WO2023216910A1 - 取代的双环杂芳基化合物作为usp1抑制剂 - Google Patents

取代的双环杂芳基化合物作为usp1抑制剂 Download PDF

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WO2023216910A1
WO2023216910A1 PCT/CN2023/091338 CN2023091338W WO2023216910A1 WO 2023216910 A1 WO2023216910 A1 WO 2023216910A1 CN 2023091338 W CN2023091338 W CN 2023091338W WO 2023216910 A1 WO2023216910 A1 WO 2023216910A1
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alkyl
haloalkyl
halogen
cycloalkyl
alkoxy
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PCT/CN2023/091338
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French (fr)
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刘彬
高峰
郭永起
景连栋
吴勇勇
王静
张鹏志
李治中
高宇
吴卓
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苏州浦合医药科技有限公司
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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
    • A61K31/495—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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/08—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to USP1 inhibitors, specifically substituted bicyclic heteroaryl compounds represented by formula (A), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorphs, hydrates or solvates.
  • the present invention also relates to methods for preparing the compounds, pharmaceutical compositions containing the compounds, and the effects of the compounds in the prevention and treatment of related cancers.
  • Synthetic lethality has been an important direction in the field of tumor treatment in recent years.
  • the application of this type of drugs generally requires specific tumor biomarkers for patient selection. While producing good drug effects, it can significantly expand the therapeutic safety window of the drug and also increase the number of patients.
  • Accessibility of drug development for certain targets with high mutation rates but difficult to drug (Nat Rev Drug Discov.2020 Jan; 19(1):23-38) (Cancer Discov.2021 Jul;11(7):1626-1635 ).
  • PARP1/2 inhibitors such as Olaparib, Rucaparib, Niraparib, etc. are currently the most successful cases in the field of synthetic lethality. These drugs have achieved excellent efficacy in the treatment of BRCA1/2 mutated ovarian cancer, breast cancer, etc., and have been approved for marketing.
  • Ubiquitin Specific Protease 1 (USP1) is also an important protease involved in DNA damage repair.
  • TLS translesion synthesis
  • intrastrand crosslink repair intrastrand crosslink repair
  • USP1-selective inhibitors will bring significant clinical benefits.
  • USP1 inhibitor of the present invention has high activity, good pharmacokinetic properties, and excellent anti-tumor effect.
  • the invention provides a compound of formula (A), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof Object:
  • X 2 and X 3 are each independently selected from CR 2 or N;
  • Ring A is a 5-6 membered heteroaryl group or a 5-6 membered heterocyclyl group, and when Ring A is a 5-membered heteroaryl group, Ring A and the pyrimidine ring are formed together
  • the ring A is optionally substituted by 1, 2, 3, 4 or 5 R2 ;
  • Ring B is a 5-12 membered heteroaryl group
  • Ring C is a 5-6 membered heteroaryl group
  • L is CH 2 or SO 2 , and the CH 2 may be optionally replaced by 1 or 2 R#;
  • Each R 1 is independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl , C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 1 can optionally be replaced by 1 , 2, 3, 4 or 5 R* substitutions;
  • Each R 2 is independently selected from H, D, halogen, CN, OR a , NR a R b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 Haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)R a , -C(O)OR a , -OC(O)R a , -C(O)NR a R b , -(CH 2 ) 1-6 -OR a , -(CH 2 ) 1-6 -C(O)R a , -(CH 2 ) 1-6 -C(O)OR a , -(CH 2 ) 1-6 -OC(O)R a , -(CH 2 ) 1-6 -C(O)NR a R b , -(CH 2 ) 1-6 -CN, -(CH 2 ) 1- 6 - NR
  • Each R 3 is independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl , C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 3 can optionally be replaced by 1 , 2, 3, 4, 5, 6, 7, 8 or more R* substitutions;
  • one R 2 and one R 3 together with the atoms to which they are respectively connected form a 6-12 membered heterocyclyl group or a 6-12 membered heteroaryl group;
  • R 4 is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 4 can optionally be replaced by 1, 2, 3, 4 or 5 R*replacement;
  • R# is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R* is selected from H, D, halogen, NH 2 , CN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 ring Alkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • R a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R a and R b together with the nitrogen atom to which they are connected form a 5-10 membered heterocyclyl group or a 5-10 membered heterocyclyl group;
  • n 1, 2 or 3;
  • n 1, 2, 3 or 4;
  • p 1 or 2.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compound:
  • X 2 and X 3 are each independently selected from CR 2 or N;
  • Ring A is a 5-6 membered heteroaryl group, and when Ring A is a 5-membered heteroaryl group, Ring A and the pyrimidine ring form together
  • Ring B is a 5-6 membered heteroaryl group
  • L is CH 2 or SO 2 , and the CH 2 may be optionally replaced by 1 or 2 R#;
  • Each R 1 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 1 can optionally be replaced by 1, 2 1, 3, 4 or 5 R* substitutions;
  • Each R is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, or C 2-6 alkynyl, the R 2 may be optionally substituted by 1, 2, 3, 4 or 5 R*;
  • Each R 3 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 3 can optionally be replaced by 1, 2 1, 3, 4 or 5 R* substitutions;
  • R 4 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl group, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 4 may optionally be replaced by 1, 2, 3, 4 or 5 R* replace;
  • R# is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R* is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • n 1, 2 or 3;
  • n 1, 2, 3 or 4;
  • p 1 or 2.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient.
  • the invention provides pharmaceutical compositions containing a compound of the invention and a pharmaceutically acceptable excipient, further comprising other therapeutic agents.
  • the invention provides the use of a compound of the invention for the preparation of a medicament for the treatment and/or prevention of USP1-mediated diseases.
  • the invention provides a method of treating and/or preventing a USP1-mediated disease in a subject, comprising administering to said subject a compound of the invention or a composition of the invention.
  • the invention provides a compound of the invention or a composition of the invention for use in the treatment and/or prevention of USP1-mediated diseases.
  • diseases treated by the present invention include cancers selected from the group consisting of: blood cancer, lymphoma, bladder cancer, ovarian cancer, breast cancer, bone cancer (such as osteosarcoma and chondrosarcoma), brain cancer (such as neuroblastoma) stromal tumors, glioblastoma, astrocytoma, medulloblastoma and meningiomas), soft tissue cancers (e.g. rhabdoid sarcoma), kidney cancer, bladder cancer, skin cancer (e.g. melanoma), lung cancer (such as non-small cell lung cancer), colon cancer, uterine cancer, neurological cancer, head and neck cancer, pancreatic cancer, and cervical cancer.
  • cancers selected from the group consisting of: blood cancer, lymphoma, bladder cancer, ovarian cancer, breast cancer, bone cancer (such as osteosarcoma and chondrosarcoma), brain cancer (such as neuroblastoma) stromal tumors, glioblastoma,
  • C 1-6 alkyl includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1 -2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5, C 3-4 , C 4-6 , C 4-5 and C 5 -6 alkyl.
  • C 1-6 alkyl refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 alkyl and C 1-2 alkyl are preferred. Examples of C 1-6 alkyl groups include: methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl base (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl ( C 5 ), 3-methyl-2-butyl (C 5 ), tert-pentyl (C 5 ) and n-hexyl (C 6 ).
  • C 1-6 alkyl also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) substitution.
  • Alkyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • alkyl abbreviations include: Me(-CH 3 ), Et(-CH 2 CH 3 ), iPr(-CH(CH 3 ) 2 ), nPr(-CH 2 CH 2 CH 3 ), n-Bu(-CH 2 CH 2 CH 2 CH 3 ) or i-Bu(-CH 2 CH(CH 3 ) 2 ).
  • C 2-6 alkenyl refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 alkenyl is preferred. Examples of C 2-6 alkenyl groups include: vinyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), etc.
  • C 2-6 alkenyl also includes Heteroalkenyl, in which one or more (eg, 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (eg, oxygen, sulfur, nitrogen, boron, silicon, phosphorus).
  • Alkenyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 2-6 alkynyl refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 alkynyl is preferred. Examples of C 2-6 alkynyl groups include, but are not limited to: ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-Butynyl (C 4 ), pentynyl (C 5 ), hexynyl (C 6 ), etc.
  • C 2-6 alkynyl also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) substitution.
  • An alkynyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • Halo or "halogen” refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • C 1-6 haloalkyl refers to the above-mentioned "C 1-6 alkyl” which is substituted by one or more halogen groups.
  • C 1-4 haloalkyl is particularly preferred, with C 1-2 haloalkyl being more preferred.
  • Exemplary haloalkyl groups include, but are not limited to: -CF 3 , -CH 2 F, -CHF 2 , -CHFCH 2 F, -CH 2 CHF 2 , -CF 2 CF 3 , -CCl 3 , -CH 2 Cl , -CHCl 2 , 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc.
  • Haloalkyl groups may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 1-6 alkoxy refers to the group -OR, where R is C 1-6 alkyl as defined above. C 1-4 alkoxy is preferred.
  • C 1-6 haloalkoxy refers to the above-mentioned "C 1-6 alkoxy” which is substituted by one or more halogen groups. In some embodiments, C 1-4 haloalkoxy is particularly preferred, with C 1-2 haloalkoxy being more preferred. Exemplary haloalkoxy groups include, but are not limited to: -OCF 3 , -OCH 2 F, -OCHF 2 , -OCHFCH 2 F, -OCH 2 CHF 2 , -OCF 2 CF 3 , -OCCl 3 , -OCH 2 Cl, -OCHCl 2 , 2,2,2-trifluoro-1,1-dimethyl-ethoxy, etc. Haloalkoxy groups may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 3-10 cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 5-7 cycloalkyl, C 3-7 cycloalkyl and C 3-5 cycloalkyl are particularly preferred, with C 5-6 cycloalkyl being more preferred. Cycloalkyl also includes ring systems in which the above-described cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues as indicated The number of carbons in a cycloalkyl system.
  • Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl ( C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptene group (C 7 ), cycloheptadienyl (C 7 ), cycloheptadienyl (C 7 ), etc.
  • a cycloalkyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • 3-12-membered heterocyclyl refers to a group of 3-12-membered non-aromatic ring system having ring carbon atoms and 1 to 6 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, Sulfur, boron, phosphorus and silicon.
  • the point of attachment may be a carbon or nitrogen atom as long as the valency permits.
  • 3-10 membered heterocyclyl is preferred, which is a 3-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 6-12 membered is preferred Heterocyclyl, which is a 6 to 12 membered non-aromatic ring system having ring carbon atoms and 1 to 6 ring heteroatoms; in some embodiments, 4 to 9 membered heterocyclyl is preferred, which is a 6 to 12 membered non-aromatic ring system having ring carbon atoms and 1 to 6 ring heteroatoms.
  • 3-8 membered non-aromatic ring system in some embodiments, 3-8 membered heterocyclyl is preferred, which is a 3-8 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; 3-7 membered is preferred Heterocyclyl, which is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 3-5-membered heterocyclyl, which is a 3- to 5-membered non-aromatic ring system having ring carbon atoms and 1 to 2 ring heteroatoms.
  • Heterocyclyl also includes ring systems in which the above-described heterocyclyl ring is fused with one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or in which the above-described heterocyclyl ring is fused with one or more aryl groups or Heteroaryl fused ring systems wherein the point of attachment is on the heterocyclyl ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system.
  • Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to: aziridinyl, oxirinyl, and thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to: tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-diketone.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: dioxolyl, oxasulfuranyl, disulfuranyl, and oxalanyl.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • the one-membered heterocyclyl group includes, but is not limited to: hexahydrotriazinyl (triazinanyl).
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azepanyl, oxpanyl, and thipanyl.
  • Exemplary 5-membered heterocyclyl fused to a C6 aryl ring include, but are not limited to: indolyl, isoindolyl , dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, etc.
  • Exemplary 6-membered heterocyclyl fused to a C6 aryl ring include, but are not limited to: tetrahydroquinolyl, tetrahydroisoquinolyl, etc.
  • Heterocyclyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 6-10 aryl refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system having 6-10 ring carbon atoms and zero heteroatoms (e.g., having a Shared 6 or 10 ⁇ electrons) group.
  • an aryl group has six ring carbon atoms ("C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms ("C 10 aryl”; eg, naphthyl, eg, 1-naphthyl and 2-naphthyl).
  • Aryl also includes ring systems in which the aryl ring described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on said aryl ring, in which case the number of carbon atoms continues to indicate The number of carbon atoms in the aryl ring system.
  • Aryl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • 5-12 membered heteroaryl refers to a 5-12 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-5 ring heteroatoms (e.g., having a 6, 10 or 14 ⁇ electrons), wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • the point of attachment may be a carbon or nitrogen atom as long as the valency permits.
  • Heteroaryl bicyclic systems may include one or more heteroatoms in one or both rings.
  • Heteroaryl also includes ring systems in which the heteroaryl ring described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the carbon atom Number continues to represent the number of carbon atoms in the heteroaryl ring system.
  • 5-10 membered heteroaryl groups are preferred, which are 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms.
  • 6-12 membered heteroaryl groups are preferred, which are 6-12 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms.
  • 5-9 membered heteroaryl groups are preferred, which are 5-9 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms.
  • 5-6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrolyl, furyl, and thienyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl (eg, 1,2,4-oxadiazolyl), and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azepantrienyl, oxetapyltrienyl, and thioheptantrienyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , benzisofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Indazinyl and purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pyridinyl, quinolinyl, isoquinolinyl, quinolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl .
  • Heteroaryl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, etc. are defined herein as optionally substituted groups.
  • Each R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa groups are combined to form heterocyclyl or Heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd groups group replacement;
  • Each R cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups are combined to form a heterocycle or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;
  • Each R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl Alkyl, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups;
  • Each R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ff groups combine to form a heterocyclyl or a heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;
  • the term "pharmaceutically acceptable salts” means those carboxylate salts and amino acid addition salts of the compounds of the present invention which are suitable for contact with patient tissue within the scope of reliable medical judgment and will not produce undue toxicity, Irritation, allergic reaction, etc., combined with be commensurate with their therapeutic benefit/risk ratio and be effective for their intended use, including, where possible, zwitterionic forms of the compounds of the invention.
  • Subjects for administration include, but are not limited to: humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young Adults, middle-aged adults or older adults) and/or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep , goats, rodents, cats and/or dogs.
  • the subject is human.
  • the subject is a non-human animal.
  • the terms "person,” “patient,” and “subject” are used interchangeably herein.
  • an "effective amount" of a compound is an amount sufficient to elicit a target biological response.
  • the effective amount of a compound of the present invention may vary depending on factors such as, for example, the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the condition of the subject. Age health conditions and symptoms.
  • the effective amount includes a therapeutically effective amount and a preventive effective amount.
  • Combination and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent.
  • the compounds of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or with other therapeutic agents in a single unit dosage form.
  • the "compound of the present invention” refers to the following compound of formula (A) (including sub-general formulas, such as formula (I), formula (II), formula (III), formula (III-1), formula (III -2), formula (III-3), formula (IV), formula (V) or formula (VI), etc.), their pharmaceutically acceptable salts, enantiomers, diastereomers, solvents compounds, hydrates or isotopic variants, and mixtures thereof.
  • the present invention relates to a compound of formula (A), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compound:
  • X 2 and X 3 are each independently selected from CR 2 or N;
  • Ring A is a 5-6 membered heteroaryl group or a 5-6 membered heterocyclyl group, and when Ring A is a 5-membered heteroaryl group, Ring A and the pyrimidine ring are formed together
  • the ring A is optionally substituted by 1, 2, 3, 4 or 5 R2 ;
  • Ring B is a 5-12 membered heteroaryl group
  • Ring C is a 5-6 membered heteroaryl group
  • L is CH 2 or SO 2 , and the CH 2 may be optionally replaced by 1 or 2 R#;
  • Each R 1 is independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl , C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 1 can optionally be replaced by 1 , 2, 3, 4 or 5 R* substitutions;
  • Each R 2 is independently selected from H, D, halogen, CN, OR a , NR a R b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 Haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)R a , -C(O)OR a , -OC(O)R a , -C(O)NR a R b , -(CH 2 ) 1-6 -OR a , -(CH 2 ) 1-6 -C(O)R a , -(CH 2 ) 1-6 -C(O)OR a , -(CH 2 ) 1-6 -OC(O)R a , -(CH 2 ) 1-6 -C(O)NR a R b , -(CH 2 ) 1-6 -CN, -(CH 2 ) 1- 6 - NR
  • Each R 3 is independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl , C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 3 can optionally be replaced by 1 , 2, 3, 4, 5, 6, 7, 8 or more R* substitutions;
  • one R 2 and one R 3 together with the atoms to which they are respectively connected form a 6-12 membered heterocyclyl group or a 6-12 membered heteroaryl group;
  • R 4 is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 4 can optionally be replaced by 1, 2, 3, 4 or 5 R*replacement;
  • R# is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R* is selected from H, D, halogen, NH 2 , CN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 ring Alkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • R a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R a and R b together with the nitrogen atom to which they are connected form a 5-10 membered heterocyclyl group or a 5-10 membered heterocyclyl group;
  • n 1, 2 or 3;
  • n 1, 2, 3 or 4;
  • p 1 or 2.
  • the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or Solvates:
  • X 2 and X 3 are each independently selected from CR 2 or N;
  • Ring A is a 5-6 membered heteroaryl group, and when Ring A is a 5-membered heteroaryl group, Ring A and the pyrimidine ring form together
  • Ring B is a 5-6 membered heteroaryl group
  • L is CH 2 or SO 2 , and the CH 2 may be optionally replaced by 1 or 2 R#;
  • Each R 1 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 1 can optionally be replaced by 1, 2 1, 3, 4 or 5 R* substitutions;
  • Each R is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, or C 2-6 alkynyl, the R 2 may be optionally substituted by 1, 2, 3, 4 or 5 R*;
  • Each R 3 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 3 can optionally be replaced by 1, 2 1, 3, 4 or 5 R* substitutions;
  • R 4 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl group, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 4 may optionally be replaced by 1, 2, 3, 4 or 5 R* replace;
  • R# is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R* is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • n 1, 2 or 3;
  • n 1, 2, 3 or 4;
  • p 1 or 2.
  • X 1 is C; in another specific embodiment, is a single bond, and X 1 is N.
  • X2 is CR2 , such as CH; in another specific embodiment, X2 is N.
  • X3 is CR2 , such as CH; in another specific embodiment, X3 is N.
  • X4 is CR2 , such as CH; in another specific embodiment, X4 is N.
  • X5 is CR2 , such as CH; in another specific embodiment, X5 is N.
  • X 6 is C; in another specific embodiment, X 6 is N.
  • X7 is C; in another specific embodiment, X7 is N.
  • L is CH 2 and the CH 2 is unsubstituted; in another embodiment, L is CH 2 and the CH 2 is substituted with 1 R#; in another embodiment, L is CH2 , and the CH2 is replaced by 2 R#; in another specific embodiment, L is SO2 .
  • Ring A is a 5-membered heteroaryl, and Ring A and the pyrimidine ring together form In another specific embodiment, Ring A is 6 membered heteroaryl.
  • Ring A is a 5-6 membered heterocyclyl.
  • Ring A is unsubstituted; in another specific embodiment, Ring A is substituted with 1 R; in another specific embodiment, Ring A is substituted with 2 R; in another In a specific embodiment, Ring A is substituted with 3 R 2 ; in another specific embodiment, Ring A is substituted with 4 R 2 ; in another specific embodiment, Ring A is substituted with 5 R 2 .
  • Ring B is 5-12 membered heteroaryl.
  • Ring B is a 5-membered heteroaryl; in another specific embodiment, Ring B is a 6-membered heteroaryl.
  • Ring C is 5-6 membered heteroaryl.
  • R 1 is H; in another specific embodiment, R 1 is D; in another specific embodiment, R 1 is halogen; in another specific embodiment, R 1 is C 1-6 alkyl; in another specific embodiment, R 1 is C 1-4 alkyl group; in another specific embodiment, R 1 is C 1-6 haloalkyl; in another specific embodiment, R 1 is C 1-4 haloalkyl; in another specific embodiment, R 1 is C 1-6 alkoxy; in another specific embodiment, R 1 is C 1-4 alkoxy, preferably C 1-2 alkoxy, such as methoxy; in another specific embodiment, R 1 is C 1-6 haloalkoxy; in another embodiment, R 1 is C 1-4 haloalkoxy; in another embodiment, R 1 is C 2-6 alkenyl; in another In a specific embodiment, R 1 is C 2-6 alkynyl; in another specific embodiment, R 1 is C 3-10 cycloalkyl; in another specific embodiment, R 1 is C 3-7 cycloalkyl Alkyl; in another
  • R 1 is unsubstituted; in another specific embodiment, R 1 is substituted with 1 R*; in another specific embodiment, R 1 is substituted with 2 R*; in another specific embodiment, R 1 is substituted with 2 R* In a specific embodiment, R 1 is substituted with 3 R*; in another specific embodiment, R 1 is substituted with 4 R*; in another specific embodiment, R 1 is substituted with 5 R*.
  • R 1 ' is halogen; in another embodiment, R 1 ' is C 1-6 alkoxy; in another embodiment, R 1 ' is C 1-4 alkyl Oxy group; in another specific embodiment, R 1 ' is C 1-6 haloalkoxy; in another specific embodiment, R 1 ' is C 1-4 haloalkoxy; in another specific embodiment , R 1 ' is C 3-7 cycloalkyl; in another specific embodiment, R 1 ' is C 3-5 cycloalkyl; in another specific embodiment, R 1 ' is 3-7 membered hetero Cyclyl; in another specific embodiment, R 1 ' is 3-5 membered heterocyclyl.
  • R 1 ' is unsubstituted; in another embodiment, R 1 ' is substituted with 1 halogen; in another embodiment, R 1 ' is substituted with 2 halogens; in another embodiment, R 1 ' is substituted with 1 halogen. In a specific embodiment, R 1 ' is substituted with 3 halogens.
  • R 2 is H; in another specific embodiment, R 2 is D; in another specific embodiment, R 2 is halogen, such as F; in another specific embodiment, R 2 is CN; in another specific embodiment, R 2 is OR a ; in another specific embodiment, R 2 is NR a R b ; in another specific embodiment, R 2 is C 1-6 alkane group; in another specific embodiment, R 2 is C 1-4 alkyl; in another specific embodiment, R 2 is C 1-6 haloalkyl; in another specific embodiment, R 2 is C 1-4 haloalkyl; in another embodiment, R 2 is C 1-6 alkoxy; in another embodiment, R 2 is C 1-4 alkoxy; in another embodiment In another specific embodiment, R 2 is C 1-6 haloalkoxy; in another specific embodiment, R 2 is C 1-4 haloalkoxy; in another specific embodiment, R 2 is C 2-6 alkenyl; In another specific embodiment, R 2 is C 2-6 alkynyl; in another specific embodiment, R 2 is -C
  • R 2 is H; in another specific embodiment, R 2 is F; in another specific embodiment, R 2 is NH 2 ; in another specific embodiment, R 2 is CHF 2 ; in another specific embodiment, R 2 is In another specific embodiment, R2 is In another specific embodiment, R2 is In another specific embodiment, R2 is In another specific embodiment, R2 is In another specific embodiment, R2 is In another specific embodiment, R2 is In another specific embodiment, R2 is In another specific embodiment, R2 is In another specific embodiment, R2 is In another specific embodiment, R2 is In another specific embodiment, R2 is In another specific embodiment, R2 is H; in another specific embodiment, R 2 is F; in another specific embodiment, R 2 is NH 2 ; in another specific embodiment, R 2 is CHF 2 ; in another specific embodiment, R 2 is In another specific embodiment, R2 is In another specific embodiment, R2 is In another specific embodiment, R2 is In another specific embodiment, R2 is In another specific embodiment, R2 is In another specific embodiment, R2 is H; in another specific embodiment, R 2 is F; in another specific
  • R is unsubstituted; in another embodiment, R is substituted with 1 R*; in another embodiment, R is substituted with 2 R*; in another In a specific embodiment, R2 is replaced by 3 R*; in another specific embodiment In one embodiment, R is substituted with 4 R*; in another embodiment, R is substituted with 5 R*; in another embodiment, R is substituted with 6 R*; in another In a specific embodiment, R 2 is substituted with 7 R*; in another specific embodiment, R 2 is substituted with 8 R*; in another specific embodiment, R 2 is substituted with more R*.
  • R 2 ' is H; in another embodiment, R 2 ' is halogen; in another embodiment, R 2 ' is C 1-6 alkyl; in another embodiment In embodiments, R 2 ' is C 1-4 alkyl.
  • R 3 is H; in another specific embodiment, R 3 is D; in another specific embodiment, R 3 is halogen; in another specific embodiment, R 3 is C 1-6 alkyl; in another specific embodiment, R 3 is C 1-4 alkyl; in another specific embodiment, R 3 is C 1-6 haloalkyl; in another specific embodiment, R 3 is C 1-4 haloalkyl, such as CF 3 ; in another embodiment, R 3 is C 1-6 alkoxy; in another embodiment, R 3 is C 1-4 alkoxy group; in another specific embodiment, R 3 is C 1-6 haloalkoxy; in another specific embodiment, R 3 is C 1-4 haloalkoxy; in another specific embodiment, R 3 is C 2-6 alkenyl; in another embodiment, R 3 is C 2-6 alkynyl; in another embodiment, R 3 is C 3-10 cycloalkyl; in another embodiment In the embodiment, R 3 is a C 3-7 cycloalkyl group; in another specific embodiment, R 3 is a 3-10 member
  • R 3 is CH 3 ; in another specific embodiment, R 3 is CD 3 ; in another specific embodiment, R 3 is CF 3 ; in another specific embodiment, R 3 is CHF 2 ; in another specific embodiment, R 3 is CH 2 CH 3 ; in another specific embodiment, R 3 is CH(CH 3 ) 2 ; in another specific embodiment, R 3 is cyclopropyl; in another specific embodiment, R 3 is In another specific embodiment, R3 is CH 3 ; in another specific embodiment, R 3 is CD 3 ; in another specific embodiment, R 3 is CF 3 ; in another specific embodiment, R 3 is CHF 2 ; in another specific embodiment, R 3 is CH 2 CH 3 ; in another specific embodiment, R 3 is CH(CH 3 ) 2 ; in another specific embodiment, R 3 is cyclopropyl; in another specific embodiment, R 3 is In another specific embodiment, R3 is CH 3 ; in another specific embodiment, R 3 is CD 3 ; in another specific embodiment, R 3 is CF 3 ; in another specific embodiment, R 3 is CHF 2 ; in
  • one R 2 and one R 3 together with the atoms to which they are respectively attached form a 6-12 membered heterocyclyl or a 6-12 membered heteroaryl.
  • R 3 is unsubstituted; in another embodiment, R 3 is substituted with 1 R*; in another embodiment, R 3 is substituted with 2 R*; in another In a specific embodiment, R3 is replaced by 3 R*; in another specific embodiment, R3 is replaced by 4 R*; in another specific embodiment, R3 is replaced by 5 R*; in another specific embodiment, R3 is replaced by 5 R*; In one embodiment, R 3 is substituted with 6 R*; in another embodiment, R 3 is substituted with 7 R*; in another embodiment, R 3 is substituted with 8 R*; in In another specific embodiment, R3 is replaced by more R*.
  • R 4 is H; in another specific embodiment, R 4 is D; in another specific embodiment, R 4 is halogen; in another specific embodiment, R 4 is C 1-6 alkyl; in another specific embodiment, R 4 is C 1-4 alkyl; in another specific embodiment, R 4 is C 1-6 haloalkyl; in another specific embodiment, R 4 is C 1-4 haloalkyl; in another embodiment, R 4 is C 1-6 alkoxy; in another embodiment, R 4 is C 1-4 alkoxy; in another embodiment In one specific embodiment, R 4 is C 2-6 alkenyl; in another specific embodiment, R 4 is C 2-6 alkynyl; in another specific embodiment, R 4 is C 3-10 ring Alkyl; in another specific embodiment, R 4 is C 3-7 cycloalkyl; in another specific embodiment, R 4 is 3-10 membered heterocyclyl; in another specific embodiment, R 4 is a 3-7 membered heterocyclyl group; in another specific embodiment, R 4 is a C 6-10 aryl group; in
  • R 4 is unsubstituted; in another embodiment, R 4 is substituted with 1 R*; in another embodiment, R 4 is substituted with 2 R*; in another In a specific embodiment, R 4 is substituted with 3 R*; in another specific embodiment, R 4 is substituted with 4 R*; in another specific embodiment, R 4 is substituted with 5 R*.
  • R# is H; in another embodiment, R# is D; in another embodiment, R# is halogen; in another embodiment, R# is C 1-6 alkyl; in another specific embodiment, R# is C 1-4 alkyl; in another specific embodiment, R# is C 1-6 haloalkyl; in another specific embodiment, R# is C 1-4 haloalkyl; in another embodiment, R# is C 2-6 alkenyl; in another embodiment, R# is C 2-6 alkynyl;
  • R* is H; in another embodiment, R* is D; in another embodiment, R* is halogen; in another embodiment, R* is NH 2 ; In another specific embodiment, R* is CN; In another specific embodiment, R* is OH; In another specific embodiment, R* is C 1-6 alkyl; In another specific embodiment, R* is C 1-4 alkyl; in another specific embodiment, R* is C 1-6 haloalkyl; in another specific embodiment, R* is C 1-4 haloalkyl; In another specific embodiment, R* is C 2-6 alkenyl; in another specific embodiment, R* is C 2-6 alkynyl; in another specific embodiment, R* is C 3- 10 cycloalkyl; in another embodiment, R* is 5-10 membered heterocyclyl; in another embodiment, R* is C 6-10 aryl; in another embodiment, R* is a 5-10 membered heteroaryl group.
  • R a is H; in another specific embodiment, R a is C 1-6 alkyl; in another specific embodiment, R a is C 1-6 haloalkyl.
  • R b is H; in another specific embodiment, R b is C 1-6 alkyl; in another specific embodiment, R b is C 1-6 haloalkyl.
  • R a and R b together with the nitrogen atom to which they are connected form a 5-10 membered heterocyclyl; in another specific embodiment, R a and R b together with the nitrogen atom to which they are connected form 5 -10-membered heterocyclyl.
  • n is 1; in another specific embodiment, m is 2; in another specific embodiment, m is 3.
  • n is 1; in another specific embodiment, n is 2; in another specific embodiment, n is 3; in another specific embodiment, n is 4.
  • p is 1; in another specific embodiment, p is 2.
  • any technical solution or any combination thereof in any of the above specific embodiments may be combined with any technical solution or any combination thereof in other specific embodiments.
  • any technical solution of X 1 or any combination thereof can be combined with X 2 -X 7 , ring A, ring B, ring C, L, R 1 , R 1 ', R 2 , R 2 ', R 3 , Any technical solution of R 4 , R#, R*, R a , R b , m, n, p, etc. or any combination thereof can be combined.
  • the present invention is intended to include combinations of all these technical solutions, and due to space limitations, they will not be listed one by one.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate:
  • X 2 and X 3 are each independently selected from CR 2 or N;
  • Ring A is a 5-6 membered heteroaryl group, and when Ring A is a 5-membered heteroaryl group, Ring A and the pyrimidine ring form together
  • Ring B is a 5-6 membered heteroaryl group
  • L is CH 2 or SO 2 , and the CH 2 may be optionally replaced by 1 or 2 R#;
  • Each R 1 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 1 can optionally be replaced by 1, 2 1, 3, 4 or 5 R* substitutions;
  • Each R is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, or C 2-6 alkynyl, the R 2 may be optionally substituted by 1, 2, 3, 4 or 5 R*;
  • Each R 3 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 3 can optionally be replaced by 1, 2 1, 3, 4 or 5 R* substitutions;
  • R 4 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl group, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 4 may optionally be replaced by 1, 2, 3, 4 or 5 R* replace;
  • R# is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R* is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • n 1, 2 or 3;
  • n 1, 2, 3 or 4;
  • p 1 or 2.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrates or solvates, wherein:
  • X 2 and X 3 are each independently selected from CR 2 or N, as long as chemically permitted;
  • Ring A is a 5-6 membered heteroaryl group, and when Ring A is a 5-membered heteroaryl group, Ring A and the pyrimidine ring form together
  • Ring B is a 5-6 membered heteroaryl group
  • L is CH 2 or SO 2 , and the CH 2 may be optionally replaced by 1 or 2 R#;
  • Each R 1 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl, the R 1 may be optionally substituted by 1, 2, 3, 4 or 5 R*;
  • Each R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • Each R 3 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, and 3-10 membered heterocyclyl, the R 3 may be optionally substituted by 1, 2, 3, 4 or 5 R*;
  • R 4 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl and 3-10 membered heterocyclyl, and the R 4 can optionally be replaced by 1, 2, 3, 4 or 5 R* substitutions;
  • R# is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R* is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 1, 2 or 3;
  • n 1, 2, 3 or 4;
  • p 1 or 2.
  • the present invention provides the above-mentioned compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrates or solvates having the following general formula:
  • X 4 and X 5 are each independently selected from CR 2 or N;
  • X 6 and X 7 are each independently selected from C or N;
  • R 1 ' is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl or 3-7 membered hetero Cyclic group, the R 1 ' may be optionally substituted by 1, 2 or 3 halogens;
  • R 3 ' is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • the invention provides compounds of formula (II), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates thereof substance or solvate:
  • X 2 , X 3 , X 4 and X 5 are each independently selected from CR 2 or N;
  • L is CH 2 or SO 2 , and the CH 2 may be optionally replaced by 1 or 2 R#;
  • Ring B is a 5-6 membered heteroaryl group
  • Each R 1 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, or 3-7 membered heterocyclyl, the R 1 may be optionally substituted by 1, 2 or 3 R*;
  • Each R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • Each R 3 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, and 3-7 membered heterocyclyl, the R 3 may be optionally substituted by 1, 2 or 3 R*;
  • R# is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R* is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 1, 2 or 3;
  • n 1, 2, 3 or 4;
  • p 1 or 2;
  • the invention provides compounds of formula (III), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates thereof substance or solvate:
  • X2 , X3 , X4 and X5 are each independently selected from CH or N, and when X2 and
  • X 6 and X 7 are each independently selected from C or N;
  • L is CH 2 or SO 2 , and the CH 2 may be optionally replaced by 1 or 2 R#;
  • R 1 is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • R 1 ' is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl or 3-7 membered hetero Cyclic group, the R 1 ' may be optionally substituted by 1, 2 or 3 halogens;
  • R 2 is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 3 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclyl, and the R 3 can optionally be replaced by 1, 2 or 3 Substituted with a substituent selected from D or C 1-6 alkyl;
  • R 3 ' is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R# is selected from H or C 1-6 alkyl
  • p 1 or 2;
  • the present invention provides the compound of formula (III) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrates or solvates, wherein:
  • X2 , X3 , X4 and X5 are each independently selected from CH or N, and when X2 and
  • X 6 and X 7 are each independently selected from C or N, and at least one of X 6 and X 7 is N;
  • L is CH 2 , which may be optionally replaced by 1 or 2 R#;
  • R 1 is selected from C 1-4 alkoxy or C 1-4 haloalkoxy
  • R 1 ' is selected from C 1-4 alkoxy, C 3-5 cycloalkyl and 3-5 membered heterocyclyl, and R 1 ' can be optionally substituted by 1, 2 or 3 halogens;
  • R 2 is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl
  • R 3 is selected from C 1-4 alkyl, C 3-5 cycloalkyl or 3-5 membered heterocyclyl, and the R 3 can optionally be selected from D or C 1 by 1, 2 or 3 -4 alkyl substituent substitution;
  • R 3 ' is selected from C 1-4 alkyl or C 1-4 haloalkyl
  • R# is selected from H or C 1-4 alkyl
  • p 1 or 2.
  • the present invention provides the compound of formula (III) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrates or solvates, wherein:
  • X2 , X3 , X4 and X5 are each independently selected from CH or N, and when X2 and
  • X 6 and X 7 are each independently selected from C or N, and at least one of X 6 and X 7 is N;
  • L is CH 2 , which may be optionally replaced by 1 or 2 R#;
  • R 1 is selected from C 1-2 alkoxy or C 1-2 haloalkoxy
  • R 1 ' is selected from methoxy, cyclopropyl and
  • R 2 is selected from H or halogen, preferably F;
  • R 3 is selected from CH 3 , CD 3 , CH 2 CH 3 , CH(CH 3 ) 2 , cyclopropyl,
  • R 3 ' is halomethyl, preferably CF 3 or CHF 2 ;
  • R# is selected from H or methyl
  • p 1 or 2.
  • the invention provides compounds of formula (IV), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates thereof substance or solvate:
  • X 4 is CH or N
  • R 1 is C 1-4 alkoxy
  • R 1 ' is C 3-7 cycloalkyl.
  • the present invention provides compounds of the above formula (IV), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrates or solvates, wherein:
  • X 4 is CH or N
  • R 1 is C 1-2 alkoxy, preferably methoxy
  • R 1 ' is C 3-5 cycloalkyl, preferably cyclopropyl.
  • the invention provides compounds of formula (V), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates thereof substance or solvate:
  • Ring A forms together with the pyrimidine ring
  • Ring B is a 5-membered heteroaryl group
  • L is CH 2 or SO 2 , and the CH 2 may be optionally replaced by 1 or 2 R#;
  • Each R 1 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, or 3-7 membered heterocyclyl;
  • Each R 2 is independently selected from H, halogen or C 1-6 alkyl
  • Each R 3 is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R# is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • n 1, 2 or 3;
  • n 1, 2 or 3;
  • p 1, 2, 3 or 4.
  • the invention provides compounds of formula (VI), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates thereof substance or solvate:
  • Ring A forms together with the pyrimidine ring
  • L is CH 2 , which may be optionally substituted by 1 or 2 R#;
  • R 1 is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • R 1 ' is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
  • R 3 is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R 3 ' is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R# is selected from H or C 1-6 alkyl.
  • the present invention provides the above-mentioned compound of formula (VI), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrates or solvates, wherein:
  • Ring A forms together with the pyrimidine ring
  • L is CH 2 , which may be optionally substituted by 1 or 2 R#;
  • R 1 is selected from C 1-6 alkoxy or C 1-6 haloalkoxy
  • R 1 ' is selected from C 3-7 cycloalkyl or 3-7 membered heterocyclyl
  • R 3 is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R 3 ' is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R# is selected from H or C 1-4 alkyl.
  • the present invention provides the above-mentioned compound of formula (VI), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrates or solvates, wherein:
  • Ring A forms together with the pyrimidine ring
  • L is CH 2 ;
  • R 1 is C 1-4 alkoxy, preferably methoxy
  • R 1 ' is C 3-5 cycloalkyl, preferably cyclopropyl
  • R 3 is C 1-4 alkyl, preferably isopropyl
  • R 3 ' is C 1-4 haloalkyl, preferably CF 3 .
  • the invention provides compounds of formula (III), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates thereof substance or solvate:
  • X 2 and X 3 are each independently selected from CR 2 or N;
  • X 4 and X 5 are each independently selected from CR 2 or N;
  • X 6 and X 7 are each independently selected from C or N;
  • L is CH 2 or SO 2 , and the CH 2 may be optionally replaced by 1 or 2 R#;
  • R 1 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkyne base, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 1 can optionally be replaced by 1, 2, or 3 , 4 or 5 R* substitutions;
  • R 1 ' is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl or 3-7 membered hetero Cyclic group, the R 1 ' may be optionally substituted by 1, 2 or 3 halogens;
  • Each R is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, or C 2-6 alkynyl, the R 2 may be optionally substituted by 1, 2, 3, 4 or 5 R*;
  • Each R 3 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 3 can optionally be replaced by 1, 2 1, 3, 4 or 5 R* substitutions;
  • R 3 ' is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R# is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R* is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • p 1 or 2;
  • the present invention provides the compound of formula (III) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrates or solvates, wherein:
  • X 2 is CR 2 ;
  • X 3 is selected from CR 2 or N;
  • X 4 is selected from CR 2 or N;
  • X 5 is CR 2 ;
  • X 6 and X 7 are each independently selected from C or N;
  • L is CH 2 or SO 2 , and the CH 2 may be optionally replaced by 1 or 2 R#;
  • R 1 is selected from H, halogen, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 yuan Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 1 may be optionally substituted by 1, 2, 3, 4 or 5 R*;
  • R 1 ' is halogen, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, and the R 1 ' can optionally be replaced by 1 , 2 or 3 halogen substitutions;
  • Each R is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, or C 2-6 alkynyl, the R 2 may be optionally substituted by 1, 2, 3, 4 or 5 R*;
  • Each R 3 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 3 can optionally be replaced by 1, 2 1, 3, 4 or 5 R* substitutions;
  • R 3 ' is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R# is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R* is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • p 1 or 2.
  • the invention provides compounds of formula (III-1), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs thereof , hydrate or solvate:
  • X 2 is CR 2 ;
  • X 3 is selected from CR 2 or N;
  • X 4 is selected from CR 2 or N;
  • X 5 is CR 2 ;
  • L is CH 2 or SO 2 , and the CH 2 may be optionally replaced by 1 or 2 R#;
  • R 1 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkyne base, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 1 can optionally be replaced by 1, 2, or 3 , 4 or 5 R* substitutions;
  • R 1 ' is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl or 3-7 membered hetero Cyclic group, the R 1 ' may be optionally substituted by 1, 2 or 3 halogens;
  • Each R is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, or C 2-6 alkynyl, the R 2 may be optionally substituted by 1, 2, 3, 4 or 5 R*;
  • Each R 3 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 yuan Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 3 may be optionally substituted by 1, 2, 3, 4 or 5 R*;
  • R 3 ' is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R# is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R* is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • p 1 or 2;
  • the present invention provides the compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein:
  • X 2 and X 3 are CR 2 ;
  • X 4 is selected from CR 2 or N;
  • X 5 is CR 2 ;
  • L is CH 2 , which may be optionally replaced by 1 or 2 R#;
  • R 1 is selected from C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, and R 1 can optionally be replaced by 1 or 2 or 3 R* substitutions;
  • R 1 ' is selected from C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, and the R 1 ' can optionally be replaced by 1, 2 or 3 halogen substitutions;
  • Each R 2 is independently selected from H, halogen or C 1-6 alkyl, preferably H;
  • R 3 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, and the R 3 can optionally be replaced by 1 or 2 , 3, 4 or 5 R* substitutions;
  • R 3 ' is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R# is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R* is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • p 1 or 2.
  • the present invention provides the compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein:
  • X 2 and X 3 are CR 2 ;
  • X 4 and X 5 are CR 2 ;
  • L is CH 2 , which may be optionally replaced by 1 or 2 R#;
  • R 1 is selected from C 1-6 alkoxy or C 1-6 haloalkoxy, and R 1 may be optionally substituted by 1, 2 or 3 R*;
  • R 1 ' is selected from C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, and the R 1 ' can optionally be replaced by 1, 2 or 3 halogen substitutions;
  • Each R 2 is independently selected from H, halogen or C 1-6 alkyl, preferably H;
  • R 3 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, and the R 3 can optionally be replaced by 1, 2, 3, 4 or 5 R* substitutions;
  • R 3 ' is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R# is selected from H or C 1-6 alkyl
  • R* is selected from H, D or C 1-6 alkyl
  • p 1 or 2.
  • the present invention provides the compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein:
  • X 2 and X 3 are CR 2 ;
  • X 4 is CR 2 ;
  • X 5 is CR 2 ;
  • L is CH 2 ;
  • R 1 is selected from C 1-6 alkoxy or C 1-6 haloalkoxy, and R 1 may be optionally substituted by 1, 2 or 3 R*;
  • R 1 ' is selected from C 1-6 alkoxy or C 3-7 cycloalkyl
  • Each R 2 is independently selected from H, halogen or C 1-6 alkyl, preferably H;
  • R 3 is selected from H, C 1-6 alkyl or C 3-10 cycloalkyl, and the R 3 can be optionally substituted by 1, 2 or 3 R*;
  • R 3 ' is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R* is selected from H or D
  • p 1 or 2.
  • the present invention provides the compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein:
  • X 2 and X 3 are CR 2 ;
  • X 4 and X 5 are CR 2 ;
  • L is CH 2 ;
  • R 1 is C 1-6 alkoxy or C 1-6 haloalkoxy, preferably OCH 3 or OCHF 2 ;
  • R 1 ' is C 3-7 cycloalkyl, and R 1 ' may be optionally substituted by 1, 2 or 3 halogens; R 1 ' is preferably cyclopropyl;
  • R 2 is H
  • R 3 is C 1-6 alkyl, preferably methyl or isopropyl
  • R 3 ' is C 1-6 haloalkyl, preferably CF 3 ;
  • p 1 or 2.
  • the invention provides compounds of formula (III-2), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs thereof , hydrate or solvate:
  • X 2 is CR 2 ;
  • X 3 is selected from CR 2 or N;
  • X 4 is selected from CR 2 or N;
  • X 5 is CR 2 ;
  • L is CH 2 or SO 2 , and the CH 2 may be optionally replaced by 1 or 2 R#;
  • R 1 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkyne base, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 1 can optionally be replaced by 1, 2, or 3 , 4 or 5 R* substitutions;
  • R 1 ' is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl or 3-7 membered hetero Cyclic group, the R 1 ' may be optionally substituted by 1, 2 or 3 halogens;
  • Each R is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, or C 2-6 alkynyl, the R 2 may be optionally substituted by 1, 2, 3, 4 or 5 R*;
  • R 3 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkyne base, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 3 can optionally be replaced by 1, 2, 3, 4 or 5 R* substitutions;
  • R 3 ' is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R# is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R* is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • p 1 or 2.
  • the present invention provides the compound of formula (III-2) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein:
  • X 2 is CR 2 ;
  • X 3 is selected from CR 2 or N;
  • X 4 and X 5 are CR 2 ;
  • L is CH 2 , which may be optionally replaced by 1 or 2 R#;
  • R 1 is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy or C 3-10 cycloalkyl;
  • R 1 ' is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 3-7 cycloalkyl;
  • Each R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • R 3 is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl or 3-10 membered heterocycle base;
  • R 3 ' is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R# is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • p 1 or 2.
  • the present invention provides the compound of formula (III-2) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein:
  • X 2 and X 3 are CR 2 ;
  • X 4 and X 5 are CR 2 ;
  • L is CH 2 ;
  • R 1 is selected from C 1-6 alkoxy or C 1-6 haloalkoxy
  • R 1 ' is C 3-7 cycloalkyl, preferably cyclopropyl
  • Each R 2 is independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl, preferably H;
  • R 3 is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-10 cycloalkyl;
  • R 3 ' is C 1-6 haloalkyl
  • p 1 or 2.
  • the invention provides compounds of formula (III-3), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs thereof , hydrate or solvate:
  • X 4 and X 5 are each independently CR 2 , preferably not CH at the same time;
  • L is CH 2 , which may be optionally replaced by 1 or 2 R#;
  • R 1 is selected from C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably OCH 3 or OCHF 2 ;
  • R 1 ' is selected from C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably cyclopropyl;
  • Each R 2 is independently selected from H, halogen, CN, OR a , NR a R b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl , C 2-6 alkynyl group, -C(O)R a , -C(O)OR a , -OC(O)R a , -C(O)NR a R b , -(CH 2 ) 1-4 -OR a , -(CH 2 ) 1-4 -C(O)R a , -(CH 2 ) 1- 4 -C(O)OR a , -(CH 2 ) 1-4 -OC(O)R a , -(CH 2 ) 1-4 -C(O)NR a R b , -(CH 2 ) 1-4 -CN, -(CH 2 ) 1-4 -NR a R b , C 3-7
  • R 3 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, and the R 3 can optionally be replaced by 1 or 2 , 3, 4 or 5 R* substitutions;
  • R 3 ' is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R# is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R* is selected from H, D, halogen, NH 2 , CN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 ring Alkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • R a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R a and R b together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclyl group or a 5-10 membered heterocyclyl group.
  • the invention provides compounds of formula (III-3), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs thereof , hydrate or solvate, wherein:
  • X 4 is CR 2 '
  • X 5 is CR 2 ;
  • L is CH 2 , which may be optionally replaced by 1 or 2 R#;
  • R 1 is C 1-6 alkoxy or C 1-6 haloalkoxy, preferably OCH 3 or OCHF 2 ;
  • R 1 ' is selected from C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably cyclopropyl;
  • R 2 is selected from H, halogen, CN, OR a , NR a R b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2- 6Alkynyl , -C(O)R a , -(CH 2 ) 1-4 -OR a , -(CH 2 ) 1-4 -CN, -(CH 2 ) 1-4 -NR a R b , C 3-7 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1, 2, 3, 4 or 5 R *replace;
  • R 2 ' is H or halogen
  • At least one of R 2 and R 2 ' is not H;
  • R 3 is selected from H, C 1-6 alkyl or C 3-7 cycloalkyl
  • R 3 ' is C 1-6 alkyl or C 1-6 haloalkyl
  • R# is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R* is selected from D, halogen, NH 2 , CN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aromatic base or 5-10 membered heteroaryl;
  • R a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R a and R b together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclyl group.
  • the invention provides compounds of formula (III-3), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs thereof , hydrate or solvate, wherein:
  • X 4 is CR 2 '
  • X 5 is CR 2 ;
  • L is CH 2 , which may be optionally replaced by 1 or 2 R#;
  • R 1 is OCH 3 or OCHF 2 ;
  • R 1 ' is cyclopropyl
  • R 2 is selected from H, halogen, CN, OH, NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, -C(O)C 1-4 alkyl, -(CH 2 ) 1-4 - OH, -(CH 2 ) 1- 4 -CN or -(CH 2 ) 1-4 -NH 2 , optionally substituted by 1, 2 or 3 R*;
  • R 2 ' is H or C 1-4 alkyl
  • R 2 and R 2 ' are not H;
  • R 3 is C 1-4 alkyl
  • R 3 ' is C 1-4 haloalkyl
  • R# is selected from H or C 1-4 alkyl
  • R* is selected from halogen, NH 2 , CN, OH, C 1-4 alkyl, C 1-4 haloalkyl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl.
  • the invention provides compounds of formula (III-3), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs thereof , hydrate or solvate, wherein:
  • X 4 is CR 2 '
  • X 5 is CR 2 ;
  • L is CH 2 ;
  • R 1 is OCH 3 ;
  • R 1 ' is cyclopropyl
  • R 2 is selected from H, F, NH 2 , CHF 2 , Preferred are H, F, NH 2 , CHF 2 ,
  • R 2 ' is H or CH 3 ;
  • R 2 and R 2 ' are not H;
  • R 3 is CH 3 or isopropyl
  • R 3 ' is CF 3 .
  • the invention provides a compound, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein said Compounds selected from:
  • the invention provides a compound, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein said Compounds selected from:
  • the compounds of the present invention may contain one or more asymmetric centers and thus may exist in multiple stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, Includes racemic mixtures and mixtures enriched in one or more stereoisomers.
  • the isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers may be separated by Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • the compounds of the invention may also exist as tautomers.
  • Compounds exist in different tautomeric forms, and a said compound is not limited to any particular tautomeric form, but is intended to encompass all tautomeric forms.
  • solvate refers to a form of a compound or a salt thereof that is combined with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, etc.
  • Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolating, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid.
  • “Solvate” includes both solution solvates and isolable solvates. Representative solvates include hydrates, ethanolates, and methoxides.
  • hydrate refers to a compound combined with water. Typically, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined.
  • a hydrate of a compound may be represented, for example, by the general formula R.xH2O , where R is the compound and x is a number greater than zero.
  • a given compound may form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1), for example, hemihydrate (R ⁇ 0.5H 2 O)) and polyhydrates (x is a number greater than 1, for example, dihydrate (R ⁇ 2H 2 O) and hexahydrate (R ⁇ 6H 2 O)).
  • monohydrate x is 1
  • lower hydrate x is a number greater than 0 and less than 1
  • hemihydrate R ⁇ 0.5H 2 O
  • polyhydrates x is a number greater than 1, for example, dihydrate (R ⁇ 2H 2 O) and hexahydrate (R ⁇ 6H 2 O)
  • the compounds of the invention may be in amorphous or crystalline forms (polymorphs). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms often have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can lead to the dominance of one crystalline form. Various polymorphs of the compounds can be prepared by crystallization under different conditions.
  • the present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (A), except that one or more atoms are represented by atoms having an atomic mass or mass number different from that common in nature. replaced.
  • isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 respectively. O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • the isotope-labeled compounds of formula (A) of the present invention and their prodrugs can generally be prepared by replacing non-isotopes with readily available isotope-labeled reagents when performing the following processes and/or the processes disclosed in the Examples and Preparation Examples. Labeled reagents.
  • prodrugs are also included within the context of the present invention.
  • the term "prodrug” as used herein refers to a compound that is converted in the body to its active form having a medical effect, for example, by hydrolysis in the blood.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each introduced This article serves as a reference.
  • the invention provides pharmaceutical compositions comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions comprise an effective amount of a compound of the invention.
  • the pharmaceutical compositions comprise a therapeutically effective amount of a compound of the invention.
  • the pharmaceutical compositions comprise a prophylactically effective amount of a compound of the invention.
  • compositions of the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compounds with which they are formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin) protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene- Block polymers, polyethylene glycols, and
  • kits eg, pharmaceutical packaging.
  • Kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and/or dispersible packaging or other) containing the compounds of the invention, other therapeutic agents. suitable container).
  • provided kits may also optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the invention and/or other therapeutic agents.
  • the compound of the invention and the other therapeutic agent provided in the first container and the second container are combined to form a unit dosage form.
  • parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration , intracerebrospinal membrane drug administration, intralesional drug administration, and intracranial injection or infusion techniques.
  • an effective amount of a compound provided herein is administered.
  • the amount of compound actually administered can be determined by the physician depending on the circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. .
  • a compound provided herein is administered to a subject at risk of developing the condition, typically on the advice of and under the supervision of a physician, at dosage levels as described above.
  • Subjects at risk of developing a particular condition generally include subjects with a family history of the condition or those who have been determined by genetic testing or screening to be particularly susceptible to developing the condition.
  • compositions provided herein can also be administered over a long period of time ("chronic administration").
  • Long-term administration refers to the administration of a compound or pharmaceutical composition thereof over a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration may be continued indefinitely, For example, the remainder of the subject's life.
  • chronic administration is intended to provide a constant level of the compound in the blood over an extended period of time, eg, within a therapeutic window.
  • a pharmaceutical composition may be administered as a bolus injection, eg, in order to increase the concentration of the compound in the blood to an effective level.
  • the bolus dose depends on the target systemic levels of the active ingredient through the body, e.g., an intramuscular or subcutaneous bolus dose provides a slow release of the active ingredient, whereas a bolus dose delivered directly into the vein (e.g., via an IV drip) ) can be delivered more quickly, allowing the concentration of active ingredients in the blood to quickly increase to effective levels.
  • the pharmaceutical composition may be administered as a continuous infusion, for example, by IV infusion, thereby providing a steady-state concentration of the active ingredient in the subject's body. Additionally, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by a continuous infusion.
  • Oral compositions may take the form of bulk liquid solutions or suspensions, or bulk powders. More typically, however, the compositions are provided in unit dosage form to facilitate precise dosing.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable to produce the desired therapeutic effect in combination with a suitable Pharmaceutical excipients.
  • Typical unit dosage forms include prefilled, premeasured ampoules or syringes for liquid compositions, or pills, tablets, capsules, and the like in the case of solid compositions.
  • the compound will generally be a minor component (from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight), with the remainder being various components useful in forming the desired administration form. carriers or excipients and processing aids.
  • a typical regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides from about 0.01 to about 20 mg/kg of a compound of the invention, with preferred doses each providing from about 0.1 to about 10 mg/kg, especially from about 1 to about 5 mg/kg.
  • a transdermal dose is generally selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • Injectable dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour from about 1 to about 120 hours, especially from 24 to 96 hours. To achieve adequate steady state levels, a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be given. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g/day.
  • Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers as well as buffering agents, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • Solid forms may include, for example, any of the following components, or compounds of similar nature: binders, for example, microcrystalline cellulose, tragacanth, or gelatin; excipients, for example, starch or lactose, disintegrants, For example, alginic acid, Primogel or corn starch; lubricant, for example, magnesium stearate; glidant, for example, colloidal silicon dioxide; sweetener, for example, sucrose or saccharin; or flavoring agent, for example, mint, water Methyl glycolate or orange flavoring.
  • binders for example, microcrystalline cellulose, tragacanth, or gelatin
  • excipients for example, starch or lactose, disintegrants, For example, alginic acid, Primogel or corn starch
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As stated previously, in such compositions the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredients.
  • the active ingredients When formulated as an ointment, the active ingredients are typically combined with a paraffin or water-miscible ointment base.
  • the active ingredient may be formulated as a cream with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art and often include other ingredients for promoting stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by this invention.
  • transdermal administration may be achieved using reservoir or porous membrane types, or a variety of solid matrix patches.
  • compositions for oral administration, injection or topical administration are merely representative.
  • Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which article is incorporated by reference.
  • the compounds of the present invention may also be administered in sustained release form or from a sustained release drug delivery system.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the invention also relates to pharmaceutically acceptable formulations of the compounds of the invention.
  • the formulation includes water.
  • the formulation contains a cyclodextrin derivative.
  • the most common cyclodextrins are ⁇ -, ⁇ - and ⁇ -cyclodextrins consisting of 6, 7 and 8 ⁇ -1,4-linked glucose units respectively, optionally including a or multiple substituents including, but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions.
  • the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, for example, sulfobutyl ether beta-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
  • the formulation includes hexapropyl-beta-cyclodextrin (eg, in water, 10-50%).
  • the reagents used in the present invention are commercial reagents purchased directly or synthesized by common methods well known in the art.
  • PE petroleum ether
  • EA ethyl acetate
  • MeOH methanol
  • DCM diichloromethane
  • DCE dichloroethane
  • CH 3 acetonitrile
  • 1,4-dioxane 1,4-dioxane Hexacyclic
  • DMSO dimethyl sulfoxide
  • HFIP hexafluoroisopropanol
  • DMF N,N-dimethylformamide
  • Hex n-hexane
  • IPA isopropyl alcohol
  • NMP N-methylpyrrolidone
  • NMO N-methylmorpholine-N-oxide
  • TEA triethylamine
  • DIEA diisopropylethylamine
  • CuI cuprous iodide
  • CuCN cuprous cyanide
  • triphosgene triphosgene
  • p -TsOH p-toluenesulfonic acid
  • Step 1 Dissolve raw materials a1-2 (21.7g, 81mmol) and sodium acetate (6.6g, 81mmol) in 40mL water, raise the temperature to 100°C and stir for 1 hour, cool to room temperature, and slowly add 4-formylbenzoic acid methyl Ester a1-1 (13.3g, 81mmol), ammonia (77mL) and methanol (330mL) were stirred for 40 minutes, then heated to 100°C and continued to react for 2 hours, then cooled to room temperature. Slowly add 200 mL of ice water to the reaction solution to quench the reaction, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate.
  • Step 2 Mix intermediate a1–3 (2.0g, 7.5mmol) and K 2 CO 3 (1.54g, 11.2mmol) in 10mL DMF, add isopropane iodide (1.9g, 11.2mmol), and raise the temperature. React at 50°C for 2 hours to stop the reaction. 50 mL of water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by flash column chromatography to obtain yellow solid a1-4 (1.4g), yield: 69 %, LCMS: ESI–MS (m/z): 313[M+H] + .
  • Step 3 In an ice bath, under nitrogen protection, dissolve the intermediate a1–4 (1.4g, 5.2mmol) in the previous step in 20mL anhydrous THF, add DIABL-H (10.4mmol), and heat to room temperature for 2 hours. Add 30 mL of saturated aqueous ammonium chloride solution to the system to quench the reaction, extract with ethyl acetate, dry with anhydrous sodium sulfate, concentrate, and separate by column chromatography to obtain oily intermediate a1-5 (810 mg), yield: 55%, LCMS :ESI–MS(m/z):285[M+H] + .
  • Step 4 Dissolve intermediate a1–5 (810 mg, 2.85 mmol) from the previous step in 10 mL dichloroethane, slowly add SOCl 2 (1.02 g, 8.47 mmol), raise the temperature to 50°C and react for 1 hour, then stop the reaction. Place the reaction solution under an ice bath, add 20 mL of ice water to the system to quench the reaction, adjust the pH to about 8 with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, wash with saturated brine, dry over anhydrous sodium sulfate, and filter. Concentrate to obtain crude product a1, which is directly used in the next reaction.
  • Step 1 Dissolve raw material a2-1 (1.0g, 6.67mmol) in 20mL ethanol, slowly add liquid bromine (1.05g, 6.67mmol, 0.34mL), react at room temperature for 4 hours, add saturated thiosulfuric acid to the system The reaction was quenched with sodium aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was separated by column chromatography (PE/EtOAc, 4/1) to obtain white solid a2-2 (750 mg, 3.28 mmol), which was collected. Rate: 49%, LCMS: ESI–MS (m/z): 229[M+H] + .
  • Step 2 Under nitrogen protection, dissolve the intermediate a2-2 (880mg, 3.86mmol), pinacol bisborate (1.96g, 7.72mmol) and KOAc (758mg, 7.72mmol) in 15mL 1,4 - Add Pd(dppf)Cl 2 (290 mg, 0.4 mmol) to dioxane, raise the temperature to 105°C and react for 6 hours to stop the reaction.
  • Step 1 Under oxygen atmosphere (1atm), combine intermediate a1–3 (1.0g, 3.7mmol), cyclopropylboronic acid (636mg, 7.4mmol), bisbipyridine (578mg, 3.7mmol), sodium carbonate (784mg, 7.4 mmol) and catalyst Cu(OAc) 2 (758 mg, 7.72 mmol) were dissolved in 10 mL of dichloroethane, and the temperature was raised to 70°C and reacted for 16 hours to stop the reaction.
  • Step 2 Under nitrogen protection, at -10°C, dissolve the intermediate a9-1 (1.0g, 3.2mmol) in the previous step in 15mL anhydrous THF, add LiAlH 4 (240mg, 6.4mmol), and stop the reaction after stirring for 1 hour. . Add 1N sodium hydroxide aqueous solution (2 mL), filtered, washed with ethyl acetate, and the solvent was evaporated under reduced pressure to obtain oily intermediate a9-2 (700 mg), yield: 69%, LCMS: ESI–MS (m/z): 283.1 [M+H] + .
  • Step 1 Dissolve the raw material 4-hydrazinobenzoic acid hydrochloride a10–1 (3.0g, 19.7mmol) in 40mL ethanol, and slowly add 1,1,1-trifluoro-2,4-pentanedione dropwise (3.04g, 19.7mmol), complete the dropping, and react at room temperature for 2 hours.
  • the solvent was evaporated under reduced pressure and separated by flash reverse column chromatography to obtain mixed yellow solid a10-3 and a10-4 (2.4g), LCMS: ESI–MS (m/z): 271.1 [M+H] + .
  • Step 2 Under nitrogen protection, at -10°C, dissolve the mixed intermediate (1.0g, 3.7mmol) in the previous step in 12mL anhydrous THF, add LiAlH 4 (210mg, 5.5mmol), raise the temperature to room temperature, react for 2 hours, and stop. reaction. Add 1N sodium hydroxide aqueous solution (2mL) to the system, filter, wash with ethyl acetate, and evaporate the solvent under reduced pressure to obtain oily mixed intermediates a10-5 and a10-6 (1.0g), LCMS: ESI–MS (m/z):257.1[M+H] + .
  • Step 3 Dissolve the mixed intermediate (1.0g) in the previous step in 20mL dichloroethane, slowly add SOCl 2 (695mg, 5.85mmol), raise the temperature to 50°C and react for 2 hours, then stop the reaction. Place the reaction solution under an ice bath, add 20 mL of ice water to the system to quench the reaction, adjust the pH to about 8 with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, wash with saturated brine, dry over anhydrous sodium sulfate, and filter. Concentrate and separate by flash reverse column chromatography to obtain intermediates a10 (350 mg) and a11 (400 mg), LCMS: ESI–MS (m/z): 275.2 [M+H] + .
  • Step 2 Under nitrogen protection, combine the previous step intermediate a12-2 (140mg, 0.87mmol), 4-bromobenzoic acid methyl ester a12-3 (374mg, 1.74mmol), copper acetate (17mg, 0.077mmol), potassium carbonate (361mg, 2.6mmol), ligand triphenylphosphine (114mg, 0.43mmol) and catalyst Pd(OAc) 2 (20mg, 0.087mmol) were dissolved in 5mL anhydrous toluene, heated to 100°C and reacted for 12 hours, then stopped React, filter.
  • Step 3 Under nitrogen protection, in an ice bath, dissolve the intermediate a12-4 (110 mg, 0.37 mmol) in the previous step in 3 mL of anhydrous tetrahydrofuran, and slowly add diisobutylaluminum hydride DIBAL-H (1.3 mL, 1 M). The temperature was raised to room temperature and the reaction was stopped for 1 hour. 20 mL of ice water was added to the system, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain oily crude product a12-5 (60 mg), LCMS: ESI–MS (m/z): 267.1 [M+H] + .
  • DIBAL-H diisobutylaluminum hydride
  • Step 4 Dissolve the crude product from the previous step (50 mg, 0.19 mmol) in 2 mL of dichloroethane, slowly add SOCl 2 (113 mg, 0.95 mmol), raise the temperature to 50°C and react for half an hour to stop the reaction. Place the reaction solution under an ice bath, add 20 mL of ice water to the system, adjust the pH to about 8 with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain The crude intermediate a12 (50 mg) was directly used in the next reaction, LCMS: ESI–MS (m/z): 285.0 [M+H] + .
  • Step 1 Mix intermediate a1–3 (1.0g, 3.7mmol) and Cs 2 CO 3 (2.41g, 7.4mmol) in 15mL DMF, add 3-iodooxetane a13-1 (1.0g ,5.6mmol), raise the temperature to 100°C and react for 16 hours to stop the reaction.
  • Step 2 Under nitrogen protection, in an ice bath, dissolve the intermediate a13-2 (270 mg, 0.83 mmol) in the previous step in 10 mL anhydrous tetrahydrofuran, and slowly add diisobutylaluminum hydride DIBAL-H (0.59 mL, 1 M). The temperature was raised to room temperature and the reaction was stopped for 2 hours. 40 mL of ice water was added to the system, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a white solid a13 (250 mg), LCMS: ESI–MS (m/z): 299.0 [M+H] + .
  • DIBAL-H diisobutylaluminum hydride
  • Step 1 Dissolve the raw materials 4-chloro-6-methoxy-pyrimidine a14-1 (3.0g, 20.8mmol) and DIEA (5.36g, 41.5mmol) in 12mL 1,4-dioxane, and add the raw materials 3,3-Difluoroazetidine b3-2 (2.69g, 20.8mmol) was heated to 110°C and reacted for 6 hours. LC–MS monitored that the reaction was complete.
  • Step 2 In an ice bath, under nitrogen protection, dissolve the intermediate a14–2 (3.5g, 17.4mmol) in the previous step in 20mL ethanol, slowly add liquid bromine (2.8g, 17.4mmol) dropwise, complete the dropping, and warm to room temperature. The reaction lasted for 16 hours, and LC–MS monitored that the reaction was complete.
  • Step 3 Under nitrogen protection, dissolve the intermediate a14–3 (1.0g, 3.57mmol), pinacol bisborate (1.81g, 7.14mmol) and KOAc (700mg, 7.14mmol) in 12mL 1, To 4-dioxane, add Pd(dppf)Cl 2 (260 mg, 0.36 mmol), raise the temperature to 120°C and react for 3 hours to stop the reaction.
  • Pd(dppf)Cl 2 260 mg, 0.36 mmol
  • Step 1 Combine the raw materials 3-trifluoromethyl-5-methyl-1H pyrazole a15-2 (500mg, 3.33mmol), 6-chloropyridine-3-carboxylic acid ethyl ester a15-1 (927mg, 5.0mmol) and Potassium carbonate (920 mg, 6.66 mmol) was dissolved in 14 mL DMF, heated to 110°C and reacted for 4 hours to stop the reaction. 60 mL of ice water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated.
  • Step 2 Under nitrogen protection, at -10°C, dissolve the intermediate a15-3 (600 mg, 2.01 mmol) in the previous step in 18 mL anhydrous THF, and slowly add diisobutylaluminum hydride DIBAL-H (4.02 mL, 1 M) After the dropping is completed, the temperature is raised to room temperature and the reaction is stopped for 2 hours. Add 1N sodium hydroxide aqueous solution (2mL) to the system, filter, wash with ethyl acetate, and evaporate the solvent under reduced pressure to obtain oily intermediate a15-4 (500mg), LCMS: ESI–MS (m/z): 258.2[M+H] + .
  • Step 3 Dissolve the crude product from the previous step (500 mg) in 20 mL of dichloroethane, slowly add SOCl 2 (346 mg, 2.91 mmol), raise the temperature to 50°C and react for 2 hours to stop the reaction. Place the reaction solution under an ice bath, add 20 mL of ice water to the system to quench the reaction, adjust the pH to about 8 with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, wash with saturated brine, dry over anhydrous sodium sulfate, and filter. Concentrate to obtain intermediate a15 (350mg), which is directly used in the next reaction.
  • Step 2 Dissolve the intermediate a18-2 (1.0g, 4.2mmol) and cesium carbonate (2.06g, 6.33mmol) in the previous step in 10mL DMF. Add isopropane iodide (1.08g, 6.33mmol), raise the temperature to 50°C and react for 2 hours to stop the reaction.
  • Step 3 Under hydrogen atmosphere (4 atm), dissolve the intermediate a18-3 (290 mg, 1.04 mmol) and ammonia water (2.0 mL) in 8 mL methanol, add Raney nickel (310 mg), and react at room temperature for 2 hours. Stop the reaction and filter. The filtrate was washed with methanol, and the solvent was evaporated under reduced pressure to obtain compound a18 (274 mg).
  • bromine 29.7g, 185.8mmol
  • Step 2 In an ice bath, under nitrogen protection, dissolve the intermediate a19–2 (200 mg, 0.93 mmol) in the previous step in 5 mL anhydrous acetonitrile, add NaH (89 mg, 3.72 mmol), stir for 30 minutes, and then add 2-fluoro Sulfonyldifluoroacetic acid (331 mg, 1.86 mmol). The temperature was raised to room temperature and the reaction was stopped for 1 hour.
  • Step 3 Under nitrogen protection, dissolve the intermediate a19-3 (170mg, 0.64mmol), pinacol diborate (240mg, 0.96mmol) and potassium carbonate (190mg, 1.92mmol) in 5mL 1,4- Add the catalyst Pd(dppf)Cl 2 (140 mg, 0.19 mmol) to dioxane, stir for 5 minutes, then raise the temperature to 90°C and react for 2 hours to stop the reaction.
  • Pd(dppf)Cl 2 140 mg, 0.19 mmol
  • Step 1 Under nitrogen protection, dissolve the raw materials a22-1 (200mg, 1.13mmol), potassium carbonate (467mg, 3.39mmol) and 4-iodophenylethanol a22-2 (528mg, 2.26mmol) in 3mL DMSO, and add the mixture.
  • the body N,N-dimethylglycine DMG (22 mg, 0.22 mmol) and the catalyst CuI (20 mg, 0.11 mmol) were heated to 130°C and reacted for 2 hours, then cooled to room temperature.
  • Step 2 Dissolve intermediate a22-3 (115 mg, 0.4 mmol) from the previous step in 5 mL of dichloroethane, slowly add SOCl 2 (500 mg), raise the temperature to 50°C and react for 1 hour to stop the reaction. Place the reaction solution under an ice bath, add 20 mL of ice water to the system to quench the reaction, adjust the pH to about 8 with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, wash with saturated brine, dry over anhydrous sodium sulfate, and filter. Concentrate to obtain intermediate a22 (95 mg), which is directly used in the next reaction.
  • Step 1 Under nitrogen protection, combine intermediate a19-2 (2.14g, 10.1mmol) and 1-(trifluoromethyl)-1,2-benzeniodoyl-3(1H)-one a24-1 (3.49g , 11.1 mmol) was dissolved in 20 mL of dichloroethane, heated to 100°C and reacted for 3 hours, then cooled to room temperature.
  • Step 2 -78°C, under nitrogen protection, dissolve the intermediate a24-2 (580 mg, 2.06 mmol) and triisopropyl borate (147 mg, 0.78 mmol) in 5 mL anhydrous tetrahydrofuran, and slowly add nBuLi (1.4 mL, 2.5M), after completion of dropping, warm to room temperature and react for 3 hours, then stop the reaction. Place the reaction solution under an ice bath, add 40 mL of ice water to the system, extract with dichloromethane, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate. The crude product is separated by flash reverse column chromatography to obtain the intermediate. a24 (300mg), LCMS: ESI–MS (m/z): 249.2[M+H] + .
  • NBS N-bromosuccinimide
  • Step 2 Dissolve the intermediate a25-1 (1.5g, 4.3mmol) and K 2 CO 3 (1.78g, 12.9mmol) in 15mL acetonitrile, add isopropane iodide (1.5g, 8.6mmol), and raise the temperature. React at 80°C for 16 hours to stop the reaction. 50 mL of water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by flash column chromatography to obtain yellow solid a25-2 (1.0g), yield: 45 %, LCMS: ESI–MS (m/z): 391.0 [M+H] + .
  • Step 3 Under nitrogen protection, dissolve the intermediate a25–2 (1.0g, 2.56mmol), potassium carbonate (1.1g, 7.69mmol) and methylboronic acid (615mg, 10.2mmol) in 10mL of ethylene glycol dimethyl. To the mixed solution of ether and water (v/v, 4/1), add the catalyst Pd(PPh 3 )Cl 2 (180 mg, 0.37 mmol), raise the temperature to 100°C and react for 16 hours, then cool to room temperature.
  • Pd(PPh 3 )Cl 2 180 mg, 0.37 mmol
  • Step 4 In an ice bath, under nitrogen protection, dissolve the intermediate a25-3 (700 mg, 2.1 mmol) in the previous step in 10 mL anhydrous tetrahydrofuran, add DIABL-H (160 mg, 4.29 mmol), and heat to room temperature for 2 hours. Add 30 mL of saturated aqueous ammonium chloride solution to the system to quench the reaction, extract with ethyl acetate, dry with anhydrous sodium sulfate, concentrate, and separate by column chromatography to obtain oily intermediate a25-4 (450 mg), yield: 72%, LCMS :ESI–MS(m/z):299.2[M+H] + .
  • Step 5 Dissolve intermediate a25-4 (450 mg, 1.51 mmol) from the previous step in 10 mL of dichloroethane, slowly add SOCl 2 (720 mg, 6.04 mmol), raise the temperature to 50°C and react for 1 hour, then stop the reaction. Place the reaction solution under an ice bath and add 30 mL to the system Quench the reaction with ice water, adjust the pH to about 8 with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate to obtain crude product a25, which is directly used in the next step of the reaction.
  • Step 1 Under nitrogen protection, dissolve raw material b1–1 (150 mg, 0.72 mmol) and N, N-diisopropylethylamine DIEA (186 mg, 1.44 mmol) in 3 mL of N, N-dimethylacetamide DMA , add methyl acrylate b1-2 (93mg, 1.08mmol), (PhCN) 2 PdCl 2 (28mg, 0.07mmol) and tris(o-methylphenyl)phosphorus (22mg, 0.07mmol), and heat to 100°C React for 8 hours and cool to room temperature.
  • Step 2 Under nitrogen protection, dissolve the intermediate b1–3 (90mg, 0.42mmol) and K 2 CO 3 (582mg, 4.21mmol) in 6mL DMA, raise the temperature to 110°C and react for 12 hours, LC–MS Monitor the reaction for completion. Filter, add 20 mL of water to the filtrate, extract with dichloromethane, dry with anhydrous sodium sulfate, filter, and concentrate to obtain crude product b1, which is directly used in the next step of the reaction, LCMS: ESI–MS (m/z): 182 [M+H ] + .
  • Step 1 4,5-diamino-2-chloropyrimidine b2-1 (200mg, 1.38mmol) and ethyl glyoxylate b2-2 (340mg, 1.66mmol) were dissolved in 10mL ethanol, and the temperature was raised to 90°C for reaction. After 6 hours, the solvent was evaporated under reduced pressure to obtain crude product b2-3, which was directly used in the next reaction.
  • Step 2 Under nitrogen protection, dissolve the intermediate b2-3 (300 mg, crude product) and K 2 CO 3 (482 mg, 3.48 mmol) in 6 mL DMA, raise the temperature to 100°C and react for 10 hours, and monitor by LC–MS. The reaction is complete. Filter, add 20 mL of water to the filtrate, extract with dichloromethane, dry with anhydrous sodium sulfate, filter, and concentrate to obtain crude product b2, which can be directly used in the next step of reaction, LCMS: ESI–MS (m/z): 183 [M+H ] + .
  • Step 1 Under nitrogen protection, dissolve raw material b3-1 (2.35g, 12.5mmol) and dihydropyran DHP (1.15g, 13.75mmol) in 15mL dichloromethane, and add p-toluenesulfonic acid (235mg, 1.25mmol) ), react at room temperature for 16 hours. Add 30 mL of water to the system, extract with dichloromethane, and evaporate the solvent under reduced pressure to obtain crude product b4-1, which is directly used in the next reaction.
  • Step 2 Under nitrogen protection, dissolve the intermediate b4-1 (crude product), cyclopropylboronic acid (2.18g, 12.95mmol) and CsF (5.63g, 25mmol) in 24mL of 1,4-dioxane and To the mixed solution of water (v/v, 5/1), add palladium acetate (194 mg, 1.25 mmol) and tricyclohexylphosphorus (194 mg, 1.25 mmol), raise the temperature to 80°C and react for 10 hours, and monitor the reaction with LC–MS. Finish.
  • Step 1 Under nitrogen protection, combine the raw materials 3-trifluoromethylindazole c1-1 (800mg, 4.3mmol), potassium carbonate (1.20g, 8.6mmol) and 4-iodophenylethyl alcohol a22-2 (1.05g, 4.52 mmol) was dissolved in 10 mL DMSO, the catalyst CuI (170 mg, 0.16 mmol) and the ligand N,N-dimethylglycine DMG (88 mg, 0.86 mmol) were added, the temperature was raised to 100°C and the reaction was carried out for 1 hour, and the reaction was stopped. Add 50 mL of water to the system, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography to obtain compound c1-2 (400 mg), yield: 32%, LCMS: ESI–MS (m/z) :293[M+H] + .
  • Step 2 Under nitrogen protection, dissolve the intermediate c1–2 (400 mg, 1.37 mmol) in the previous step in 5 mL of methylene chloride, slowly add SOCl 2 (250 mg, 2.05 mmol) dropwise, and raise the temperature to 50°C to react for 1 hour.
  • LC–MS monitored reaction completion. Place the reaction solution under an ice bath, slowly add saturated sodium bicarbonate aqueous solution to adjust the pH to about 8, extract with dichloromethane, dry with anhydrous sodium sulfate, and concentrate to obtain light yellow oily substance c1 (300 mg), with a yield of 70%.
  • Step 1 Under nitrogen protection, dissolve intermediate a25-1 (1.4g, 4.03mmol) and potassium carbonate (1.10g, 8.1mmol) in 20mL DMF, add propenyl bromide c2-1 (575mg, 4.83mmol), Raise the temperature to 60°C and react for 2 hours to stop the reaction. Add 50 mL of water to the system, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography to obtain compound c2-2 (1.0 g), which is collected. Rate: 64%, LCMS: ESI–MS (m/z): 389[M+H] + .
  • Step 2 Under nitrogen protection, dissolve the intermediate c2-2 (1.0g, 2.57mmol), cesium carbonate (1.67g, 5.1mmol) and vinyl borate pinacol ester c2-3 (593mg, 3.85mmol). To 18 mL of a mixed solution of 1,4-dioxane and water (v/v, 5/1), add the catalyst Pd(dppf)Cl 2 (146 mg, 0.2 mmol), and raise the temperature to 80°C to react for 16 hours. Stop the reaction and filter. Add 50 mL of water to the system, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE/EA, 2/1) to obtain compound c2-4 (270 mg), yield: 32%, LCMS :ESI–MS(m/z):337[M+H] + .
  • Step 3 Under nitrogen protection, dissolve the intermediate c2-4 (270 mg, 0.8 mmol) in the previous step in 8 mL of methylene chloride, add the catalyst HOVEYDA-GRUBBS (26 mg, 0.04 mmol), and react at room temperature for 16 hours. Stop the reaction. filter. The solvent was evaporated under reduced pressure, and the crude product was separated by column chromatography (PE/EA, 1/1) to obtain compound c2-5 (120 mg), yield: 49%, LCMS: ESI–MS (m/z): 309 [ M+H] + .
  • Step 4 Under a hydrogen atmosphere, dissolve the intermediate c2-5 (120 mg, 0.39 mmol) in the previous step in 3 mL of methanol, add the catalyst Pd/C (20 mg), react under hydrogen (4 atm) at room temperature for 4 hours, and stop the reaction. ,filter. The solvent was evaporated under reduced pressure to obtain compound c2-6 (120 mg), LCMS: ESI–MS (m/z): 311 [M+H] + .
  • Step 5 Under nitrogen protection, dissolve the intermediate c2-6 (120 mg, 0.39 mmol) in the previous step in 2 mL of methylene chloride, slowly add SOCl 2 (95 mg, 0.8 mmol) dropwise, and raise the temperature to 50°C to react for 1 hour.
  • LC–MS monitored reaction completion. Place the reaction solution under an ice bath, slowly add saturated sodium bicarbonate aqueous solution to adjust the pH to about 8, extract with dichloromethane, dry with anhydrous sodium sulfate, and concentrate to obtain light yellow oily substance c2 (70 mg), with a yield of 60%.
  • Step 1 Under nitrogen protection, dissolve raw materials d1-1 (2.0g, 11.8mmol) and potassium carbonate (2.45g, 17.7mmol) in 10mL DMF, and add methyl acetoacetate d1-2 (1.92g, 16.5mmol) , raise the temperature to 90°C and react for 12 hours, then stop the reaction. Add 80 mL of water to the system, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography to obtain compound d1 (900 mg), yield: 32%, LCMS: ESI–MS (m/z): 236 [M+H] + .
  • the mixed solution v/v, 91/
  • add the catalyst Pd(dppf)Cl 2 232 mg, 0.32 mmol
  • the crude product is separated by column chromatography (DCM/MeOH, 10/1) to obtain yellow solid d8 (550 mg), yield: 63%, LCMS: ESI–MS(m/z):272[M+H] + .
  • Step 1 Under nitrogen protection, dissolve crude product b1 (80mg, 0.42mmol), K 2 CO 3 (582mg, 4.21mmol) and intermediate a1 (130mg, 0.42mmol) in 4mL DMA, heat to 50°C and react 1 hours, LC–MS monitored the reaction to completion. 30 mL of ice water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE/EtOAc, 2/1) to obtain yellow oil P1-1 (130 mg), yield: 69%, LCMS: ESI–MS (m/z): 448 [M+H ] + .
  • Step 2 Under nitrogen protection, the intermediate P1-1 (130mg, 0.29mmol), K 2 CO 3 (80mg, 0.58mmol) and intermediate a2 (80mg, 0.29mmol) from the previous step were dissolved in 12mL of 1,4-dioxy To the mixed solution of hexacyclic ring and water (v/v, 5/1), add Pd(dppf)Cl 2 (21 mg, 0.03 mmol), raise the temperature to 100°C and react for 2 hours. LC–MS monitors the reaction to be completed. 30 mL of ice water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE/EtOAc, 1/2) to obtain white solid P1 (57 mg), yield: 35%, LCMS: ESI–MS (m/z): 562 [M+H] + .
  • Step 1 Ice bath, under nitrogen protection, dissolve LiCl (309 mg, 7.37 mmol) in 10 mL anhydrous THF, add Grignard reagent iPrMgCl (3.7 mL, 2M), stir for 10 minutes under ice bath, slowly add raw material a2- 2 (1.4g, 6.14mmol) in tetrahydrofuran (14mL) and continue stirring for 30 minutes. Add the P3-1 (1.4g, 6.14mmol, 5mL) tetrahydrofuran solution prepared in advance to the reaction solution, heat to room temperature and react for 2 hours. LC-MS monitors the reaction to be completed.
  • Step 2 Under nitrogen protection, dissolve the crude intermediate P3-2 (1.7g) in the previous step in 20 mL of methylene chloride, add 5 mL of trifluoroacetic acid dropwise, and react at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and a saturated sodium bicarbonate aqueous solution was added to the system to adjust the pH to about 8. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE/EtOAc, 2/1) to obtain yellow solid P3-3 (750 mg), yield: 83%, LCMS: ESI–MS (m/z): 181 [M+H] + .
  • Step 3 Under nitrogen protection, the intermediate P3-3 (750 mg, 4.16 mmol) and raw material P3-4 (840 mg, 5.0 mmol) of the previous step were dissolved in 10 mL of ethanol, and the temperature was raised to reflux for 16 hours. The solvent was evaporated under reduced pressure, and the crude product was separated by column chromatography (PE/EtOAc, 1/1). White solid P3-5 (320 mg) was obtained, yield: 27%, LCMS: ESI–MS (m/z): 285 [M+H] + .
  • Step 4 Under nitrogen protection, dissolve the intermediate P3-5 (100mg, 0.35mmol), K 2 CO 3 (51mg, 0.36mmol) and intermediate a1 (106mg, 0.35mmol) in the previous step in 4mL DMF, and heat to The reaction was carried out for 1 hour at 50°C, and the reaction was completed after monitoring by LC–MS. 30 mL of ice water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse column chromatography (acetonitrile/water) to obtain white solid P3 (11.2 mg), yield: 6%, LCMS: ESI–MS (m/z): 551 [M+H] + .
  • Step 1 Under nitrogen protection, intermediate b4 (900mg, 3.24mmol), Cs 2 CO 3 (2.11g, 6.48mmol) and intermediate a2 (1.34g, 4.86mmol) were dissolved in 12mL of 1,4-dioxane To the mixed solution with water (v/v, 5/1), add Pd(dppf)Cl 2 (24 mg, 0.032 mmol), raise the temperature to 100°C and react for 8 hours. LC–MS monitors the reaction to completion. 40 mL of ice water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE/EtOAc, 4/1) to obtain white solid P6-1 (288 mg), yield: 23%, LCMS: ESI–MS (m/z): 393 [M+H] + .
  • Step 2 Under nitrogen protection, dissolve the compound P6-1 (288 mg, 0.734 mmol) in 5 mL of methylene chloride, add 2 mL of trifluoroacetic acid, react at room temperature for 1 hour, and evaporate the solvent under reduced pressure to obtain crude product P6- 2. Proceed directly to the next step of reaction.
  • Step 3 Under nitrogen protection, dissolve crude product P6-2 (crude product), K 2 CO 3 (135 mg, 0.97 mmol) and intermediate a1 (161 mg, 0.53 mmol) in 5 mL DMF, heat to 50°C and react for 6 hours. , LC–MS monitored the reaction completion. 30 mL of ice water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE/EtOAc, 4/1) to obtain white solid P6 (40 mg), two-step yield: 10%, LCMS: ESI–MS (m/z): 575 [M+H] + .
  • Step 1 Ice bath, dissolve intermediate a13 (140mg, 0.47mmol) and triethylamine (143mg, 1.41mmol) in 12mL dichloroethane, slowly add methanesulfonic anhydride (65mg, 0.56mmol), at 0°C The reaction was continued for 1 hour and the reaction was stopped. 40 mL of ice water was added to the system, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain oil P18-1 (180 mg), which was directly used in the next reaction.
  • Step 2 In an ice bath, under nitrogen protection, dissolve the intermediate P22-2 (320 mg, 1.13 mmol) in the previous step in 12 mL acetonitrile, slowly add liquid bromine (362 mg, 2.26 mmol), and raise the temperature to 50°C to react for 16 hours.
  • Step 3 Under nitrogen protection, dissolve the intermediate P22-3 (50 mg, 0.14 mmol), potassium acetate (28 mg, 0.28 mmol) and pinacol bisborate (71 mg, 0.28 mmol) in 4 mL 1,4 -To dioxane, add Pd(dppf)Cl 2 (10mg, 0.014mmol), The temperature was raised to 90°C and the reaction was carried out for 4 hours, and LC–MS monitored the completion of the reaction. 20 mL of ice water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated.
  • Step 2 In ice bath, under nitrogen protection, dissolve the intermediate P24-2 (2.0g, 6.92mmol) from the previous step in 22mL acetonitrile, slowly add tert-butylamine (560mg, 7.61mmol), and warm to room temperature for reaction 12 hours, LC–MS monitored the reaction to completion. Add 80 mL of water to the reaction solution, extract with dichloromethane, dry with anhydrous sodium sulfate, and concentrate to obtain oil P24-3 (1.0 g), yield: 56%, LCMS: ESI–MS (m/z): 234.1 [M+H] + .
  • Step 5 Under nitrogen protection, dissolve the intermediate P24-5 (150 mg, 0.3 mmol), K 3 PO 4 (159 mg, 0.75 mmol) and intermediate a2 (124 mg, 0.45 mmol) in 6 mL of 1,4-bis To the mixed solution of oxane and water (v/v, 5/1), add Pd(dppf)Cl 2 (22 mg, 0.03 mmol), raise the temperature to 90°C and react for 3 hours. LC–MS monitors the completion of the reaction. 30 mL of ice water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated.
  • Step 6 Under nitrogen protection, dissolve the intermediate P24-6 (15 mg, 0.024 mmol) in the previous step in 5 mL trifluoroacetic acid, raise the temperature to 70°C and react for 1 hour.
  • Steps: Dissolve compound P24 (12 mg, 0.02 mmol) in 3 mL of toluene, add the oxidant 2,3-dichloro-5,6-dicyanobenzoquinone DDQ (9.2 mg, 0.04 mmol), and heat to 50°C for reaction. After 2 hours, LC–MS monitored the reaction to be completed. The solvent was evaporated under reduced pressure, and the crude product was separated by TLC thin layer chromatography (DCM/MeOH 10/1) to obtain light yellow solid P25 (2mg), LCMS: ESI–MS (m/z): 563.2[M+H] + .
  • Step 1 Dissolve intermediate d2 (310 mg, 0.65 mmol) in 5 mL chloroform, slowly add m-chloroperoxybenzoic acid m-CPBA (338 mg, 1.96 mmol), raise the temperature to 50°C and react for 2 hours, LC– MS monitored reaction completion. 30 mL of saturated sodium thiosulfate aqueous solution was added to the reaction solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. Obtained yellow oil P45-1 (306 mg), yield: 95%, LCMS: ESI–MS (m/z): 490 [M+H] + .
  • Step 2 Dissolve the intermediate P45-1 (306 mg, 0.61 mmol) from the previous step in a mixed solution of 6 mL tetrahydrofuran and water (v/v, 1/1). KOH (170 mg, 3.03 mmol) was slowly added, the temperature was raised to 40°C and the reaction was carried out for 2 hours, and LC–MS monitored the reaction to completion. Slowly add 2M dilute hydrochloric acid to the reaction solution to adjust the pH to about 6, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. Obtained yellow oil P45-2 (236 mg), yield: 86%, LCMS: ESI–MS (m/z): 444 [M+H] + .
  • Step 3 Dissolve the intermediate P45-2 (185 mg, 0.42 mmol) from the previous step in 4 mL of a mixed solution of acetonitrile and phosphorus oxychloride (v/v, 1/1), raise the temperature to 90°C and react for 2 hours, LC – MS monitors reaction completion. 20 mL of ice water was slowly added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. Obtained yellow solid P45-3 (185 mg), yield: 96%, LCMS: ESI–MS (m/z): 462 [M+H] + .
  • Step 4 Under nitrogen protection, the intermediate P45-3 (185mg, 0.40mmol), K 2 CO 3 (111mg, 0.80mmol) and intermediate a2 (155mg, 0.80mmol) from the previous step were dissolved in 5mL of 1,4-dioxo To the mixed solution of hexacyclic ring and water (v/v, 4/1), add Pd(dppf)Cl 2 (59 mg, 0.08 mmol), raise the temperature to 100°C and react for 2 hours. LC–MS monitors the reaction to completion. 30 mL of ice water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (DCM/MeOH, 20/1) to obtain white solid P45 (22 mg), yield: 7%, LCMS: ESI–MS (m/z): 576 [M+H] + .
  • Step 1 Under nitrogen protection, dissolve compound P47 (240 mg, 0.42 mmol) and TEA (130 mg, 1.26 mmol) in 3 mL of tert-butanol, add diphenyl phosphate azide dppa (490 mg, 1.26 mmol), and heat to 90 The reaction was carried out for 2 hours at °C, and the reaction was completed after monitoring by LC–MS. Di-tert-butyl dicarbonate Boc 2 O (275 mg, 1.26 mmol) was added to the reaction solution, and the reaction was continued at room temperature for 2 hours to stop the reaction. 100 mL of water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (DCM/MeOH, 20/1) to obtain yellow solid P50-1 (200 mg), yield: 73%, LCMS: ESI–MS (m/z): 649 [M+H] + .
  • Step 2 Dissolve the compound P50-1 (200 mg, 0.31 mmol) in 3 mL of hydrogen chloride in 1,4-dioxane solution (2M), react at room temperature for 1 hour, and then stop the reaction. Add 30 mL of water to the reaction solution, adjust the pH to about 8 with saturated aqueous sodium bicarbonate solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product was separated by column chromatography (DCM/MeOH, 20/1) to obtain yellow solid P50 (20 mg), yield: 11%, LCMS: ESI–MS (m/z): 549 [M+H] + .
  • DCM/MeOH 1,4-dioxane solution
  • Inhibition rate (%) [(RFU average vehicle control - RFU average test compound)/(RFU average vehicle control - RFU average positive compound)] ⁇ 100
  • the molecules of the present invention have good inhibitory effects on USP1; the activity of some molecules is greatly improved compared to the control molecules A1 or A2. For example, the activity of molecule P1 is increased by more than 10 times compared with A1; and the activity is increased by more than 100 times compared with A2.
  • Promega CellTiter–Glo reagent was used to detect the effect of small molecule inhibitors on the proliferation of BRCA1 mutant cell line breast cancer cells (MDA-MB-436) and the proliferation of BRCA wild-type breast cancer cell line HCC1954.
  • Cultures were cultured in a medium containing 15% fetal calf serum (Gibco, Cat. No. 10099141), 10 ⁇ g/mL insulin (Invitrogen, Cat. No. 12585-014), 16 ⁇ g/mL glutathione (Sigma, Cat. No.
  • G6013 1% green chain MDA-MB-436 cells (or HCC1954) in Mycomycin's L15 medium (Gibco, catalog number 11415-064) were seeded into a 384-well microplate, 35 ⁇ L per well, and incubated overnight in a 37°C CO2 incubator ; A 4-fold concentration gradient dilution series of compounds was added to a 384-well plate using ECHO (Labcyte, model 550), 35 nL per well. Incubate and culture in a 37°C CO 2 incubator for 7 days.
  • the parameters include the maximum and minimum inhibition rates of cells, and IC 50 values.
  • liver microsome stability test study on the compounds of the present invention.
  • the compounds to be tested are co-incubated with liver microsomes of different species with or without the addition of NADPH.
  • the final concentration of the compounds to be tested in the test system is 1 ⁇ M, and the final concentration of NADPH is 1 ⁇ M. is 1mM, and the final concentration of liver microsomes is 0.5mg/ml. Detect the compound concentration in the incubation supernatant at different time points within 60 minutes and calculate pharmacokinetic parameters (such as clearance Clint).
  • CD1 female mice were used as test animals, and the drug was administered orally/intravenously (the oral dosage was 10 mg/kg, the intravenous dosage was 2 mg/kg, and the solvent was: DMSO-Solutol-H 2 O).
  • mice There are three animals in each group of the oral group and three animals in each group of the intravenous group.
  • LC/MS/MS method was used to measure the blood concentration of plasma after oral and intravenous administration in mice, and the collected data were calculated using AB Sciex QTRAP6500 software.
  • mice from Ovarian cancer xenograft model OV0589 tumor-bearing mice were harvested from tumor tissue, cut into tumor pieces with a diameter of 2-3 mm, and inoculated subcutaneously in the right front scapula of BALB/c Nude mice. All mice were vaccinated subcutaneously. Mice were cultured in an SPF-grade experimental environment, and all mice had free access to a commercially certified standard diet. When the tumors grow to an average volume of approximately 152.54mm3 , they will be randomly divided into groups for administration based on tumor size. The 16 mice enrolled were evenly divided into 4 groups, with 4 mice in each group.
  • the molecule of the present invention has good in vivo efficacy (inhibiting the growth of human ovarian cancer), and has good synergistic inhibitory effect with the marketed drug Olaparib. It is expected to treat ovarian cancer patients with BRCA1/2 mutations in future clinical trials.

Abstract

本发明提供了一类新的式(A)所示的取代的双环杂芳基化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物作为USP1抑制剂。本发明还提供了所述化合物的制备方法、包含所述化合物的药物组合物，以及所述化合物在预防和治疗相关癌症中的作用。

Description

取代的双环杂芳基化合物作为USP1抑制剂
本发明要求享受如下优先权：
CN202210492308.7，申请日为2022年5月7日；
CN202211540430.3，申请日为2022年12月2日。
技术领域
本发明涉及USP1抑制剂，具体为式(A)所示的取代的双环杂芳基化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物。本发明还涉及所述化合物的制备方法、包含所述化合物的药物组合物，以及所述化合物在预防和治疗相关癌症中的作用。
背景技术
合成致死是近年来肿瘤治疗领域的重要方向，这类药物的应用一般要求有特异性的肿瘤生物标记物进行患者选择，在产生良好药效的同时可以明显扩大药物的治疗安全窗，也增加了某些高突变率但难成药的靶点的药物开发可及性(Nat Rev Drug Discov.2020 Jan；19(1):23-38)(Cancer Discov.2021 Jul；11(7):1626-1635)。PARP1/2抑制剂例如Olaparib、Rucaparib、Niraparib等是当前合成致死领域最成功的案例，这些药物在BRCA1/2突变卵巢癌、乳腺癌等的治疗中获得了优异的疗效并已经相继获批上市，在一些非BRCA1/2的其他同源重组缺陷的癌症患者中也观测到了良好药效(Nat Rev Drug Discov.2020 Oct；19(10):711-736)(Nat Rev Drug Discov.2019 Oct；18(11):814)(Nat Rev Clin Oncol.2020 Mar；17(3):136-137)。PARP抑制剂的巨大成功也大大激励了合成致死药物靶点的发现和药物研发。
与PARP1/2功能相似，泛素特异性蛋白酶1(Ubiquitin Specific Protease 1，USP1)也是参与DNA损伤修复的重要蛋白酶。通过对其功能底物PCNA、FANCD2等进行去泛素化调节，USP1在跨损伤合成(translesion synthesis,TLS)和链内交联修复(intrastrand crosslink repair)这两个DNA损伤修复重要通路中具有关键作用(Nat Commun.2019 Jun 28；10(1):2849.)(Front Oncol.2022 Feb 7；11:822500)。当前，研究已经显示USP1抑制和BRCA1突变具有合成致死作用；同时，抑制USP1可以有效克服PARP抑制剂的耐药，且USP1抑制剂与PARP抑制剂联用显示了优于PARP抑制剂单用的优异抗肿瘤药效(Mol Cell.2018；72(6):925-941)(Oncogene.2021Apr；40(17):3001-3014.)(Cancer Res.2021 Dec 1；81(23):5806-5809.)。鉴于肿瘤中BRCA1/2突变的广谱性以及PARP抑制剂在临床上的广泛应用，USP1抑制剂单用或与PARP抑制剂联用具有巨大的临床应用前景。
因此开发USP1选择性的抑制剂将带来显著的临床获益，目前尚无USP1抑制剂上市，本发明的USP1抑制剂具有高活性，良好的药代性质，具有优异的抗肿瘤效果。
发明内容
在一个方面，本发明提供了式(A)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中：
表示单键或双键；
当为双键时，X1为C；
当为单键时，X1为N；
X2和X3各自独立地选自CR2或N；
环A为5-6元杂芳基或5-6元杂环基，并且当环A为5元杂芳基时，环A和嘧啶环一起形成 所述环A任选地被1个、2个、3个、4个或5个R2取代；
环B为5-12元杂芳基；
环C为5-6元杂芳基；
L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
每个R1独立地选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R1可任选地被1个、2个、3个、4个或5个R*取代；
每个R2独立地选自H、D、卤素、CN、ORa、NRaRb、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1- 6卤代烷氧基、C2-6烯基、C2-6炔基、-C(O)Ra、-C(O)ORa、-OC(O)Ra、-C(O)NRaRb、-(CH2)1-6-ORa、-(CH2)1-6-C(O)Ra、-(CH2)1-6-C(O)ORa、-(CH2)1-6-OC(O)Ra、-(CH2)1-6-C(O)NRaRb、-(CH2)1-6-CN、-(CH2)1- 6-NRaRb、C3-7环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基，所述R2可任选地被1个、2个、3个、4个、5个、6个、7个、8个或更多个R*取代；或者同一碳原子上的两个R2形成＝O或＝S；
每个R3独立地选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R3可任选地被1个、2个、3个、4个、5个、6个、7个、8个或更多个R*取代；
或者，一个R2和一个R3与它们分别连接的原子一起形成6-12元杂环基或6-12元杂芳基；
R4选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R4可任选地被1个、2个、3个、4个或5个R*取代；
R#选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
R*选自H、D、卤素、NH2、CN、OH、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基；
Ra选自H、C1-6烷基或C1-6卤代烷基；
Rb选自H、C1-6烷基或C1-6卤代烷基；
或者，Ra和Rb与它们连接的氮原子一起形成5-10元杂环基或5-10元杂环基；
m为1、2或3；
n为1、2、3或4；
p为1或2。
在另一个方面，本发明提供了式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中：
表示单键或双键；
当为双键时，X1为C；
当为单键时，X1为N；
X2和X3各自独立地选自CR2或N；
环A为5-6元杂芳基，并且当环A为5元杂芳基时，环A和嘧啶环一起形成
环B为5-6元杂芳基；
L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
每个R1独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R1可任选地被1个、2个、3个、4个或5个R*取代；
每个R2独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基或C2-6炔基，所述R2可任选地被1个、2个、3个、4个或5个R*取代；
每个R3独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R3可任选地被1个、2个、3个、4个或5个R*取代；
R4选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R4可任选地被1个、2个、3个、4个或5个R*取代；
R#选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
R*选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
m为1、2或3；
n为1、2、3或4；
p为1或2。
在另一个方面，本发明提供了一种药物组合物，所述药物组合物含有本发明化合物，和任选地药学上可接受的赋形剂。
在另一个方面，本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物，其还含有其它治疗剂。
在另一个方面，本发明提供了本发明化合物在制备用于治疗和/或预防USP1介导的疾病的药物中的用途。
在另一个方面，本发明提供了在受试者中治疗和/或预防USP1介导的疾病的方法，包括向所述受试者给药本发明化合物或本发明组合物。
在另一个方面，本发明提供了本发明化合物或本发明组合物，其用于治疗和/或预防USP1介导的疾病。
在具体实施方案中，本发明治疗的疾病包括选自以下的癌症：血液癌症、淋巴癌、膀胱癌、卵巢癌、乳腺癌、骨癌(例如骨肉瘤和软骨肉瘤)、脑癌(例如神经胶质瘤、成胶质细胞瘤、星形细胞瘤、髓母细胞瘤和脑脊髓膜瘤)、软组织癌(例如横纹肌样肉瘤)、肾癌、膀胱癌、皮肤癌(例如黑素瘤)、肺癌(例如非小细胞肺癌)、结肠癌、子宫癌、神经系统癌症、头颈癌、胰腺癌和子宫颈癌。
由随后的具体实施方案、实施例和权利要求，本发明的其它目的和优点将对于本领域技术人员显而易见。
定义
化学定义
下面更详细地描述具体官能团和化学术语的定义。
当列出数值范围时，既定包括每个值和在所述范围内的子范围。例如“C1-6烷基”包括C1、C2、C3、C4、C5、C6、C1-6、C1-5、C1-4、C1-3、C1-2、C2-6、C2-5、C2-4、C2-3、C3-6、C3-5、C3-4、C4-6、C4-5和C5-6烷基。
“C1-6烷基”是指具有1至6个碳原子的直链或支链饱和烃基团。在一些实施方案中，C1-4烷基和C1-2烷基是优选的。C1-6烷基的例子包括：甲基(C1)、乙基(C2)、正丙基(C3)、异丙基(C3)、正丁基(C4)、叔丁基(C4)、仲丁基(C4)、异丁基(C4)、正戊基(C5)、3-戊基(C5)、戊基(C5)、新戊基(C5)、3-甲基-2-丁基(C5)、叔戊基(C5)和正己基(C6)。术语“C1-6烷基”还包括杂烷基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。烷基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。常规烷基缩写包括：Me(-CH3)、Et(-CH2CH3)、iPr(-CH(CH3)2)、nPr(-CH2CH2CH3)、n-Bu(-CH2CH2CH2CH3)或i-Bu(-CH2CH(CH3)2)。
“C2-6烯基”是指具有2至6个碳原子和至少一个碳碳双键的直链或支链烃基团。在一些实施方案中，C2-4烯基是优选的。C2-6烯基的例子包括：乙烯基(C2)、1-丙烯基(C3)、2-丙烯基(C3)、1-丁烯基(C4)、2-丁烯基(C4)、丁二烯基(C4)、戊烯基(C5)、戊二烯基(C5)、己烯基(C6)，等等。术语“C2-6烯基”还包括 杂烯基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。烯基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“C2-6炔基”是指具有2至6个碳原子、至少一个碳-碳叁键以及任选地一个或多个碳-碳双键的直链或支链烃基团。在一些实施方案中，C2-4炔基是优选的。C2-6炔基的例子包括但不限于：乙炔基(C2)、1-丙炔基(C3)、2-丙炔基(C3)、1-丁炔基(C4)、2-丁炔基(C4)，戊炔基(C5)、己炔基(C6)，等等。术语“C2- 6炔基”还包括杂炔基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。炔基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。
因此，“C1-6卤代烷基”是指上述“C1-6烷基”，其被一个或多个卤素基团取代。在一些实施方案中，C1-4卤代烷基是特别优选的，更优选C1-2卤代烷基。示例性的所述卤代烷基包括但不限于：-CF3、-CH2F、-CHF2、-CHFCH2F、-CH2CHF2、-CF2CF3、-CCl3、-CH2Cl、-CHCl2、2,2,2-三氟-1,1-二甲基-乙基，等等。卤代烷基基团可以在任何可用的连接点上被取代，例如，1至5个取代基、1至3个取代基或1个取代基。
“C1-6烷氧基”是指-OR基团，其中R为上文定义的C1-6烷基。C1-4烷氧基是优选的。
“C1-6卤代烷氧基”是指上述“C1-6烷氧基”，其被一个或多个卤素基团取代。在一些实施方案中，C1- 4卤代烷氧基是特别优选的，更优选C1-2卤代烷氧基。示例性的所述卤代烷氧基包括但不限于：-OCF3、-OCH2F、-OCHF2、-OCHFCH2F、-OCH2CHF2、-OCF2CF3、-OCCl3、-OCH2Cl、-OCHCl2、2,2,2-三氟-1,1-二甲基-乙氧基，等等。卤代烷氧基基团可以在任何可用的连接点上被取代，例如，1至5个取代基、1至3个取代基或1个取代基。
“C3-10环烷基”是指具有3至10个环碳原子和零个杂原子的非芳香环烃基团。在一些实施方案中，C5-7环烷基、C3-7环烷基和C3-5环烷基是特别优选的，更优选C5-6环烷基。环烷基还包括其中上述环烷基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在环烷基环上，且在这样的情况中，碳的数目继续表示环烷基体系中的碳的数目。示例性的所述环烷基包括但不限于：环丙基(C3)、环丙烯基(C3)、环丁基(C4)、环丁烯基(C4)、环戊基(C5)、环戊烯基(C5)、环己基(C6)、环己烯基(C6)、环已二烯基(C6)、环庚基(C7)、环庚烯基(C7)、环庚二烯基(C7)、环庚三烯基(C7)，等等。环烷基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“3-12元杂环基”是指具有环碳原子和1至6个环杂原子的3至12元非芳香环系的基团，其中，每个杂原子独立地选自氮、氧、硫、硼、磷和硅。在包含一个或多个氮原子的杂环基中，只要化合价允许，连接点可为碳或氮原子。在一些实施方案中，优选3-10元杂环基，其为具有环碳原子和1至5个环杂原子的3至10元非芳香环系；在一些实施方案中，优选6-12元杂环基，其为具有环碳原子和1至6个环杂原子的6至12元非芳香环系；在一些实施方案中，优选4-9元杂环基，其为具有环碳原子和1至5个环杂原子的4至9元非芳香环系；在一些实施方案中，优选5-8元杂环基，其为具有环碳原子和1至5个环杂原子的5至8元非芳香环系；在一些实施方案中，优选3-8元杂环基，其为具有环碳原子和1至4个环杂原子的3至8元非芳香环系；优选3-7元杂环基，其为具有环碳原子和1至3个环杂原子的3至7元非芳香环系；优选3-5元杂环基，其为具有环碳原子和1至2个环杂原子的3至5元非芳香环系；优选4-7元杂环基，其为具有环碳原子和1至3个环杂原子的4至7元非芳香环系；优选4-6元杂环基，其为具有环碳原子和1至3个环杂原子的4至6元非芳香环系；更优选5-6元杂环基，其为具有环碳原子和1至3个环杂原子的5至6元非芳香环系。杂环基还包括其中上述杂环基环与一个或多个环烷基稠合的环体系，其中连接点在环烷基环上，或其中上述杂环基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在杂环基环上；且在这样的情况下，环成员的数目继续表示在杂环基环体系中环成员的数目。示例性的包含一个杂原子的3元杂环基包括但不限于：氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基(thiorenyl)。示例性的含有一个杂原子的4元杂环基包括但不限于：氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基。示例性的含有一个杂原子的5元杂环基包括但不限于：四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、吡咯烷基、二氢吡咯基和吡咯基-2,5-二酮。示例性的包含两个杂原子的5元杂环基包括但不限于：二氧杂环戊烷基、氧硫杂环戊烷基(oxasulfuranyl)、二硫杂环戊烷基(disulfuranyl)和噁唑烷-2-酮。示例性的包含三个杂原子的5元杂环基包括但不限于：三唑啉基、噁二唑啉基和噻二唑啉基。示例性的包含一个杂原子的6元杂环基包括但不限于：哌啶基、四氢吡喃基、二氢吡啶基和硫杂环己烷基(thianyl)。示例性的包含两个杂原子的6元杂环基包括但不限于：哌嗪基、吗啉基、二硫杂环己烷基、二噁烷基。示例性的包含三个杂原子的6 元杂环基包括但不限于：六氢三嗪基(triazinanyl)。示例性的含有一个杂原子的7元杂环基包括但不限于：氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。示例性的与C6芳基环稠合的5元杂环基(在本文中也称作5,6-双环杂环基)包括但不限于：二氢吲哚基、异二氢吲哚基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基，等等。示例性的与C6芳基环稠合的6元杂环基(本文还指的是6,6-双环杂环基)包括但不限于：四氢喹啉基、四氢异喹啉基，等等。杂环基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“C6-10芳基”是指具有6-10个环碳原子和零个杂原子的单环或多环的(例如，双环)4n+2芳族环体系(例如，具有以环状排列共享的6或10个π电子)的基团。在一些实施方案中，芳基具有六个环碳原子(“C6芳基”；例如，苯基)。在一些实施方案中，芳基具有十个环碳原子(“C10芳基”；例如，萘基，例如，1-萘基和2-萘基)。芳基还包括其中上述芳基环与一个或多个环烷基或杂环基稠合的环系统，而且连接点在所述芳基环上，在这种情况下，碳原子的数目继续表示所述芳基环系统中的碳原子数目。芳基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“5-12元杂芳基”是指具有环碳原子和1-5个环杂原子的5-12元单环或双环的4n+2芳族环体系(例如，具有以环状排列共享的6、10或14个π电子)的基团，其中每个杂原子独立地选自氮、氧和硫。在含有一个或多个氮原子的杂芳基中，只要化合价允许，连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。杂芳基还包括其中上述杂芳基环与一个或多个环烷基或杂环基稠合的环系统，而且连接点在所述杂芳基环上，在这种情况下，碳原子的数目继续表示所述杂芳基环系统中的碳原子数目。在一些实施方案中，5-10元杂芳基是优选的，其为具有环碳原子和1-4个环杂原子的5-10元单环或双环的4n+2芳族环体系。在另一些实施方案中，6-12元杂芳基是优选的，其为具有环碳原子和1-4个环杂原子的6-12元单环或双环的4n+2芳族环体系。在另一些实施方案中，5-9元杂芳基是优选的，其为具有环碳原子和1-4个环杂原子的5-9元单环或双环的4n+2芳族环体系。在另一些实施方案中，5-6元杂芳基是特别优选的，其为具有环碳原子和1-4个环杂原子的5-6元单环或双环的4n+2芳族环体系。示例性的含有一个杂原子的5元杂芳基包括但不限于：吡咯基、呋喃基和噻吩基。示例性的含有两个杂原子的5元杂芳基包括但不限于：咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基和异噻唑基。示例性的含有三个杂原子的5元杂芳基包括但不限于：三唑基、噁二唑基(例如，1,2,4-噁二唑基)和噻二唑基。示例性的含有四个杂原子的5元杂芳基包括但不限于：四唑基。示例性的含有一个杂原子的6元杂芳基包括但不限于：吡啶基。示例性的含有两个杂原子的6元杂芳基包括但不限于：哒嗪基、嘧啶基和吡嗪基。示例性的含有三个或四个杂原子的6元杂芳基分别包括但不限于：三嗪基和四嗪基。示例性的含有一个杂原子的7元杂芳基包括但不限于：氮杂环庚三烯基、氧杂环庚三烯基和硫杂环庚三烯基。示例性的5,6-双环杂芳基包括但不限于：吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基和嘌呤基。示例性的6,6-双环杂芳基包括但不限于：萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。杂芳基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
本文定义的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基等为任选取代的基团。
示例性的碳原子上的取代基包括但不局限于：卤素、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-ORaa、-ON(Rbb)2、-N(Rbb)2、-N(Rbb)3 +X-、-N(ORcc)Rbb、-SH、-SRaa、-SSRcc、-C(＝O)Raa、-CO2H、-CHO、-C(ORcc)2、-CO2Raa、-OC(＝O)Raa、-OCO2Raa、-C(＝O)N(Rbb)2、-OC(＝O)N(Rbb)2、-NRbbC(＝O)Raa、-NRbbCO2Raa、-NRbbC(＝O)N(Rbb)2、-C(＝NRbb)Raa、-C(＝NRbb)ORaa、-OC(＝NRbb)Raa、-OC(＝NRbb)ORaa、-C(＝NRbb)N(Rbb)2、-OC(＝NRbb)N(Rbb)2、-NRbbC(＝NRbb)N(Rbb)2、-C(＝O)NRbbSO2Raa、-NRbbSO2Raa、-SO2N(Rbb)2、-SO2Raa、-SO2ORaa、-OSO2Raa、-S(＝O)Raa、-OS(＝O)Raa、-Si(Raa)3、-OSi(Raa)3、-C(＝S)N(Rbb)2、-C(＝O)SRaa、-C(＝S)SRaa、-SC(＝S)SRaa、-SC(＝O)SRaa、-OC(＝O)SRaa、-SC(＝O)ORaa、-SC(＝O)Raa、-P(＝O)2Raa、-OP(＝O)2Raa、-P(＝O)(Raa)2、-OP(＝O)(Raa)2、-OP(＝O)(ORcc)2、-P(＝O)2N(Rbb)2、-OP(＝O)2N(Rbb)2、-P(＝O)(NRbb)2、-OP(＝O)(NRbb)2、-NRbbP(＝O)(ORcc)2、-NRbbP(＝O)(NRbb)2、-P(Rcc)2、-P(Rcc)3、-OP(Rcc)2、-OP(Rcc)3、-B(Raa)2、-B(ORcc)2、-BRaa(ORcc)、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代；
或者在碳原子上的两个偕氢被基团＝O、＝S、＝NN(Rbb)2、＝NNRbbC(＝O)Raa、＝NNRbbC(＝O)ORaa、＝NNRbbS(＝O)2Raa、＝NRbb或＝NORcc取代；
Raa的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个Raa基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代；
Rbb的每个独立地选自：氢、-OH、-ORaa、-N(Rcc)2、-CN、-C(＝O)Raa、-C(＝O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(＝NRcc)ORaa、-C(＝NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(＝S)N(Rcc)2、-C(＝O)SRcc、-C(＝S)SRcc、-P(＝O)2Raa、-P(＝O)(Raa)2、-P(＝O)2N(Rcc)2、-P(＝O)(NRcc)2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个Rbb基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代；
Rcc的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个Rcc基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代；
Rdd的每个独立地选自：卤素、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-ORee、-ON(Rff)2、-N(Rff)2,、-N(Rff)3 +X-、-N(ORee)Rff、-SH、-SRee、-SSRee、-C(＝O)Ree、-CO2H、-CO2Ree、-OC(＝O)Ree、-OCO2Ree、-C(＝O)N(Rff)2、-OC(＝O)N(Rff)2、-NRffC(＝O)Ree、-NRffCO2Ree、-NRffC(＝O)N(Rff)2、-C(＝NRff)ORee、-OC(＝NRff)Ree、-OC(＝NRff)ORee、-C(＝NRff)N(Rff)2、-OC(＝NRff)N(Rff)2、-NRffC(＝NRff)N(Rff)2、-NRffSO2Ree、-SO2N(Rff)2、-SO2Ree、-SO2ORee、-OSO2Ree、-S(＝O)Ree、-Si(Ree)3、-OSi(Ree)3、-C(＝S)N(Rff)2、-C(＝O)SRee、-C(＝S)SRee、-SC(＝S)SRee、-P(＝O)2Ree、-P(＝O)(Ree)2、-OP(＝O)(Ree)2、-OP(＝O)(ORee)2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代，或者两个偕Rdd取代基可结合以形成＝O或＝S；
Ree的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、芳基、杂环基和杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代；
Rff的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个Rff基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代；
Rgg的每个独立地是：卤素、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-OC1-6烷基、-ON(C1-6烷基)2、-N(C1-6烷基)2、-N(C1-6烷基)3 +X-、-NH(C1-6烷基)2 +X-、-NH2(C1-6烷基)+X-、-NH3 +X-、-N(OC1-6烷基)(C1-6烷基)、-N(OH)(C1-6烷基)、-NH(OH)、-SH、-SC1-6烷基、-SS(C1-6烷基)、-C(＝O)(C1-6烷基)、-CO2H、-CO2(C1-6烷基)、-OC(＝O)(C1-6烷基)、-OCO2(C1-6烷基)、-C(＝O)NH2、-C(＝O)N(C1-6烷基)2、-OC(＝O)NH(C1-6烷基)、-NHC(＝O)(C1-6烷基)、-N(C1-6烷基)C(＝O)(C1-6烷基)、-NHCO2(C1-6烷基)、-NHC(＝O)N(C1-6烷基)2、-NHC(＝O)NH(C1-6烷基)、-NHC(＝O)NH2、-C(＝NH)O(C1-6烷基)、-OC(＝NH)(C1- 6烷基)、-OC(＝NH)OC1-6烷基、-C(＝NH)N(C1-6烷基)2、-C(＝NH)NH(C1-6烷基)、-C(＝NH)NH2、-OC(＝NH)N(C1-6烷基)2、-OC(NH)NH(C1-6烷基)、-OC(NH)NH2、-NHC(NH)N(C1-6烷基)2、-NHC(＝NH)NH2、-NHSO2(C1-6烷基)、-SO2N(C1-6烷基)2、-SO2NH(C1-6烷基)、-SO2NH2、-SO2C1-6烷基、-SO2OC1-6烷基、-OSO2C1-6烷基、-SOC1-6烷基、-Si(C1-6烷基)3、-OSi(C1-6烷基)3、-C(＝S)N(C1-6烷基)2、C(＝S)NH(C1-6烷基)、C(＝S)NH2、-C(＝O)S(C1-6烷基)、-C(＝S)SC1-6烷基、-SC(＝S)SC1-6烷基、-P(＝O)2(C1-6烷基)、-P(＝O)(C1- 6烷基)2、-OP(＝O)(C1-6烷基)2、-OP(＝O)(OC1-6烷基)2、C1-6烷基、C1-6卤代烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、C3-C7杂环基、C5-C10杂芳基；或者两个偕Rgg取代基可结合形成＝O或＝S；其中，X-为反离子。
示例性的氮原子上取代基包括但不局限于：氢、-OH、-ORaa、-N(Rcc)2、-CN、-C(＝O)Raa、-C(＝O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(＝NRbb)Raa、-C(＝NRcc)ORaa、-C(＝NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(＝S)N(Rcc)2、-C(＝O)SRcc、-C(＝S)SRcc、-P(＝O)2Raa、-P(＝O)(Raa)2、-P(＝O)2N(Rcc)2、-P(＝O)(NRcc)2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者连接至氮原子的两个Rcc基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代，且其中Raa、Rbb、Rcc和Rdd如上所述。
其它定义
本文所用的术语“药学上可接受的盐”表示本发明化合物的那些羧酸盐、氨基酸加成盐，它们在可靠的医学判断范围内适用于与患者组织接触，不会产生不恰当的毒性、刺激作用、变态反应等，与合 理的益处/风险比相称，就它们的预期应用而言是有效的，包括(可能的话)本发明化合物的两性离子形式。
给药的“受试者”包括但不限于：人(即，任何年龄组的男性或女性，例如，儿科受试者(例如，婴儿、儿童、青少年)或成人受试者(例如，年轻的成人、中年的成人或年长的成人))和/或非人的动物，例如，哺乳动物，例如，灵长类(例如，食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中，受试者是人。在一些实施方案中，受试者是非人动物。本文可互换使用术语“人”、“患者”和“受试者”。
“疾病”、“障碍”和“病症”在本文中可互换地使用。
通常，化合物的“有效量”是指足以引起目标生物反应的数量。正如本领域普通技术人员所理解的那样，本发明化合物的有效量可以根据下列因素而改变：例如，生物学目标、化合物的药代动力学、所治疗的疾病、给药模式以及受试者的年龄健康情况和症状。有效量包括治疗有效量和预防有效量。
“组合”以及相关术语是指同时或依次给药本发明化合物和其它治疗剂。例如，本发明化合物可以与其它治疗剂以分开的单位剂型同时或依次给药，或与其它治疗剂一起在单一单位剂型中同时给药。
具体实施方案
本文中，“本发明化合物”指的是以下的式(A)化合物(包括子通式，例如式(I)、式(II)、式(III)、式(III-1)、式(III-2)、式(III-3)、式(IV)、式(V)或式(VI)等)、其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，以及它们的混合物。
在一个实施方案中，本发明涉及式(A)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中：
表示单键或双键；
当为双键时，X1为C；
当为单键时，X1为N；
X2和X3各自独立地选自CR2或N；
环A为5-6元杂芳基或5-6元杂环基，并且当环A为5元杂芳基时，环A和嘧啶环一起形成所述环A任选地被1个、2个、3个、4个或5个R2取代；
环B为5-12元杂芳基；
环C为5-6元杂芳基；
L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
每个R1独立地选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R1可任选地被1个、2个、3个、4个或5个R*取代；
每个R2独立地选自H、D、卤素、CN、ORa、NRaRb、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1- 6卤代烷氧基、C2-6烯基、C2-6炔基、-C(O)Ra、-C(O)ORa、-OC(O)Ra、-C(O)NRaRb、-(CH2)1-6-ORa、-(CH2)1-6-C(O)Ra、-(CH2)1-6-C(O)ORa、-(CH2)1-6-OC(O)Ra、-(CH2)1-6-C(O)NRaRb、-(CH2)1-6-CN、-(CH2)1- 6-NRaRb、C3-7环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基，所述R2可任选地被1个、2个、3个、4个、5个、6个、7个、8个或更多个R*取代；或者同一碳原子上的两个R2形成＝O或＝S；
每个R3独立地选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R3可任选地被1个、2个、3个、4个、5个、6个、7个、8个或更多个R*取代；
或者，一个R2和一个R3与它们分别连接的原子一起形成6-12元杂环基或6-12元杂芳基；
R4选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R4可任选地被1个、2个、3个、4个或5个R*取代；
R#选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
R*选自H、D、卤素、NH2、CN、OH、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基；
Ra选自H、C1-6烷基或C1-6卤代烷基；
Rb选自H、C1-6烷基或C1-6卤代烷基；
或者，Ra和Rb与它们连接的氮原子一起形成5-10元杂环基或5-10元杂环基；
m为1、2或3；
n为1、2、3或4；
p为1或2。
在另一个实施方案中，本发明涉及式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中：
表示单键或双键；
当为双键时，X1为C；
当为单键时，X1为N；
X2和X3各自独立地选自CR2或N；
环A为5-6元杂芳基，并且当环A为5元杂芳基时，环A和嘧啶环一起形成
环B为5-6元杂芳基；
L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
每个R1独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R1可任选地被1个、2个、3个、4个或5个R*取代；
每个R2独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基或C2-6炔基，所述R2可任选地被1个、2个、3个、4个或5个R*取代；
每个R3独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R3可任选地被1个、2个、3个、4个或5个R*取代；
R4选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R4可任选地被1个、2个、3个、4个或5个R*取代；
R#选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
R*选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
m为1、2或3；
n为1、2、3或4；
p为1或2。
和X1
在一个具体实施方案中，为双键，X1为C；在另一个具体实施方案中，为单键，X1为N。
X2
在一个具体实施方案中，X2为CR2，例如CH；在另一个具体实施方案中，X2为N。
X3
在一个具体实施方案中，X3为CR2，例如CH；在另一个具体实施方案中，X3为N。
X4
在一个具体实施方案中，X4为CR2，例如CH；在另一个具体实施方案中，X4为N。
X5
在一个具体实施方案中，X5为CR2，例如CH；在另一个具体实施方案中，X5为N。
X6
在一个具体实施方案中，X6为C；在另一个具体实施方案中，X6为N。
X7
在一个具体实施方案中，X7为C；在另一个具体实施方案中，X7为N。
L
在一个具体实施方案中，L为CH2，且所述CH2未被取代；在另一个具体实施方案中，L为CH2，且所述CH2被1个R#取代；在另一个具体实施方案中，L为CH2，且所述CH2被2个R#取代；在另一个具体实施方案中，L为SO2。
环A
在一个具体实施方案中，环A为5元杂芳基，且环A和嘧啶环一起形成在另一个具体实施方案中，环A为6元杂芳基。
在一个具体实施方案中，环A为5-6元杂环基。
在一个具体实施方案中，环A未被取代；在另一个具体实施方案中，环A被1个R2取代；在另一个具体实施方案中，环A被2个R2取代；在另一个具体实施方案中，环A被3个R2取代；在另一个具体实施方案中，环A被4个R2取代；在另一个具体实施方案中，环A被5个R2取代。
环B
在一个具体实施方案中，环B为5-12元杂芳基。
在一个具体实施方案中，环B为5元杂芳基；在另一个具体实施方案中，环B为6元杂芳基。
环C
在一个具体实施方案中，环C为5-6元杂芳基。
R1
在一个具体实施方案中，R1为H；在另一个具体实施方案中，R1为D；在另一个具体实施方案中，R1为卤素；在另一个具体实施方案中，R1为C1-6烷基；在另一个具体实施方案中，R1为C1-4烷 基；在另一个具体实施方案中，R1为C1-6卤代烷基；在另一个具体实施方案中，R1为C1-4卤代烷基；在另一个具体实施方案中，R1为C1-6烷氧基；在另一个具体实施方案中，R1为C1-4烷氧基，优选为C1-2烷氧基，例如甲氧基；在另一个具体实施方案中，R1为C1-6卤代烷氧基；在另一个具体实施方案中，R1为C1-4卤代烷氧基；在另一个具体实施方案中，R1为C2-6烯基；在另一个具体实施方案中，R1为C2-6炔基；在另一个具体实施方案中，R1为C3-10环烷基；在另一个具体实施方案中，R1为C3-7环烷基；在另一个具体实施方案中，R1为C3-5环烷基，例如环丙基；在另一个具体实施方案中，R1为3-10元杂环基；在另一个具体实施方案中，R1为3-7元杂环基，例如在另一个具体实施方案中，R1为C6-10芳基；在另一个具体实施方案中，R1为5-10元杂芳基。
在一个具体实施方案中，R1未被取代；在另一个具体实施方案中，R1被1个R*取代；在另一个具体实施方案中，R1被2个R*取代；在另一个具体实施方案中，R1被3个R*取代；在另一个具体实施方案中，R1被4个R*取代；在另一个具体实施方案中，R1被5个R*取代。
R1’
在一个具体实施方案中，R1’为卤素；在另一个具体实施方案中，R1’为C1-6烷氧基；在另一个具体实施方案中，R1’为C1-4烷氧基；在另一个具体实施方案中，R1’为C1-6卤代烷氧基；在另一个具体实施方案中，R1’为C1-4卤代烷氧基；在另一个具体实施方案中，R1’为C3-7环烷基；在另一个具体实施方案中，R1’为C3-5环烷基；在另一个具体实施方案中，R1’为3-7元杂环基；在另一个具体实施方案中，R1’为3-5元杂环基。
在一个具体实施方案中，R1’未被取代；在另一个具体实施方案中，R1’被1个卤素取代；在另一个具体实施方案中，R1’被2个卤素取代；在另一个具体实施方案中，R1’被3个卤素取代。
R2
在一个具体实施方案中，R2为H；在另一个具体实施方案中，R2为D；在另一个具体实施方案中，R2为卤素，例如F；在另一个具体实施方案中，R2为CN；在另一个具体实施方案中，R2为ORa；在另一个具体实施方案中，R2为NRaRb；在另一个具体实施方案中，R2为C1-6烷基；在另一个具体实施方案中，R2为C1-4烷基；在另一个具体实施方案中，R2为C1-6卤代烷基；在另一个具体实施方案中，R2为C1-4卤代烷基；在另一个具体实施方案中，R2为C1-6烷氧基；在另一个具体实施方案中，R2为C1-4烷氧基；在另一个具体实施方案中，R2为C1-6卤代烷氧基；在另一个具体实施方案中，R2为C1-4卤代烷氧基；在另一个具体实施方案中，R2为C2-6烯基；在另一个具体实施方案中，R2为C2-6炔基；在另一个具体实施方案中，R2为-C(O)Ra；在另一个具体实施方案中，R2为-C(O)ORa；在另一个具体实施方案中，R2为-OC(O)Ra；在另一个具体实施方案中，R2为-C(O)NRaRb；在另一个具体实施方案中，R2为-(CH2)1-6-ORa；在另一个具体实施方案中，R2为-(CH2)1-6-C(O)Ra；在另一个具体实施方案中，R2为-(CH2)1-6-C(O)ORa；在另一个具体实施方案中，R2为-(CH2)1-6-OC(O)Ra；在另一个具体实施方案中，R2为-(CH2)1-6-C(O)NRaRb；在另一个具体实施方案中，R2为-(CH2)1-6-CN；在另一个具体实施方案中，R2为-(CH2)1-6-NRaRb；在另一个具体实施方案中，R2为C3-7环烷基；在另一个具体实施方案中，R2为5-10元杂环基；在另一个具体实施方案中，R2为C6-10芳基；在另一个具体实施方案中，R2为5-10元杂芳基；在另一个具体实施方案中，同一碳原子上的两个R2形成＝O；在另一个具体实施方案中，同一碳原子上的两个R2形成＝S。
在一个具体实施方案中，R2为H；在另一个具体实施方案中，R2为F；在另一个具体实施方案中，R2为NH2；在另一个具体实施方案中，R2为CHF2；在另一个具体实施方案中，R2为在另一个具体实施方案中，R2为在另一个具体实施方案中，R2为在另一个具体实施方案中，R2为在另一个具体实施方案中，R2为在另一个具体实施方案中，R2为在另一个具体实施方案中，R2为在另一个具体实施方案中，R2为在另一个具体实施方案中，R2为在另一个具体实施方案中，R2为
在一个具体实施方案中，R2未被取代；在另一个具体实施方案中，R2被1个R*取代；在另一个具体实施方案中，R2被2个R*取代；在另一个具体实施方案中，R2被3个R*取代；在另一个具体实 施方案中，R2被4个R*取代；在另一个具体实施方案中，R2被5个R*取代；在另一个具体实施方案中，R2被6个R*取代；在另一个具体实施方案中，R2被7个R*取代；在另一个具体实施方案中，R2被8个R*取代；在另一个具体实施方案中，R2被更多个R*取代。
R2’
在一个具体实施方案中，R2’为H；在另一个具体实施方案中，R2’为卤素；在另一个具体实施方案中，R2’为C1-6烷基；在另一个具体实施方案中，R2’为C1-4烷基。
R3
在一个具体实施方案中，R3为H；在另一个具体实施方案中，R3为D；在另一个具体实施方案中，R3为卤素；在另一个具体实施方案中，R3为C1-6烷基；在另一个具体实施方案中，R3为C1-4烷基；在另一个具体实施方案中，R3为C1-6卤代烷基；在另一个具体实施方案中，R3为C1-4卤代烷基，例如CF3；在另一个具体实施方案中，R3为C1-6烷氧基；在另一个具体实施方案中，R3为C1-4烷氧基；在另一个具体实施方案中，R3为C1-6卤代烷氧基；在另一个具体实施方案中，R3为C1-4卤代烷氧基；在另一个具体实施方案中，R3为C2-6烯基；在另一个具体实施方案中，R3为C2-6炔基；在另一个具体实施方案中，R3为C3-10环烷基；在另一个具体实施方案中，R3为C3-7环烷基；在另一个具体实施方案中，R3为3-10元杂环基；在另一个具体实施方案中，R3为3-7元杂环基；在另一个具体实施方案中，R3为C6-10芳基；在另一个具体实施方案中，R3为5-10元杂芳基。
在一个具体实施方案中，R3为CH3；在另一个具体实施方案中，R3为CD3；在另一个具体实施方案中，R3为CF3；在另一个具体实施方案中，R3为CHF2；在另一个具体实施方案中，R3为CH2CH3；在另一个具体实施方案中，R3为CH(CH3)2；在另一个具体实施方案中，R3为环丙基；在另一个具体实施方案中，R3为在另一个具体实施方案中，R3为
在一个具体实施方案中，一个R2和一个R3与它们分别连接的原子一起形成6-12元杂环基或6-12元杂芳基。
在一个具体实施方案中，R3未被取代；在另一个具体实施方案中，R3被1个R*取代；在另一个具体实施方案中，R3被2个R*取代；在另一个具体实施方案中，R3被3个R*取代；在另一个具体实施方案中，R3被4个R*取代；在另一个具体实施方案中，R3被5个R*取代；在另一个具体实施方案中，R3被6个R*取代；在另一个具体实施方案中，R3被7个R*取代；在另一个具体实施方案中，R3被8个R*取代；在另一个具体实施方案中，R3被更多个R*取代。
R4
在一个具体实施方案中，R4为H；在另一个具体实施方案中，R4为D；在另一个具体实施方案中，R4为卤素；在另一个具体实施方案中，R4为C1-6烷基；在另一个具体实施方案中，R4为C1-4烷基；在另一个具体实施方案中，R4为C1-6卤代烷基；在另一个具体实施方案中，R4为C1-4卤代烷基；在另一个具体实施方案中，R4为C1-6烷氧基；在另一个具体实施方案中，R4为C1-4烷氧基；在另一个具体实施方案中，R4为C2-6烯基；在另一个具体实施方案中，R4为C2-6炔基；在另一个具体实施方案中，R4为C3-10环烷基；在另一个具体实施方案中，R4为C3-7环烷基；在另一个具体实施方案中，R4为3-10元杂环基；在另一个具体实施方案中，R4为3-7元杂环基；在另一个具体实施方案中，R4为C6-10芳基；在另一个具体实施方案中，R4为5-10元杂芳基。
在一个具体实施方案中，R4未被取代；在另一个具体实施方案中，R4被1个R*取代；在另一个具体实施方案中，R4被2个R*取代；在另一个具体实施方案中，R4被3个R*取代；在另一个具体实施方案中，R4被4个R*取代；在另一个具体实施方案中，R4被5个R*取代。
R#
在一个具体实施方案中，R#为H；在另一个具体实施方案中，R#为D；在另一个具体实施方案中，R#为卤素；在另一个具体实施方案中，R#为C1-6烷基；在另一个具体实施方案中，R#为C1-4烷基；在另一个具体实施方案中，R#为C1-6卤代烷基；在另一个具体实施方案中，R#为C1-4卤代烷基；在另一个具体实施方案中，R#为C2-6烯基；在另一个具体实施方案中，R#为C2-6炔基；
R*
在一个具体实施方案中，R*为H；在另一个具体实施方案中，R*为D；在另一个具体实施方案中，R*为卤素；在另一个具体实施方案中，R*为NH2；在另一个具体实施方案中，R*为CN；在另一个具体实施方案中，R*为OH；在另一个具体实施方案中，R*为C1-6烷基；在另一个具体实施方案中，R*为C1-4烷基；在另一个具体实施方案中，R*为C1-6卤代烷基；在另一个具体实施方案中，R*为C1- 4卤代烷基；在另一个具体实施方案中，R*为C2-6烯基；在另一个具体实施方案中，R*为C2-6炔基；在另一个具体实施方案中，R*为C3-10环烷基；在另一个具体实施方案中，R*为5-10元杂环基；在另一个具体实施方案中，R*为C6-10芳基；在另一个具体实施方案中，R*为5-10元杂芳基。
Ra和Rb
在一个具体实施方案中，Ra为H；在另一个具体实施方案中，Ra为C1-6烷基；在另一个具体实施方案中，Ra为C1-6卤代烷基。
在一个具体实施方案中，Rb为H；在另一个具体实施方案中，Rb为C1-6烷基；在另一个具体实施方案中，Rb为C1-6卤代烷基。
在一个具体实施方案中，Ra和Rb与它们连接的氮原子一起形成5-10元杂环基；在另一个具体实施方案中，Ra和Rb与它们连接的氮原子一起形成5-10元杂环基。
m
在一个具体实施方案中，m为1；在另一个具体实施方案中，m为2；在另一个具体实施方案中，m为3。
n
在一个具体实施方案中，n为1；在另一个具体实施方案中，n为2；在另一个具体实施方案中，n为3；在另一个具体实施方案中，n为4。
p
在一个具体实施方案中，p为1；在另一个具体实施方案中，p为2。
在一个具体实施方案中，本申请所述化合物不为
以上任一具体实施方案中的任一技术方案或其任意组合，可以与其它具体实施方案中的任一技术方案或其任意组合进行组合。例如，X1的任一技术方案或其任意组合，可以与X2-X7、环A、环B、环C、L、R1、R1’、R2、R2’、R3、R4、R#、R*、Ra、Rb、m、n和p等的任一技术方案或其任意组合进行组合。本发明旨在包括所有这些技术方案的组合，限于篇幅，不再一一列出。
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中：
表示单键或双键；
当为双键时，X1为C；
当为单键时，X1为N；
X2和X3各自独立地选自CR2或N；
环A为5-6元杂芳基，并且当环A为5元杂芳基时，环A和嘧啶环一起形成
环B为5-6元杂芳基；
L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
每个R1独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R1可任选地被1个、2个、3个、4个或5个R*取代；
每个R2独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基或C2-6炔基，所述R2可任选地被1个、2个、3个、4个或5个R*取代；
每个R3独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R3可任选地被1个、2个、3个、4个或5个R*取代；
R4选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R4可任选地被1个、2个、3个、4个或5个R*取代；
R#选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
R*选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
m为1、2或3；
n为1、2、3或4；
p为1或2。
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
表示单键或双键；
当为双键时，X1为C；
当为单键时，X1为N；
X2和X3各自独立地选自CR2或N，只要化学上允许；
环A为5-6元杂芳基，并且当环A为5元杂芳基时，环A和嘧啶环一起形成
环B为5-6元杂芳基；
L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
每个R1独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-10环烷基或3-10元杂环基，所述R1可任选地被1个、2个、3个、4个或5个R*取代；
每个R2独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；
每个R3独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-10环烷基和3-10元杂环基，所述R3可任选地被1个、2个、3个、4个或5个R*取代；
R4选自H、卤素、C1-6烷基、C1-6卤代烷基、C3-10环烷基和3-10元杂环基，所述R4可任选地被1个、2个、3个、4个或5个R*取代；
R#选自H、D、卤素、C1-6烷基或C1-6卤代烷基；
R*选自H、D、卤素、C1-6烷基或C1-6卤代烷基；
m为1、2或3；
n为1、2、3或4；
p为1或2。
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其具有以下通式：
其中：
X4和X5各自独立地选自CR2或N；
X6和X7各自独立地选自C或N；
R1’选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，所述R1’可任选地被1个、2个或3个卤素取代；
R3’选自C1-6烷基或C1-6卤代烷基；
其他各基团如上文所定义；
前提是，所述化合物不为
在更具体的实施方案中，本发明提供了式(II)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中：
X2、X3、X4和X5各自独立地选自CR2或N；
L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
环B为5-6元杂芳基；
每个R1独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，所述R1可任选地被1个、2个或3个R*取代；
每个R2独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；
每个R3独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基和3-7元杂环基，所述R3可任选地被1个、2个或3个R*取代；
R#选自H、C1-6烷基或C1-6卤代烷基；
R*选自H、D、卤素、C1-6烷基或C1-6卤代烷基；
m为1、2或3；
n为1、2、3或4；
p为1或2；
前提是，所述化合物不为
在更具体的实施方案中，本发明提供了式(III)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中：
X2、X3、X4和X5各自独立地选自CH或N，并且X2和X3为CH时，其中的H可任选地被R2取代；
X6和X7各自独立地选自C或N；
L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
R1选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；
R1’选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，所述R1’可任选地被1个、2个或3个卤素取代；
R2选自H、卤素、C1-6烷基或C1-6卤代烷基；
R3选自C1-6烷基、C1-6卤代烷基、C3-7环烷基和3-7元杂环基，所述R3可任选地被1个、2个或3个选自D或C1-6烷基的取代基取代；
R3’选自C1-6烷基或C1-6卤代烷基；
R#选自H或C1-6烷基；
p为1或2；
前提是，所述化合物不为
在更具体的实施方案中，本发明提供了上述式(III)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
X2、X3、X4和X5各自独立地选自CH或N，并且X2和X3为CH时，其中的H可任选地被R2取代；
X6和X7各自独立地选自C或N，且X6和X7中的至少一个为N；
L为CH2，所述CH2可任选地被1个或2个R#取代；
R1选自C1-4烷氧基或C1-4卤代烷氧基；
R1’选自C1-4烷氧基、C3-5环烷基和3-5元杂环基，所述R1’可任选地被1个、2个或3个卤素取代；
R2选自H、卤素、C1-4烷基或C1-4卤代烷基；
R3选自C1-4烷基、C3-5环烷基或3-5元杂环基，所述R3可任选地被1个、2个或3个选自D或C1-4烷基的取代基取代；
R3’选自C1-4烷基或C1-4卤代烷基；
R#选自H或C1-4烷基；
p为1或2。
在更具体的实施方案中，本发明提供了上述式(III)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
X2、X3、X4、X5各自独立地选自CH或N，并且X2和X3为CH时，其中的H可任选地被R2取代；
X6和X7各自独立地选自C或N，且X6和X7中的至少一个为N；
L为CH2，所述CH2可任选地被1个或2个R#取代；
R1选自C1-2烷氧基或C1-2卤代烷氧基；
R1’选自甲氧基、环丙基和
R2选自H或卤素，优选F；
R3选自CH3、CD3、CH2CH3、CH(CH3)2、环丙基、
R3’为卤代甲基，优选为CF3、CHF2；
R#选自H或甲基；
p为1或2。
在更具体的实施方案中，本发明提供了式(IV)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中：
X4为CH或N；
R1为C1-4烷氧基；
R1’为C3-7环烷基。
在更具体的实施方案中，本发明提供了上述式(IV)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
X4为CH或N；
R1为C1-2烷氧基，优选为甲氧基；
R1’为C3-5环烷基，优选为环丙基。
在更具体的实施方案中，本发明提供了式(V)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中：
表示单键或双键；
当为双键时，X1为C；
当为单键时，X1为N；
环A与嘧啶环一起形成
环B为5元杂芳基；
L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
每个R1独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基；
每个R2独立地选自H、卤素或C1-6烷基；
每个R3独立地选自H、C1-6烷基或C1-6卤代烷基；
R#选自H、C1-6烷基或C1-6卤代烷基；
m为1、2或3；
n为1、2或3；
p为1、2、3或4。
在更具体的实施方案中，本发明提供了式(VI)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中：
表示单键或双键；
当为双键时，X1为C；
当为单键时，X1为N；
环A与嘧啶环一起形成
L为CH2，其可任选地被1个或2个R#取代；
R1选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；
R1’选自卤素、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；
R3选自C1-6烷基或C1-6卤代烷基；
R3’选自C1-6烷基或C1-6卤代烷基；
R#选自H或C1-6烷基。
在更具体的实施方案中，本发明提供了上述式(VI)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
表示单键或双键；
当为双键时，X1为C；
当为单键时，X1为N；
环A与嘧啶环一起形成
L为CH2，其可任选地被1个或2个R#取代；
R1选自C1-6烷氧基或C1-6卤代烷氧基；
R1’选自C3-7环烷基或3-7元杂环基；
R3选自C1-6烷基或C1-6卤代烷基；
R3’选自C1-6烷基或C1-6卤代烷基；
R#选自H或C1-4烷基。
在更具体的实施方案中，本发明提供了上述式(VI)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
表示单键或双键；
当为双键时，X1为C；
当为单键时，X1为N；
环A与嘧啶环一起形成
L为CH2；
R1为C1-4烷氧基，优选为甲氧基；
R1’为C3-5环烷基，优选为环丙基；
R3为C1-4烷基，优选为异丙基；
R3’为C1-4卤代烷基，优选为CF3。
在更具体的实施方案中，本发明提供了式(III)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中：
X2和X3各自独立地选自CR2或N；
X4和X5各自独立地选自CR2或N；
X6和X7各自独立地选自C或N；
L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
R1选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R1可任选地被1个、2个、3个、4个或5个R*取代；
R1’选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，所述R1’可任选地被1个、2个或3个卤素取代；
每个R2独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基或C2-6炔基，所述R2可任选地被1个、2个、3个、4个或5个R*取代；
每个R3独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R3可任选地被1个、2个、3个、4个或5个R*取代；
R3’选自C1-6烷基或C1-6卤代烷基；
R#选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
R*选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
p为1或2；
前提是，所述化合物不为
在更具体的实施方案中，本发明提供了上述式(III)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
X2为CR2；
X3选自CR2或N；
X4选自CR2或N；
X5为CR2；
X6和X7各自独立地选自C或N；
L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
R1选自H、卤素、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R1可任选地被1个、2个、3个、4个或5个R*取代；
R1’为卤素、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，所述R1’可任选地被1个、2个或3个卤素取代；
每个R2独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基或C2-6炔基，所述R2可任选地被1个、2个、3个、4个或5个R*取代；
每个R3独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R3可任选地被1个、2个、3个、4个或5个R*取代；
R3’选自C1-6烷基或C1-6卤代烷基；
R#选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
R*选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
p为1或2。
在更具体的实施方案中，本发明提供了式(III-1)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中：
X2为CR2；
X3选自CR2或N；
X4选自CR2或N；
X5为CR2；
L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
R1选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R1可任选地被1个、2个、3个、4个或5个R*取代；
R1’选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，所述R1’可任选地被1个、2个或3个卤素取代；
每个R2独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基或C2-6炔基，所述R2可任选地被1个、2个、3个、4个或5个R*取代；
每个R3独立地选自H、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R3可任选地被1个、2个、3个、4个或5个R*取代；
R3’选自C1-6烷基或C1-6卤代烷基；
R#选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
R*选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
p为1或2；
前提是，所述化合物不为
在更具体的实施方案中，本发明提供了上述式(III-1)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
X2和X3为CR2；
X4选自CR2或N；
X5为CR2；
L为CH2，所述CH2可任选地被1个或2个R#取代；
R1选自C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，所述R1可任选地被1个、2个或3个R*取代；
R1’选自C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，所述R1’可任选地被1个、2个或3个卤素取代；
每个R2独立地选自H、卤素或C1-6烷基，优选为H；
R3选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基，所述R3可任选地被1个、2个、3个、4个或5个R*取代；
R3’选自C1-6烷基或C1-6卤代烷基；
R#选自H、D、卤素、C1-6烷基或C1-6卤代烷基；
R*选自H、D、卤素、C1-6烷基或C1-6卤代烷基；
p为1或2。
在更具体的实施方案中，本发明提供了上述式(III-1)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
X2和X3为CR2；
X4和X5为CR2；
L为CH2，所述CH2可任选地被1个或2个R#取代；
R1选自C1-6烷氧基或C1-6卤代烷氧基，所述R1可任选地被1个、2个或3个R*取代；
R1’选自C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，所述R1’可任选地被1个、2个或3个卤素取代；
每个R2独立地选自H、卤素或C1-6烷基，优选为H；
R3选自H、C1-6烷基、C3-10环烷基或3-10元杂环基，所述R3可任选地被1个、2个、3个、4个或5个R*取代；
R3’选自C1-6烷基或C1-6卤代烷基；
R#选自H或C1-6烷基；
R*选自H、D或C1-6烷基；
p为1或2。
在更具体的实施方案中，本发明提供了上述式(III-1)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
X2和X3为CR2；
X4为CR2；
X5为CR2；
L为CH2；
R1选自C1-6烷氧基或C1-6卤代烷氧基，所述R1可任选地被1个、2个或3个R*取代；
R1’选自C1-6烷氧基或C3-7环烷基；
每个R2独立地选自H、卤素或C1-6烷基，优选为H；
R3选自H、C1-6烷基或C3-10环烷基，所述R3可任选地被1个、2个或3个R*取代；
R3’选自C1-6烷基或C1-6卤代烷基；
R*选自H或D；
p为1或2。
在更具体的实施方案中，本发明提供了上述式(III-1)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
X2和X3为CR2；
X4和X5为CR2；
L为CH2；
R1为C1-6烷氧基或C1-6卤代烷氧基，优选为OCH3或OCHF2；
R1’为C3-7环烷基，所述R1’可任选地被1个、2个或3个卤素取代；R1’优选为环丙基；
R2为H；
R3为C1-6烷基，优选为甲基或异丙基；
R3’为C1-6卤代烷基，优选为CF3；
p为1或2。
在更具体的实施方案中，本发明提供了式(III-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中：
X2为CR2；
X3选自CR2或N；
X4选自CR2或N；
X5为CR2；
L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
R1选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R1可任选地被1个、2个、3个、4个或5个R*取代；
R1’选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，所述R1’可任选地被1个、2个或3个卤素取代；
每个R2独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基或C2-6炔基，所述R2可任选地被1个、2个、3个、4个或5个R*取代；
R3选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、 C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R3可任选地被1个、2个、3个、4个或5个R*取代；
R3’选自C1-6烷基或C1-6卤代烷基；
R#选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
R*选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
p为1或2。
在更具体的实施方案中，本发明提供了上述式(III-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
X2为CR2；
X3选自CR2或N；
X4和X5为CR2；
L为CH2，所述CH2可任选地被1个或2个R#取代；
R1选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基或C3-10环烷基；
R1’选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基或C3-7环烷基；
每个R2独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；
R3选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-10环烷基或3-10元杂环基；
R3’选自C1-6烷基或C1-6卤代烷基；
R#选自H、D、卤素、C1-6烷基或C1-6卤代烷基；
p为1或2。
在更具体的实施方案中，本发明提供了上述式(III-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
X2和X3为CR2；
X4和X5为CR2；
L为CH2；
R1选自C1-6烷氧基或C1-6卤代烷氧基；
R1’为C3-7环烷基，优选为环丙基；
每个R2独立地选自H、卤素、C1-6烷基或C1-6卤代烷基，优选为H；
R3选自C1-6烷基、C1-6卤代烷基或C3-10环烷基；
R3’为C1-6卤代烷基；
p为1或2。
在更具体的实施方案中，本发明提供了式(III-3)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中：
X4和X5各自独立地为CR2，优选不同时为CH；
L为CH2，所述CH2可任选地被1个或2个R#取代；
R1选自C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，优选为OCH3或OCHF2；
R1’选自C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，优选为环丙基；
每个R2独立地选自H、卤素、CN、ORa、NRaRb、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-C(O)Ra、-C(O)ORa、-OC(O)Ra、-C(O)NRaRb、-(CH2)1-4-ORa、-(CH2)1-4-C(O)Ra、-(CH2)1- 4-C(O)ORa、-(CH2)1-4-OC(O)Ra、-(CH2)1-4-C(O)NRaRb、-(CH2)1-4-CN、-(CH2)1-4-NRaRb、C3-7环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1个、2个、3个、4个、5个、6个、7个、8个或更多个R*取代；
R3选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基，所述R3可任选地被1个、2个、3个、4个或5个R*取代；
R3’选自C1-6烷基或C1-6卤代烷基；
R#选自H、D、卤素、C1-6烷基或C1-6卤代烷基；
R*选自H、D、卤素、NH2、CN、OH、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基；
Ra选自H、C1-6烷基或C1-6卤代烷基；
Rb选自H、C1-6烷基或C1-6卤代烷基；
或者，Ra和Rb与它们连接的氮原子一起形成5-10元杂环基或5-10元杂环基。
在更具体的实施方案中，本发明提供了式(III-3)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
X4为CR2’；
X5为CR2；
L为CH2，所述CH2可任选地被1个或2个R#取代；
R1为C1-6烷氧基或C1-6卤代烷氧基，优选为OCH3或OCHF2；
R1’选自C3-7环烷基或3-7元杂环基，优选为环丙基；
R2选自H、卤素、CN、ORa、NRaRb、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-C(O)Ra、-(CH2)1-4-ORa、-(CH2)1-4-CN、-(CH2)1-4-NRaRb、C3-7环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1个、2个、3个、4个或5个R*取代；
R2’为H或卤素；
优选R2和R2’中至少一个不为H；
R3选自H、C1-6烷基或C3-7环烷基；
R3’为C1-6烷基或C1-6卤代烷基；
R#选自H、C1-6烷基或C1-6卤代烷基；
R*选自D、卤素、NH2、CN、OH、C1-6烷基、C1-6卤代烷基、C3-7环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基；
Ra选自H、C1-6烷基或C1-6卤代烷基；
Rb选自H、C1-6烷基或C1-6卤代烷基；
或者，Ra和Rb与它们连接的氮原子一起形成5-10元杂环基。
在更具体的实施方案中，本发明提供了式(III-3)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
X4为CR2’；
X5为CR2；
L为CH2，所述CH2可任选地被1个或2个R#取代；
R1为OCH3或OCHF2；
R1’为环丙基；
R2选自H、卤素、CN、OH、NH2、C1-4烷基、C1-4卤代烷基、-C(O)C1-4烷基、-(CH2)1-4-OH、-(CH2)1- 4-CN或-(CH2)1-4-NH2，其任选地被1个、2个或3个R*取代；
R2’为H或C1-4烷基；
并且R2和R2’中至少一个不为H；
R3为C1-4烷基；
R3’为C1-4卤代烷基；
R#选自H或C1-4烷基；
R*选自卤素、NH2、CN、OH、C1-4烷基、C1-4卤代烷基、5-10元杂环基或5-10元杂芳基。
在更具体的实施方案中，本发明提供了式(III-3)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
X4为CR2’；
X5为CR2；
L为CH2；
R1为OCH3；
R1’为环丙基；
R2选自H、F、NH2、CHF2、 优选为H、F、NH2、CHF2、
R2’为H或CH3；
并且R2和R2’中至少一个不为H；
R3为CH3或异丙基；
R3’为CF3。
在更具体的实施方案中，本发明提供了化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物选自：

在更具体的实施方案中，本发明提供了化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物选自：


本发明化合物可包括一个或多个不对称中心，且因此可以存在多种立体异构体形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋体混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。
本发明化合物还可能以互变异构体存在。在不同的互变异构形式存在的化合物，一个所述化合物并不局限于任何特定的互变异构体，而是旨在涵盖所有的互变异构形式。
本领域技术人员将理解，有机化合物可以与溶剂形成复合物，其在该溶剂中发生反应或从该溶剂中沉淀或结晶出来。这些复合物称为“溶剂合物”。当溶剂是水时，复合物称为“水合物”。本发明涵盖了本发明化合物的所有溶剂合物。
术语“溶剂合物”是指通常由溶剂分解反应形成的与溶剂相结合的化合物或其盐的形式。这个物理缔合可包括氢键键合。常规溶剂包括水、甲醇、乙醇、乙酸、DMSO、THF、乙醚等。本文所述的化合物可制备成，例如，结晶形式，且可被溶剂化。合适的溶剂合物包括药学上可接受的溶剂合物且进一步包括化学计量的溶剂合物和非化学计量的溶剂合物。在一些情况下，所述溶剂合物将能够分离，例如，当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液状态的溶剂合物和可分离的溶剂合物。代表性的溶剂合物包括水合物、乙醇合物和甲醇合物。
术语“水合物”是指与水相结合的化合物。通常，包含在化合物的水合物中的水分子数与该水合物中该化合物分子数的比率确定。因此，化合物的水合物可用例如通式R·x H2O代表，其中R是该化合物，和x是大于0的数。给定化合物可形成超过一种水合物类型，包括，例如，单水合物(x为1)、低级水合物(x是大于0且小于1的数，例如，半水合物(R·0.5H2O))和多水合物(x为大于1的数，例如，二水合物(R·2H2O)和六水合物(R·6H2O))。
本发明化合物可以是无定形或结晶形式(多晶型)。此外，本发明化合物可以以一种或多种结晶形式存在。因此，本发明在其范围内包括本发明化合物的所有无定形或结晶形式。术语“多晶型物”是指特定晶体堆积排列的化合物的结晶形式(或其盐、水合物或溶剂合物)。所有的多晶型物具有相同的元素组成。不同的结晶形式通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光电性质、稳定性和溶解度。重结晶溶剂、结晶速率、贮存温度和其他因素可导致一种结晶形式占优。化合物的各种多晶型物可在不同的条件下通过结晶制备。
本发明还包括同位素标记的化合物(同位素变体)，它们等同于式(A)所述的那些，但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如3H和14C)的那些可用于药物和/或底物组织分布测定。氚、即3H和碳-14、即14C同位素是特别优选的，因为它们容易制备和检测。进而，被更重的同位素取代，例如氘、即2H，由于代谢稳定性更高可以提供治疗上的益处，例如延长体内半衰期或减少剂量需求，因而在有些情况下可能是优选的。同位素标记的本发明式(A)化合物及其前体药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。
此外，前药也包括在本发明的上下文内。本文所用的术语“前药”是指在体内通过例如在血液中水解转变成其具有医学效应的活性形式的化合物。药学上可接受的前药描述于T.Higuchi和V.Stella，Prodrugs as Novel Delivery Systems，A.C.S.Symposium Series的Vol.14，Edward B.Roche，ed.，Bioreversible Carriers in Drug Design，American Pharmaceutical Association and Pergamon Press，1987，以及D.Fleisher、S.Ramon和H.Barbra“Improved oral drug delivery：solubility limitations overcome by the use of prodrugs”，Advanced Drug Delivery Reviews(1996)19(2)115-130，每篇引入本文作为参考。
药物组合物和试剂盒
在另一方面，本发明提供了药物组合物，其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中，所述药物组合物包含有效量的本发明化合物。在一些实施方案中，所述药物组合物包含治疗有效量的本发明化合物。在一些实施方案中，所述药物组合物包含预防有效量的本发明化合物。
用于本发明的药学上可接受的赋形剂是指不会破坏一起调配的化合物的药理学活性的无毒载剂、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载剂、佐剂或媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。
本发明还包括试剂盒(例如，药物包装)。所提供的试剂盒可以包括本发明化合物、其它治疗剂，以及含有本发明化合物、其它治疗剂的第一和第二容器(例如，小瓶、安瓿瓶、瓶、注射器和/或可分散包装或其它合适的容器)。在一些实施方案中，提供的试剂盒还可以任选包括第三容器，其含有用于稀释或悬浮本发明化合物和/或其它治疗剂的药用赋形剂。在一些实施方案中，提供在第一容器和第二容器中的本发明化合物和其它治疗剂组合形成一个单位剂型。
给药
本发明提供的药物组合物可以通过许多途径给药，包括但不限于：口服给药、肠胃外给药、吸入给药、局部给药、直肠给药、鼻腔给药、口腔给药、阴道给药、通过植入剂给药或其它给药方式。例如，本文使用的肠胃外给药包括皮下给药、皮内给药、静脉内给药、肌肉内给药、关节内给药、动脉内给药、滑膜腔内给药、胸骨内给药、脑脊髓膜内给药、病灶内给药、和颅内的注射或输液技术。
通常，给予有效量的本文所提供的化合物。按照有关情况，包括所治疗的病症、选择的给药途径、实际给予的化合物、个体患者的年龄、体重和响应、患者症状的严重程度，等等，可以由医生确定实际上给予的化合物的量。
当用于预防本发明所述病症时，给予处于形成所述病症危险之中的受试者本文所提供的化合物，典型地基于医生的建议并在医生监督下给药，剂量水平如上所述。处于形成具体病症的危险之中的受试者，通常包括具有所述病症的家族史的受试者，或通过遗传试验或筛选确定尤其对形成所述病症敏感的那些受试者。
还可以长期给予本文所提供的药物组合物(“长期给药”)。长期给药是指在长时间内给予化合物或其药物组合物，例如，3个月、6个月、1年、2年、3年、5年等等，或者可无限期地持续给药，例如，受试者的余生。在一些实施方案中，长期给药意欲在长时间内在血液中提供所述化合物的恒定水平，例如，在治疗窗内。
可以使用各种给药方法，进一步递送本发明的药物组合物。例如，在一些实施方案中，可以推注给药药物组合物，例如，为了使化合物在血液中的浓度提高至有效水平。推注剂量取决于通过身体的活性组分的目标全身性水平，例如，肌内或皮下的推注剂量使活性组分缓慢释放，而直接递送至静脉的推注(例如，通过IV静脉滴注)能够更加快速地递送，使得活性组分在血液中的浓度快速升高至有效水平。在其它实施方案中，可以以持续输液形式给予药物组合物，例如，通过IV静脉滴注，从而在受试者身体中提供稳态浓度的活性组分。此外，在其它实施方案中，可以首先给予推注剂量的药物组合物，而后持续输液。
口服组合物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而，更通常，为了便于精确地剂量给药，以单位剂量形式提供所述组合物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位，每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适 药学赋形剂。典型的单位剂量形式包括液体组合物的预装填的、预先测量的安瓿或注射器，或者在固体组合物情况下的丸剂、片剂、胶囊剂等。在这种组合物中，所述化合物通常为较少的组分(约0.1至约50重量％，或优选约1至约40重量％)，剩余部分为对于形成所需给药形式有用的各种载体或赋形剂以及加工助剂。
对于口服剂量，代表性的方案是，每天一个至五个口服剂量，尤其是两个至四个口服剂量，典型地是三个口服剂量。使用这些剂量给药模式，每个剂量提供大约0.01至大约20mg/kg的本发明化合物，优选的剂量各自提供大约0.1至大约10mg/kg，尤其是大约1至大约5mg/kg。
为了提供与使用注射剂量类似的血液水平，或比使用注射剂量更低的血液水平，通常选择透皮剂量，数量为大约0.01至大约20％重量，优选大约0.1至大约20％重量，优选大约0.1至大约10％重量，且更优选大约0.5至大约15％重量。
从大约1至大约120小时，尤其是24至96小时，注射剂量水平在大约0.1mg/kg/小时至至少10mg/kg/小时的范围。为了获得足够的稳定状态水平，还可以给予大约0.1mg/kg至大约10mg/kg或更多的预载推注。对于40至80kg的人类患者来说，最大总剂量不能超过大约2g/天。
适于口服给药的液体形式可包括合适的水性或非水载体以及缓冲剂、悬浮剂和分散剂、着色剂、调味剂，等等。固体形式可包括，例如，任何下列组份，或具有类似性质的化合物：粘合剂，例如，微晶纤维素、黄蓍胶或明胶；赋形剂，例如，淀粉或乳糖，崩解剂，例如，褐藻酸、Primogel或玉米淀粉；润滑剂，例如，硬脂酸镁；助流剂，例如，胶体二氧化硅；甜味剂，例如，蔗糖或糖精；或调味剂，例如，薄荷、水杨酸甲酯或橙味调味剂。
可注射的组合物典型地基于可注射用的无菌盐水或磷酸盐缓冲盐水，或本领域中已知的其它可注射的赋形剂。如前所述，在这种组合物中，活性化合物典型地为较少的组分，经常为约0.05至10％重量，剩余部分为可注射的赋形剂等。
典型地将透皮组合物配制为含有活性组分的局部软膏剂或乳膏剂。当配制为软膏剂时，活性组分典型地与石蜡或可与水混溶的软膏基质组合。或者，活性组分可与例如水包油型乳膏基质一起配制为乳膏剂。这种透皮制剂是本领域中公知的，且通常包括用于提升活性组分或制剂的稳定的皮肤渗透的其它组份。所有这种已知的透皮制剂和组份包括在本发明提供的范围内。
本发明化合物还可通过经皮装置给予。因此，经皮给药可使用贮存器(reservoir)或多孔膜类型、或者多种固体基质的贴剂实现。
用于口服给予、注射或局部给予的组合物的上述组份仅仅是代表性的。其它材料以及加工技术等阐述于Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania的第8部分中，本文以引用的方式引入该文献。
本发明化合物还可以以持续释放形式给予，或从持续释放给药系统中给予。代表性的持续释放材料的描述可在Remington's Pharmaceutical Sciences中找到。
本发明还涉及本发明化合物的药学上可接受的制剂。在一个实施方案中，所述制剂包含水。在另一个实施方案中，所述制剂包含环糊精衍生物。最常见的环糊精为分别由6、7和8个α-1,4-连接的葡萄糖单元组成的α-、β-和γ-环糊精，其在连接的糖部分上任选包括一个或多个取代基，其包括但不限于：甲基化的、羟基烷基化的、酰化的和磺烷基醚取代。在一些实施方案中，所述环糊精为磺烷基醚β-环糊精，例如，磺丁基醚β-环糊精，也称作Captisol。参见，例如，U.S.5,376,645。在一些实施方案中，所述制剂包括六丙基-β-环糊精(例如，在水中，10-50％)。
实施例
本发明所采用的试剂为直接购买的商业化试剂或经本领域熟知的常用方法合成。
常用缩略词注释：
缩略词：PE＝石油醚；EA＝乙酸乙酯；MeOH＝甲醇；DCM＝二氯甲烷；DCE＝二氯乙烷；CH3CN＝乙腈；1,4-dioxane＝1,4-二氧六环；DMSO＝二甲基亚砜；HFIP＝六氟异丙醇；DMF＝N,N-二甲基甲酰胺；Hex＝正己烷；IPA＝异丙醇；NMP＝N-甲基吡咯烷酮；NMO＝N-甲基吗啉-N-氧化物；TEA＝三乙胺；DIEA＝二异丙基乙基胺；CuI＝碘化亚铜；CuCN＝氰化亚铜；triphosgene＝三光气；p-TsOH＝对甲苯磺酸；T3P＝1-丙基磷酸环酐；TsN3＝对甲苯磺酰基叠氮；PPA＝多聚磷酸；dppa＝叠氮磷酸二苯酯。
如下示例的具体反应路线或步骤为本发明所用，具体如下：
实施例1
关键中间体的制备
中间体a1，a4-a8，a20，a23的合成
步骤1：将原料a1–2(21.7g,81mmol)和醋酸钠(6.6g,81mmol)溶于40mL水中，升温至100℃下搅拌1小时，冷却至室温，缓慢加入4-甲酰基苯甲酸甲酯a1-1(13.3g,81mmol)、氨水(77mL)和甲醇(330mL)，搅拌40分钟后，升温至100℃并继续反应2小时，冷却至室温。向反应液中缓慢加入200mL冰水淬灭反应，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。残余物经柱层析分离(PE/EtOAc,10/1)，得到白色固体a1–3(15.1g)，收率：69％，LCMS：ESI–MS(m/z):271[M+H]+。
步骤2：将上步中间体a1–3(2.0g,7.5mmol)和K2CO3(1.54g,11.2mmol)混于10mL DMF中，加入碘代异丙烷(1.9g,11.2mmol)，升温至50℃下反应2小时，停止反应。向该反应液中加入50mL水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，flash柱层析分离，得到黄色固体a1–4(1.4g)，收率:69％，LCMS：ESI–MS(m/z):313[M+H]+。
步骤3：冰浴，氮气保护下，将上步中间体a1–4(1.4g,5.2mmol)溶于20mL无水THF中，加入DIABL-H(10.4mmol)，升温至室温反应2小时。向体系中加入30mL饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，柱层析分离，得到油状中间体a1–5(810mg)，收率：55％，LCMS：ESI–MS(m/z):285[M+H]+。
步骤4：将上步中间体a1–5(810mg,2.85mmol)溶于10mL二氯乙烷中，缓慢加入SOCl2(1.02g,8.47mmol)，升温至50℃下反应1小时，停止反应。将反应液置于冰浴下，向体系中加入20mL冰水淬灭反应，用饱和碳酸氢钠水溶液调节pH至8左右，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到粗品a1，直接用于下一步反应。LCMS：ESI–MS(m/z):303[M+H]+。
参照化合物a1的合成路线，采用类似的原料/骨架结构，合成如下中间体。

中间体a2-a3,a27的合成
步骤1：将原料a2–1(1.0g,6.67mmol)溶于20mL乙醇中，缓慢加入液溴(1.05g,6.67mmol,0.34mL)，室温下反应4小时，向体系中加入饱和硫代硫酸钠水溶液淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，残余物经柱层析分离(PE/EtOAc,4/1)，得到白色固体a2–2(750mg,3.28mmol)，收率：49％，LCMS：ESI–MS(m/z):229[M+H]+。
步骤2：氮气保护下，将上步中间体a2–2(880mg,3.86mmol)、双联硼酸频哪醇酯(1.96g,7.72mmol)和KOAc(758mg,7.72mmol)溶解于15mL 1,4-二氧六环中，加入Pd(dppf)Cl2(290mg,0.4mmol)，升温至105℃下反应6小时，停止反应。向该反应液中加入50mL水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，flash柱层析分离，得到黄色固体a2(730mg)，收率:69％，LCMS：ESI–MS(m/z):277[M+H]+。
参照化合物a2的合成路线，采用类似的原料/骨架结构，合成如下分子。
中间体a9的合成
步骤1：氧气氛围下(1atm)，将中间体a1–3(1.0g,3.7mmol)、环丙基硼酸(636mg,7.4mmol)、双联吡啶(578mg,3.7mmol)、碳酸钠(784mg,7.4mmol)和催化剂Cu(OAc)2(758mg,7.72mmol)溶解于10mL二氯乙烷中，升温至70℃下反应16小时，停止反应。向该反应液中加入50mL水，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，flash柱层析分离，得到黄色固体a9-1(1.0g)，收率:87％，LCMS：ESI–MS(m/z):311.0[M+H]+。
步骤2：氮气保护下，-10℃，将上步中间体a9–1(1.0g,3.2mmol)溶于15mL无水THF中，加入LiAlH4(240mg,6.4mmol)，搅拌1小时后停止反应。向体系中加入1N浓度的氢氧化钠水溶液(2 mL)，过滤，乙酸乙酯洗涤，减压蒸除溶剂，得到油状中间体a9–2(700mg)，收率：69％，LCMS：ESI–MS(m/z):283.1[M+H]+。
步骤3：将上步中间体a9–2(700mg,2.48mmol)溶于5mL二氯乙烷中，缓慢加入SOCl2(295mg,2.48mmol)，升温至50℃下反应3小时，停止反应。将反应液置于冰浴下，向体系中加入20mL冰水淬灭反应，用饱和碳酸氢钠水溶液调节pH至8左右，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离(PE/EA＝1/1)，得到中间体a9(700mg)，LCMS：ESI–MS(m/z):301.0[M+H]+。
中间体a10-a11，a21的合成
步骤1：将原料4-肼基苯甲酸盐酸盐a10–1(3.0g,19.7mmol)溶于40mL乙醇中，缓慢滴加1,1,1-三氟-2,4-戊二酮(3.04g,19.7mmol)，滴毕，室温下反应2小时。减压蒸除溶剂，flash反向柱层析分离，得到混合黄色固体a10-3和a10-4(2.4g)，LCMS：ESI–MS(m/z):271.1[M+H]+。
步骤2：氮气保护下，-10℃，将上步混合中间体(1.0g,3.7mmol)溶于12mL无水THF中，加入LiAlH4(210mg,5.5mmol)，升温至室温反应2小时，停止反应。向体系中加入1N浓度的氢氧化钠水溶液(2mL)，过滤，乙酸乙酯洗涤，减压蒸除溶剂，得到油状混合中间体a10–5和a10-6(1.0g)，LCMS：ESI–MS(m/z):257.1[M+H]+。
步骤3：将上步混合中间体(1.0g)溶于20mL二氯乙烷中，缓慢加入SOCl2(695mg,5.85mmol)，升温至50℃下反应2小时，停止反应。将反应液置于冰浴下，向体系中加入20mL冰水淬灭反应，用饱和碳酸氢钠水溶液调节pH至8左右，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，flash反向柱层析分离，得到中间体a10(350mg)和a11(400mg)，LCMS：ESI–MS(m/z):275.2[M+H]+。
参照化合物a10的合成路线，采用类似的原料/骨架结构，合成如下分子。
中间体a12的合成
步骤1：氮气保护下，-15℃，将原料1-异丙基-1H-咪唑-4-甲醛(2.0g,14.5mmol)溶于20mL二氯甲烷中，缓慢滴加二乙胺基三氟化硫DAST(7.04g,43.4mmol)，滴毕，升温至0℃反应12小时，停止反应。向反应液中加入50mL饱和碳酸氢钠水溶液，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经flash柱层析分离(PE/EA＝1/2)，得到黄色固体a12-2(140mg)，LCMS：ESI–MS(m/z):161.0[M+H]+。
步骤2：氮气保护下，将上步中间体a12–2(140mg,0.87mmol)、4-溴苯甲酸甲酯a12-3(374mg,1.74mmol)、醋酸铜(17mg,0.077mmol)、碳酸钾(361mg,2.6mmol)、配体三苯基膦(114mg,0.43mmol)和催化剂Pd(OAc)2(20mg,0.087mmol)溶解于5mL无水甲苯中，升温至100℃下反应12小时，停止反应，过滤。乙酸乙酯洗涤，减压蒸除溶剂，flash柱层析分离(PE/EA＝1/1)，得到黄色固体a12-4(110mg)，收率:87％，LCMS：ESI–MS(m/z):295.0[M+H]+。
步骤3：氮气保护下，冰浴，将上步中间体a12-4(110mg,0.37mmol)溶于3mL无水四氢呋喃中，缓慢加入二异丁基氢化铝DIBAL-H(1.3mL,1M)，升温至室温反应1小时，停止反应。向体系中加入20mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，得到油状粗品a12-5(60mg)，LCMS：ESI–MS(m/z):267.1[M+H]+。
步骤4：将上步粗品(50mg,0.19mmol)溶于2mL二氯乙烷中，缓慢加入SOCl2(113mg,0.95mmol)，升温至50℃下反应半小时，停止反应。将反应液置于冰浴下，向体系中加入20mL冰水，用饱和碳酸氢钠水溶液调节pH至8左右，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到粗品中间体a12(50mg)，直接用于下一步反应，LCMS：ESI–MS(m/z):285.0[M+H]+。
中间体a13的合成
步骤1：将中间体a1–3(1.0g,3.7mmol)和Cs2CO3(2.41g,7.4mmol)混于15mL DMF中，加入3-碘代氧杂环丁烷a13-1(1.0g,5.6mmol)，升温至100℃下反应16小时，停止反应。向该反应液中加入50mL水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，flash柱层析分离(PE/EA＝4/1)，得到黄色固体a13–2(390mg)，收率:29％，LCMS：ESI–MS(m/z):327.8[M+H]+。
步骤2：氮气保护下，冰浴，将上步中间体a13-2(270mg,0.83mmol)溶于10mL无水四氢呋喃中，缓慢加入二异丁基氢化铝DIBAL-H(0.59mL,1M)，升温至室温反应2小时，停止反应。向体系中加入40mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，得到白色固体a13(250mg)，LCMS：ESI–MS(m/z):299.0[M+H]+。
中间体a14的合成
步骤1：将原料4-氯-6-甲氧基-嘧啶a14–1(3.0g,20.8mmol)和DIEA(5.36g,41.5mmol)溶于12mL 1,4-二氧六环中，加入原料3,3-二氟氮杂环丁烷b3-2(2.69g,20.8mmol)，升温至110℃下反应6小时，LC–MS监测反应完全。向反应液加入50mL水，二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩，flash柱层析分离(PE/EA＝5/1)，得到化合物a14-2(3.5g)，收率：75％，LCMS：ESI–MS(m/z):202.1[M+H]+。
步骤2：冰浴，氮气保护下，将上步中间体a14–2(3.5g,17.4mmol)溶于20mL乙醇中，缓慢滴加液溴(2.8g,17.4mmol)，滴毕，升温至室温反应16小时，LC–MS监测反应完全。向反应液加入60mL饱和硫代硫酸钠水溶液，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，flash柱层析分离(PE/EA＝10/1)，得到化合物a14-3(3.0g)，收率：55％，LCMS：ESI–MS(m/z):280.0[M+H]+。
步骤3：氮气保护下，将上步中间体a14–3(1.0g,3.57mmol)、双联硼酸频那醇酯(1.81g,7.14mmol)和KOAc(700mg,7.14mmol)溶解于12mL 1,4-二氧六环中，加入Pd(dppf)Cl2(260mg,0.36mmol)，升温至120℃下反应3小时，停止反应。向该反应液中加入70mL水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，flash柱层析分离(PE/EA＝10/1)，得到黄色固体a14(800mg)，收率:69％，LCMS：ESI–MS(m/z):328.2[M+H]+。
中间体a15-a16的合成
步骤1：将原料3-三氟甲基-5-甲基-1H吡唑a15–2(500mg,3.33mmol)、6-氯吡啶-3-甲酸乙酯a15-1(927mg,5.0mmol)和碳酸钾(920mg,6.66mmol)溶于14mL DMF中，升温至110℃下反应4小时，停止反应。向反应液中加入60mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash柱层析分离(DCM/MeOH＝40/1)，得到白色固体a15-3(700mg)，收率：70％，LCMS：ESI–MS(m/z):300.0[M+H]+。
步骤2：氮气保护下，-10℃，将上步中间体a15-3(600mg,2.01mmol)溶于18mL无水THF中，缓慢加入二异丁基氢化铝DIBAL-H(4.02mL,1M)滴毕，升温至室温反应2小时，停止反应。向体系中加入1N浓度的氢氧化钠水溶液(2mL)，过滤，乙酸乙酯洗涤，减压蒸除溶剂，得到油状中间体a15-4(500mg)，LCMS：ESI–MS(m/z):258.2[M+H]+。
步骤3：将上步粗品(500mg)溶于20mL二氯乙烷中，缓慢加入SOCl2(346mg,2.91mmol)，升温至50℃下反应2小时，停止反应。将反应液置于冰浴下，向体系中加入20mL冰水淬灭反应，用饱和碳酸氢钠水溶液调节pH至8左右，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到中间体a15(350mg)，直接用于下一步反应，LCMS：ESI–MS(m/z):276.2[M+H]+。
参照化合物a15的合成路线，采用类似的原料/骨架结构，合成如下中间体。
中间体a17的合成
步骤：将中间体a1–5(810mg,2.85mmol)、三苯基膦(747mg,2.85mmol)溶于20mL二氯甲烷中，缓慢加入CBr4(1.13g,3.42mmol)，室温下反应6小时，停止反应。将反应液置于冰浴下，向体系中加入50mL冰水，用饱和碳酸氢钠水溶液调节pH至8左右，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到粗品a17，直接用于下一步反应。LCMS：ESI–MS(m/z):347[M+H]+。
中间体a18的合成
步骤1：将原料a1–2(6.82g,25.4mmol)和醋酸钠(2.1g,25.6mmol)溶于14mL水中，升温至100℃下搅拌1小时，冷却至室温，缓慢加入4-氰基苯甲醛a18-1(3.0g,22.9mmol)、氨水(24mL)和甲醇(103mL)，搅拌40分钟后，升温至100℃并继续反应2小时，冷却至室温。向反应液中缓慢加入200mL冰水淬灭反应，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。残余物经柱层析分离(PE/EA＝3/1)，得到黄色固体a18–2(1.5g)，收率：25％，LCMS：ESI–MS(m/z):238.0[M+H]+。
步骤2：将上步中间体a18–2(1.0g,4.2mmol)和碳酸铯(2.06g,6.33mmol)溶于10mL DMF中， 加入碘代异丙烷(1.08g,6.33mmol)，升温至50℃下反应2小时，停止反应。向该反应液中加入70mL水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，flash柱层析分离(PE/EA＝1/1)，得到黄色固体a18–3(290mg)，收率:22％，LCMS：ESI–MS(m/z):280.0[M+H]+。
步骤3：氢气氛围下(4atm)，将上步中间体a18–3(290mg,1.04mmol)和氨水(2.0mL)溶于8mL甲醇中，加入雷尼镍(310mg)，室温下反应2小时，停止反应，过滤。甲醇洗涤，滤液减压蒸除溶剂，得到化合物a18(274mg)，LCMS：ESI–MS(m/z):284.1[M+H]+。
中间体a19的合成
步骤1：冰浴，将原料4-环丙基-6-羟基嘧啶a19–1(23.0g,169mmol)溶于200mL乙醇中，缓慢滴加溴素(29.7g,185.8mmol)，滴毕，升温至室温下反应16小时，停止反应。向反应液中缓慢加入500mL饱和硫代硫酸钠溶液，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。残余物经柱层析分离(PE/EA＝1/1)，得到黄色固体a19–2(11.0g)，收率：31％，LCMS：ESI–MS(m/z):218.0[M+H]+。
步骤2：冰浴，氮气保护下，将上步中间体a19–2(200mg,0.93mmol)溶于5mL无水乙腈中，加入NaH(89mg,3.72mmol)，搅拌30分钟后，加入2-氟磺酰基二氟乙酸(331mg,1.86mmol)。升温至室温反应1小时，停止反应。向该反应液中加入30mL水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，flash柱层析分离(PE/EA＝10/1)，得到黄色固体a19–3(170mg)，收率:69％。
步骤3：氮气保护下，将上步中间体a19–3(170mg,0.64mmol)、联硼酸频哪醇酯(240mg,0.96mmol)和碳酸钾(190mg,1.92mmol)溶于5mL 1,4-二氧六环中，加入催化剂Pd(dppf)Cl2(140mg,0.19mmol)，搅拌5分钟后，升温至90℃下反应2小时，停止反应。向该反应液中加入30mL水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，flash反向柱层析分离(PE/EA＝5/1)，得到黄色固体a19(45mg)，收率:22％。LCMS：ESI–MS(m/z):231.1[M+H]+。
中间体a22的合成
步骤1：氮气保护下，将原料a22–1(200mg,1.13mmol)、碳酸钾(467mg,3.39mmol)和4-碘苯乙醇a22-2(528mg,2.26mmol)溶于3mL DMSO中，加入配体N,N-二甲基甘氨酸DMG(22mg,0.22mmol)和催化剂CuI(20mg,0.11mmol)，升温至130℃下反应2小时，冷却至室温。向反应液中加入30mL冰水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离(PE/EA＝3/1)，得到化合物a22–3(115mg)，收率：35％，LCMS：ESI–MS(m/z):283.1[M+H]+。
步骤2：将上步中间体a22-3(115mg,0.4mmol)溶于5mL二氯乙烷中，缓慢加入SOCl2(500mg)，升温至50℃下反应1小时，停止反应。将反应液置于冰浴下，向体系中加入20mL冰水淬灭反应，用饱和碳酸氢钠水溶液调节pH至8左右，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到中间体a22(95mg)，直接用于下一步反应，LCMS：ESI–MS(m/z):301.2[M+H]+。
中间体a24，a26的合成
步骤1：氮气保护下，将中间体a19–2(2.14g,10.1mmol)和1-(三氟甲基)-1,2-苯碘酰-3(1H)-酮a24-1(3.49g,11.1mmol)溶于20mL二氯乙烷中，升温至100℃下反应3小时，冷却至室温。向反应液中加入50mL冰水，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离(PE/EA＝3/1)，得到化合物a24–2(580mg)，收率：21％，LCMS：ESI–MS(m/z):283.0[M+H]+。
步骤2：-78℃，氮气保护下，将上步中间体a24-2(580mg,2.06mmol)和硼酸三异丙酯(147mg,0.78mmol)溶于5mL无水四氢呋喃中，缓慢加入nBuLi(1.4mL,2.5M)，滴毕，升温至室温下反应3小时，停止反应。将反应液置于冰浴下，向体系中加入40mL冰水，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗品经flash反向柱层析分离，得到中间体a24(300mg)，LCMS：ESI–MS(m/z):249.2[M+H]+。
参照化合物a25的合成路线，采用类似的原料/骨架结构，合成如下中间体。
中间体a25的合成
步骤1：氮气保护下，将中间体a1–3(3.0g,11.1mmol)溶于20mL DMF中，缓慢加入N-溴代琥珀酰亚胺NBS(3.95g,22.2mmol)，升温至80℃下反应2小时，冷却至室温。向反应液中加入80mL冰水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离(PE/EA＝1/1)，得到化合物a25–1(2.0g)，收率：52％，LCMS：ESI–MS(m/z):348.2[M+H]+。
步骤2：将上步中间体a25–1(1.5g,4.3mmol)和K2CO3(1.78g,12.9mmol)溶于15mL乙腈中，加入碘代异丙烷(1.5g,8.6mmol)，升温至80℃下反应16小时，停止反应。向该反应液中加入50mL水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，flash柱层析分离，得到黄色固体a25–2(1.0g)，收率:45％，LCMS：ESI–MS(m/z):391.0[M+H]+。
步骤3：氮气保护下，将上步中间体a25–2(1.0g,2.56mmol)、碳酸钾(1.1g,7.69mmol)和甲基硼酸(615mg,10.2mmol)溶于10mL乙二醇二甲醚和水的混合溶液中(v/v,4/1)，加入催化剂Pd(PPh3)Cl2(180mg,0.37mmol)，升温至100℃下反应16小时，冷却至室温。向反应液中加入40mL冰水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离(PE/EA＝1/2)，得到化合物a25-3(700mg)，收率：84％，LCMS：ESI–MS(m/z):327.3[M+H]+。
步骤4：冰浴，氮气保护下，将上步中间体a25–3(700mg,2.1mmol)溶于10mL无水四氢呋喃中，加入DIABL-H(160mg,4.29mmol)，升温至室温反应2小时。向体系中加入30mL饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，柱层析分离，得到油状中间体a25–4(450mg)，收率：72％，LCMS：ESI–MS(m/z):299.2[M+H]+。
步骤5：将上步中间体a25–4(450mg,1.51mmol)溶于10mL二氯乙烷中，缓慢加入SOCl2(720mg,6.04mmol)，升温至50℃下反应1小时，停止反应。将反应液置于冰浴下，向体系中加入30mL 冰水淬灭反应，用饱和碳酸氢钠水溶液调节pH至8左右，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到粗品a25，直接用于下一步反应。LCMS：ESI–MS(m/z):317.0[M+H]+。
中间体b1，b5-b6的合成
步骤1：氮气保护下，将原料b1–1(150mg,0.72mmol)和N,N-二异丙基乙基胺DIEA(186mg,1.44mmol)溶于3mL N,N-二甲基乙酰胺DMA中，加入丙烯酸甲酯b1-2(93mg,1.08mmol)、(PhCN)2PdCl2(28mg,0.07mmol)和三(邻甲基苯基)磷(22mg,0.07mmol)，升温至100℃下反应8小时，冷却至室温。向反应液中加入30mL冰水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离(PE/EtOAc,1/2)，得到化合物b1–3(90mg)，收率：58％，LCMS：ESI–MS(m/z):214[M+H]+。
步骤2：氮气保护下，将上步中间体b1–3(90mg,0.42mmol)和K2CO3(582mg,4.21mmol)溶于6mL DMA中，升温至110℃下反应12小时，LC–MS监测反应完成。过滤，滤液中加入20mL水，二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩，得到粗品b1，直接用于下一步反应，LCMS：ESI–MS(m/z):182[M+H]+。
参照化合物b1的合成路线，采用类似的原料/骨架结构，合成如下中间体。
中间体b2的合成
步骤1：4,5-二氨基-2-氯嘧啶b2-1(200mg,1.38mmol)和乙醛酸乙酯b2-2(340mg,1.66mmol)溶于10mL乙醇中，升温至90℃下反应6小时，减压蒸除溶剂，得到粗品b2-3，直接用于下一步反应，LCMS：ESI–MS(m/z):229[M+H]+。
步骤2：氮气保护下，将上步中间体b2–3(300mg,粗品)和K2CO3(482mg,3.48mmol)溶于6mL DMA中，升温至100℃下反应10小时，LC–MS监测反应完成。过滤，滤液中加入20mL水，二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩，得到粗品b2，直接用于下一步反应，LCMS：ESI–MS(m/z):183[M+H]+。
中间体b3的合成
步骤：将原料b3–1(756mg,4.0mmol)和DIEA(1.03g,8.0mmol)溶于12mL二氯甲烷中，加入原料3,3-二氟氮杂环丁烷b3-2(570mg,4.4mmol)，室温下反应10小时，LC–MS监测反应完成。向反应液加入30mL水，二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩，flash柱层析分离，得到化合物b3 (950mg)，收率：96％，LCMS：ESI–MS(m/z):246[M+H]+。
中间体b4的合成
步骤1：氮气保护下，将原料b3-1(2.35g,12.5mmol)和二氢吡喃DHP(1.15g,13.75mmol)溶于15mL二氯甲烷中，加入对甲苯磺酸(235mg,1.25mmol)，室温下反应16小时。向体系加水30mL，二氯甲烷萃取，减压蒸除溶剂，得到粗品b4-1，直接用于下一步反应，LCMS：ESI–MS(m/z):273[M+H]+。
步骤2：氮气保护下，将上步中间体b4–1(粗品)，环丙基硼酸(2.18g,12.95mmol)和CsF(5.63g,25mmol)溶于24mL 1,4-二氧六环和水的混合溶液中(v/v,5/1)，加入醋酸钯(194mg,1.25mmol)和三环己基磷(194mg,1.25mmol)，升温至80℃下反应10小时，LC–MS监测反应完成。过滤，滤液中加入40mL水，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，柱层析分离(PE/EtOAc,4/1)，得到淡黄色固体b4(900mg)，两步收率26％，LCMS：ESI–MS(m/z):279[M+H]+。
中间体c1的合成
步骤1：氮气保护下，将原料3-三氟甲基吲唑c1-1(800mg,4.3mmol)、碳酸钾(1.20g,8.6mmol)和4-碘苯乙醇a22-2(1.05g,4.52mmol)溶于10mL DMSO中，加入催化剂CuI(170mg,0.16mmol)和配体N,N-二甲基甘氨酸DMG(88mg,0.86mmol)，升温至100℃下反应1小时，停止反应。向体系加水50mL，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经柱层析分离，得到化合物c1-2(400mg)，收率：32％，LCMS：ESI–MS(m/z):293[M+H]+。
步骤2：氮气保护下，将上步中间体c1–2(400mg,1.37mmol)溶于5mL二氯甲烷中，缓慢滴加SOCl2(250mg,2.05mmol)，升温至50℃下反应1小时，LC–MS监测反应完成。将反应液置于冰浴下，缓慢加入饱和碳酸氢钠水溶液调节pH至8左右，二氯甲烷萃取，无水硫酸钠干燥，浓缩，得到淡黄色油状物c1(300mg)，收率70％，LCMS：ESI–MS(m/z):311[M+H]+。
中间体c2的合成
步骤1：氮气保护下，将中间体a25-1(1.4g,4.03mmol)和碳酸钾(1.10g,8.1mmol)溶于20mL DMF中，加入丙烯基溴c2-1(575mg,4.83mmol)，升温至60℃下反应2小时，停止反应。向体系加水50mL，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析分离，得到化合物c2-2(1.0g)，收 率：64％，LCMS：ESI–MS(m/z):389[M+H]+。
步骤2：氮气保护下，将上步中间体c2-2(1.0g,2.57mmol)、碳酸铯(1.67g,5.1mmol)和乙烯基硼酸频哪醇酯c2-3(593mg,3.85mmol)溶于18mL 1,4-二氧六环和水的混合溶液中(v/v,5/1)，加入催化剂Pd(dppf)Cl2(146mg,0.2mmol)，升温至80℃下反应16小时，停止反应，过滤。向体系加水50mL，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经柱层析分离(PE/EA,2/1)，得到化合物c2-4(270mg)，收率：32％，LCMS：ESI–MS(m/z):337[M+H]+。
步骤3：氮气保护下，将上步中间体c2-4(270mg,0.8mmol)溶于8mL二氯甲烷中，加入催化剂HOVEYDA-GRUBBS(26mg,0.04mmol)，室温下反应16小时，停止反应，过滤。减压蒸除溶剂，粗品经柱层析分离(PE/EA,1/1)，得到化合物c2-5(120mg)，收率：49％，LCMS：ESI–MS(m/z):309[M+H]+。
步骤4：氢气氛围下，将上步中间体c2-5(120mg,0.39mmol)溶于3mL甲醇中，加入催化剂Pd/C(20mg)，室温下在氢气(4atm)下反应4小时，停止反应，过滤。减压蒸除溶剂，得到化合物c2-6(120mg)，LCMS：ESI–MS(m/z):311[M+H]+。
步骤5：氮气保护下，将上步中间体c2–6(120mg,0.39mmol)溶于2mL二氯甲烷中，缓慢滴加SOCl2(95mg,0.8mmol)，升温至50℃下反应1小时，LC–MS监测反应完成。将反应液置于冰浴下，缓慢加入饱和碳酸氢钠水溶液调节pH至8左右，二氯甲烷萃取，无水硫酸钠干燥，浓缩，得到淡黄色油状物c2(70mg)，收率60％，LCMS：ESI–MS(m/z):301[M+H]+。
中间体d1,d5-d6的合成
步骤1：氮气保护下，将原料d1-1(2.0g,11.8mmol)和碳酸钾(2.45g,17.7mmol)溶于10mL DMF中，加入乙酰乙酸甲酯d1-2(1.92g,16.5mmol)，升温至90℃下反应12小时，停止反应。向体系加水80mL，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析分离，得到化合物d1(900mg)，收率：32％，LCMS：ESI–MS(m/z):236[M+H]+。
参照化合物d1的合成路线，采用类似的原料/骨架结构，合成如下中间体。
中间体d2-d4的合成
步骤：氮气保护下，将中间体d1(900mg,3.83mmol)和碳酸钾(1.06g,7.7mmol)溶于10mL DMF中，加入中间体a4(609mg,1.91mmol)，升温至60℃下反应2小时，停止反应。向体系加水60mL，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析分离，得到化合物d2(310mg)，收率：17％，LCMS：ESI–MS(m/z):474[M+H]+。
参照化合物d2的合成路线，采用类似的原料/骨架结构，合成如下中间体。
中间体d7的合成
步骤：氮气保护下，-78℃，将原料d7-1(150mg,0.95mmol)和原料d7-2(230mg,1.1mmol)溶于3mL无水四氢呋喃中，滴加LiHMDS(3.8mL,1.0M)，缓慢升温至室温并反应1小时，停止反应。向体系加水80mL，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析分离(DCM/MeOH,20/1)，得到黄色固体d7(200mg)，收率：70％，LCMS：ESI–MS(m/z):295[M+H]+。
中间体d8的合成
步骤：氮气保护下，将原料d7-1(500mg,3.17mmol)、碳酸钾(1.31g,9.51mmol)和中间体a2(923mg,4.75mmol)溶于10mL 1,4-二氧六环和水的混合溶液中(v/v,91/)，加入催化剂Pd(dppf)Cl2(232mg,0.32mmol)，升温至80℃下反应16小时，停止反应。向体系加水80mL，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析分离(DCM/MeOH,10/1)，得到黄色固体d8(550mg)，收率：63％，LCMS：ESI–MS(m/z):272[M+H]+。
中间体d9-d10的合成
步骤：将中间体d8(370mg,1.36mmol)、碳酸钾(564mg,4.1mmol)和中间体a4(651mg,2.2mmol)溶于4mL DMF中，升温至40℃下反应16小时，停止反应。向体系加水80mL，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析分离(PE/EA,1/1)，得到黄色固体d9(300mg)，收率：43％，LCMS：ESI–MS(m/z):510[M+H]+。
参照化合物d9的合成路线，采用类似的原料/骨架结构，合成如下中间体。

实施例2
目标分子P1-P2，P4-P5，P7-P17，P19-P21，P26-P44，P49的制备
步骤1：氮气保护下，将粗品b1(80mg,0.42mmol)，K2CO3(582mg,4.21mmol)和中间体a1(130mg,0.42mmol)溶于4mL DMA中，升温至50℃下反应1小时，LC–MS监测反应完成。向反应液中加入30mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。粗品经柱层析色谱分离(PE/EtOAc,2/1)，得到黄色油状物P1-1(130mg)，收率:69％，LCMS：ESI–MS(m/z):448[M+H]+。
步骤2：氮气保护下，上步中间体P1-1(130mg,0.29mmol)，K2CO3(80mg,0.58mmol)和中间体a2(80mg,0.29mmol)溶于12mL 1,4-二氧六环和水的混合溶液中(v/v,5/1)，加入Pd(dppf)Cl2(21mg,0.03mmol)，升温至100℃下反应2小时，LC–MS监测反应完成。向反应液中加入30mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。粗品经柱层析色谱分离(PE/EtOAc,1/2)，得到白色固体P1(57mg)，收率:35％，LCMS：ESI–MS(m/z):562[M+H]+。
1HNMR(400MHz,CD3OD)δ9.17(s,1H),8.61(s,1H),8.09(d,J＝9.5Hz,1H),7.89(s,1H),7.54(d,J＝8.2Hz,2H),7.47(d,J＝8.2Hz,2H),6.89(d,J＝9.5Hz,1H),5.72(s,2H),4.53–4.46(m,1H),3.91(s,3H),1.76–1.70(m,1H),1.42(d,J＝6.7Hz,6H),1.15–1.08(m,2H),0.87–0.78(m,2H).
参照化合物P1的合成路线，采用类似的原料/中间体，合成如下目标分子。




实施例3
目标分子P3的制备
步骤1：冰浴，氮气保护下，将LiCl(309mg,7.37mmol)溶于10mL无水THF中，加入格氏试剂iPrMgCl(3.7mL,2M)，冰浴下搅拌10分钟，缓慢加入原料a2-2(1.4g,6.14mmol)的四氢呋喃溶液(14mL)，继续搅拌30分钟。向反应液中加入提前配置的P3-1(1.4g,6.14mmol,5mL)四氢呋喃溶液，升温至室温反应2小时，LC–MS监测反应完成。向反应液中加入30mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，得到粗品黄色固体P3-2(1.7g)，收率:73％，LCMS：ESI–MS(m/z):381[M+H]+。
步骤2：氮气保护下，上步粗品中间体P3-2(1.7g)溶于20mL二氯甲烷中，滴加5mL三氟乙酸，室温反应2小时。减压蒸除溶剂，向体系加入饱和碳酸氢钠水溶液调节pH至8左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。粗品经柱层析色谱分离(PE/EtOAc,2/1)，得到黄色固体P3-3(750mg)，收率:83％，LCMS：ESI–MS(m/z):181[M+H]+。
步骤3：氮气保护下，上步中间体P3-3(750mg,4.16mmol)和原料P3-4(840mg,5.0mmol)溶于10mL乙醇中，升温至回流反应16小时。减压蒸除溶剂，粗品经柱层析色谱分离(PE/EtOAc,1/1)， 得到白色固体P3-5(320mg)，收率:27％，LCMS：ESI–MS(m/z):285[M+H]+。
步骤4：氮气保护下，将上步中间体P3-5(100mg,0.35mmol)，K2CO3(51mg,0.36mmol)和中间体a1(106mg,0.35mmol)溶于4mL DMF中，升温至50℃下反应1小时，LC–MS监测反应完成。向反应液中加入30mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。粗品经flash反向柱层析色谱分离(乙腈/水)，得到白色固体P3(11.2mg)，收率:6％，LCMS：ESI–MS(m/z):551[M+H]+。
1HNMR(400MHz,CDCl3)δ8.64(s,1H),8.34(s,1H),8.01(s,1H),7.59(d,J＝8.2Hz,2H),7.50(d,J＝8.2Hz,2H),7.40(s,1H),5.99(s,2H),4.56–4.48(m,1H),3.96(s,3H),1.70–1.64(m,1H),1.43(d,J＝6.7Hz,6H),1.28–1.22(m,2H),1.01–0.92(m,2H)。
实施例4
目标分子P6的制备
步骤1：氮气保护下，中间体b4(900mg,3.24mmol)，Cs2CO3(2.11g,6.48mmol)和中间体a2(1.34g,4.86mmol)溶于12mL 1,4-二氧六环和水的混合溶液中(v/v,5/1)，加入Pd(dppf)Cl2(24mg,0.032mmol)，升温至100℃下反应8小时，LC–MS监测反应完成。向反应液中加入40mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。粗品经柱层析色谱分离(PE/EtOAc,4/1)，得到白色固体P6-1(288mg)，收率:23％，LCMS：ESI–MS(m/z):393[M+H]+。
步骤2：氮气保护下，将上步化合物P6-1(288mg,0.734mmol)溶于5mL二氯甲烷中，加入2mL三氟乙酸，室温下反应1小时，减压蒸除溶剂，得到粗品P6-2，直接进行下一步反应。LCMS：ESI–MS(m/z):309[M+H]+。
步骤3：氮气保护下，将粗品P6-2(粗品)，K2CO3(135mg,0.97mmol)和中间体a1(161mg,0.53mmol)溶于5mL DMF中，升温至50℃下反应6小时，LC–MS监测反应完成。向反应液中加入30mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。粗品经柱层析色谱分离(PE/EtOAc,4/1)，得到白色固体P6(40mg)，两步收率:10％，LCMS：ESI–MS(m/z):575[M+H]+。
1HNMR(400MHz,CDCl3)δ8.65(s,1H),8.23(s,1H),7.48(s,4H),7.40(s,1H),5.72(s,2H),4.56–4.45(m,1H),2.51–2.41(m,1H),1.76–1.68(m,1H),1.42(d,J＝6.7Hz,6H),1.30–1.19(m,6H),0.86(dd,J＝8.0,2.9Hz,2H).
实施例5
目标分子P18的制备
步骤1：冰浴，将中间体a13(140mg,0.47mmol)和三乙胺(143mg,1.41mmol)溶于12mL二氯乙烷中，缓慢加入甲磺酸酐(65mg,0.56mmol)，在0℃下反应1小时，停止反应。向体系中加入40mL冰水，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到油状物P18-1(180mg)，直接用于下一步反应。
步骤2：氮气保护下，将粗品P18-1(180mg,0.48mmol)，Cs2CO3(518mg,1.59mmol)和中间体b1(192mg,1.06mmol)溶于10mL DMF中，室温下反应16小时，LC–MS监测反应完成。向反应液中加入50mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。粗品经柱层析色谱分离(PE/EA＝1/1)，得到黄色油状物P18-2(140mg)，收率:51％，LCMS：ESI–MS(m/z):462.0[M+H]+。
步骤3：氮气保护下，上步中间体P18-2(50mg,0.089mmol)、K3PO4(47mg,0.22mmol)和中间体a2(33mg,0.11mmol)溶于6mL 1,4-二氧六环和水的混合溶液中(v/v,5/1)，加入Pd(dppf)Cl2(7mg,0.009mmol)，升温至90℃下反应4小时，LC–MS监测反应完成。向反应液中加入30mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。粗品经柱层析色谱分离(PE/EA＝1/10)，得到白色固体P18(7.7mg)，收率:13％，LCMS：ESI–MS(m/z):576.0[M+H]+。
1HNMR(400MHz,DMSO-d6)δ9.30(s,1H),8.69(s,1H),8.48(s,1H),8.17(d,J＝9.5Hz,1H),7.45–7.39(m,4H),6.91(d,J＝9.5Hz,1H),5.57(s,2H),5.49–5.42(m,1H),4.85–4.76(m,4H),3.83(s,3H),2.04–1.94(m,1H),1.07–1.02(m,2H),0.85–0.77(m,2H).
实施例6
目标分子P22的制备
步骤1：氮气保护下，将原料2-氯噻吩并[3,2-d]嘧啶P22-1(380mg,2.23mmol)、K3PO4(1.10g,5.2mmol)和中间体a2(520mg,2.68mmol)溶于12mL 1,4-二氧六环和水的混合溶液中(v/v,5/1)，加入Pd(dppf)Cl2(82mg,0.11mmol)，升温至90℃下反应4小时，LC–MS监测反应完成。向反应液中加入40mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。粗品经柱层析色谱分离(PE/EA＝2/3)，得到油状物P22-2(450mg)，收率:64％，LCMS：ESI–MS(m/z):285.1[M+H]+。
步骤2：冰浴，氮气保护下，将上步中间体P22-2(320mg,1.13mmol)溶于12mL乙腈中，缓慢加入液溴(362mg,2.26mmol)，升温至50℃下反应16小时，LC–MS监测反应完成。向反应液中加入40mL饱和硫代硫酸钠水溶液，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。粗品经柱层析色谱分离(PE/EA＝1/1)，得到油状物P22-3(180mg)，收率:40％，LCMS：ESI–MS(m/z):363.0[M+H]+。
1H NMR(400MHz,CDCl3)δ9.42(s,1H),8.70(s,1H),8.09(s,1H),3.93(s,3H),1.71–1.66(m,1H),1.30–1.26(m,2H),0.96–0.90(m,2H).
步骤3：氮气保护下，将上步中间体P22-3(50mg,0.14mmol)、醋酸钾(28mg,0.28mmol)和双联硼酸频那醇酯(71mg,0.28mmol)溶于4mL 1,4-二氧六环中，加入Pd(dppf)Cl2(10mg,0.014mmol)， 升温至90℃下反应4小时，LC–MS监测反应完成。向反应液中加入20mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经TLC薄层色谱分离(DCM/MeOH＝10/1)，得到淡黄色固体P22-4(33mg)，收率:72％，LCMS：ESI–MS(m/z):329.1[M+H]+。
步骤4：氮气保护下，将上步中间体P22-2(33mg,0.10mmol)、K3PO4(69mg,0.33mmol)和中间体a17(50mg,0.14mmol)溶于6mL 1,4-二氧六环和水的混合溶液中(v/v,5/1)，加入Pd(dppf)Cl2(10mg,0.014mmol)，升温至90℃下反应4小时，LC–MS监测反应完成。向反应液中加入20mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。粗品经柱层析色谱分离(PE/EA＝1/10)，得到淡黄色固体P22(16.1mg)，收率:29％，LCMS：ESI–MS(m/z):550.8[M+H]+。
1HNMR(400MHz,DMSO-d6)δ9.66(s,1H),8.71(s,1H),8.31(s,1H),8.16(s,1H),7.51–7.41(m,4H),4.46–4.41(m,1H),4.33(s,2H),3.85(s,3H),1.68–1.62(m,1H),1.38(d,J＝6.6Hz,6H),1.08–1.01(m,2H),0.85–0.81(m,2H).
参照化合物P22的合成路线，采用类似的原料/中间体，合成如下目标分子。
实施例7
目标分子P24-P25的制备
步骤1：氮气保护下，将原料2,4-二氯-5-(氯甲基)嘧啶P24-1(2.38g,12.1mmol)和NaI(1.99g,13.3mmol)溶于12mL丙酮中，升温至65℃下反应3小时，LC–MS监测反应完成。向反应液中加入40mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。粗品经柱层析色谱分离(PE/EA＝1/1)，得到黄色固体P24-2(2.0g)，收率:46％。
步骤2：冰浴，氮气保护下，将上步中间体P24-2(2.0g,6.92mmol)溶于22mL乙腈中，缓慢加入叔丁基胺(560mg,7.61mmol)，升温至室温下反应12小时，LC–MS监测反应完成。向反应液中加入80mL水，二氯甲烷萃取，无水硫酸钠干燥，浓缩，得到油状物P24-3(1.0g)，收率:56％，LCMS：ESI–MS(m/z):234.1[M+H]+。
步骤3：氮气保护下，将上步中间体P24-3(160mg,0.68mmol)、碳酸钾(190mg,1.36mmol)和中间体a18(212mg,0.75mmol)溶于3mL DMF中，室温下反应4小时，LC–MS监测反应完成。向反应液中加入30mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash柱层析色谱分离(PE/EA＝1/2)，得到淡黄色固体P24-4(210mg)，收率:64％，LCMS：ESI–MS(m/z):481.1[M+H]+。
步骤4：将上步中间体P24-4(205mg,0.43mmol)和三乙胺TEA(130mg,1.29mmol)溶于8mL四氢呋喃中，缓慢加入三光气BTC(140mg,0.47mmol)，升温至70℃下反应1小时，LC–MS监测反应完成。向反应液中加入30mL饱和碳酸氢钠水溶液，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash柱层析色谱分离(PE/EA＝1/3)，得到淡黄色固体P24-5(200mg)，收率:83％，LCMS：ESI–MS(m/z):506.8[M+H]+。
步骤5：氮气保护下，将上步中间体P24-5(150mg,0.3mmol)、K3PO4(159mg,0.75mmol)和中间体a2(124mg,0.45mmol)溶于6mL 1,4-二氧六环和水的混合溶液中(v/v,5/1)，加入Pd(dppf)Cl2(22mg,0.03mmol)，升温至90℃下反应3小时，LC–MS监测反应完成。向反应液中加入30mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。粗品经柱层析色谱分离(DCM/MeOH＝10/1)，得到淡黄色固体P24-6(40mg)，收率:19％，LCMS：ESI–MS(m/z):621.2[M+H]+。
步骤6：氮气保护下，将上步中间体P24-6(15mg,0.024mmol)溶于5mL三氟乙酸中，升温至70℃下反应1小时，LC–MS监测反应完成。向反应液中加入30mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。粗品经TLC薄层色谱分离(DCM/MeOH＝10/1)，得到淡黄色固体P24(2mg)，LCMS：ESI–MS(m/z):565.3[M+H]+。
1HNMR(400MHz,DMSO-d6)δ8.63(s,1H),8.55(s,1H),8.17(s,1H),7.71(s,1H),7.47(d,J＝8.1Hz,2H),7.38(d,J＝8.1Hz,2H),5.17(s,2H),4.53(s,2H),4.43(dt,J＝13.2,6.5Hz,1H),3.79(s,3H),1.63(ddd,J＝12.6,8.2Hz,4.7Hz,1H),1.39(d,J＝6.6Hz,6H),0.94(d,J＝3.5Hz,2H),0.72(d,J＝7.6,3.1Hz,2H).
步骤：将化合物P24(12mg,0.02mmol)溶于3mL甲苯中，加入氧化剂2,3-二氯-5,6-二氰对苯醌DDQ(9.2mg,0.04mmol)，升温至50℃下反应2小时，LC–MS监测反应完成。减压蒸除溶剂，粗品经TLC薄层色谱分离(DCM/MeOH＝10/1)，得到淡黄色固体P25(2mg)，LCMS：ESI–MS(m/z):563.2[M+H]+。
1HNMR(400MHz,DMSO-d6)δ9.28(s,1H),8.17(d,J＝8.0Hz,1H),7.44(s,4H),6.91(d,J＝12.0Hz,1H),6.80(s,1H),5.59(s,2H),3.83(s,3H),2.95-2.91(m,1H),1.76-1.68(m,1H),1.12(d,J＝8.0Hz,6H),1.04–0.98(m,2H),0.78-0.73(m,2H).
实施例8
目标分子P45-P48的制备
步骤1：将中间体d2(310mg,0.65mmol)溶于5mL三氯甲烷中，缓慢加入间氯过氧苯甲酸m-CPBA(338mg,1.96mmol)，升温至50℃下反应2小时，LC–MS监测反应完成。向反应液中加入30mL饱和硫代硫酸钠水溶液，二氯甲烷萃取，无水硫酸钠干燥，浓缩。得到黄色油状物P45-1(306mg)，收率:95％，LCMS：ESI–MS(m/z):490[M+H]+。
步骤2：将上步中间体P45-1(306mg,0.61mmol)溶于6mL四氢呋喃和水的混合溶液中(v/v,1/1)， 缓慢加入KOH(170mg,3.03mmol)，升温至40℃下反应2小时，LC–MS监测反应完成。向反应液中缓慢加入2M浓度稀盐酸调节pH至6左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。得到黄色油状物P45-2(236mg)，收率:86％，LCMS：ESI–MS(m/z):444[M+H]+。
步骤3：将上步中间体P45-2(185mg,0.42mmol)溶于4mL乙腈和三氯氧磷的混合溶液中(v/v,1/1)，升温至90℃下反应2小时，LC–MS监测反应完成。向反应液中缓慢加入20mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。得到黄色固体P45-3(185mg)，收率:96％，LCMS：ESI–MS(m/z):462[M+H]+。
步骤4：氮气保护下，上步中间体P45-3(185mg,0.40mmol)，K2CO3(111mg,0.80mmol)和中间体a2(155mg,0.80mmol)溶于5mL 1,4-二氧六环和水的混合溶液中(v/v,4/1)，加入Pd(dppf)Cl2(59mg,0.08mmol)，升温至100℃下反应2小时，LC–MS监测反应完成。向反应液中加入30mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。粗品经柱层析色谱分离(DCM/MeOH,20/1)，得到白色固体P45(22mg)，收率:7％，LCMS：ESI–MS(m/z):576[M+H]+。
1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),8.68(d,J＝10.9Hz,2H),7.92(s,1H),7.63(d,J＝8.3Hz,2H),7.44(d,J＝8.3Hz,2H),5.61(s,2H),3.83(s,3H),3.74(s,3H),2.63(s,3H),1.75(m,1H),1.05–0.98(m,2H),0.77–0.73(m,2H).
参照化合物P45的合成路线，采用类似的原料/中间体，合成如下目标分子。
实施例9
目标分子P50的制备
步骤1：氮气保护下，将化合物P47(240mg,0.42mmol)和TEA(130mg,1.26mmol)溶于3mL叔丁醇中，加入叠氮磷酸二苯酯dppa(490mg,1.26mmol)，升温至90℃下反应2小时，LC–MS监测反应完成。向反应液中加入二碳酸二叔丁酯Boc2O(275mg,1.26mmol)，继续在室温下反应2小时，停止反应。向反应液中加入100mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。粗品经柱层析色谱分离(DCM/MeOH,20/1)，得到黄色固体P50-1(200mg)，收率:73％，LCMS：ESI–MS(m/z):649[M+H]+。
步骤2：将上步化合物P50-1(200mg,0.31mmol)溶于3mL氯化氢的1,4-二氧六环溶液中(2M)，室温下反应1小时，停止反应。向反应液中加入30mL水，饱和碳酸氢钠水溶液调节pH至8左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。粗品经柱层析色谱分离(DCM/MeOH,20/1)，得到黄色固体P50(20mg)，收率:11％，LCMS：ESI–MS(m/z):549[M+H]+。
1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.65(s,1H),7.91(d,J＝0.9Hz,1H),7.63(d,J＝8.3Hz, 2H),7.39(d,J＝8.3Hz,2H),6.83(s,1H),6.21(s,2H),5.65(s,2H),3.82(s,3H),3.73(s,3H),1.80–1.63(m,1H),1.01–0.97(m,2H),0.77–0.73(m,2H).
实施例10
目标分子P51-P54的制备
步骤：氮气保护下，-78℃，将中间体d9(150mg,0.29mmol)和原料P51-1(249mg,1.16mmol)溶于3mL无水四氢呋喃中，滴加LiHMDS(2.4mL,1.0M)，缓慢升温至升温并反应1小时，停止反应。向体系加水80mL，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析分离(DCM/MeOH,10/1)，得到黄色固体P51(20mg)，收率：9％，LCMS：ESI–MS(m/z):660[M+H]+。
1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),8.68(s,1H),8.29(s,1H),8.03(s,1H),7.90(s,1H),7.62(d,J＝8.2Hz,2H),7.39(d,J＝8.3Hz,2H),5.59(s,2H),3.82(s,3H),3.73(s,3H),2.77(t,J＝7.2Hz,2H),2.58(t,J＝7.2Hz,2H),2.49–2.38(m,4H),2.37–2.23(m,4H),2.14(s,3H),1.75–1.68(m,1H),1.01(dt,J＝7.0,3.4Hz,2H),0.79–0.73(m,2H).
参照化合物P51的合成路线，采用类似的原料/中间体，合成如下目标分子。
实施例11
本发明化合物对于USP1-UAF1活性抑制效果：
使用ECHO(Labcyte，型号550)将120nL溶媒对照或待测化合物(4倍稀释10个浓度梯度)加入384孔板(Proxi-384plus,PerkinElmer,目录号6008260)中，在每孔中加入6μL 2×His6-
USP1/His6-UAF1复合物工作液(R&D，目录号E-568-050)，震荡混匀30秒，25℃温孵15分钟；在每孔中加入2×泛素罗丹明底物工作液(R&D，目录号U-555-050)，封板25℃温孵2小时；使用Envision 2105扫版并记录荧光信号值。
数据分析：
抑制率(％)＝[(RFU平均值溶媒对照-RFU平均值待测化合物)/(RFU平均值溶媒对照-RFU平均值阳性化合物)]×100
RFU：相对荧光信号值
IC50值计算：Y＝下平台信号+(上平台信号-下平台信号)/(1+10^((LogIC50-X)×希尔斜率))
X:化合物浓度log值；Y:抑制率(％)
表1：化合物对于USP1-UAF1抑制实验结果
N.D.＝未测试
以上结果表明，本发明分子对于USP1具有良好的抑制效果；部分分子相比对照分子A1或A2活性有大幅度改善，比如分子P1相比A1提升10倍活性以上；相比A2提升100倍以上
实施例12
利用Promega CellTiter–Glo试剂检测小分子抑制剂对BRCA1突变细胞系乳腺癌细胞(MDA-MB-436)增殖的影响和BRCA野生型乳腺癌细胞系HCC1954的增殖影响。
将培养于包含15％胎牛血清(Gibco，目录号10099141)、10μg/mL胰岛素(Invitrogen，目录号12585-014)、16μg/mL谷胱甘肽(Sigma，目录号G6013)、1％青链霉素的L15培养基(Gibco，目录号11415-064)中的MDA-MB-436细胞(或HCC1954)接种至384孔微板中，每孔35μL，在37℃CO2孵箱中温育过夜；使用ECHO(Labcyte，型号550)将4倍浓度梯度稀释的系列化合物加入384孔板中，每孔35nL。在37℃CO2孵箱中温孵培养7天，每孔中加入20μL CTG试剂(Promega，目录号G7573)，室温孵育30分钟，用Envision多功能酶标仪(Perkin Elmer，型号Envision 2104)读取发光值，光信号和体系中ATP量成正比，而ATP的含量直接表征体系中的活细胞数。
在EXCEL中计算不同浓度化合物对应的抑制率，然后用GraphPad Prism软件作抑制率曲线图并计算相关参数，参数包括细胞最大和最小抑制率，IC50值。
表2：优异代表化合物对于BRCA1野生型细胞的抗增殖抑制效果
N.D.＝未测试
表3：优异代表化合物对于BRCA1突变细胞(MDA-MB-436)的抗增殖抑制效果
以上实验结果表明：本发明分子对于BRCA1突变细胞具有良好的抗增殖效果。
实施例13
化合物的肝微粒体稳定性实验。具体如下：
对本发明化合物进行肝微粒体稳定性试验研究，将待测化合物在加入或不加入NADPH情况下与不同种属的肝微粒体进行共孵育，试验体系中待测化合物终浓度为1μM，NADPH终浓度为1mM，肝微粒体终浓度为0.5mg/ml。检测60分钟内不同时间点孵育上清中的化合物浓度并计算药代动力学参数(例如清除率Clint)。
该结果表明本发明分子具有较好的代谢稳定性(尤其在人体中，具有较好的代谢稳定性)。

N.D.＝未测试
实施例14
化合物的小鼠体内药代动力学实验。具体如下：
以CD1雌性小鼠为受试动物，口服/静脉给药(口服给药量为10mg/kg，静脉为2mg/kg，溶媒为：DMSO-Solutol-H2O)。
实验方案：口服组每组3只，静脉组每组三只。口服：收集给药前(0h)和给药后(0.25,0.5,1,2,4,8,24h)的血浆样品；静脉：收集给药前(0h)和给药后(0.083,0.25,0.5,1,2,4,8,24h)的血浆样品；用LC/MS/MS法分别测定小鼠口服和静脉给药后的血浆的血液浓度，采集的数据用AB Sciex QTRAP6500软件计算，实验结果如下：
以上实验结果表明，本发明化合物具有良好的口服吸收效果。
实施例15：
评价本发明分子在卵巢癌OV0589皮下异种移植BALB/c Nude雌性小鼠模型中抗肿瘤作用。(PDX模型)。具体如下：
从卵巢癌异种移植模型OV0589荷瘤小鼠收取肿瘤组织，切成直径为2-3mm的瘤块接种于BALB/c Nude小鼠右前肩胛处皮下。所有小鼠皮下接种。小鼠培养于SPF级实验环境中，所有小鼠可自由获取商业认证的标准饮食。待肿瘤生长至平均体积约152.54mm3时根据肿瘤大小随机分组给药。入组16只小鼠平均分成4组，每组4只。给药剂量为：空白组溶媒(5％DMAc+5％NMP+45％(10％(v/v)E-TPGS)+45％(10％(w/v)Soluplus)，给药组(溶媒同上)，olaparib(0.5％(w/v)HPMC E5+0.1％Tween 80)给药剂量为50mg/kg，每日1次。肿瘤体积一周2次用二维卡尺测量，每天动物称重。连续给药38天后，根据最终肿瘤体积计算抑制率(TGI/100％)。体积计算公式为：V＝1/2a*b2，a代表肿瘤长径，b代表肿瘤短径。
该结果表明本发明分子具有较好体内药效(抑制人源卵巢癌的生长)，且和上市药物Olaparib具有良好的协同抑制效果，未来临床可有望治疗BRCA1/2突变的卵巢癌患者。

Claims (26)

  1. 式(A)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
    其中：
    表示单键或双键；
    当为双键时，X1为C；
    当为单键时，X1为N；
    X2和X3各自独立地选自CR2或N；
    环A为6元杂芳基；所述环A任选地被1个、2个、3个、4个或5个R2取代；
    环B为5-12元杂芳基；
    环C为5-6元杂芳基；
    L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
    每个R1独立地选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R1可任选地被1个、2个、3个、4个或5个R*取代；
    每个R2独立地选自H、D、卤素、CN、ORa、NRaRb、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1- 6卤代烷氧基、C2-6烯基、C2-6炔基、-C(O)Ra、-C(O)ORa、-OC(O)Ra、-C(O)NRaRb、-(CH2)1-6-ORa、-(CH2)1-6-C(O)Ra、-(CH2)1-6-C(O)ORa、-(CH2)1-6-OC(O)Ra、-(CH2)1-6-C(O)NRaRb、-(CH2)1-6-CN、-(CH2)1- 6-NRaRb、C3-7环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基，所述R2可任选地被1个、2个、3个、4个、5个、6个、7个、8个或更多个R*取代；或者同一碳原子上的两个R2形成＝O或＝S；
    每个R3独立地选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R3可任选地被1个、2个、3个、4个、5个、6个、7个、8个或更多个R*取代；
    或者，一个R2和一个R3与它们分别连接的原子一起形成6-12元杂环基或6-12元杂芳基；
    R4选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R4可任选地被1个、2个、3个、4个或5个R*取代；
    R#选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
    R*选自H、D、卤素、NH2、CN、OH、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基；
    Ra选自H、C1-6烷基或C1-6卤代烷基；
    Rb选自H、C1-6烷基或C1-6卤代烷基；
    或者，Ra和Rb与它们连接的氮原子一起形成5-10元杂环基或5-10元杂环基；
    m为1、2或3；
    n为1、2、3或4；
    p为1或2。
  2. 式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
    其中：
    表示单键或双键；
    当为双键时，X1为C；
    当为单键时，X1为N；
    X2和X3各自独立地选自CR2或N，只要化学上允许；
    环A为6元杂芳基；
    环B为5-6元杂芳基；
    L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
    每个R1独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-10环烷基或3-10元杂环基，所述R1可任选地被1个、2个、3个、4个或5个R*取代；
    每个R2独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；
    每个R3独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-10环烷基和3-10元杂环基，所述R3可任选地被1个、2个、3个、4个或5个R*取代；
    R4选自H、卤素、C1-6烷基、C1-6卤代烷基、C3-10环烷基和3-10元杂环基，所述R4可任选地被1个、2个、3个、4个或5个R*取代；
    R#选自H、D、卤素、C1-6烷基或C1-6卤代烷基；
    R*选自H、D、卤素、C1-6烷基或C1-6卤代烷基；
    m为1、2或3；
    n为1、2、3或4；
    p为1或2。
  3. 权利要求1或2的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其具有以下通式：
    其中：
    X4和X5各自独立地选自CR2或N；
    X6和X7各自独立地选自C或N；
    R1’选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，所述R1’可任选地被1个、2个或3个卤素取代；
    R3’选自C1-6烷基或C1-6卤代烷基；
    其他各基团如权利要求1或2所定义；
    前提是，所述化合物不为
  4. 权利要求3的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(II)：
    其中：
    X2、X3、X4和X5各自独立地选自CR2或N；
    L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
    环B为5-6元杂芳基；
    每个R1独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，所述R1可任选地被1个、2个或3个R*取代；
    每个R2独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；
    每个R3独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基和3-7元杂环基，所述R3可任选地被1个、2个或3个R*取代；
    R#选自H、C1-6烷基或C1-6卤代烷基；
    R*选自H、D、卤素、C1-6烷基或C1-6卤代烷基；
    m为1、2或3；
    n为1、2、3或4；
    p为1或2；
    前提是，所述化合物不为
  5. 权利要求4的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(III)：
    其中：
    X2、X3、X4和X5各自独立地选自CH或N，并且X2和X3为CH时，其中的H可任选地被R2取代；
    X6和X7各自独立地选自C或N；
    L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
    R1选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；
    R1’选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，所述R1’可任选地被1个、2个或3个卤素取代；
    R2选自H、卤素、C1-6烷基或C1-6卤代烷基；
    R3选自C1-6烷基、C1-6卤代烷基、C3-7环烷基和3-7元杂环基，所述R3可任选地被1个、2个或3个选自D或C1-6烷基的取代基取代；
    R3’选自C1-6烷基或C1-6卤代烷基；
    R#选自H或C1-6烷基；
    p为1或2；
    前提是，所述化合物不为
  6. 权利要求5的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    X2、X3、X4和X5各自独立地选自CH或N，并且X2和X3为CH时，其中的H可任选地被R2取代；
    X6和X7各自独立地选自C或N，且X6和X7中的至少一个为N；
    L为CH2，所述CH2可任选地被1个或2个R#取代；
    R1选自C1-4烷氧基或C1-4卤代烷氧基；
    R1’选自C1-4烷氧基、C3-5环烷基和3-5元杂环基，所述R1’可任选地被1个、2个或3个卤素取代；
    R2选自H、卤素、C1-4烷基或C1-4卤代烷基；
    R3选自C1-4烷基、C3-5环烷基或3-5元杂环基，所述R3可任选地被1个、2个或3个选自D或C1-4烷基的取代基取代；
    R3’选自C1-4烷基或C1-4卤代烷基；
    R#选自H或C1-4烷基；
    p为1或2。
  7. 权利要求5或6的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    X2、X3、X4、X5各自独立地选自CH或N，并且X2和X3为CH时，其中的H可任选地被R2取代；
    X6和X7各自独立地选自C或N，且X6和X7中的至少一个为N；
    L为CH2，所述CH2可任选地被1个或2个R#取代；
    R1选自C1-2烷氧基或C1-2卤代烷氧基；
    R1’选自甲氧基、环丙基和
    R2选自H或F；
    R3选自CH3、CD3、CH2CH3、CH(CH3)2、环丙基、
    R3’为卤代甲基，优选为CF3、CHF2；
    R#选自H或甲基；
    p为1或2。
  8. 权利要求3的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(IV)：
    其中：
    X4为CH或N；
    R1为C1-2烷氧基，优选为甲氧基；
    R1’为C3-5环烷基，优选为环丙基。
  9. 权利要求3的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(III)：
    其中：
    X2和X3各自独立地选自CR2或N；
    X4和X5各自独立地选自CR2或N；
    X6和X7各自独立地选自C或N；
    L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
    R1选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R1可任选地被1个、2个、3个、4个或5个R*取代；
    R1’选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，所述R1’可任选地被1个、2个或3个卤素取代；
    每个R2独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基或C2-6炔基，所述R2可任选地被1个、2个、3个、4个或5个R*取代；
    每个R3独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R3可任选地被1个、2个、3个、4个或5个R*取代；
    R3’选自C1-6烷基或C1-6卤代烷基；
    R#选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
    R*选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
    p为1或2；
    前提是，所述化合物不为
  10. 权利要求9的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    X2为CR2；
    X3选自CR2或N；
    X4选自CR2或N；
    X5为CR2；
    X6和X7各自独立地选自C或N；
    L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
    R1选自H、卤素、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R1可任选地被1个、2个、3个、4个或5个R*取代；
    R1’为卤素、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，所述R1’可任选地被1个、2个或3个卤素取代；
    每个R2独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基 或C2-6炔
    基，所述R2可任选地被1个、2个、3个、4个或5个R*取代；
    每个R3独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R3可任选地被1个、2个、3个、4个或5个R*取代；
    R3’选自C1-6烷基或C1-6卤代烷基；
    R#选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
    R*选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
    p为1或2。
  11. 权利要求3的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(III-1)：
    其中：
    X2为CR2；
    X3选自CR2或N；
    X4选自CR2或N；
    X5为CR2；
    L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
    R1选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R1可任选地被1个、2个、3个、4个或5个R*取代；
    R1’选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，所述R1’可任选地被1个、2个或3个卤素取代；
    每个R2独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基或C2-6炔基，所述R2可任选地被1个、2个、3个、4个或5个R*取代；
    每个R3独立地选自H、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R3可任选地被1个、2个、3个、4个或5个R*取代；
    R3’选自C1-6烷基或C1-6卤代烷基；
    R#选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
    R*选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
    p为1或2；
    前提是，所述化合物不为
  12. 权利要求11的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    X2和X3为CR2；
    X4选自CR2或N；
    X5为CR2；
    L为CH2，所述CH2可任选地被1个或2个R#取代；
    R1选自C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，所述R1可任选地被1个、2 个或3个R*取代；
    R1’选自C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，所述R1’可任选地被1个、2个或3个卤素取代；
    每个R2独立地选自H、卤素或C1-6烷基，优选为H；
    R3选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基，所述R3可任选地被1个、2个、3个、4个或5个R*取代；
    R3’选自C1-6烷基或C1-6卤代烷基；
    R#选自H、D、卤素、C1-6烷基或C1-6卤代烷基；
    R*选自H、D、卤素、C1-6烷基或C1-6卤代烷基；
    p为1或2。
  13. 权利要求11或12的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    X2和X3为CR2；
    X4为CR2；
    X5为CR2；
    L为CH2；
    R1选自C1-6烷氧基或C1-6卤代烷氧基，所述R1可任选地被1个、2个或3个R*取代；
    R1’选自C1-6烷氧基或C3-7环烷基；
    每个R2独立地选自H、卤素或C1-6烷基，优选为H；
    R3选自H、C1-6烷基或C3-10环烷基，所述R3可任选地被1个、2个或3个R*取代；
    R3’选自C1-6烷基或C1-6卤代烷基；
    R*选自H或D；
    p为1或2。
  14. 权利要求3的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(III-2)：
    其中：
    X2为CR2；
    X3选自CR2或N；
    X4选自CR2或N；
    X5为CR2；
    L为CH2或SO2，所述CH2可任选地被1个或2个R#取代；
    R1选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R1可任选地被1个、2个、3个、4个或5个R*取代；
    R1’选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，所述R1’可任选地被1个、2个或3个卤素取代；
    每个R2独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基或C2-6炔基，所述R2可任选地被1个、2个、3个、4个或5个R*取代；
    R3选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述R3可任选地被1个、2个、3个、4个 或5个R*取代；
    R3’选自C1-6烷基或C1-6卤代烷基；
    R#选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
    R*选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
    p为1或2。
  15. 权利要求14的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    X2为CR2；
    X3选自CR2或N；
    X4和X5为CR2；
    L为CH2，所述CH2可任选地被1个或2个R#取代；
    R1选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基或C3-10环烷基；
    R1’选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基或C3-7环烷基；
    每个R2独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；
    R3选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-10环烷基或3-10元杂环基；
    R3’选自C1-6烷基或C1-6卤代烷基；
    R#选自H、D、卤素、C1-6烷基或C1-6卤代烷基；
    p为1或2。
  16. 权利要求3的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(III-3)：
    其中：
    X4和X5各自独立地为CR2，优选不同时为CH；
    L为CH2，所述CH2可任选地被1个或2个R#取代；
    R1选自C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，优选为OCH3或OCHF2；
    R1’选自C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，优选为环丙基；
    每个R2独立地选自H、卤素、CN、ORa、NRaRb、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-C(O)Ra、-C(O)ORa、-OC(O)Ra、-C(O)NRaRb、-(CH2)1-4-ORa、-(CH2)1-4-C(O)Ra、-(CH2)1- 4-C(O)ORa、-(CH2)1-4-OC(O)Ra、-(CH2)1-4-C(O)NRaRb、-(CH2)1-4-CN、-(CH2)1-4-NRaRb、C3-7环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1个、2个、3个、4个、5个、6个、7个、8个或更多个R*取代；
    R3选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基，所述R3可任选地被1个、2个、3个、4个或5个R*取代；
    R3’选自C1-6烷基或C1-6卤代烷基；
    R#选自H、D、卤素、C1-6烷基或C1-6卤代烷基；
    R*选自H、D、卤素、NH2、CN、OH、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基；
    Ra选自H、C1-6烷基或C1-6卤代烷基；
    Rb选自H、C1-6烷基或C1-6卤代烷基；
    或者，Ra和Rb与它们连接的氮原子一起形成5-10元杂环基或5-10元杂环基。
  17. 权利要求16的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    X4为CR2’；
    X5为CR2；
    L为CH2，所述CH2可任选地被1个或2个R#取代；
    R1为C1-6烷氧基或C1-6卤代烷氧基，优选为OCH3或OCHF2；
    R1’选自C3-7环烷基或3-7元杂环基，优选为环丙基；
    R2选自H、卤素、CN、ORa、NRaRb、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-C(O)Ra、-(CH2)1-4-ORa、-(CH2)1-4-CN、-(CH2)1-4-NRaRb、C3-7环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1个、2个、3个、4个或5个R*取代；
    R2’为H或卤素；
    优选R2和R2’中至少一个不为H；
    R3选自H、C1-6烷基或C3-7环烷基；
    R3’为C1-6烷基或C1-6卤代烷基；
    R#选自H、C1-6烷基或C1-6卤代烷基；
    R*选自D、卤素、NH2、CN、OH、C1-6烷基、C1-6卤代烷基、C3-7环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基；
    Ra选自H、C1-6烷基或C1-6卤代烷基；
    Rb选自H、C1-6烷基或C1-6卤代烷基；
    或者，Ra和Rb与它们连接的氮原子一起形成5-10元杂环基。
  18. 权利要求16或17的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    X4为CR2’；
    X5为CR2；
    L为CH2；
    R1为OCH3；
    R1’为环丙基；
    R2选自H、F、NH2、CHF2、 优选为H、F、NH2、CHF2、
    R2’为H或CH3；
    并且R2和R2’中至少一个不为H；
    R3为CH3或异丙基；
    R3’为CF3。
  19. 化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物选自：

  20. 化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物选自：


  21. 药物组合物，其包含权利要求1-20中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，和药学上可接受的载体、佐剂或媒介物，任选地其它治疗剂。
  22. 权利要求1-20中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物在制备用于治疗或预防USP1介导的疾病的药物中的用途。
  23. 一种在受试者中治疗或预防USP1介导的疾病的方法，包括向所述受试者给药权利要求1-20中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，或权利要求21的药物组合物。
  24. 权利要求1-20中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，或权利要求21的药物组合物，其用于治疗或预防USP1介导的疾病。
  25. 权利要求22的用途或权利要求23的方法或权利要求24的化合物或药物组合物的用途，其中所述USP1介导的疾病为癌症。
  26. 权利要求22的用途或权利要求23的方法或权利要求24的化合物或药物组合物的用途，其中所述USP1介导的疾病选自血液癌症、淋巴癌、膀胱癌、卵巢癌、乳腺癌、骨癌(例如骨肉瘤和软骨肉瘤)、脑癌(例如神经胶质瘤、成胶质细胞瘤、星形细胞瘤、髓母细胞瘤和脑脊髓膜瘤)、软组织癌(例如横纹肌样肉瘤)、肾癌、膀胱癌、皮肤癌(例如黑素瘤)、肺癌(例如非小细胞肺癌)、结肠癌、子宫癌、神经系统癌症、头颈癌、胰腺癌和子宫颈癌。
PCT/CN2023/091338 2022-05-07 2023-04-27 取代的双环杂芳基化合物作为usp1抑制剂 WO2023216910A1 (zh)

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