 3.49–3.42 (m, 2H), 2.88–2.62 (m, 6H), 2.60–2.42 (m, 2H), 2.39–2.15 (m, 4H), 2.12–1.98 (m, 4H). 19 F NMR (376 MHz, CD 3 OD) δ -111.88 (1F), -151.17 (1F), -174.01 (1F).
实施例8：化合物8的合成
Example 8: Synthesis of Compound 8
以3,3-二氟环戊烷-1-醇作为原料，参考实施例2的方法得到36mg黄色固体化合物8。LC-MS(ESI,pos.ion)m/z:721.4[M+H]+；HRMS(ESI):721.2904[M+H]+.Using 3,3-difluorocyclopentane-1-ol as the raw material, 36 mg of yellow solid compound 8 was obtained by referring to the method of Example 2. LC-MS (ESI, pos.ion) m/z: 721.4 [M+H] + ; HRMS (ESI): 721.2904 [M+H] + .
实施例9：化合物9的合成
Example 9: Synthesis of Compound 9
实施例9的合成参考实施例2，以3-羟基环戊酮替代3-氟环丁烷-1-醇进行合成，最终得到21mg黄色固体化合物9，LC-MS(ESI,pos.ion)m/z:699.5[M+H]+；HRMS(ESI):699.2935[M+H]+.The synthesis of Example 9 was performed by referring to Example 2, and 3-hydroxycyclopentanone was used instead of 3-fluorocyclobutane-1-ol to obtain 21 mg of yellow solid compound 9, LC-MS (ESI, pos.ion) m/z: 699.5 [M+H] + ; HRMS (ESI): 699.2935 [M+H] + .
实施例10：化合物10的合成
Example 10: Synthesis of Compound 10
实施例10的合成参考实施例2，以1-甲基环戊醇替代3-氟环丁烷-1-醇进行合成，最终得到32mg黄色固体化合物10。LC-MS(ESI,pos.ion)m/z:699.5[M+H]+；HRMS(ESI):699.3250[M+H]+.The synthesis of Example 10 was performed by referring to Example 2, and 1-methylcyclopentanol was used instead of 3-fluorocyclobutane-1-ol to obtain 32 mg of yellow solid compound 10. LC-MS (ESI, pos.ion) m/z: 699.5 [M+H] + ; HRMS (ESI): 699.3250 [M+H] + .
实施例11：化合物11的合成
Example 11: Synthesis of Compound 11
实施例11的合成参考实施例2，以双环[3.1.0]己-3-醇替代3-氟环丁烷-1-醇进行合成，最终得到45mg黄色固体化合物11，LC-MS(ESI,pos.ion)m/z:697.5[M+H]+；HRMS(ESI):697.3124[M+H]+.The synthesis of Example 11 was carried out with reference to Example 2, and bicyclo[3.1.0]hexan-3-ol was substituted for 3-fluorocyclobutane-1-ol to obtain 45 mg of yellow solid compound 11, LC-MS (ESI, pos.ion) m/z: 697.5 [M+H] + ; HRMS (ESI): 697.3124 [M+H] + .
实施例12：化合物12的合成
Example 12: Synthesis of Compound 12
实施例12的合成参考实施例2，以2-茚醇替代3-氟环丁烷-1-醇进行合成，最终得到30mg黄色固体化合物12，LC-MS(ESI,pos.ion)m/z:733.5[M+H]+；HRMS(ESI):733.3136[M+H]+. The synthesis of Example 12 was carried out in accordance with Example 2, with 2-indanol replacing 3-fluorocyclobutane-1-ol, and finally 30 mg of yellow solid compound 12 was obtained, LC-MS (ESI, pos.ion) m/z: 733.5 [M+H] + ; HRMS (ESI): 733.3136 [M+H] + .
实施例13：化合物13的合成
Example 13: Synthesis of Compound 13
实施例13的合成参考实施例2，以环己醇替代3-氟环丁烷-1-醇进行合成，最终得到40mg黄色固体化合物13，LC-MS(ESI,pos.ion)m/z:699.5[M+H]+；HRMS(ESI):699.3246[M+H]+.The synthesis of Example 13 was carried out in accordance with Example 2, with cyclohexanol replacing 3-fluorocyclobutane-1-ol, and finally 40 mg of yellow solid compound 13 was obtained, LC-MS (ESI, pos.ion) m/z: 699.5 [M+H] + ; HRMS (ESI): 699.3246 [M+H] + .
实施例14：化合物14的合成
Example 14: Synthesis of Compound 14
实施例14的合成参考实施例2，以苯酚替代3-氟环丁烷-1-醇进行合成，最终得到20mg黄色固体化合物14，LC-MS(ESI,pos.ion)m/z:693.0[M+H]+；HRMS(ESI):693.2788[M+H]+.The synthesis of Example 14 was carried out in accordance with Example 2, with phenol replacing 3-fluorocyclobutane-1-ol, and finally 20 mg of yellow solid compound 14 was obtained, LC-MS (ESI, pos.ion) m/z: 693.0 [M+H] + ; HRMS (ESI): 693.2788 [M+H] + .
实施例15：化合物15的合成
Example 15: Synthesis of Compound 15
实施例15的合成参考实施例2，以3-羟基吡啶替代3-氟环丁烷-1-醇进行合成，最终得到10mg黄色固体化合物15，LC-MS(ESI,pos.ion)m/z:694.2[M+H]+；HRMS(ESI):694.2732[M+H]+.The synthesis of Example 15 was carried out in accordance with Example 2, with 3-hydroxypyridine replacing 3-fluorocyclobutane-1-ol, and finally 10 mg of yellow solid compound 15 was obtained, LC-MS (ESI, pos.ion) m/z: 694.2 [M+H] + ; HRMS (ESI): 694.2732 [M+H] + .
实施例16：化合物16的合成

Example 16: Synthesis of Compound 16

步骤1：化合物16-1的合成Step 1: Synthesis of compound 16-1
于25mL的双口瓶中加入化合物1-9(300mg,0.47mmol)、2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(338mg,0.94mmol)、Xphos Pd G3(80mg,0.094mmol)、K3PO4·7H2O(480mg,1.41mmol)和THF/H2O(3mL/0.5mL)，氮气置换三次，35℃搅拌18h，停止反应，加入饱和氯化铵溶液(5mL)，用EA(10mL×2)萃取，有机相合并后用无水硫酸钠干燥，浓缩，用DCM/MeOH(v/v＝49/1)洗脱液柱层析纯化，得到273mg黄色固体化合物16-1，产率68％。LC-MS(ESI,pos.ion)m/z:855.5[M+H]+.Compound 1-9 (300 mg, 0.47 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (338 mg, 0.94 mmol), Xphos Pd G3 (80 mg, 0.094 mmol), K 3 PO 4 ·7H 2 O (480 mg, 1.41 mmol) and THF/H 2 O (3 mL/0.5 mL) were added to a 25 mL two-necked flask, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at 35° C. for 18 h to stop the reaction, and saturated ammonium chloride solution (5 mL) was added. The mixture was extracted with EA (10 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM/MeOH (v/v=49/1) as the eluent to obtain 273 mg of yellow solid compound 16-1 with a yield of 68%. LC-MS (ESI, pos.ion) m/z: 855.5 [M+H] + .
步骤2：化合物16的合成Step 2: Synthesis of compound 16
室温下加入16-1(273mg,0.32mmol)和ACN(6mL)，降温至0℃，加入TMSOTf(0.35g,1.6mmol)，0℃反应0.5h。停止反应，加入饱和碳酸氢钠(20mL)淬灭，EA(20mL)萃取分液，有机相旋蒸干得产物黄色固体，粗产物用DCM/MeOH/TEA(v/v/v＝6/1/0.2)洗脱液薄层色谱制备板纯化，得到33mg黄色固体化合物16，产率14.5％，LC-MS(ESI,pos.ion)m/z:711.4[M+H]+；HRMS(ESI):711.3076[M+H]+；16-1 (273 mg, 0.32 mmol) and ACN (6 mL) were added at room temperature, the temperature was lowered to 0°C, TMSOTf (0.35 g, 1.6 mmol) was added, and the reaction was continued at 0°C for 0.5 h. The reaction was stopped, saturated sodium bicarbonate (20 mL) was added to quench, EA (20 mL) was used to extract and separate the liquids, and the organic phase was evaporated to dryness to obtain a yellow solid product. The crude product was purified by TLC preparation plate with DCM/MeOH/TEA (v/v/v=6/1/0.2) eluent to obtain 33 mg of yellow solid compound 16, with a yield of 14.5%, LC-MS (ESI, pos.ion) m/z: 711.4 [M+H] + ; HRMS (ESI): 711.3076 [M+H] + ;
实施例17：化合物17的合成
Example 17: Synthesis of Compound 17
步骤1：化合物17-1的合成Step 1: Synthesis of compound 17-1
于25mL的双口瓶中加入化合物1-9(300mg,0.47mmol)、2-(8-氯-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(327mg,0.94mmol)、Xphos Pd G3(80mg,0.094mmol)、K3PO4·7H2O(480mg,1.41mmol)和THF/H2O(3mL/0.5mL)，氮气置换三次，35℃搅拌20h，停止反应，加入饱和氯化铵溶液(5mL)，用EA(10mL×2)萃取，有机相合并后用无水硫酸钠干燥，浓缩，用DCM/MeOH(v/v＝49/1)洗脱液柱层析纯化，得到242mg黄色固体化合物17-1，产率61％。LC-MS(ESI,pos.ion)m/z:843.5[M+H]+. 步骤2：化合物17的合成Compound 1-9 (300 mg, 0.47 mmol), 2-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (327 mg, 0.94 mmol), Xphos Pd G3 (80 mg, 0.094 mmol), K 3 PO 4 ·7H 2 O (480 mg, 1.41 mmol) and THF/H 2 O (3 mL/0.5 mL) were added to a 25 mL two-necked flask, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at 35° C. for 20 h to stop the reaction, and saturated ammonium chloride solution (5 mL) was added. The mixture was extracted with EA (10 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM/MeOH (v/v=49/1) as the eluent to obtain 242 mg of yellow solid compound 17-1 with a yield of 61%. LC-MS (ESI, pos.ion) m/z: 843.5 [M+H] + . Step 2: Synthesis of compound 17
室温下加入17-1(242mg,0.287mmol)和ACN(6mL)，降温至0℃，加入TMSOTf(0.32g,1.4mmol)，0℃反应0.5h。停止反应，加入20mL饱和碳酸氢钠(20mL)淬灭，EA(20mL)萃取分液，有机相旋蒸干得产物黄色固体，粗产物用DCM/MeOH/TEA(v/v/v＝6/1/0.2)洗脱液薄层色谱制备板纯化，得到24mg黄色固体化合物17，产率12％，LC-MS(ESI,pos.ion)m/z:699.4[M+H]+；HRMS(ESI):699.2486[M+H]+.17-1 (242 mg, 0.287 mmol) and ACN (6 mL) were added at room temperature, the temperature was lowered to 0°C, TMSOTf (0.32 g, 1.4 mmol) was added, and the reaction was continued at 0°C for 0.5 h. The reaction was stopped, quenched by adding 20 mL of saturated sodium bicarbonate (20 mL), extracted with EA (20 mL), and the organic phase was evaporated to dryness to obtain a yellow solid product. The crude product was purified by TLC preparation using DCM/MeOH/TEA (v/v/v=6/1/0.2) as eluent to obtain 24 mg of yellow solid compound 17 with a yield of 12%. LC-MS (ESI, pos.ion) m/z: 699.4 [M+H] + ; HRMS (ESI): 699.2486 [M+H] + .
实施例18：化合物18的合成
Example 18: Synthesis of Compound 18
步骤1：化合物18-1的合成Step 1: Synthesis of compound 18-1
于25mL的双口瓶中加入化合物1-9(300mg,0.47mmol)、2-(8-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(312mg,0.94mmol)、Xphos Pd G3(80mg,0.094mmol)、K3PO4·7H2O(480mg,1.41mmol)和THF/H2O(3mL/0.5mL)，氮气置换三次，35℃搅拌20h，停止反应，加入饱和氯化铵溶液(5mL)，用EA(10mL×2)萃取，有机相合并后用无水硫酸钠干燥，浓缩，用DCM/MeOH(v/v＝49/1)洗脱液柱层析纯化，得到276mg黄色固体化合物18-1，产率71％。LC-MS(ESI,pos.ion)m/z:827.7[M+H]+.步骤2：化合物18的合成Compound 1-9 (300 mg, 0.47 mmol), 2-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (312 mg, 0.94 mmol), Xphos Pd G3 (80 mg, 0.094 mmol), K 3 PO 4 ·7H 2 O (480 mg, 1.41 mmol) and THF/H 2 O (3 mL/0.5 mL) were added to a 25 mL two-necked flask, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at 35° C. for 20 h to stop the reaction, and saturated ammonium chloride solution (5 mL) was added. The mixture was extracted with EA (10 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM/MeOH (v/v=49/1) as the eluent to obtain 276 mg of yellow solid compound 18-1 with a yield of 71%. LC-MS (ESI, pos.ion) m/z: 827.7 [M+H] + . Step 2: Synthesis of compound 18
室温下加入18-1(276mg,0.33mmol)，ACN(6mL)，降温至0℃，加入TMSOTf(0.38g,1.65mmol)，0℃反应0.5h。停止反应，加入20mL饱和碳酸氢钠淬灭，20mL EA萃取分液，有机相旋蒸干得产物黄色固体，粗产物用DCM/MeOH/TEA(v/v/v＝6/1/0.2)洗脱液薄层色谱制备板纯化，得到49mg黄色固体化合物17，产率22％，LC-MS(ESI,pos.ion)m/z:683.5[M+H]+；HRMS(ESI):683.2781[M+H]+.18-1 (276 mg, 0.33 mmol) and ACN (6 mL) were added at room temperature, the temperature was lowered to 0°C, TMSOTf (0.38 g, 1.65 mmol) was added, and the reaction was continued at 0°C for 0.5 h. The reaction was stopped, quenched with 20 mL of saturated sodium bicarbonate, extracted with 20 mL of EA, and the organic phase was evaporated to dryness to obtain a yellow solid product. The crude product was purified by TLC preparation using DCM/MeOH/TEA (v/v/v=6/1/0.2) as eluent to obtain 49 mg of yellow solid compound 17 with a yield of 22%. LC-MS (ESI, pos.ion) m/z: 683.5 [M+H] + ; HRMS (ESI): 683.2781 [M+H] + .
实施例19：化合物19的合成
Example 19: Synthesis of Compound 19
实施例19的合成参考实施例16，以叔丁基(3-氰基-7-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯并[b]噻吩-2-基)氨基甲酸酯替代2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷进行合成，最终得到12mg黄色固体化合物19，LC-MS(ESI,pos.ion)m/z:713.4[M+H]+；HRMS(ESI):713.2424[M+H]+.Synthesis of Example 19 Referring to Example 16, tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzo[b]thiophene-2-yl)carbamate was used to replace 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for synthesis, and finally 12 mg of yellow solid compound 19 was obtained, LC-MS (ESI, pos.ion) m/z: 713.4 [M+H] + ; HRMS (ESI): 713.2424 [M+H] + .
实施例20：化合物20的合成
Example 20: Synthesis of Compound 20
实施例20的合成参考实施例16中的各步骤，以2-(叔丁氧基羰基氨基)-7-氟-1,3-苯并噻唑-4-基]硼酸替代2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷进行合成，最终得到15mg黄色固体化合物20，LC-MS(ESI,pos.ion)m/z:689.2[M+H]+；HRMS(ESI):689.2468[M+H]+.Synthesis of Example 20 Referring to the steps in Example 16, 2-(tert-butoxycarbonylamino)-7-fluoro-1,3-benzothiazol-4-yl]boric acid was used instead of 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane to synthesize, and finally 15 mg of yellow solid compound 20 was obtained, LC-MS (ESI, pos.ion) m/z: 689.2 [M+H] + ; HRMS (ESI): 689.2468 [M+H] + .
实施例21：化合物21的合成
Example 21: Synthesis of Compound 21
步骤1：化合物21-1的合成Step 1: Synthesis of compound 21-1
于100mL的单口瓶中，加入化合物1-8(200mg,0.37mmol)、1,4-二氧六环(4mL)、(六氢-1H-吡咯啉-7a-基)甲醇(78mg,0.55mmol)和DIPEA(0.18mL,1.11mmol)，升温至100℃搅拌反应24h，停止搅拌， 浓缩，加入乙酸乙酯(40mL)，依次用饱和氯化铵溶液(20mL)和饱和氯化钠溶液(20mL)洗涤有机相，分液，有机相无水硫酸钠干燥，浓缩，用DCM/MeOH(v/v＝12/1)洗脱液进行柱层析纯化，得到130mg黄色固体，收率为51％。LC-MS(ESI,pos.ion)m/z:639.4[M+H]+.In a 100 mL single-necked bottle, compound 1-8 (200 mg, 0.37 mmol), 1,4-dioxane (4 mL), (hexahydro-1H-pyrrolidine-7a-yl)methanol (78 mg, 0.55 mmol) and DIPEA (0.18 mL, 1.11 mmol) were added, the temperature was raised to 100 °C and stirred for 24 h, and the stirring was stopped. Concentrate, add ethyl acetate (40 mL), wash the organic phase with saturated ammonium chloride solution (20 mL) and saturated sodium chloride solution (20 mL) in sequence, separate the liquids, dry the organic phase over anhydrous sodium sulfate, concentrate, and purify by column chromatography using DCM/MeOH (v/v=12/1) as eluent to obtain 130 mg of a yellow solid with a yield of 51%. LC-MS (ESI, pos.ion) m/z: 639.4 [M+H] + .
步骤2：化合物21-2的合成Step 2: Synthesis of compound 21-2
于25mL的两口瓶中，加入化合物21-1(130mg,0.20mmol)、M3(160mg,0.32mmol,上海思阔化学科技有限公司)、无水磷酸钾(110mg,0.53mmol)和XPhos Pd G3(36mg,0.042mmol)，氮气置换3次，加入水(1mL)和THF(4.5mL)，氮气置换3次，35℃搅拌反应20h，停止搅拌，硅藻土过滤，滤液浓缩，浓缩物中依次加入DCM(15mL)和饱和氯化铵溶液(30mL)，分液，用DCM(20mL×2)萃取水相，合并有机相，无水硫酸钠干燥，浓缩，残留物用DCM/MeOH(v/v＝98/2)洗脱液进行柱层析纯化纯化，得到148mg褐色固体，收率为75％。LC-MS(ESI,pos.ion)m/z:989.6[M+H]+.In a 25 mL two-necked bottle, compound 21-1 (130 mg, 0.20 mmol), M3 (160 mg, 0.32 mmol, Shanghai Siko Chemical Technology Co., Ltd.), anhydrous potassium phosphate (110 mg, 0.53 mmol) and XPhos Pd G3 (36 mg, 0.042 mmol) were added, and the atmosphere was replaced with nitrogen three times. Water (1 mL) and THF (4.5 mL) were added, and the atmosphere was replaced with nitrogen three times. The reaction was stirred at 35 ° C for 20 h, and the stirring was stopped. The filtrate was filtered through diatomaceous earth, and the filtrate was concentrated. DCM (15 mL) and saturated ammonium chloride solution (30 mL) were added to the concentrate in turn, and the liquids were separated. The aqueous phase was extracted with DCM (20 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography with DCM/MeOH (v/v＝98/2) as the eluent to obtain 148 mg of a brown solid with a yield of 75%. LC-MS (ESI, pos.ion) m/z: 989.6 [M+H] + .
步骤3：化合物21-3的合成Step 3: Synthesis of compound 21-3
于25mL的单口瓶中，加入化合物21-2(148mg,0.15mmol)和二氯甲烷(4mL)，0℃滴加氯化氢的1,4-二氧六环溶液(0.75mL,3mmol,4M)，升温至室温搅拌反应1h，停止搅拌，浓缩，得到150mg黄色固体，收率按照100％计算。LC-MS(ESI,pos.ion)m/z:845.2[M+H]+.Compound 21-2 (148 mg, 0.15 mmol) and dichloromethane (4 mL) were added to a 25 mL single-mouth bottle, and a solution of hydrogen chloride in 1,4-dioxane (0.75 mL, 3 mmol, 4 M) was added dropwise at 0°C. The mixture was heated to room temperature and stirred for 1 h. Stirring was stopped and the mixture was concentrated to obtain 150 mg of a yellow solid. The yield was calculated as 100%. LC-MS (ESI, pos.ion) m/z: 845.2 [M+H] + .
步骤4：化合物21的合成Step 4: Synthesis of compound 21
于25mL的单口瓶中，加入化合物21-3(127mg,0.20mmol)、DMF(1mL)和氟化铯(460mg,3mmol)，氮气置换3次，室温搅拌反应16h，停止搅拌，反应液用反相柱H2O/MeCN(v/v＝0-46/54)洗脱液纯化，得到34mg黄色固体，收率为25％。LC-MS(ESI,pos.ion)m/z:689.5[M+H]+；HRMS(ESI):689.2850[M+H]+；Compound 21-3 (127 mg, 0.20 mmol), DMF (1 mL) and cesium fluoride (460 mg, 3 mmol) were added to a 25 mL single-mouth bottle, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at room temperature for 16 h, and the stirring was stopped. The reaction solution was purified by reverse phase column H 2 O/MeCN (v/v=0-46/54) eluent to obtain 34 mg of a yellow solid with a yield of 25%. LC-MS (ESI, pos.ion) m/z: 689.5 [M+H] + ; HRMS (ESI): 689.2850 [M+H] + ;
实施例22：化合物22的合成
Example 22: Synthesis of Compound 22
实施例22的合成参考实施例21，以N-甲基-L-脯氨醇替代(六氢-1H-吡咯啉-7a-基)甲醇进行合成，最终得到18mg黄色固体化合物22，LC-MS(ESI,pos.ion)m/z:663.5[M+H]+；HRMS(ESI):663.2730[M+H]+.The synthesis of Example 22 was performed with reference to Example 21, and N-methyl-L-prolinol was used instead of (hexahydro-1H-pyrroline-7a-yl)methanol to obtain 18 mg of yellow solid compound 22. LC-MS (ESI, pos.ion) m/z: 663.5 [M+H] + ; HRMS (ESI): 663.2730 [M+H] + .
实施例23：化合物23的合成
Example 23: Synthesis of Compound 23
实施例23的合成参考实施例21，以N-甲基-D-脯氨醇替代(六氢-1H-吡咯啉-7a-基)甲醇进行合成，最终得到10mg黄色固体化合物23，LC-MS(ESI,pos.ion)m/z:663.6[M+H]+；HRMS(ESI):663.2715[M+H]+.The synthesis of Example 23 was performed with reference to Example 21, and N-methyl-D-prolinol was used instead of (hexahydro-1H-pyrroline-7a-yl)methanol to obtain 10 mg of yellow solid compound 23. LC-MS (ESI, pos.ion) m/z: 663.6 [M+H] + ; HRMS (ESI): 663.2715 [M+H] + .
实施例24：化合物24的合成
Example 24: Synthesis of Compound 24
实施例24的合成参考实施例21，以{1-[(二甲氨基)甲基]环丙基}甲醇替代(六氢-1H-吡咯啉-7a-基)甲醇进行合成，最终得到9mg黄色固体化合物23，LC-MS(ESI,pos.ion)m/z:677.3[M+H]+；HRMS(ESI):677.2869[M+H]+.The synthesis of Example 24 was performed with reference to Example 21, and (hexahydro-1H-pyrrolidine-7a-yl)methanol was substituted with {1-[(dimethylamino)methyl]cyclopropyl}methanol to obtain 9 mg of yellow solid compound 23. LC-MS (ESI, pos.ion) m/z: 677.3 [M+H] + ; HRMS (ESI): 677.2869 [M+H] + .
实施例25：化合物25的合成
Example 25: Synthesis of Compound 25
实施例25的合成参考实施例21，以[1-(吗啉-4-基甲基)环丙基]甲醇替代(六氢-1H-吡咯啉-7a-基)甲醇进行合成，最终得到16mg黄色固体化合物25，LC-MS(ESI,pos.ion)m/z:719.5[M+H]+；HRMS(ESI):719.2985[M+H]+.Synthesis of Example 25 Referring to Example 21, [1-(morpholin-4-ylmethyl)cyclopropyl]methanol was substituted for (hexahydro-1H-pyrrolidine-7a-yl)methanol to obtain 16 mg of yellow solid compound 25, LC-MS (ESI, pos.ion) m/z: 719.5 [M+H] + ; HRMS (ESI): 719.2985 [M+H] + .
实施例26：化合物26的合成
Example 26: Synthesis of Compound 26
实施例26的合成参考实施例21，以(2,6-二亚甲基四氢-1H-吡咯啉-7a(5H)-基)甲醇替代(六氢-1H-吡咯啉-7a-基)甲醇进行合成，最终得到8mg黄色固体化合物26，LC-MS(ESI,pos.ion)m/z:713.6[M+H]+；HRMS(ESI):713.2856[M+H]+.The synthesis of Example 26 was performed with reference to Example 21, and (2,6-dimethyltetrahydro-1H-pyrroline-7a(5H)-yl)methanol was substituted for (hexahydro-1H-pyrroline-7a-yl)methanol to obtain 8 mg of yellow solid compound 26. LC-MS (ESI, pos.ion) m/z: 713.6 [M+H] + ; HRMS (ESI): 713.2856 [M+H] + .
活性测试实施例Activity Test Example
一、KRAS G12D/cRAF结合实验1. KRAS G12D/cRAF binding experiment
实验步骤：Experimental steps:
(1)用DMSO配制化合物，并用DMSO对化合物进行3倍梯度稀释。 (1) Compounds were prepared with DMSO and diluted 3-fold in series with DMSO.
(2)往384孔板中加入0.1μl梯度稀释的化合物。(2) Add 0.1 μl of serially diluted compounds to a 384-well plate.
(3)继续往384孔板中加入5μl特定浓度的Tag2-KRASG12D&GTP，1000rpm离心1分钟。(3) Add 5 μl of specific concentration of Tag2-KRASG12D&GTP to the 384-well plate and centrifuge at 1000 rpm for 1 minute.
(4)继续往384孔板中加入5μl特定浓度的Tag1-cRAF，1000rpm离心1分钟。(4) Add 5 μl of Tag1-cRAF of a specific concentration to the 384-well plate and centrifuge at 1000 rpm for 1 minute.
(5)25℃孵育15分钟。(5) Incubate at 25°C for 15 minutes.
(6)继续往384孔板中加入10μl的anti-Tag1-Tb3+和anti-Tag2-XL665的混合物。(6) Add 10 μl of the mixture of anti-Tag1-Tb 3+ and anti-Tag2-XL665 to the 384-well plate.
(7)1000rpm离心1分钟，4℃孵育3小时。(7) Centrifuge at 1000 rpm for 1 minute and incubate at 4°C for 3 hours.
(8)酶标仪读取665/615nm比值。(8) Read the 665/615 nm ratio using an ELISA reader.
(9)数据分析：化合物浓度的log值为横坐标，以665/615nm比值为纵坐标，应用GraphPad Prism 8.0软件对数据进行分析并计算IC50值，具体实验结果参见表1。(9) Data analysis: The log value of the compound concentration was used as the horizontal axis, and the 665/615 nm ratio was used as the vertical axis. GraphPad Prism 8.0 software was used to analyze the data and calculate the IC50 value. The specific experimental results are shown in Table 1.
二、KRAS G12D/SOS1结合实验2. KRAS G12D/SOS1 binding experiment
实验步骤：Experimental steps:
(1)用DMSO配制化合物，并用DMSO对化合物进行3倍梯度稀释。(1) Compounds were prepared with DMSO and diluted 3-fold in series with DMSO.
(2)往384孔板中加入0.1μl梯度稀释的化合物。(2) Add 0.1 μl of serially diluted compounds to a 384-well plate.
(3)继续往384孔板中加入5μl特定浓度的Tag2-KRASG12D&GTP，1000rpm离心1分钟。(3) Add 5 μl of specific concentration of Tag2-KRASG12D&GTP to the 384-well plate and centrifuge at 1000 rpm for 1 minute.
(4)继续往384孔板中加入5μl特定浓度的Tag1-SOS1，1000rpm离心1分钟。(4) Add 5 μl of Tag1-SOS1 of a specific concentration to the 384-well plate and centrifuge at 1000 rpm for 1 minute.
(5)25℃孵育15分钟。(5) Incubate at 25°C for 15 minutes.
(6)继续往384孔板中加入10μl的anti-Tag1-Tb3+和anti-Tag2-XL665的混合物。(6) Add 10 μl of the mixture of anti-Tag1-Tb 3+ and anti-Tag2-XL665 to the 384-well plate.
(7)1000rpm离心1分钟，4℃孵育3小时。(7) Centrifuge at 1000 rpm for 1 minute and incubate at 4°C for 3 hours.
(8)酶标仪读取665/615nm比值。(8) Read the 665/615 nm ratio using an ELISA reader.
(9)数据分析：以化合物浓度的log值为横坐标，以665/615nm比值为纵坐标，应用GraphPad Prism 8.0软件对数据进行分析并计算IC50值，具体实验结果参见表1。(9) Data analysis: The log value of the compound concentration was used as the horizontal axis and the 665/615 nm ratio was used as the vertical axis. GraphPad Prism 8.0 software was used to analyze the data and calculate the IC50 value. The specific experimental results are shown in Table 1.
三、In-cell Western方法检测化合物对细胞内pERK的抑制作用：3. In-cell Western method to detect the inhibitory effect of compounds on intracellular pERK:
实验步骤：Experimental steps:
(1)第一天，用含10％胎牛血清的1640培养基复苏AGS细胞；(1) On the first day, AGS cells were revived using 1640 medium containing 10% fetal bovine serum;
(2)第二天，用PBS润洗一次细胞，加入预热的胰酶，放入37℃的5％CO2培养箱消化3分钟；加入适量1640完全培养液(含10％胎牛血清)终止消化，并将其转移至离心管中，1000rpm离心5分钟。(2) On the next day, rinse the cells once with PBS, add preheated trypsin, and place in a 37°C 5% CO2 incubator for digestion for 3 minutes; add an appropriate amount of 1640 complete culture medium (containing 10% fetal bovine serum) to terminate digestion, transfer the cells to a centrifuge tube, and centrifuge at 1000 rpm for 5 minutes.
(3)用完全培养液重悬细胞，计数。(3) Resuspend the cells in complete culture medium and count them.
(4)用完全培养液调整至合适的细胞浓度，将细胞加入96孔板中，放入37℃的5％CO2培养箱孵育过夜。(4) Adjust the cell concentration to an appropriate level with complete culture medium, add the cells to a 96-well plate, and incubate in a 37°C 5% CO 2 incubator overnight.
(5)第三天，配制10×梯度稀释的化合物。(5) On the third day, 10× serial dilutions of the compounds were prepared.
(6)取10μl配制好的10×梯度稀释化合物加入96孔板中，放入37℃的5％CO2培养箱中孵育3小时。(6) Take 10 μl of the prepared 10× gradient dilution compound and add it to a 96-well plate, and incubate it in a 37°C 5% CO 2 incubator for 3 hours.
(7)取出96孔板，弃孔中液体，每孔加入100μl的4％多聚甲醛固定细胞30分钟以上。(7) Take out the 96-well plate, discard the liquid in the wells, and add 100 μl of 4% paraformaldehyde to each well to fix the cells for more than 30 minutes.
(8)用含1％的trizol-x100的PBS洗液洗涤3次，每次5分钟。(8) Wash three times with PBS containing 1% trizol-x100, each time for 5 minutes.
(9)加入封闭液，室温，300rpm振荡1小时。(9) Add blocking solution and shake at 300 rpm for 1 hour at room temperature.
(10)弃封闭液，加入一抗，4℃孵育过夜。(10) Discard the blocking solution, add primary antibody, and incubate at 4°C overnight.
(11)第四天，将96孔板放置振板器上300rpm室温振荡30分钟。(11) On the fourth day, place the 96-well plate on a plate shaker and shake at 300 rpm at room temperature for 30 minutes.
(12)弃一抗，用TBST洗3次，每次5分钟。 (12) Discard the primary antibody and wash the membrane three times with TBST, 5 minutes each time.
(13)弃TBST，加入二抗，室温，避光，300rpm振荡1小时。(13) Discard TBST, add secondary antibody, shake at 300 rpm for 1 hour at room temperature in the dark.
(14)弃二抗，用TBST洗3次，每次5分钟。(14) Discard the secondary antibody and wash the membrane three times with TBST, 5 minutes each time.
(15)用Odyssey CLx扫描96孔板。(15) Scan 96-well plates using Odyssey CLx.
(16)数据分析：(16) Data analysis:
a)相对信号值＝(目的蛋白对应通道的信号值/内参蛋白对应通道的信号值)×10000a) Relative signal value = (signal value of the channel corresponding to the target protein/signal value of the channel corresponding to the internal reference protein) × 10000
b)抑制率＝100-(化合物孔值/空白值)×100b) Inhibition rate = 100-(compound well value/blank value) × 100
c)以化合物浓度的log值为横坐标，以抑制率为纵坐标，应用GraphPad Prism 5.0软件对数据进行分析并计算IC50值，具体实验结果参见表2。c) The log value of the compound concentration was taken as the horizontal axis and the inhibition rate was taken as the vertical axis. GraphPad Prism 5.0 software was used to analyze the data and calculate the IC50 value. The specific experimental results are shown in Table 2.
表1化合物对KRAS G12D-GTP/cRAF以及KRAS G12D-GTP/SOS1的竞争性结合作用
Table 1 Competitive binding of compounds to KRAS G12D-GTP/cRAF and KRAS G12D-GTP/SOS1
由表1可知，本发明化合物能够有效地与KRAS G12D-GTP结合，阻碍KRAS与cRAF及SOS1蛋白的结合。As can be seen from Table 1, the compounds of the present invention can effectively bind to KRAS G12D-GTP, inhibiting the binding of KRAS to cRAF and SOS1 proteins.
表2化合物对细胞内pERK的抑制作用
Table 2 Inhibitory effect of compounds on intracellular pERK
由表2可知，本发明化合物能够有效地抑制KRAS下游pERK。As shown in Table 2, the compounds of the present invention can effectively inhibit pERK downstream of KRAS.
四、大鼠、犬静脉给药本发明化合物的药代动力学评价IV. Pharmacokinetic evaluation of the compounds of the present invention after intravenous administration in rats and dogs
发明人在大鼠体内对本发明的化合物进行了药代动力学评估。其中，动物信息详见表3。The inventors conducted a pharmacokinetic evaluation of the compound of the present invention in rats. The animal information is shown in Table 3.
表3本发明受试动物信息表
Table 3 Information of the test animals of the present invention
实验方法experimental method
将本发明化合物以5％DMSO+30％PEG400+65％生理盐水、10％DMSO+10％Kolliphor HS15+ 80％Saline、10％DMSO+89％(25％SBE-B-CD)+(2％HCl)、20％PEG400+80％灭菌注射用水或10％DMA+10％HS15+30％PEG400+50％灭菌注射用水溶液形式，对受试动物进行给药，给药前动物禁食12h，自由饮水。对于静脉注射给药组，大鼠给药剂量为1mg/kg，给药后在以下时间点静脉取血(取血量约0.15mL)：0.083、0.25、0.5、1.0、2.0、5.0、7.0和24h(大鼠)，采血管内预先加入EDTA-K2作为抗凝剂，血样在12,000rpm下离心2分钟，收集血浆，并于-20℃或-70℃下保存。The compound of the present invention was diluted with 5% DMSO + 30% PEG400 + 65% saline, 10% DMSO + 10% Kolliphor HS15 + The animals were administered with 80% Saline, 10% DMSO + 89% (25% SBE-B-CD) + (2% HCl), 20% PEG400 + 80% sterile water for injection or 10% DMA + 10% HS15 + 30% PEG400 + 50% sterile aqueous solution for injection. The animals were fasted for 12 hours before administration and had free access to water. For the intravenous administration group, the rats were administered a dose of 1 mg/kg. After administration, blood was collected venously at the following time points (blood volume of about 0.15 mL): 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hours (rats). EDTA-K 2 was added to the blood collection tube as an anticoagulant in advance. The blood samples were centrifuged at 12,000 rpm for 2 minutes, and the plasma was collected and stored at -20°C or -70°C.
对上述收集的血浆样品进行处理(冰冻血浆于室温下融化后，涡旋15s混匀，取10-20μL血浆，加入含内标的乙腈溶液120-150μL，涡旋5min混匀，4,000rpm下离心5分钟，取上清液100μL，加入120-150μL甲醇/水(v/v＝1/1)混匀)后，采用LC-MS/MS分析血浆中化合物的浓度。分析结果表明，本发明化合物在大鼠体内具有较好的药代动力学性质。说明本发明化合物成药性更好，具有更好的临床应用前景。其中，本发明化合物在大鼠体内的药代动力学参数分别详见表4。表4中的MRTX1133结构为： After processing the above collected plasma samples (after the frozen plasma is thawed at room temperature, vortex for 15 seconds to mix, take 10-20 μL of plasma, add 120-150 μL of acetonitrile solution containing internal standard, vortex for 5 minutes to mix, centrifuge at 4,000 rpm for 5 minutes, take 100 μL of supernatant, add 120-150 μL of methanol/water (v/v=1/1) to mix), LC-MS/MS was used to analyze the concentration of the compound in plasma. The analysis results show that the compounds of the present invention have better pharmacokinetic properties in rats. This shows that the compounds of the present invention have better drugability and better clinical application prospects. Among them, the pharmacokinetic parameters of the compounds of the present invention in rats are detailed in Table 4. The structure of MRTX1133 in Table 4 is:
表4本发明化合物在大鼠体内静脉给药的药代动力学参数
Table 4 Pharmacokinetic parameters of the compounds of the present invention after intravenous administration in rats
表4结果表明，本发明化合物在大鼠中具有较高的Cmax和AUC值，以及较低的清除率，说明本发明化合物成药性好，具有更好的临床应用前景。The results in Table 4 show that the compounds of the present invention have higher C max and AUC values and lower clearance rates in rats, indicating that the compounds of the present invention have good drugability and better clinical application prospects.
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“一些实施方案”、“示例”、“具体示例”或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不一定指的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例、实施方案或示例以及不同实施例、实施方案或示例的特征进行结合和组合。In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "some implementation schemes", "example", "specific example" or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments, implementation schemes or examples described in this specification and the features of the different embodiments, implementation schemes or examples, without contradiction.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在不脱离本发明的原理和宗旨的情况下在本发明的范围内可以对上述实施例进行变化、修改、替换和变型，本发明的范围由权利要求及其等同物限定。 Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, substitute and vary the above embodiments within the scope of the present invention without departing from the principles and intent of the present invention. The scope of the present invention is defined by the claims and their equivalents.

Claims (16)

  1. 一种化合物，其为式(I)所示的化合物，或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
    A compound, which is a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I),
    其中，in,
    Q为O或S；Q is O or S;
    环A为C3-6碳环基、C7-12碳环基、3-6元杂环基、7-12元杂环基、C6-12芳基或5-12元杂芳基；Ring A is a C 3-6 carbocyclyl, a C 7-12 carbocyclyl, a 3-6 membered heterocyclyl, a 7-12 membered heterocyclyl, a C 6-12 aryl or a 5-12 membered heteroaryl;
    各R1独立地为-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、-NO2、-C(＝O)R6a、-C(＝O)OR6a、-C(＝O)NR6R7、-NR6C(＝O)R7、-NR6R7、-NR6S(＝O)2R7、氧代、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氰基烷基、C1-6羟基烷基、C1-6卤代烷基、C2-6卤代烯基、C2-6卤代炔基、C1-6烷氧基C1-6烷基、C1-6羧基烷基、C1-6氨基烷基、C1-6巯基烷基、C1-6烷氧基、C3-6环烷基、3-6元杂环基、C6-12芳基或5-12元杂芳基；each R 1 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -NO 2 , -C(=O)R 6a , -C(=O)OR 6a , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -NR 6 R 7 , -NR 6 S(=O) 2 R 7 , oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 carboxyalkyl, C 1-6 aminoalkyl, C 1-6 mercaptoalkyl, C 1-6 alkoxy, C 1-6 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;
    环B为C6-12芳基或5-12元杂芳基；Ring B is C 6-12 aryl or 5-12 membered heteroaryl;
    各R2独立地为-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、-CH2C(＝O)NR6bR7b、-C(＝O)R6c、-C(＝O)OR6c、-C(＝O)NR6bR7b、-NR6bC(＝O)R7b、-NR6bR7b、C1-6烷基、C1-6烷硫基、C2-6烯基、C2-6炔基、C2-6羟基炔基、C1-6烷氧基、C1-6氰基烷基、C1-6羟基烷基、C1-6卤代烷基、C2-6卤代烯基、C2-6卤代炔基、C1-6卤代烷氧基、C1-6卤代烷硫基、6-12元芳基、5-12元杂芳基、C3-6环烷基或3-6元杂环基，其中所述的C1-6烷基、C1-6烷硫基、C2-6烯基、C2-6炔基、C2-6羟基炔基、C1-6烷氧基、C1-6氰基烷基、C1-6羟基烷基、C1-6卤代烷基、C2-6卤代烯基、C2-6卤代炔基、C1-6卤代烷氧基、C1-6卤代烷硫基、6-12元芳基、5-12元杂芳基、C3-6环烷基和3-6元杂环基各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、-C(＝O)H、-C(＝O)OH、C1-6烷基、C1-6烷氧基、C3-6环烷基和3-6元杂环基的取代基所取代；each R2 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C (=O ) NR6bR7b , -C (=O) R6c , -C(=O)OR6c, -C(=O)NR6bR7b, -NR6bC(=O)R7b, -NR6bR7b , C1-6alkyl , C1-6alkylthio , C2-6alkenyl , C2-6alkynyl , C2-6hydroxyalkynyl , C1-6alkoxy, C1-6cyanoalkyl , C1-6hydroxyalkyl , C1-6haloalkyl , C2-6haloalkenyl , C2-6haloalkynyl , C1-6haloalkoxy , C1-6 C1-6 alkylthio, C2-6 alkenyl, C2-6 alkynyl, C2-6 hydroxyalkynyl, C1-6 alkoxy, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, C1-6 haloalkoxy, C1-6 haloalkylthio, 6-12 membered aryl, 5-12 membered heteroaryl, C3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the C1-6 alkyl, C1-6 alkylthio, C2-6 alkenyl, C2-6 alkynyl, C2-6 hydroxyalkynyl, C1-6 alkoxy , C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, C1-6 haloalkoxy, C1-6 haloalkylthio, 6-12 membered aryl, 5-12 membered heteroaryl, C3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2 , -C(=O)H, -C(=O)OH, C substituted by a C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, and 3-6 membered heterocyclic group;
    R3为-H、-D、-OH、-SH、-F、-Cl、-Br、-I、-CN、甲基、乙基、正丙基、异丙基、正丁基或C1-4卤代烷基； R3 is -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl or C1-4 haloalkyl;
    Y为键、O或S；Y is a bond, O or S;
    R4为-H、-D、C1-6烷基、3-10元杂环基、-L-(3-10元杂环基)、-L-C3-10环烷基、-L-(5-12元杂芳基)、-L-(C6-10芳基)、-L-NR6R7、-NR6R7、-L-NHC(＝NH)NH2或-L-C(＝O)NR6R7，其中所述的C1-6烷基、3-10元杂环基、-L-(3-10元杂环基)、-L-C3-10环烷基、-L-(5-12元杂芳基)和-L-(C6-10芳基)各自独立任选地被1、2、3或4 个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NR6dR7d、-C(＝O)NR6dR7d、-CH2NR6dR7d、-CH2OC(＝O)NR6dR7d、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C6-10芳基C1-6烷基、(5-12元杂芳基)-C1-6烷基、(3-6元杂环基)-C1-6烷基、C3-6环烷基C1-6烷基、C3-6环烷基和3-6元杂环基的取代基所取代，或，所述的-L-(3-10元杂环基)中的3-10元杂环基上的任意位置任意个数的环碳原子上的两个氢原子被取代，其中所述取代基中的C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C6-10芳基C1-6烷基、(5-12元杂芳基)-C1-6烷基、(3-6元杂环基)-C1-6烷基、C3-6环烷基C1-6烷基、C3-6环烷基和3-6元杂环基各自独立任选地被1、2、3或4个选自-D、-F、-Cl、-Br、-I、-OH、-CN、-NR6eR7e、-C(＝O)C1-6烷基和C1-6烷基的取代基所取代； R4 is -H, -D, C1-6 alkyl, 3-10 membered heterocyclyl, -L-(3-10 membered heterocyclyl), -LC3-10 cycloalkyl, -L-(5-12 membered heteroaryl ) , -L-( C6-10 aryl), -L- NR6R7 , -NR6R7 , -L -NHC(=NH) NH2 or -LC(=O) NR6R7 , wherein the C1-6 alkyl, 3-10 membered heterocyclyl, -L-(3-10 membered heterocyclyl), -LC3-10 cycloalkyl, -L-(5-12 membered heteroaryl) and -L-( C6-10 aryl) are each independently optionally substituted by 1, 2, 3 or 4 The -L-(3-10 membered heterocyclyl) is substituted with a substituent selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d , -C(═O)NR 6d R 7d , -CH 2 NR 6d R 7d , -CH 2 OC(═O)NR 6d R 7d , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 arylC 1-6 alkyl, (5-12 membered heteroaryl)-C 1-6 alkyl, (3-6 membered heterocyclyl)-C 1-6 alkyl, C 3-6 cycloalkylC 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; or, two hydrogen atoms on any number of ring carbon atoms at any position on the 3-10 membered heterocyclyl in the -L-( 3-10 membered heterocyclyl) are replaced with a substituent selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d , -C(═O)NR 6d R 7d , -CH 2 NR 6d R 7d , -CH 2 OC(═O)NR 6d R 7d substituted, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 arylC 1-6 alkyl, (5-12 membered heteroaryl)-C 1-6 alkyl, (3-6 membered heterocyclyl)-C 1-6 alkyl, C 3-6 cycloalkylC 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl in the substituent are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -F, -Cl, -Br, -I, -OH, -CN, -NR 6e R 7e , -C(＝O)C 1-6 alkyl and C 1-6 alkyl;
    L为C1-6亚烷基；L is a C 1-6 alkylene group;
    为至少含有两个环N原子的5-12元杂环； is a 5-12 membered heterocyclic ring containing at least two ring N atoms;
    R5为-H、-D、-OH、-SH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OR6a、-C(＝O)NR6R7、C1-6烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基或5-6元杂芳基；R 5 is -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OR 6a , -C(=O)NR 6 R 7 , C 1-6 alkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or 5-6 membered heteroaryl;
    R6、R7、R6b、R7b、R6d、R7d、R6e和R7e各自独立地为-H、-D或C1-6烷基，其中所述的C1-6烷基任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、C1-6烷氧基、C6-12芳基、C3-6环烷基和3-6元杂环基的取代基所取代；R 6 , R 7 , R 6b , R 7b , R 6d , R 7d , R 6e and R 7e are each independently -H, -D or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(═O)H, -C(═O)OH, -NR 6g R 7g , C 1-6 alkoxy, C 6-12 aryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
    或R6和R7、或R6b和R7b、或R6d和R7d、或R6e和R7e，分别和与之相连的N原子一起形成4-6元杂环，其中所述的4-6元杂环任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、C1-6烷基、C1-6烷氨基、C3-6环烷基、3-6元杂环基、C1-6烷氧基、C1-6氰基烷基、C1-6羟基烷基、C1-6卤代烷氧基和C1-6卤代烷基的取代基所取代；or R 6 and R 7 , or R 6b and R 7b , or R 6d and R 7d , or R 6e and R 7e , together with the N atom to which they are attached, form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 1-6 alkoxy, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy and C 1-6 haloalkyl;
    R6a、R6c、R6g和R7g各自独立地为-H、-D或C1-6烷基；R 6a , R 6c , R 6g and R 7g are each independently -H, -D or C 1-6 alkyl;
    m和n各自独立地为0、1、2、3、4、5、6或7。m and n are each independently 0, 1, 2, 3, 4, 5, 6 or 7.
  2. 根据权利要求1所述的化合物，其中，环A为环丙基、环丁基、环戊基、环己基、环戊烯基、八氢并环戊二烯基、双环[3.1.0]环己基、2,3-二氢-1H-茚基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、四氢吡喃基、吗啉基、哌嗪基、哌啶基、苯基、吡啶基、吡咯基、咪唑基、嘧啶基或苯并呋喃基。The compound according to claim 1, wherein Ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, octahydropentalenyl, bicyclo[3.1.0]cyclohexyl, 2,3-dihydro-1H-indenyl, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, piperidinyl, phenyl, pyridinyl, pyrrolyl, imidazolyl, pyrimidinyl or benzofuranyl.
  3. 根据权利要求1或2所述的化合物，其中，各R1独立地为-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、-NO2、-C(＝O)R6a、-C(＝O)OR6a、-C(＝O)NR6R7、-NR6C(＝O)R7、-NR6R7、-NR6S(＝O)2R7、氧代、C1-4烷基、C2-4烯基、C2-4炔基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷基、C2-4卤代烯基、C2-4卤代炔基、C1-4烷 氧基C1-4烷基、C1-4羧基烷基、C1-4氨基烷基、C1-4巯基烷基、C1-4烷氧基、C3-6环烷基、3-6元杂环基、C6-12芳基或5-12元杂芳基；The compound according to claim 1 or 2, wherein each R 1 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -NO 2 , -C(＝O)R 6a , -C(＝O)OR 6a , -C(＝O)NR 6 R 7 , -NR 6 C(＝O)R 7 , -NR 6 R 7 , -NR 6 S(＝O) 2 R 7 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 2-4 haloalkenyl , C 2-4 haloalkynyl , C 1-4 alkane OxyC 1-4 alkyl, C 1-4 carboxyalkyl, C 1-4 aminoalkyl, C 1-4 mercaptoalkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;
    R6和R7各自独立地为-H、-D或C1-4烷基，其中所述的C1-4烷基任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、C1-4烷氧基、6-10元芳基、C3-6环烷基和3-6元杂环基的取代基所取代； R6 and R7 are each independently -H, -D or C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR6gR7g , C1-4 alkoxy, 6-10 membered aryl, C3-6 cycloalkyl and 3-6 membered heterocyclyl;
    或R6、R7和与之相连的N原子一起形成4-6元杂环，其中所述的4-6元杂环任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、C1-4烷基、C1-4烷氨基、C3-6环烷基、3-6元杂环基、C1-4烷氧基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷氧基和C1-4卤代烷基的取代基所取代；or R 6 , R 7 and the N atom to which they are attached together form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted by 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl;
    R6a、R6g和R7g各自独立地为-H、-D或C1-4烷基。R 6a , R 6g and R 7g are each independently -H, -D or C 1-4 alkyl.
  4. 根据权利要求1-3任意一项所述的化合物，其中，R1为-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、-NO2、-C(＝O)R6a、-C(＝O)OR6a、-C(＝O)NR6R7、-NR6C(＝O)R7、-NR6R7、-NR6S(＝O)2R7、氧代、-CH3、-CH2CH3、-(CH2)2CH3、-(CH2)3CH3、-C(CH3)3、-CH(CH3)2、-CH＝CH2、-CH＝CHCH3、-CH2CH＝CH2、-CHFCH＝CH2、-CH＝CHF、-CH＝CHCl、-CH＝CHCH2F、-CH＝CHCH3、-C≡CH、-C≡CCH3、-CH2C≡CH、-C≡CCH2F、-CH2CN、-(CH2)2CN、-(CH2)3CN、-CH2OH、-(CH2)2OH、-(CH2)3OH、-CH(OH)CH3、-CF3、-CHF2、-CH2F、-(CH2)2F、-(CH2)2Cl、-CH2CF3、-CH2OCH3、-(CH2)2OCH3、-(CH2)2OCH2CH3、-CH2OCH2CH3、-CH2C(＝O)OH、-(CH2)2C(＝O)OH、-(CH2)3C(＝O)OH、-CH2NH2、-(CH2)2NH2、-CH2SH、-(CH2)2SH、-OCH3、-OCH2CH3、-O(CH2)2CH3、-OCH2CH(CH3)2、-OCH(CH3)2、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氧杂环丁基、四氢呋喃基、吡咯烷基、苯基、吡啶基、嘧啶基、吡唑基或咪唑基；The compound according to any one of claims 1 to 3, wherein R 1 is -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -NO 2 , -C(＝O)R 6a , -C(＝O)OR 6a , -C(＝O)NR 6 R 7 , -NR 6 C(＝O)R 7 , -NR 6 R 7 , -NR 6 S(＝O) 2 R 7 , oxo, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -C(CH 3 ) 3 , -CH(CH 3 ) 2 , -CH＝CH 2 , -CH＝CHCH 3 , -CH 2 CH＝CH 2 , -CHFCH＝CH 2 , -CH＝CHF, -CH＝CHCl, -CH＝CHCH 2 F, -CH=CHCH 3 , -C≡CH, -C≡CCH 3 , -CH 2 C≡CH, -C≡CCH 2 F, -CH 2 CN, -(CH 2 ) 2 CN, -(CH 2 ) 3 CN, -CH 2 OH, -(CH 2 ) 2 OH, -(CH 2 ) 3 OH, -CH(OH)CH 3 , -CF 3 , -CHF 2 , -CH 2 F, -(CH 2 ) 2 F, -(CH 2 ) 2 Cl, -CH 2 CF 3 , -CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , -(CH 2 ) 2 OCH 2 CH 3 , -CH 2 OCH 2 CH 3 , -CH 2 C(=O)OH, -(CH 2 ) 2 C(═O)OH, —(CH 2 ) 3 C(═O)OH, —CH 2 NH 2 , —(CH 2 ) 2 NH 2 , —CH 2 SH, —(CH 2 ) 2 SH, —OCH 3 , —OCH 2 CH 3 , —O(CH 2 ) 2 CH 3 , —OCH 2 CH(CH 3 ) 2 , —OCH(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazolyl or imidazolyl;
    R6和R7各自独立地为-H、-D、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基各自任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、甲氧基、乙氧基、正丙氧基、异丙氧基、异丁氧基、环丙基、环丁基、环戊基、环己基、苯基、环氧乙烷基、氧杂环丁基、氮杂环丁基和吡咯烷基的取代基所取代； R6 and R7 are each independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl are each optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR6gR7g , methoxy, ethoxy, n-propoxy, isopropoxy , isobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxiranyl, oxetanyl, azetidinyl and pyrrolidinyl;
    或R6、R7和与之相连的N原子一起形成吡咯烷、哌嗪、哌啶、吗啉、恶唑烷或咪唑烷，其中所述的吡咯烷、哌嗪、哌啶、吗啉、恶唑烷和咪唑烷各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氨基、二甲氨基、乙氨基、环丙基、环戊基、吡咯烷基、甲氧基、乙氧基、异丙氧基、氰基甲基、羟基甲基、羟基乙基、三氟甲氧基、一氟甲基、二氟甲基、三氟甲基和1,2-二氯乙基的取代基所取代；or R 6 , R 7 and the N atom to which they are attached together form pyrrolidine, piperazine, piperidine, morpholine, oxazolidine or imidazolidine, wherein the pyrrolidine, piperazine, piperidine, morpholine, oxazolidine and imidazolidine are each independently and optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy, ethoxy, isopropoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl and 1,2-dichloroethyl;
    R6a、R6g和R7g各自独立地为-H、-D、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。R 6a , R 6g and R 7g are each independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  5. 根据权利要求1-4任意一项所述的化合物，其中，环B为以下其中子结构之一，
    The compound according to any one of claims 1 to 4, wherein ring B is one of the following substructures,
  6. 根据权利要求1-5任意一项所述的化合物，其中，The compound according to any one of claims 1 to 5, wherein
    各R2独立地为-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、-CH2C(＝O)NR6bR7b、-C(＝O)R6c、-C(＝O)OR6c、-C(＝O)NR6bR7b、-NR6bC(＝O)R7b、-NR6bR7b、C1-4烷基、C1-4烷硫基、C2-4烯基、C2-4炔基、C2-4羟基炔基、C1-4烷氧基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷基、C2-4卤代烯基、C2-4卤代炔基、C1-4卤代烷氧基、C1-4卤代烷硫基、6-12元芳基、5-12元杂芳基、C3-6环烷基或3-6元杂环基，其中所述的C1-4烷基、C1-4烷硫基、C2-4烯基、C2-4炔基、C2-4羟基炔基、C1-4烷氧基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷基、C2-4卤代烯基、C2-4卤代炔基、C1-4卤代烷氧基、C1-4卤代烷硫基、C6-10芳基、5-10元杂芳基、C3-6环烷基和3-6元杂环基各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、-C(＝O)H、-C(＝O)OH、C1-4烷基、C1-4烷氧基、C3-6环烷基和3-6元杂环基的取代基所取代；each R2 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C (=O ) NR6bR7b , -C (=O) R6c , -C(=O)OR6c, -C(=O)NR6bR7b, -NR6bC(=O)R7b, -NR6bR7b , C1-4alkyl , C1-4alkylthio , C2-4alkenyl , C2-4alkynyl , C2-4hydroxyalkynyl, C1-4alkoxy, C1-4cyanoalkyl, C1-4hydroxyalkyl , C1-4haloalkyl , C2-4haloalkenyl , C2-4haloalkynyl , C1-4haloalkoxy, C1-4 C 1-4 alkyl, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 hydroxyalkynyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 2-4 haloalkenyl, C 2-4 haloalkynyl, C 1-4 haloalkoxy, C 1-4 haloalkylthio, C 6-10 aryl, 5-10 membered heteroaryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted by 1, 2 , 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , -C(=O)H, -C(=O)OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocyclic substituents;
    各R6c独立地为-H、-D或C1-4烷基；Each R 6c is independently -H, -D or C 1-4 alkyl;
    R6b和R7b各自独立地为-H、-D或C1-4烷基，其中所述的C1-4烷基任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、C1-4烷氧基、C6-10芳基、C3-6环烷基和3-6元杂环基的取代基所取代；R 6b and R 7b are each independently -H, -D or C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted by 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g , C 1-4 alkoxy, C 6-10 aryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
    或R6b、R7b和与之相连的N原子一起形成4-6元杂环，其中所述的4-6元杂环任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、C1-4烷基、C1-4烷氨基、C3-6环烷基、3-6元杂环基、C1-4烷氧基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷氧基和C1-4卤代烷基的取代基所取代。Or R 6b , R 7b and the N atom to which they are attached form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted by 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl.
  7. 根据权利要求1-6任意一项所述的化合物，其中，The compound according to any one of claims 1 to 6, wherein
    各R2独立地为-D、-OH、-F、-Cl、-Br、-I、-CN、-SH、-CH2C(＝O)NR6bR7b、-C(＝O)R6c、-C(＝O)OR6c、-C(＝O)NR6bR7b、-NR6bC(＝O)R7b、-NR6bR7b、-CH3、-CH2CH3、-(CH2)2CH3、-(CH2)3CH3、-C(CH3)3、-CH(CH3)2、-SCH3、-SCH2CH3、-CH＝CH2、-CH＝CHCH3、-CH2CH＝CH2、-C≡CH、-C≡CCH3、-CH2C≡CH、-C≡CCH2OH、-C≡C(CH2)2OH、-OCH3、-OCH2CH3、-O(CH2)2CH3、-CH2CN、-(CH2)2CN、-(CH2)3CN、-CH2OH、-(CH2)2OH、-(CH2)3OH、-CH(OH)CH3、-(CH2)2F、-CH2CHF2、-CF3、-CH2CF3、-CHF2、-CH2F、-(CH2)2Cl、-CH＝CHF、 -CH＝CHCl、-CH＝CHCH2F、-C≡CCH2F、-C≡C(CH2)2F、-C≡CF、-OCF3、-OCHF2、-OCH2CHF2、-OCH2CF3、-OCHClCHCl2、-OCH2CH2F、-SCF3、-SCH2CF3、-SCH2CHF2、苯基、萘基、吡啶基、嘧啶基、环丙基、环丁基、环戊基、环己基、吡咯烷基、恶唑烷基、四氢呋喃基、哌啶基或哌嗪基，其中所述的-CH3、-CH2CH3、-(CH2)2CH3、-(CH2)3CH3、-C(CH3)3、-CH(CH3)2、-SCH3、-SCH2CH3、-CH＝CH2、-CH＝CHCH3、-CH2CH＝CH2、-C≡CH、-C≡CCH3、-CH2C≡CH、-C≡CCH2OH、-C≡C(CH2)2OH、-OCH3、-OCH2CH3、-O(CH2)2CH3、-CH2CN、-(CH2)2CN、-(CH2)3CN、-CH2OH、-(CH2)2OH、-(CH2)3OH、-CH(OH)CH3、-(CH2)2F、-CH2CHF2、-CH2CF3、-CHF2、-CH2F、-(CH2)2Cl、-CH＝CHF、-CH＝CHCl、-CH＝CHCH2F、-C≡CCH2F、-C≡C(CH2)2F、-OCHF2、-OCH2CHF2、-OCH2CF3、-OCHClCHCl2、-OCH2CH2F、-SCH2CF3、-SCH2CHF2、苯基、萘基、吡啶基、嘧啶基、环丙基、环丁基、环戊基、环己基、吡咯烷基、恶唑烷基、四氢呋喃基、哌啶基和哌嗪基各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、-C(＝O)H、-C(＝O)OH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、吡咯烷基、恶唑烷基、四氢呋喃基、哌啶基和哌嗪基的取代基所取代；each R2 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C (=O ) NR6bR7b , -C(=O) R6c , -C(=O) OR6c , -C(=O) NR6bR7b , -NR6bC (=O) R7b , -NR6bR7b , -CH3 , -CH2CH3 , -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3 , -CH ( CH3)2 , -SCH3 , -SCH2CH3 , -CH = CH2 , -CH = CHCH3 , -CH2CH= CH2 , -C≡CH, -C≡CCH3, -CH 2 C≡CH, -C≡CCH 2 OH, -C≡C(CH 2 ) 2 OH, -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -CH 2 CN, -(CH 2 ) 2 CN, -(CH 2 ) 3 CN, -CH 2 OH, -(CH 2 ) 2 OH, -(CH 2 ) 3 OH, -CH(OH)CH 3 , -(CH 2 ) 2 F, -CH 2 CHF 2 , -CF 3 , -CH 2 CF 3 , -CHF 2 , -CH 2 F, -(CH 2 ) 2 Cl, -CH＝CHF, -CH= CHCl , -CH=CHCH2F , -C≡CCH2F, -C≡C( CH2 ) 2F , -C≡CF , -OCF3 , -OCHF2 , -OCH2CHF2 , -OCH2CF3 , -OCHClCHCl2 , -OCH2CH2F , -SCF3 , -SCH2CF3, -SCH2CHF2, phenyl, naphthyl , pyridyl , pyrimidyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl or piperazinyl, wherein -CH3 , -CH2CH3 , -( CH2 ) 2CH3 , -( CH2 ) 3CH3 , -C( CH3 ) 3 , -CH( CH3 ) 2 , -SCH 3 , -SCH 2 CH 3 , -CH＝CH 2 , -CH＝CHCH 3 , -CH 2 CH＝CH 2 , -C≡CH, -C≡CCH 3 , -CH 2 C≡CH, -C≡CCH 2 OH, -C≡C(CH 2 ) 2 OH, -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -CH 2 CN, -(CH 2 ) 2 CN, -(CH 2 ) 3 CN, -CH 2 OH, -(CH 2 ) 2 OH, -(CH 2 ) 3 OH, -CH(OH)CH 3 , -(CH 2 ) 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CHF 2 , -CH 2 F, -(CH 2 ) 2 Cl, -CH═CHF, -CH═CHCl, -CH═CHCH 2 F, -C≡CCH 2 F, -C≡C(CH 2 ) 2 F, -OCHF 2 , -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCHClCHCl 2 , -OCH 2 CH 2 F, -SCH 2 CF 3 , -SCH 2 CHF 2 , phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl and piperazinyl are each independently optionally substituted by 1, 2, 3 or 4 radicals selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , -C(=O)H, -C(=O)OH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl and piperazinyl substituents;
    各R6c独立地为-H、-D、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；Each R 6c is independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
    R6b和R7b各自独立地为-H、-D、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基各自任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、甲氧基、乙氧基、正丙氧基、异丙氧基、异丁氧基、苯基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氧杂环丁基、氮杂环丁基和吡咯烷基的取代基所取代；R 6b and R 7b are each independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl are each optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g , methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, azetidinyl and pyrrolidinyl;
    或R6b、R7b和与之相连的N原子一起形成吡咯烷、哌嗪、哌啶、吗啉、恶唑烷或咪唑烷，其中所述的吡咯烷、哌嗪、哌啶、吗啉、恶唑烷和咪唑烷各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氨基、二甲氨基、乙氨基、环丙基、环戊基、吡咯烷基、甲氧基、乙氧基、异丙氧基、氰基甲基、羟基甲基、羟基乙基、三氟甲氧基、一氟甲基、二氟甲基、三氟甲基和1,2-二氯乙基的取代基所取代。or R 6b , R 7b together with the N atom to which they are attached form pyrrolidine, piperazine, piperidine, morpholine, oxazolidine or imidazolidine, wherein the pyrrolidine, piperazine, piperidine, morpholine, oxazolidine and imidazolidine are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy, ethoxy, isopropoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl and 1,2-dichloroethyl.
  8. 根据权利要求1-7任意一项所述的化合物，其中，The compound according to any one of claims 1 to 7, wherein
    R4为-H、-D、C1-4烷基、3-6元杂环基、7-10元杂环基、 -L-吡咯烷基、-L-吗啉基、-L-氧杂环丁基、-L-氧杂环丙基、-L-四氢呋喃基、-L-八氢吲哚嗪基、-L-环丙基、-L-环戊基、-L-八氢并环戊二烯基、-L-八氢-1H-茚基、-L-十氢萘基、-L-吡啶基、-L-吡唑基、-L-苯基、-L-NR6R7、-NR6R7、-L-NHC(＝NH)NH2或-L-C(＝O)NR6R7，其中所述的C1-4 烷基、3-6元杂环基、7-10元杂环基、 -L-吡咯烷基、-L-吗啉基、-L-氧杂环丁基、-L-氧杂环丙基、-L-四氢呋喃基、-L-八氢吲哚嗪基、-L-环丙基、-L-环戊基、-L-八氢并环戊二烯基、-L-八氢-1H-茚基、-L-十氢萘基、-L-吡啶基、-L-吡唑基和-L-苯基各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NR6dR7d、-C(＝O)NR6dR7d、-CH2NR6dR7d、-CH2OC(＝O)NR6dR7d、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基、苯基C1-4烷基、5-6元杂芳基C1-4烷基、(3-6元杂环基)-C1-4烷基、C3-6环烷基C1-4烷基、C3-6环烷基和3-6元杂环基的取代基所取代，或，所述的中的中的中的中的中的各自任意位置任意个数的环碳原子上的两个氢原子被取代，其中所述取代基中的C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基、苯基C1-4烷基、5-6元杂芳基C1-4烷基、(3-6元杂环基)-C1-4烷基、C3-6环烷基C1-4烷基、C3-6环烷基和3-6元杂环基各自独立任选地被1、2、3或4个选自-D、-F、-Cl、-Br、-I、-OH、-CN、-NR6eR7e、-C(＝O)C1-4烷基和C1-4烷基的取代基所取代； R4 is -H, -D, C1-4 alkyl, 3-6 membered heterocyclic group, 7-10 membered heterocyclic group, -L-pyrrolidinyl, -L-morpholinyl, -L-oxetanyl, -L-oxetanyl, -L-tetrahydrofuranyl, -L-octahydroindolizinyl, -L-cyclopropyl, -L-cyclopentyl, -L-octahydropentalenyl, -L-octahydro-1H-indenyl, -L-decalinyl, -L-pyridinyl, -L-pyrazolyl, -L-phenyl, -L-NR 6 R 7 , -NR 6 R 7 , -L-NHC(═NH)NH 2 or -LC(═O)NR 6 R 7 , wherein the C 1-4 Alkyl, 3-6 membered heterocyclic group, 7-10 membered heterocyclic group, -L-pyrrolidinyl, -L-morpholinyl, -L-oxetanyl, -L-oxetanyl, -L-tetrahydrofuranyl, -L-octahydroindolizinyl, -L-cyclopropyl, -L-cyclopentyl, -L-octahydropentalenyl, -L-octahydro-1H-indenyl, -L-decalinyl, -L-pyridinyl, -L-pyrazolyl and -L-phenyl are each independently optionally substituted by 1, 2, 3 or 4 groups selected from -D, -OH, -F , -Cl , -Br, -I , -CN, -NR6dR7d , -C(=O) NR6dR7d, -CH2NR6dR7d, -CH2OC(=O)NR6dR7d , C1-4alkyl , C1-4alkoxy , C1-4haloalkyl , C1-4haloalkoxy , phenylC1-4 C 1-4 alkyl, 5-6 membered heteroaryl C 1-4 alkyl, (3-6 membered heterocyclic)-C 1-4 alkyl, C 3-6 cycloalkyl C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic substituents, or, middle middle middle middle middle Two hydrogen atoms on any number of ring carbon atoms at any position are substituted, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl C 1-4 alkyl, 5-6 membered heteroaryl C 1-4 alkyl, (3-6 membered heterocyclyl)-C 1-4 alkyl, C 3-6 cycloalkyl C 1-4 alkyl , C 3-6 cycloalkyl and 3-6 membered heterocyclyl in the substituent are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -F, -Cl, -Br, -I, -OH, -CN, -NR 6e R 7e , -C(＝O)C 1-4 alkyl and C 1-4 alkyl;
    L为C1-4亚烷基；L is a C 1-4 alkylene group;
    R6d、R7d、R6e和R7e各自独立地为-H、-D或C1-4烷基，其中所述的C1-4烷基任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、C1-4烷氧基、C6-10芳基、C3-6环烷基和3-6元杂环基的取代基所取代；R 6d , R 7d , R 6e and R 7e are each independently -H, -D or C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(═O)H, -C(═O)OH, -NR 6g R 7g , C 1-4 alkoxy, C 6-10 aryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
    或R6d和R7d、或R6e和R7e，分别和与之相连的N原子一起形成4-6元杂环，其中所述的4-6元杂环任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、C1-4烷基、C1-4烷氨基、C3-6环烷基、3-6元杂环基、C1-4烷氧基、C1-4氰基烷基、C1-4羟基烷基、C1-4卤代烷氧基和C1-4卤代烷基的取代基所取代。Or R 6d and R 7d , or R 6e and R 7e , respectively, together with the N atom to which they are connected, form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted by 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl.
  9. 根据权利要求1-8任意一项所述的化合物，其中，The compound according to any one of claims 1 to 8, wherein
    R4为-H、-D、-CH3、-CH2CH3、-(CH2)2CH3、哌啶基、哌嗪基、吡咯烷基、咪唑烷基、 -CH2-吡咯烷基、-CH2-吗啉基、-(CH2)2-吗啉基、-CH2-氧杂环丁基、-CH2-氧杂环丙基、-CH2-四氢呋喃基、-CH2-八氢吲哚嗪基、-CH2-环丙基、-CH2-环戊基、-CH2-八氢并环戊二烯基、-CH2-八氢-1H-茚基、-CH2-十氢萘基、-CH2-吡啶基、-(CH2)2-吡啶基、-CH2-吡唑基、-(CH2)2-吡唑基、-CH2-苯基、-CH2-NR6R7、-(CH2)2-NR6R7、-CH(CH3)CH2NR6R7、-NR6R7、-CH2-NHC(＝NH)NH2或-CH2-C(＝O)NR6R7，其中所述的-CH3、-CH2CH3、-(CH2)2CH3、哌啶基、哌嗪基、吡咯烷基、咪唑烷基、 -CH2-吡咯烷基、-CH2-吗啉基、-(CH2)2-吗啉基、-CH2-氧杂环丁基、-CH2-氧杂环丙基、-CH2-四氢呋喃基、-CH2-八氢吲哚嗪基、-CH2-环丙基、-CH2-环戊基、-CH2-八氢并环戊二烯基、-CH2-八氢-1H-茚基、-CH2-十氢萘基、-CH2-吡啶基、-(CH2)2-吡啶基、-CH2-吡唑基、-(CH2)2-吡唑基和-CH2-苯基各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NR6dR7d、-C(＝O)NR6dR7d、-CH2NR6dR7d、-CH2OC(＝O)NR6dR7d、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、异丙氧基、-CHF2、-CF3、-OCF3、苯基甲基、吡啶基甲基、吡唑基甲基、吗啉基甲基、吡咯烷基甲基、哌嗪基甲基、氮杂环丁烷基甲基、哌啶基甲基、环丙基甲基、环戊基甲基、环己基甲基、环戊基、环己基、吗啉基、哌啶基、吡咯烷基、哌嗪基和氮杂环丁烷基的取代基所取代，其中所述取代基中的甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、异丙氧基、-CHF2、苯基甲基、吡啶基甲基、吡唑基甲基、吗啉基甲基、吡咯烷基甲基、哌嗪基甲基、氮杂环丁烷基甲基、哌啶基甲基、环丙基甲基、环戊基甲基、环己基甲基、环戊基、环己基、吗啉基、哌啶基、吡咯烷基、哌嗪基和氮杂环丁烷基各自独立任选地被1、2、3或4个选自-D、-F、-Cl、-Br、-I、-OH、-CN、-NH2、-NHCH3、-N(CH3)2、-NHCH2CH3、-C(＝O)CH3、-C(＝O)CH2CH3、甲基、乙基、正丙基和异丙基的取代基所取代，或，R4为 R 4 is -H, -D, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, -CH 2 -pyrrolidinyl, -CH 2 -morpholinyl, -(CH 2 ) 2 -morpholinyl, -CH 2 -oxetanyl, -CH 2 -oxiranyl, -CH 2 -tetrahydrofuranyl, -CH 2 -octahydroindolizinyl, -CH 2 -cyclopropyl, -CH 2 -cyclopentyl, -CH 2 -octahydropentalenyl, -CH 2 -octahydro-1H-indenyl, -CH 2 -decalinyl, -CH 2 -pyridinyl , -(CH 2 ) 2 -pyridinyl, -CH 2 -pyrazolyl, -(CH 2 ) 2 -pyrazolyl, -CH 2 -phenyl, -CH 2 -NR 6 R 7 , -(CH 2 ) 2 -NR 6 R 7 , -CH (CH 3 )CH 2 NR 6 R 7 , -NR 6 R 7 , -CH 2 -NHC(=NH)NH 2 or -CH 2 -C(=O)NR 6 R 7 , wherein the -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, -CH2 -pyrrolidinyl, -CH2 -morpholinyl, -( CH2 ) 2 -morpholinyl, -CH2 - oxetanyl, -CH2-oxiranepropyl, -CH2-tetrahydrofuranyl, -CH2-octahydroindolizinyl, -CH2 -cyclopropyl, -CH2 -cyclopentyl, -CH2 -octahydropentalenyl, -CH2 -octahydro-1H-indenyl, -CH2 -decalinyl, -CH2 -pyridinyl, -( CH2 ) 2 -pyridinyl, -CH2 -pyrazolyl, -( CH2 ) 2 -pyrazolyl and -CH2 -phenyl are each independently optionally substituted by 1, 2 , 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN , -NR6dR7d , -C(=O) NR6dR7d , -CH 2 NR 6d R 7d , -CH 2 OC(＝O)NR 6d R 7d , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, isopropyloxy, -CHF 2 , -CF 3 , -OCF 3 , phenylmethyl, pyridylmethyl, pyrazolylmethyl, morpholinylmethyl, pyrrolidinylmethyl, piperazinylmethyl, azetidinylmethyl, piperidinylmethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl and azetidinyl substituents, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, isopropyloxy, -CHF 2 , -CF 3 , -OCF 3 , phenylmethyl, pyridylmethyl, pyrazolylmethyl, morpholinylmethyl, pyrrolidinylmethyl, piperazinylmethyl, azetidinylmethyl, piperidinylmethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl and azetidinyl substituents are substituted. wherein R4 is 4-(6-oxo)-1, 4-oxo-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-pyrrolidino-1, 4-pyrrolidino-1, 4-pyrrolidino-1, 4-pyrrolidino-1, 4 -pyrrolidino- 1 , 4-pyrrolidino- 1 , 4-pyrrolidino- 1 , 4 -pyrrolidino- 1 , 4-pyrrolidino- 1 , 4-pyrrolidino- 1 , 4-pyrrolidino-1, 4-pyrrolidino-1, 4-pyrrolidino- 1 , 4-pyrrolidino-1, 4-pyrrolidino- 1 , 4-pyrrolidino-1
    R6d和R7d各自独立地为-H、-D、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基各自任选地被1、2、3或4个选自-D、-OH、 -F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-NR6gR7g、甲氧基、乙氧基、正丙氧基、异丙氧基、异丁氧基、苯基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氧杂环丁基、氮杂环丁基和吡咯烷基的取代基所取代；R 6d and R 7d are each independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl are each optionally substituted by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g , methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, azetidinyl and pyrrolidinyl substituents;
    或R6d、R7d和与之相连的N原子一起形成氮杂环丁烷、吡咯烷、哌嗪、哌啶、吗啉、恶唑烷或咪唑烷，其中所述的氮杂环丁烷、吡咯烷、哌嗪、哌啶、吗啉、恶唑烷和咪唑烷各自独立任选地被1、2、3或4个选自-D、-OH、-F、-Cl、-Br、-I、-CN、-NH2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氨基、二甲氨基、乙氨基、环丙基、环戊基、吡咯烷基、甲氧基、乙氧基、异丙氧基、氰基甲基、羟基甲基、羟基乙基、三氟甲氧基、一氟甲基、二氟甲基、三氟甲基和1,2-二氯乙基的取代基所取代。or R 6d , R 7d and the N atom to which they are attached together form azetidine, pyrrolidine, piperazine, piperidine, morpholine, oxazolidine or imidazolidine, wherein the azetidine, pyrrolidine, piperazine, piperidine, morpholine, oxazolidine and imidazolidine are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy, ethoxy, isopropoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl and 1,2-dichloroethyl.
  10. 根据权利要求1-9任意一项所述的化合物，其中，为其中以下子结构之一，
    The compound according to any one of claims 1 to 9, wherein is one of the following substructures,
    R5为-H、-D、-OH、-SH、-F、-Cl、-Br、-I、-CN、-C(＝O)H、-C(＝O)OH、-C(＝O)OCH3、-C(＝O)NH2、-CH3、-CH2CH3、C3-4烷基、-CH2OH、-(CH2)2OH、-CH2CN、-(CH2)2CN、-CF3、-CHF2、-CH2F、-OCF3、-OCH3或-OCH2CH3。 R5 is -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O) OH, -C(=O)OCH3, -C(=O)NH2, -CH3, -CH2CH3, C3-4 alkyl , -CH2OH , - ( CH2 ) 2OH , -CH2CN, -( CH2 ) 2CN , -CF3 , -CHF2 , -CH2F , -OCF3 , -OCH3 , or -OCH2CH3 .
  11. 根据权利要求1-10任意一项所述的化合物，其为式(I-1)所示的化合物，或式(I-1)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
    The compound according to any one of claims 1 to 10, which is a compound represented by formula (I-1), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-1),
    其中，m、n、R1、R3、Y、R4、R5和环A各自具有如权利要求1-10任意一项所述的定义；wherein m, n, R 1 , R 3 , Y, R 4 , R 5 and ring A each have the definition as described in any one of claims 1 to 10;
    R2a、R2b和R2c各自具有如权利要求1-10任意一项中R2所述相同的定义。R 2a , R 2b and R 2c each have the same definition as described for R 2 in any one of claims 1 to 10.
  12. 根据权利要求1-11任意一项所述的化合物，其为以下结构的化合物，或所述结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，

    The compound according to any one of claims 1 to 11, which is a compound of the following structure, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure,

  13. 一种药物组合物，包含权利要求1-12任意一项所述的化合物；任选地，所述药物组合物进一步包含药学上可接受的辅剂。A pharmaceutical composition comprising the compound according to any one of claims 1 to 12; optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant.
  14. 权利要求1-12任意一项所述的化合物或权利要求13所述的药物组合物在制备用于预防、治疗或减轻KRAS G12D相关疾病的药物中的用途。Use of the compound according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 13 in the preparation of a medicament for preventing, treating or alleviating KRAS G12D-related diseases.
  15. 根据权利要求14所述的用途，其中，所述KRAS G12D相关疾病为癌症。The use according to claim 14, wherein the KRAS G12D-related disease is cancer.
  16. 根据权利要求15所述的用途，其中，所述癌症为非小细胞肺癌、小细胞肺癌、结直肠癌、直肠癌、结肠癌、小肠癌、胰腺癌、子宫癌、胃癌、食道癌、前列腺癌、卵巢癌、乳腺癌、白血病、黑色素瘤、淋巴瘤或神经瘤。 The use according to claim 15, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, colon cancer, small intestine cancer, pancreatic cancer, uterine cancer, gastric cancer, esophageal cancer, prostate cancer, ovarian cancer, breast cancer, leukemia, melanoma, lymphoma or neuroma.
PCT/CN2023/124140 2022-10-13 2023-10-12 Pyrimidopyridine compound, and pharmaceutical composition and use thereof WO2024078555A1 (en)

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