WO2024037607A1 - Prmt5抑制剂 - Google Patents

Prmt5抑制剂 Download PDF

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WO2024037607A1
WO2024037607A1 PCT/CN2023/113643 CN2023113643W WO2024037607A1 WO 2024037607 A1 WO2024037607 A1 WO 2024037607A1 CN 2023113643 W CN2023113643 W CN 2023113643W WO 2024037607 A1 WO2024037607 A1 WO 2024037607A1
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alkyl
haloalkyl
halogen
atom
optionally substituted
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PCT/CN2023/113643
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English (en)
French (fr)
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杨旭
孟庆华
刘磊
王虎庭
石磊
杜豪林
高蓓蓉
王建浩
孔德升
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北京望实智慧科技有限公司
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic 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
    • C07D471/02Heterocyclic 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
    • C07D471/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04Ortho-condensed systems
    • C07D491/044Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04Ortho-condensed systems
    • C07D491/044Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the present invention requires priority for the Chinese application CN202211003217.9 submitted on August 19, 2022, the Chinese application CN202310465126.5 submitted on April 26, 2023, and the Chinese application CN202310997144.8 submitted on August 9, 2023 rights, they are incorporated herein by reference in their entirety.
  • the present invention relates to a new class of PRMT5 inhibitors, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof.
  • the present invention also relates to methods for preparing the compounds, pharmaceutical compositions containing the compounds, and the effects of the compounds in preventing and treating PRMT5-mediated diseases such as cancer.
  • Protein arginine methyltransferase 5 belongs to type II PRMT. It is a type of S-adenosylmethionine (SAM)-dependent methyltransferase, which is mainly responsible for converting the methyl group of SAM. Symmetrically transferred to the guanidine nitrogen atom at the end of an arginine residue in histones or other proteins.
  • SAM S-adenosylmethionine
  • PRMT5 forms a complex with MEP50 (methylosome protein 50) to recognize the substrate and localize it. At the same time, the complex shape is also required for PRMT5 to catalyze the methyl transfer activity of histone 2A and histone 4.
  • PRMT5 is a general transcriptional repressor that can regulate gene transcription and protein modification processes. At the same time, PRMT5 plays an important role in the proliferation, differentiation, and apoptosis of tumor cells and is a highly potential tumor treatment target. However, PRMT5 is also an essential gene for normal cells. PRMT5 knockout and siRNA knockdown studies have shown that inhibiting the activity of PRMT5 in normal tissues may cause many toxic side effects such as thrombocytopenia, infertility, skeletal muscle loss, and cardiac hypertrophy.
  • MTAP methylthioadenosine phosphorylase
  • PRMT5 inhibitors under investigation include SAM competitive inhibitors, substrate competitive inhibitors, SAM and substrate dual competitive inhibitors, and MTA synergistic inhibitors.
  • Non-MTA synergistic PRMT5 inhibitors indiscriminately inhibit the activity of PRMT5, and dose-limiting toxic side effects such as thrombocytopenia, anemia, and neutropenia have been found.
  • MTA synergistic inhibitors target the PRMT5/MTA complex and are expected to inhibit MTAP-deficient tumor cells while eliminating the impact on MTAP WT cells, which can improve the treatment window.
  • the present invention uses the PRMT5/MTA complex as a target and develops a new class of small molecule inhibitors that can be used to treat various cancers.
  • the compound of the present invention targets the PRMT5/MTA complex, is an MTA synergistic PRMT5 inhibitor, has excellent PRMT5/MTA inhibitory activity, and has obvious selectivity for the PRMT5/SAM complex.
  • the compounds of the present invention have good ADMET (absorption-distribution-metabolism-excretion-toxicity) properties.
  • the invention provides compounds of formula (I) or (I'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs thereof, Hydrate or solvate:
  • L 1 is NH or CHR x ;
  • L 2 is CR x R y ;
  • R x and R y are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
  • L 1 is CHR x and L 2 is CR x R y , the two R x groups can be combined to form a chemical bond or a C 1-4 alkylene group;
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from H, D, CN, OR a , NR b R c , C(O)OR a or C(O)NR b R c ;
  • R 2b is selected from H, D, halogen, C(O)OR a , C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3- 10-membered heterocyclyl;
  • R 2c is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 5-10 cycloalkyl, 5-10 membered hetero Ring group, C 6-10 aryl group or 5-10 membered heteroaryl group;
  • Ar 1 is phenyl or 5-6 membered heteroaryl, which is substituted by m R 1 ;
  • R 1 is selected from H, D, halogen, CN, NO 2 , -L-OR a , -L-SR a , -L-NR b R c , SF 5 , C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , S(O)R a , S(O) 2 R a , S(O)OR a , S (O) 2 OR a , S(O)NR b R c , S(O) 2 NR b R c , P(O)(R a ) 2 , P(O) 2 R a , C 1-6 alkyl , C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl (such as C 5-10 cycloalkyl), 4-10
  • n 0, 1, 2, 3, 4 or 5;
  • twin or adjacent two R 1s and the atoms to which they are connected together form a C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally replaced by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • L is a chemical bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, which is optionally 1, 2 or 3 selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group substitution;
  • R 3 , R 3a and R 3b are independently selected from H, D, halogen, OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , OC (O)R a , NR b C(O)R c , C 1-6 alkyl, C 1-6 haloalkyl, 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;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 5-10 membered heterocyclyl group ;
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant or vehicle.
  • the invention provides a pharmaceutical composition containing a compound of the invention and a pharmaceutically acceptable excipient, which also contains other therapeutic agents, such as selected from the following target drugs/cell activity modulators, including CDK4/ 6 inhibitors, MAT2A inhibitors, MAPK1/MAPK3 inhibitors, Type I PRMT inhibitors, EGFR inhibitors, SHP2 inhibitors, pan-KRAS inhibitors, KRASG12C inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, Bcl -2 inhibitors, SOS1 inhibitors, PARP inhibitors, MALT1 inhibitors, MALT2 inhibitors, BTK inhibitors, PI3K inhibitors, AKT inhibitors, FGFR inhibitors, DNA methyltransferase (DNMT) inhibitors, EZH1/ 2 inhibitors, EZH2 inhibitors, Menin-MLL inhibitors, IDH1 inhibitors, IDH2 inhibitors, IDH1/2 inhibitors, chemotherapy drugs, radiotherapy, STING agonists or immune checkpoint inhibitors/modul
  • the invention provides the use of a compound of the invention for the preparation of a medicament for the treatment and/or prevention of PRMT5-mediated diseases.
  • the invention provides a method of treating and/or preventing a PRMT5-mediated disease in a subject, comprising administering to said subject a compound of the invention or a pharmaceutical composition of the invention.
  • the invention provides a compound of the invention or a pharmaceutical composition of the invention for use in the treatment and/or prevention of PRMT5-mediated diseases.
  • the present invention is used to treat and/or prevent cancer.
  • the present invention is used for the treatment and/or prevention of the following cancers: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas and teratomas.
  • bronchial carcinoma squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma
  • alveolar (bronchiolar) carcinoma bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma, mesothelial carcinoma Tumors
  • gastrointestinal tract esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastric Secretinoma, carcinoid tumor, hemangioma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor), Kaposi's sarcoma, leiomyoma, hemangioma
  • the PRMT5-mediated disease of the invention is selected from the following cancers: malignant peripheral nerve sheath tumors, mesothelioma, glioblastoma multiforme, pancreatic cancer, cholangiocarcinoma, prostate cancer, Breast cancer, brain cancer, skin cancer, cervical cancer, bladder cancer, astrocytoma, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, thymoma, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung squamous cell carcinoma , lung adenocarcinoma, oral cancer, ovarian cancer, kidney cancer and thyroid cancer, and sarcoma.
  • cancers malignant peripheral nerve sheath tumors, mesothelioma, glioblastoma multiforme, pancreatic cancer, cholangiocarcinoma, prostate cancer, Breast cancer, brain cancer, skin cancer, cervical cancer, bladder cancer, astrocytoma, colore
  • the PRMT5-mediated disease of the invention is selected from MTAP-related cancers, such as hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer or head and neck cancer.
  • MTAP-related cancers such as hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer or head and neck cancer.
  • 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 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.
  • 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 group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. chain or branched hydrocarbon groups. 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.
  • C 1-6 alkylene refers to a divalent group formed by removing another hydrogen of C 1-6 alkyl, and may be substituted or unsubstituted. In some embodiments, C 1-4 alkylene, C 2-4 alkylene, and C 1-3 alkylene are preferred.
  • the unsubstituted alkylene group includes, but is not limited to: methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), ethylene Base (-CH 2 CH 2 CH 2 CH 2 -), pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -) ,etc.
  • alkylene groups substituted by one or more alkyl (methyl) include, but are not limited to: substituted methylene (-CH(CH 3 )- , -C(CH 3 ) 2 -), substituted ethylene (-CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2- ), substituted propylene (-CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 ) -, -C(CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 C(CH 3 ) 2 -), etc.
  • C 2-6 alkynylene refers to a divalent group formed by removing the other hydrogen of the C 2-6 alkynyl group, and may be substituted or unsubstituted. In some embodiments, C 2-4 alkynylene is particularly preferred. Exemplary alkynylene groups include, but are not limited to: ethynylene (-C ⁇ C-), substituted or unsubstituted propynylene (-C ⁇ CCH 2 -), and the like.
  • C 0-6 alkylene means a chemical bond and the above-mentioned “C 1-6 alkylene”
  • C 0-4 alkylene means a chemical bond and the above-mentioned "C 1-4 alkylene”.
  • 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 3-10 cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms, optionally containing 1, 2 or 3 double or triple bonds. In some embodiments, C 5-10 cycloalkyl, C 3-7 cycloalkyl and C 3-6 cycloalkyl are particularly preferred, with C 5-7 cycloalkyl and C 5-6 cycloalkyl being more preferred base.
  • 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. Cycloalkyl also includes the above-mentioned cycloalkyl rings, in which the substituents on any non-adjacent carbon atoms are connected to form a bridged ring, which together form a polycyclic alkane sharing two or more carbon atoms.
  • Cycloalkyl also includes the above-mentioned cycloalkyl rings, in which substituents on the same carbon atom are connected to form a ring, and together form a polycyclic alkane sharing one carbon atom.
  • 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
  • C 3-10 cycloalkylene refers to a divalent group formed by removing another hydrogen of C 3-10 cycloalkyl, and may be substituted or unsubstituted.
  • C 3-6 cycloalkylene and C 3-4 cycloalkylene are particularly preferred, with cyclopropylene being particularly preferred.
  • 3-10 membered heterocyclyl refers to a saturated or unsaturated group of 3 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from Nitrogen, oxygen, sulfur, boron, phosphorus and silicon, optionally containing 1, 2 or 3 double or triple bonds.
  • the point of attachment may be a carbon or nitrogen atom as long as the valency permits.
  • 5-10 membered heterocyclyl is preferred, which is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 3-7 membered is preferred Heterocyclyl, which is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; preferably 5-7-membered heterocyclyl, which is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 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 heterocyclyl 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.
  • Heterocyclyl also includes the above-mentioned heterocyclyl rings, in which the substituents on any non-adjacent carbon or nitrogen atoms are connected to form a bridged ring, which together form a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms.
  • Heterocyclyl also includes the above-mentioned heterocyclyl rings, in which substituents on the same carbon atom are connected to form a ring and together form a polycyclic heteroalkane sharing one carbon atom.
  • 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: pyrazolidinyl, dioxolyl, oxasulfuranyl, dithiolyl (disulfuranyl) and oxazolidin-2-one.
  • 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.
  • Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are 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 C 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 also includes the above-mentioned heterocyclyl sharing one or two atoms with a cycloalkyl, heterocyclyl, aryl or heteroaryl to form a bridged ring or spiro ring. As long as the valency allows, the shared atoms can be carbon or Nitrogen atom. Heterocyclyl also includes the above-mentioned heterocyclyl and heterocyclyl groups may be optionally substituted by one or more substituents, for example, by 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 (e.g., having 6-10 ring carbon atoms and zero heteroatoms arranged in a cyclic 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.
  • 5-14 membered heteroaryl refers to a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 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.
  • 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 or pyridonyl.
  • 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 thiepeptatrienyl.
  • 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.
  • the divalent groups formed by removing another hydrogen from the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups defined above are collectively referred to as "subunits".
  • Ring-forming groups such as cycloalkyl, heterocyclyl, aryl and heteroaryl are collectively referred to as "cyclic groups”.
  • 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 groups are independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups;
  • Each Rcc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two Rcc 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;
  • cancer includes, but is not limited to, the following cancers: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas and teratomas; Lung: bronchial carcinoma (squamous cell carcinoma) cystic cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma) cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (duct
  • cancer includes, but is not limited to, the following cancers: malignant peripheral nerve sheath tumors, mesothelioma, glioblastoma multiforme, pancreatic cancer, cholangiocarcinoma, prostate cancer, breast cancer, brain cancer , skin cancer, cervical cancer, bladder cancer, astrocytoma, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, thymoma, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung squamous cell carcinoma, lung adenocarcinoma, Oral, ovarian, renal and thyroid cancers and sarcomas.
  • cancer includes, but is not limited to, the following cancers: hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer.
  • treatment refers to reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition.
  • noun “treat” refers to the action of the verb treat, as just defined.
  • 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 effects, allergic reactions, etc., commensurate with a reasonable benefit/risk ratio, are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the invention.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines.
  • metals used as cations are sodium, potassium, magnesium, calcium, etc.
  • suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.
  • Base addition salts of acidic compounds may be prepared in conventional manner by contacting the free acid form with a sufficient amount of the desired base to form the salt.
  • the free acid can be regenerated by contacting the salt form with the acid and isolating the free acid in the usual manner.
  • the free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention the salts are nevertheless equivalent to their respective free acids.
  • the salts may be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates prepared from inorganic acids Salt, chloride, bromide, iodide, acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc.
  • Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate Acid, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, Methanesulfonate, glucoheptonate, lactobionate, lauryl sulfonate and isethionate, etc.
  • Salts may also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like.
  • organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like.
  • Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malonate Lenate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylbenzoate Acid, citrate, lactate, maleate, tartrate, methanesulfonate, etc.
  • Pharmaceutically acceptable salts may include alkali and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethyl Ammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Also covered are salts of amino acids, such as arginates, gluconates, galacturonates, etc. (see, for example, Berge S.M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66:1- 19, incorporated by reference).
  • 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.
  • treatment includes an action in a subject suffering from a specific disease, disorder or condition that reduces the severity of the disease, disorder or condition, or delays or slows down the disease, disorder or the development of a condition ("therapeutic treatment”), and also includes effects that occur before a subject begins to suffer from a specific disease, disorder or condition ("preventive treatment").
  • 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: biological goals, pharmacokinetics of the compound, The disease being treated, the mode of administration, and the age, health, and symptoms of the subject.
  • the effective amount includes a therapeutically effective amount and a preventive effective amount.
  • a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit in treating a disease, disorder, or condition, or to cause one or more symptoms associated with the disease, disorder, or condition The amount to delay or minimize.
  • a therapeutically effective amount of a compound is that amount of therapeutic agent that, when used alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a disease, disorder, or condition.
  • the term "therapeutically effective amount” may include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic effect of other therapeutic agents.
  • a prophylactically effective amount of a compound as used herein is an amount sufficient to prevent a disease, disorder or condition, or to prevent one or more symptoms associated with a disease, disorder or condition, or to prevent a disease , the amount of recurrence of a disorder or condition.
  • a prophylactically effective amount of a compound is that amount of therapeutic agent that, when used alone or in combination with other agents, provides a prophylactic benefit in preventing a disease, disorder, or condition.
  • the term “prophylactically effective amount” may include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic effect of other prophylactic agents.
  • 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.
  • Figures 1 and 2 show the results of in vivo pharmacodynamic studies in the LU99CDX model.
  • the "compounds of the present invention” refer to the following compounds of formula (I), formula (II), and their pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs , polymorphs, hydrates or solvates.
  • the present invention relates to compounds of formula (I) or (I'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs thereof , hydrate or solvate:
  • L 1 is NH or CHR x ;
  • L 2 is CR x R y ;
  • R x and R y are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
  • L 1 is CHR x and L 2 is CR x R y , the two R x groups can be combined to form a chemical bond or a C 1-4 alkylene group;
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from H, D, CN, OR a , NR b R c , C(O)OR a or C(O)NR b R c ;
  • R 2b is selected from H, D, halogen, C(O)OR a , C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3- 10-membered heterocyclyl;
  • R 2c is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 5-10 cycloalkyl, 5-10 membered hetero Ring group, C 6-10 aryl group or 5-10 membered heteroaryl group;
  • Ar 1 is phenyl or 5-6 membered heteroaryl, which is substituted by m R 1 ;
  • R 1 is selected from H, D, halogen, CN, NO 2 , -L-OR a , -L-SR a , -L-NR b R c , SF 5 , C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , S(O)R a , S(O) 2 R a , S(O)OR a , S (O) 2 OR a , S(O)NR b R c , S(O) 2 NR b R c , P(O)(R a ) 2 , P(O) 2 R a , C 1-6 alkyl , C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl (such as C 5-10 cycloalkyl), 4-10
  • n 0, 1, 2, 3, 4 or 5;
  • twin or adjacent two R 1s and the atoms to which they are connected together form a C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally replaced by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • L is a chemical bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, which is optionally 1, 2 or 3 selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group substitution;
  • R 3 , R 3a and R 3b are independently selected from H, D, halogen, OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , OC (O)R a , NR b C(O)R c , C 1-6 alkyl, C 1-6 haloalkyl, 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;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 5-10 membered heterocyclyl group ;
  • L 1 is NH; in another embodiment, L 1 is CHRx ; in another embodiment, L 1 is NH and L 2 is CR x Ry , preferably More preferably More preferably More preferably In another embodiment, L 1 is CHR x and L 2 is CR x Ry , preferably More preferably More preferably
  • X 1 is a C atom; in another embodiment, X 1 is an N atom; in another embodiment, X 1 is CR 2b ; in another embodiment, X 1 is NR 2b ; In one embodiment, X 2 is a C atom; in another embodiment, X 2 is an N atom; in another embodiment, X 2 is CR 2c ; in another embodiment, X 2 is NR 2c ; in one embodiment, X 3 is CR 2d ; in another embodiment, X 3 is N.
  • X 1 , X 2 and their substituents together form a C 5-10 cycloalkyl group; in another more specific embodiment, X 1 , X 2 and their substituents together form Forming a 5-10 membered heterocyclyl group; in another more specific embodiment, X 1 , X 2 and their substituents together form a C 6-10 aryl group; in another more specific embodiment, X 1 , X 2 and their substituents together form a 5-10 membered heteroaryl; in another more specific embodiment, X 1 , 7-membered heterocyclyl, phenyl or 5-6-membered heteroaryl; in another more specific embodiment, X 1 , X 2 and their The bases are formed together Preferably
  • R 2a is H; in another embodiment, R 2a is D; in another embodiment, R 2a is CN; in another embodiment, R 2a is OR a ; in another In one embodiment, R 2a is NR b R c ; in another embodiment, R 2a is C(O)OR a ; in another embodiment, R 2a is C(O)NR b R c .
  • R 2a is selected from H, D, CN, OR a or NR b R c ; in another more specific embodiment, R 2a is selected from OR a or NR b R c , preferably is NH 2 .
  • R 2b is H; in another embodiment, R 2b is D; in another embodiment, R 2b is halogen; in another embodiment, R 2b is C(O)OR a ; In another embodiment, R 2b is C(O)NR b R c ; In another embodiment, R 2b is C 1-6 alkyl; In another embodiment, R 2b is C 1 -6 haloalkyl; in another embodiment, R 2b is C 3-10 cycloalkyl; in another embodiment, R 2b is 3-10 membered heterocyclyl.
  • R 2b is selected from H, D, halogen, C(O)OR a , C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 2b is selected from H, D, halogen, C(O)NR b R c , C 1-6 alkyl , C 1-6 haloalkyl or 4-6 membered heterocyclyl; in another more specific embodiment, R 2b is selected from H, F, Cl, Br, Me, CH 2 CH 3 , C(O)NH 2 or
  • R 2c is H; in another embodiment, R 2c is D; in another embodiment, R 2c is halogen; in another embodiment, R 2c is C 1-6 alkane group; in another embodiment, R 2c is C 1-6 haloalkyl.
  • R 2c is selected from H or Me.
  • R 2d is H; in another embodiment, R 2d is D; in another embodiment, R 2d is halogen; in another embodiment, R 2d is CN; in another In an embodiment, R 2d is NO 2 ; in another embodiment, R 2d is OR a ; in another embodiment, R 2d is NR b R c ; in another embodiment, R 2d is C 1 -6 alkyl; in another embodiment, R 2d is C 1-6 haloalkyl; in another embodiment, R 2d is C 5-10 cycloalkyl; in another embodiment, R 2d is 5-10 membered heterocyclyl; in another embodiment, R 2d is C 6-10 aryl; in another embodiment, R 2d is 5-10 membered heteroaryl.
  • R 2d is selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 2d is selected from H or D.
  • Ar 1 is phenyl; in another embodiment, Ar 1 is 5-6 membered heteroaryl, preferably 5-membered heteroaryl; In another embodiment, Ar 1 is phenyl, pyridyl, or thienyl.
  • Ar 1 is For example preferred In a specific implementation, Preferably In a specific implementation, Preferably in a tool In the specific implementation, Preferably In a specific implementation, Preferably In a specific implementation, Preferably In a specific implementation, Preferably In a specific implementation, Preferably In a specific implementation, Preferably In a specific implementation, Preferably In another specific embodiment, Preferably In another specific embodiment, Preferably In another specific embodiment, Preferably In another specific embodiment, Preferably In another specific embodiment, Preferably In another specific embodiment, Preferably In another specific embodiment, Preferably In another specific embodiment, Preferably In another specific embodiment, Preferably In another specific embodiment, Preferably In another specific embodiment, Preferably In another specific embodiment, Preferably In another specific embodiment, Preferably In another specific embodiment, Preferably In another specific embodiment, Preferably In another specific embodiment, Preferably In another specific embodiment, Preferably In another specific embodiment, Preferably In another specific embodiment, Preferably In another specific embodiment, Preferably In another specific embodiment
  • R 1s is H, Me, Et, iPr, Preferably H, In one specific embodiment, R 1s is H; in one specific embodiment, R 1s is Me; in one specific embodiment, R 1s is Et; in one specific embodiment, R 1s is iPr; in another In a specific implementation, R 1s is In a specific embodiment, R 1s is In another specific embodiment, R 1s is In a specific embodiment, R 1s is In a specific embodiment, R 1s is In another specific embodiment, R 1s is In another specific embodiment, R 1s is In another specific embodiment, R 1s is In another specific embodiment, R 1s is In another specific embodiment, R 1s is In another specific embodiment, R 1s is In another specific embodiment, R 1s is In another specific embodiment, R 1s is In another specific embodiment, R 1s is In another specific embodiment, R 1s is In another specific embodiment, R 1s is In another specific embodiment, R 1s is In another specific embodiment, R 1s is In another specific embodiment, R 1s is In another specific embodiment, R 1s is In
  • R 1 is H; in another embodiment, R 1 is D; in another embodiment, R 1 is halogen; in another embodiment, R 1 is CN; in another In an embodiment, R 1 is NO 2 ; in another embodiment, R 1 is -L-OR a ; in another embodiment, R 1 is -L-SR a ; in another embodiment, R 1 is -L-NR b R c ; in another embodiment, R 1 is SF 5 ; in another embodiment, R 1 is C(O) Ra ; in another embodiment, R 1 is C(O)OR a ; In another embodiment, R 1 is C(O)NR b R c ; In another embodiment, R 1 is OC(O)R a ; In another embodiment, R 1 is NR b C(O)R c ; in another embodiment, R 1 is S(O)R a ; in another embodiment, R 1 is S(O) 2 R a ; in another In one embodiment, R 1 is S(O)OR a ; in another embodiment
  • R 1 is selected from H, D, halogen, CN, -L-OR a , -L-SR a , -L-NR b R c , SF 5 , C 1-6 alkyl , C 1-6 haloalkyl, C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; in another more specific embodiment, R 1 is selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 5-7 cycloalkyl or 5-7 Membered heterocyclyl; in another more specific embodiment, two adjacent R 1 and the atoms to which they are connected together form a C 5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5- 6-membered heteroaryl.
  • R 1s is C 1-6 haloalkyl; in another embodiment, R 1s is C 2-6 alkenyl; in another embodiment, R 1s is C 2-6 alkyne base; in another In one embodiment, R 1s is -LC 3-10 cycloalkyl; in another embodiment, R 1s is -L-3-10 membered heterocyclyl; in another embodiment, R 1s is -LC 6-10 aryl; in another embodiment, R 1s is -L-5-10 membered heteroaryl; in another embodiment, the two R 1s in the gem position and the atoms they are connected together form C 3 -6 cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, preferably C 3-6 cycloalkyl, preferably 4-6 membered heterocyclyl, preferably phenyl, Preferably it is a 5-6 membered heteroaryl; in another embodiment, the ring formed by the two R 1s in the gem
  • L is a chemical bond; in another embodiment, L is C 1-6 alkylene; in another embodiment, L is C 2-6 alkenylene; in another embodiment , L is C 2-6 alkynylene; in another embodiment, L is optionally substituted by 1, 2 or 3 R.
  • R 3 is H; in another embodiment, R 3 is D; in another embodiment, R 3 is halogen; in another embodiment, R 3 is OR a ; in another embodiment, R 3 is OR In one embodiment, R 3 is NR b R c ; in another embodiment, R 3 is C(O)R a ; in another embodiment, R 3 is C(O)OR a ; in another In one embodiment, R 3 is C(O)NR b R c ; in another embodiment, R 3 is OC(O)R a ; in another embodiment, R 3 is NR b C(O)R c ; In another embodiment, R 3 is C 1-6 alkyl; In another embodiment, R 3 is C 1-6 haloalkyl; In another 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, R 3 is a 3-10 membered heterocyclyl group; in
  • R 3a is H; in another embodiment, R 3a is D; in another embodiment, R 3a is halogen; in another embodiment, R 3a is OR a ; in another In one embodiment, R 3a is NR b R c ; in another embodiment, R 3a is C(O)R a ; in another embodiment, R 3a is C(O)OR a ; in another In one embodiment, R 3a is C(O)NR b R c ; in another embodiment, R 3a is OC(O)R a ; in another embodiment, R 3a is NR b C(O)R c ; In another embodiment, R 3a is C 1-6 alkyl; in another embodiment, R 3a is C 1-6 haloalkyl; in another embodiment, R 3a is C 2-6 Alkenyl; in another embodiment, R 3a is C 2-6 alkynyl; in another embodiment, R 3a is C 3-10 cycloalkyl; in another embodiment, R 3a is 3- 10-membere
  • R 3b is H; in another embodiment, R 3b is D; in another embodiment, R 3b is halogen; in another embodiment, R 3b is OR a ; in another In one embodiment, R 3b is NR b R c ; in another embodiment, R 3b is C(O)R a ; in another embodiment, R 3b is C(O)OR a ; in another In one embodiment, R 3b is C(O)NR b R c ; in another embodiment, R 3b is OC(O)R a ; in another embodiment, R 3b is NR b C(O)R c ; In another embodiment, R 3b is C 1-6 alkyl; in another embodiment, R 3b is C 1-6 haloalkyl; in another embodiment, R 3b is C 2-6 Alkenyl; in another embodiment, R 3b is C 2-6 alkynyl; in another embodiment, R 3b is C 3-10 cycloalkyl; in another embodiment, R 3b is 3- 10-membere
  • R 3 is selected from H, D, halogen, OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl; in another more specific In embodiments, R 3 is selected from H, D, halogen, OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , C 1-6 alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 3 is selected from H, D, halogen, OR a , NR b R c , C(
  • one of R 3a and R 3b is C 1-6 alkyl or C 1-6 haloalkyl, and the other is H; in another more specific embodiment, R 3a and R One of 3b is Me and the other is H; in another more specific embodiment, R 3a is H and R 3b is Me.
  • Ra , Rb , and Rc are independently H; in another embodiment, Ra , Rb, and Rc are independently D; in another embodiment, Ra , R b and R c are independently C 1-6 alkyl; in another embodiment, R a , R b and R c are independently C 1-6 haloalkyl; in another embodiment, R b , R c and the atoms to which they are connected together form a 5-10 membered heterocyclyl group, preferably a 5-6 membered heterocyclyl group.
  • any technical solution in any of the above specific embodiments or any combination thereof can be combined with any technical solution in other specific embodiments. scheme or any combination thereof.
  • any technical solution of L 1 or any combination thereof can be combined with L 2 , R x , Ry , X 1 , X 2 , X 3 , R 2a , R 2b , R 2c , R 2d , Ar 1 , R 1 , m, R 1s , L, R 2s , R 3 , R 3a , R 3b , n, R a , R b and R c , etc., or any combination thereof.
  • 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 invention provides compounds of formula (I) or (I'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
  • L 1 is NH or CHR x ;
  • L 2 is CR x R y ;
  • R x and R y are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
  • L 1 is CHR x and L 2 is CR x R y , the two R x groups can be combined to form a chemical bond or a C 1-4 alkylene group;
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from H, D, CN, OR a , NR b R c , C(O)OR a or C(O)NR b R c ;
  • R 2b is selected from H, D, halogen, C(O)OR a , C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3- 10-membered heterocyclyl;
  • R 2c is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 5-10 cycloalkyl, 5-10 membered hetero Ring group, C 6-10 aryl group or 5-10 membered heteroaryl group;
  • Ar 1 is phenyl or 5-6 membered heteroaryl, which is substituted by m R 1 ;
  • R 1 is selected from H, D, halogen, CN, NO 2 , -L-OR a , -L-SR a , -L-NR b R c , SF 5 , C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , S(O)R a , S(O) 2 R a , S(O)OR a , S (O) 2 OR a , S(O)NR b R c , S(O) 2 NR b R c , P(O)(R a ) 2 , P(O) 2 R a , C 1-6 alkyl , C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl (such as C 5-10 cycloalkyl), 4-10
  • n 0, 1, 2, 3, 4 or 5;
  • twin or adjacent two R 1s and the atoms to which they are connected together form a C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally replaced by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • L is a chemical bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, which is optionally 1, 2 or 3 selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group substitution;
  • R 3 , R 3a and R 3b are independently selected from H, D, halogen, OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , OC (O)R a , NR b C(O)R c , C 1-6 alkyl, C 1-6 haloalkyl, 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;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 5-10 membered heterocyclyl group ;
  • the present invention provides compounds of the above formula (I) or (I'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, Prodrug, polymorph, hydrate or solvate, wherein Ar 1 is phenyl or 5-membered heteroaryl; or Ar 1 is phenyl or 6-membered heteroaryl; Ar 1 is preferably phenyl or pyridyl Or thienyl; Ar 1 is more preferably Ar 1 example For example preferred More preferably Preferably, R 1s is H, Me, Et, iPr, Preferably H, More preferably
  • the present invention provides compounds of the above formula (I) or (I'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, Prodrug, polymorph, hydrate or solvate, wherein L 1 is NH and L 2 is CR x R y ; preferably More preferred
  • the present invention provides compounds of the above formula (I) or (I'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, Prodrug, polymorph, hydrate or solvate, wherein L 1 is CHR x and L 2 is CR x R y ; preferably More preferred
  • the present invention provides compounds of the above formula (I) or (I'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, Prodrug, polymorph, hydrate or solvate, wherein R 1 is selected from H, D, halogen, CN, NO 2 , -L-OR a , -L-SR a , -L-NR b R c , SF 5 , C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , S(O)R a , S(O) 2 R a , S(O)OR a , S(O) 2 OR a , S(O)NR b R c , S(O) 2 NR b R c , P(O)(R a ) 2.
  • the present invention provides compounds of the above formula (I) or (I'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, Prodrugs, polymorphs, hydrates or solvates, wherein, Selected from
  • the present invention provides compounds of the above formula (I) or (I'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, Prodrug, polymorph, hydrate or solvate, wherein R 2a is selected from H, D, CN, OR a or NR b R c ; preferably selected from OR a or NR b R c ; preferably NH 2 .
  • the present invention provides compounds of the above formula (I) or (I'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, Prodrug, polymorph, hydrate or solvate, wherein R 2b is selected from H, D, halogen, C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl or 4 -6-membered heterocyclyl; preferably selected from H, F, Cl, Br, Me, CH 2 CH 3 , C(O)NH 2 or
  • the present invention provides compounds of the above formula (I) or (I'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, Prodrug, polymorph, hydrate or solvate, wherein R 2c is selected from H or Me.
  • the present invention provides compounds of the above formula (I) or (I'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, Prodrug, polymorph, hydrate or solvate, wherein X 1 , X 2 and their substituents together form C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl Or 5-10 membered heteroaryl; preferably forming C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; preferably forming Preferably form It is more preferred to form
  • the present invention provides compounds of the above formula (I) or (I'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, Prodrug, polymorph, hydrate or solvate, wherein R 2d is selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; preferably H or D.
  • the present invention provides the compound of formula (I) or (I') above, or a pharmaceutically acceptable salt thereof, the same Isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein one of R 3a and R 3b is C 1-6 alkyl or C 1- 6 haloalkyl, the other is H; one of R 3a and R 3b is Me, the other is H; preferably, R 3a is H and R 3b is Me.
  • the present invention provides compounds of the above formula (I) or (I'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, Prodrug, polymorph, hydrate or solvate, wherein R 3 is selected from H, D, halogen, OR a , NR b R c , C(O)R a , C(O)OR a , C( O)NR b R c , OC(O)R a , NR b C(O)R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl ;
  • R 3 is selected from H, D, halogen, OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c
  • the present invention provides compounds of the above formula (I) or (I'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, Prodrugs, polymorphs, hydrates or solvates having the following structural formula:
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • L 1 is NH or CHR x ;
  • L 2 is CR x R y ;
  • R x and R y are independently H, D, C 1-6 alkyl or C 1-6 haloalkyl
  • L 1 is CHR x and L 2 is CR x R y , the two R x groups can be combined to form a chemical bond or a C 1-4 alkylene group;
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein -L 1 -L 2 - is selected from
  • the present invention provides the above-mentioned compound of formula (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, where,
  • L 1 is NH or CHR x ;
  • L 2 is CR x R y ;
  • R x and R y are independently H, D, C 1-6 alkyl or C 1-6 haloalkyl
  • L 1 is CHR x and L 2 is CR x R y , the two R x groups can be combined to form a chemical bond or a C 1-4 alkylene group;
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from H, D, OR a or NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 5-10 cycloalkyl, 5-10 membered hetero Ring group, C 6-10 aryl group or 5-10 membered heteroaryl group;
  • R 1 , R 1a , R 1b and R 1c are independently selected from H, D, halogen, CN, -L-OR a , -L-SR a , -L-NR b R c , SF 5 , C 1-6 Alkyl, C 1-6 haloalkyl, C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1, 2 or 3 R 1s substituted;
  • n 0, 1 or 2;
  • the two R 1s in the twin or ortho positions and the atoms to which they are connected together form a C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally replaced by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • L is a chemical bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, which is optionally 1, 2 or 3 selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group substitution;
  • R 3 , R 3a and R 3b are independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4- 6-membered heterocyclyl, preferably H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 5-10 membered heterocyclyl group ;
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • L 1 is NH or CHR x ;
  • L 2 is CR x R y ;
  • R x and R y are independently H, D, C 1-6 alkyl or C 1-6 haloalkyl
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from OR a or NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 5-7 cycloalkyl or 5-7 membered hetero Ring group;
  • R 1 , R 1a , R 1b and R 1c are independently selected from H, D, halogen, CN, -L-OR a , -L-SR a , -L-NR b R c , SF 5 , C 1-6 Alkyl, C 1-6 haloalkyl, C 5-7 cycloalkyl or 5-7 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1s ;
  • n 0, 1 or 2;
  • the two R 1s in the twin or ortho positions and the atoms to which they are connected together form a C 3-6 cycloalkyl or 4-6 membered heterocyclyl, which is optionally replaced by 1, 2 or 3 selected from H, D , halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group substitution;
  • L is a chemical bond or C 1-6 alkylene group, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3 , R 3a and R 3b are independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2, 3, 4 or 5;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 5-6 membered heterocyclyl group .
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • L 1 is NH or CHR x ;
  • L 2 is CR x R y ;
  • R x and R y are independently H, D, C 1-6 alkyl or C 1-6 haloalkyl
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1 , R 1a , R 1b and R 1c are independently selected from H, D, halogen, CN, -L-OR a , -L-SR a , -L-NR b R c , SF 5 , C 1-6 Alkyl, C 1-6 haloalkyl, C 5-6 cycloalkyl or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1s ;
  • n 0, 1 or 2;
  • the two R 1s in the twin or ortho position and the atoms to which they are connected together form a C 3-6 cycloalkyl or 4-6 membered heterocyclyl, which is optionally replaced by 1, 2 or 3 selected from H, D , halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group substitution;
  • L is a chemical bond or C 1-6 alkylene group, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3 , R 3a and R 3b are independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2 or 3;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 5-6 membered heterocyclyl group .
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt or isotope thereof Variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d ;
  • R 2a is NH 2 ;
  • R 2d is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1 is selected from H, D, halogen, CN, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1a , R 1b and R 1c are independently selected from H, D, halogen, CN, -L-OR a , -L-SR a , -L-NR b R c , C 1-6 alkyl, C 1- 6 haloalkyl, C 5-6 cycloalkyl or 5-6 membered heterocyclyl, preferably H, D, halogen, CN, -L-NR b R c , C 1-6 alkyl, C 1-6 haloalkyl , C 5-6 cycloalkyl or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1s ;
  • n 0, 1 or 2;
  • the two R 1s in the twin or ortho position and the atoms to which they are connected together form a C 3-6 cycloalkyl or 4-6 membered heterocyclyl, which is optionally replaced by 1, 2 or 3 selected from H, D , halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group substitution;
  • L is a chemical bond or C 1-6 alkylene group, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3 is selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3a and R 3b is C 1-6 alkyl or C 1-6 haloalkyl, and the other is H or D;
  • n 0, 1, 2 or 3;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 5-6 membered heterocyclyl group ;
  • X 1 , X 2 and their substituents together form a group selected from: Preferably selected from Preferably
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • L 1 is NH
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from OR a or NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1 , R 1a , R 1b and R 1c are independently selected from H, D, halogen, CN, OR a , SRa , NR b R c , SF 5 , C 1-6 alkyl or C 1-6 haloalkyl. , which is optionally substituted by 1, 2 or 3 R 1s ;
  • n 0, 1 or 2;
  • R 3 , R 3a and R 3b are independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 5-10 membered heterocyclyl group ;
  • each of the above-mentioned R 1 , R 1a , R 1b , R 1c , R 2a , R 2d , R 1s , R 2s , R 3 , R 3a , R 3b , R a , R b and R c is defined as any Selected sites are deuterated until fully deuterated.
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, where
  • L 1 is NH
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d ;
  • R 2a is NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1 is selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF 5 , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1 or 2;
  • R 3 , R 3a and R 3b are independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 5-10 membered heterocyclyl group .
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, where
  • L 1 is NH
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d ;
  • R 2a is NH 2 ;
  • R 2d is selected from H or D
  • R 1 is selected from H, D, F or Me
  • n 0, 1 or 2;
  • R 3 , R 3a and R 3b are independently selected from H, D or Me.
  • R 3b is Me;
  • n 0, 1, 2, 3, 4, 5, 6 or 7.
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, where
  • L 1 is NH
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from OR a or NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1 , R 1a , R 1b and R 1c are independently selected from H, D, halogen, CN, -L-OR a , -L-SR a , -L-NR b R c , SF 5 , C 1-6 Alkyl or C 1-6 haloalkyl;
  • L is a chemical bond or C 1-6 alkylene group, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1 or 2;
  • R 3 , R 3a and R 3b are independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
  • each of the above-mentioned R 1 , R 1a , R 1b , R 1c , R 2a , R 2d , R 2s , R 3 , R 3a , R 3b , R a , R b and R c is optionally defined by Deuterated, until completely deuterated.
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, where
  • L 1 is NH
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d ;
  • R 2a is NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1 is selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF 5 , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1 or 2;
  • R 3 , R 3a and R 3b are independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, where
  • L 1 is NH
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d ;
  • R 2a is NH 2 ;
  • R 2d is selected from H or D
  • R 1 is selected from H, D, F or Me
  • n 0, 1 or 2;
  • R 3 , R 3a and R 3b are independently selected from H, D or Me.
  • R 3b is Me;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, where
  • L 1 is NH
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from OR a or NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1 , R 1a , R 1b and R 1c are independently selected from H, D, halogen, CN, -L-OR a , -L-SR a , -L-NR b R c , SF 5 , C 1-6 Alkyl or C 1-6 haloalkyl;
  • L is a chemical bond or C 1-6 alkylene group, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1 or 2;
  • R 3 , R 3a and R 3b are independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
  • each of the above defined groups of R 1 , R 1a , R 1b , R 1c , R 2a , R 2d , R 3 , R 3a , R 3b , R a , R b and R c is optionally deuterated, until completely deuterated.
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, where
  • L 1 is NH
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d ;
  • R 2a is NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1 is selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF 5 , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1 or 2;
  • R 3 , R 3a and R 3b are independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, where
  • L 1 is NH
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d ;
  • R 2a is NH 2 ;
  • R 2d is selected from H or D
  • R 1 is selected from H, D, F or Me
  • n 0, 1 or 2;
  • R 3 , R 3a and R 3b are independently selected from H, D or Me.
  • R 3b is Me;
  • n 0, 1, 2, 3, 4, 5, 6 or 7.
  • the present invention provides the above-mentioned compound of formula (III), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, where
  • L 1 is NH
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • R 2s is substituted, preferably a 5-7-membered heterocyclyl group or a 5-6-membered heteroaryl group, which is optionally substituted by 1, 2 or 3 R 2s ;
  • X 3 is CR 2d or N
  • R 2a is selected from OR a or NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1 is selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF 5 , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2 or 3;
  • L is a chemical bond or C 1-6 alkylene group, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3 , R 3a and R 3b are independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the above-mentioned compound of formula (III), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, where
  • L 1 is NH
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d ;
  • R 2a is NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1 is selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF 5 , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2 or 3;
  • R 1s is H, D, C 1-6 alkyl, C 1-6 haloalkyl,
  • R 3 , R 3a and R 3b are independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the above-mentioned compound of formula (III), or a pharmaceutically acceptable salt or isotope thereof Variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein
  • L 1 is NH
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d ;
  • R 2a is NH 2 ;
  • R 2d is selected from H or D
  • R 1 is selected from H, D, F or Me
  • n 0, 1, 2 or 3;
  • R 1s is H, Me, Et, iPr,
  • R 3 , R 3a and R 3b are independently selected from H, D or Me.
  • R 3b is Me;
  • n 0, 1, 2, 3, 4, 5, 6 or 7.
  • the present invention provides the above-mentioned compound of formula (III), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • L 1 is NH or CHR x ;
  • L 2 is CR x R y ;
  • R x and R y are independently H, D, C 1-6 alkyl or C 1-6 haloalkyl
  • L 1 is CHR x and L 2 is CR x R y , the two R x groups can be combined to form a chemical bond or a C 1-4 alkylene group;
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from H, D, OR a or NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 5-10 cycloalkyl, 5-10 One-membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group;
  • R 1 is selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 5-7 cycloalkyl or 5- 7-membered heterocyclyl, optionally substituted by 1, 2 or 3 R 1s ;
  • n 0, 1, 2 or 3;
  • L is a chemical bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, which is optionally 1, 2 or 3 selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group substitution;
  • R 3 , R 3a and R 3b are independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 5-10 membered heterocyclyl group ;
  • the present invention provides the above-mentioned compound of formula (III), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • L 1 is NH or CHR x ;
  • L 2 is CR x R y ;
  • R x and R y are independently H, D, C 1-6 alkyl or C 1-6 haloalkyl
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from OR a or NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 5-7 cycloalkyl or 5-7 membered hetero Ring group;
  • R 1 is selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 5-7 cycloalkyl or 5- 7-membered heterocyclyl, optionally substituted by 1, 2 or 3 R 1s ;
  • n 0, 1 or 2;
  • L is a chemical bond or C 1-6 alkylene group, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3 , R 3a and R 3b are independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2, 3, 4 or 5;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 5-6 membered heterocyclyl group .
  • the present invention provides the above-mentioned compound of formula (III), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • L 1 is NH or CHR x ;
  • L 2 is CR x R y ;
  • R x and R y are independently H, D, C 1-6 alkyl or C 1-6 haloalkyl
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1 is selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 5-7 cycloalkyl or 5- 7-membered heterocyclyl, optionally substituted by 1, 2 or 3 R 1s ;
  • n 0, 1 or 2;
  • L is a chemical bond or C 1-6 alkylene group, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3 , R 3a and R 3b are independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2 or 3;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 5-6 membered heterocyclyl group .
  • the present invention provides the above-mentioned compound of formula (III), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d ;
  • R 2a is NH 2 ;
  • R 2d is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1 is selected from H, D, halogen, CN, C 1-6 alkyl or C 1-6 haloalkyl, which is optionally substituted by 1, 2 or 3 R 1s ;
  • n 0, 1 or 2;
  • L is a chemical bond or C 1-6 alkylene group, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3 is selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3a and R 3b is C 1-6 alkyl or C 1-6 haloalkyl, and the other is H or D;
  • n 0, 1, 2 or 3;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 5-6 membered heterocyclyl group ;
  • X 1 , X 2 and their substituents together form a group selected from: Preferably selected from
  • R 1s is selected from H, Preferably
  • the present invention provides the compound of formula (IV) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, where,
  • L 1 is NH or CHR x ;
  • L 2 is CR x R y ;
  • R x and R y are independently H, D, C 1-6 alkyl or C 1-6 haloalkyl
  • L 1 is CHR x and L 2 is CR x R y , the two R x groups can be combined to form a chemical bond or a C 1-4 alkylene group;
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from H, D, OR a or NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 5-10 cycloalkyl, 5-10 membered hetero Ring group, C 6-10 aryl group or 5-10 membered heteroaryl group;
  • R 1 is selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 5-7 cycloalkyl or 5- 7-membered heterocyclyl, optionally substituted by 1, 2 or 3 R 1s ;
  • n 0, 1, 2 or 3;
  • n 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
  • R 1s is selected from H, D, halogen, C(O)OR a , C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 5-7 cycloalkyl or 5- 7-membered heterocyclyl;
  • R 3 is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 5-10 membered heterocyclyl group ;
  • each of the above-mentioned L 1 , L 2 , R x , Ry , R 1 , R 2a , R 2d , R 1s , R 2s , R 3 , R a , R b and R c is optionally defined by Deuterated, until completely deuterated.
  • the present invention provides the compound of formula (IV) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, where,
  • L 1 is NH or CHR x ;
  • L 2 is CR x R y ;
  • R x and R y are independently H, D, C 1-6 alkyl or C 1-6 haloalkyl
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from OR a or NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 5-7 cycloalkyl or 5-7 membered hetero Ring group;
  • R 1 is selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 5-7 cycloalkyl or 5- 7-membered heterocyclyl, optionally substituted by 1, 2 or 3 R 1s ;
  • n 0, 1, 2 or 3;
  • n 0, 1, 2, 3, 4 or 5;
  • R 1s is selected from H, D, halogen, C(O)OR a , C(O)NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3 is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2, 3, 4 or 5;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 5-6 membered heterocyclyl group .
  • the present invention provides the compound of formula (IV) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d ;
  • R 2a is NH 2 ;
  • R 2d is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1 is selected from H, D, halogen, CN, C 1-6 alkyl or C 1-6 haloalkyl, which is optionally substituted by 1, 2 or 3 R 1s ;
  • n 0, 1 or 2;
  • n 0, 1, 2 or 3;
  • R 1s is selected from H, D, halogen, C(O)OR a , C(O)NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3 is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2 or 3;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected - Form a 5-6 membered heterocyclic group;
  • X 1 , X 2 and their substituents together form a group selected from: Preferably selected from
  • the invention provides compounds of formula (Va) or (Vb), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof , polymorph, hydrate or solvate, wherein
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from OR a or NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • Ar 1 is a 5-6 membered heteroaryl group, which is substituted by m R 1s ;
  • R 1 is selected from H, D, halogen, CN, NO 2 , -L-OR a , -L-SR a , -L-NR b R c , SF 5 , C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , S(O)R a , S(O) 2 R a , S(O)OR a , S (O) 2 OR a , S(O)NR b R c , S(O) 2 NR b R c , P(O)(R a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl
  • n 0, 1, 2, 3, 4 or 5;
  • R 3 and R 3b are independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1 , R 1s , R 2a , R 2d , R 3 , R 3b , R a , R b and R c are optionally deuterated until completely deuterated.
  • the present invention provides compounds of the above formula (Va) or (Vb), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, pro- drug, polymorph, hydrate or solvate, of which
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d ;
  • R 2a is NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • Ar 1 is a 5-6 membered heteroaryl group, which is substituted by m R 1s ;
  • R 1 is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 4-6 yuan Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s ;
  • n 0, 1, 2 or 3;
  • R 3 and R 3b are independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides compounds of the above formula (Va) or (Vb), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, pro- drug, polymorph, hydrate or solvate, in which
  • X 1 is a C atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d ;
  • R 2a is NH 2 ;
  • R 2d is selected from H or D
  • Ar 1 is a 5-6 membered heteroaryl group, which is substituted by m R 1s ; preferably, Ar 1 is selected from:
  • R 1 is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or 4-6 yuan Heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1s ;
  • n 0, 1 or 2;
  • R 1s or atoms to which they are connected together form a phenyl group or a 5-6 membered heteroaryl group, which is optionally substituted by 1, 2 or 3 R 1s ;
  • R 3 and R 3b are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides compounds of formula (I) or (I') above, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein the compound is selected from the following:
  • the present invention provides compounds of the above formula (I) or (I'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, Prodrugs, polymorphs, hydrates or solvates, wherein the compound is selected from the following:
  • the present invention provides compounds of the above formula (I) or (I'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, Prodrugs, polymorphs, hydrates or solvates, wherein the compound is selected from the following:
  • 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.
  • compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (eg, cis and trans isomers), or may be in the form of mixtures of stereoisomers, including 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
  • Tautomers are functional group isomers produced by the rapid movement of an atom in a molecule between two positions.
  • a tautomer is a special functional group isomer.
  • a pair of tautomers can interact with each other. conversion, but usually one of the more stable isomers is its main form of existence. The most important examples are the enol and keto tautomers.
  • 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 ⁇ 0.5 H 2 O)) and polyhydrates (x is a number greater than 1, for example, dihydrate (R ⁇ 2 H 2 O) and hexahydrate (R ⁇ 6 H 2 O)).
  • monohydrate x is 1
  • lower hydrate x is a number greater than 0 and less than 1
  • hemihydrate R ⁇ 0.5 H 2 O
  • polyhydrates x is a number greater than 1, for example, dihydrate (R ⁇ 2 H 2 O) and hexahydrate (R ⁇ 6 H 2 O)
  • the compounds of the invention may be in amorphous or crystalline 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 (I), except that one or more atoms are surrounded 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” refers to a substance that is absorbed in the body by, for example, water in the blood. A compound that is decomposed into its active form that has a medical effect.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of ACSSymposium 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 in this article Reference.
  • a prodrug is any covalently bonded compound of the invention that releases the parent compound in the body when administered to a patient.
  • Prodrugs are typically prepared by modifying functional groups in a manner such that the modification can be cleaved by conventional manipulations or in vivo to yield the parent compound.
  • Prodrugs include, for example, compounds of the invention in which a hydroxyl, amino or thiol group is bonded to any group that can be cleaved to form a hydroxyl, amino or thiol group when administered to a patient.
  • representative examples of prodrugs include, but are not limited to, acetate/amide, formate/amide and benzoate/amide derivatives of the hydroxyl, thiol and amino functionality of the compound of formula (A).
  • esters such as methyl ester, ethyl ester, etc. can be used.
  • the ester itself may be reactive and/or hydrolyzable under human body conditions.
  • Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that readily break down in the human body to release the parent acid or salt thereof.
  • the present invention also provides pharmaceutical preparations, comprising a therapeutically effective amount of a compound of formula (A) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All these forms belong to the invention.
  • 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
  • Suitable formulations for administering the compounds of the invention will be apparent to those of ordinary skill in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, lozenges, solutions (especially injections (subcutaneous, intravenous solution for intramuscular administration) and infusion (injection)), elixir, syrup, cachet, emulsion, inhalation or dispersible powder.
  • the content of one or more pharmaceutically active compounds should range from 0.1 to 90% by weight, preferably from 0.5 to 50% by weight of the composition as a whole, ie an amount sufficient to achieve the dosage ranges specified below. If necessary, the specified dose may be administered several times per day.
  • 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 administration, intralesional 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.
  • dosage unit 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 association with a suitable pharmaceutical excipient.
  • 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 vehicles as well as buffers, suspending and dispersing agents, coloring agents, Flavorings, etc.
  • 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%).
  • MTA-synergistic PRMT5 inhibitors can provide therapeutic benefits to a large number of tumor patients.
  • the compounds of the present invention exert therapeutic effects by negatively regulating the activity of MTA-bound PRMT5 in tumor cells, especially against MTAP-deficient cells or various MTAP-related tumor cells.
  • MTA synergistic PRMT5 inhibitors of the invention can treat a variety of cancers, including but not limited to tumor types, such as malignant peripheral nerve sheath tumors, mesothelioma, glioblastoma multiforme, Pancreatic cancer, bile duct cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, bladder cancer, astrocytoma, colorectal cancer, endometrial cancer, esophageal cancer, stomach cancer, thymoma, head and neck cancer, liver Cell carcinoma, laryngeal cancer, lung squamous cell carcinoma, lung adenocarcinoma, oral cancer, ovarian cancer, renal cancer and thyroid cancer, and sarcomas.
  • tumor types such as malignant peripheral nerve sheath tumors, mesothelioma, glioblastoma multiforme, Pancreatic cancer, bile duct cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, bladder cancer,
  • these compounds are useful in the treatment of: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, etc.), myxoma, rhabdomyomas, fibromas, lipomas and teratomas; Lung: bronchial carcinoma ( Squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, etc.), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (Squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, etc.), stomach (tumor, lymphoma, leiomyosarcoma, etc.), pancreas (ductal adenodeno
  • the MTA synergistic PRMT5 inhibitor of the present invention can be combined with other drugs to treat cancer, and contains at least one target drug/cell activity regulator, including CDK4/6 inhibitors, MAT2A inhibitors, MAPK1/MAPK3 inhibitors, Type I PRMT inhibitor, EGFR inhibitor, SHP2 inhibitor, pan-KRAS inhibitor, KRASG12C inhibitor, RAF inhibitor, MEK inhibitor, ERK inhibitor, Bcl-2 inhibitor, SOS1 inhibitor, PARP inhibitor, MALT1 inhibitor Agent, MALT2 inhibitor, BTK inhibitor, PI3K inhibitor, AKT inhibitor, FGFR inhibitor, DNA methyltransferase (DNMT) inhibitor, EZH1/2 inhibitor, EZH2 inhibitor, Menin-MLL inhibitor, IDH1 Inhibitors, IDH2 inhibitors, IDH1/2 inhibitors, chemotherapy drugs, radiotherapy, STING agonists or immune checkpoint inhibitors/modulators, etc.
  • target drug/cell activity regulator including CDK4/6 inhibitors, MAT2A inhibitors, MAPK1/MAPK3 inhibitor
  • Trifluoroacetic acid (15 mL) was added to a solution of 1-6 (6.4 g) in dichloromethane (15 mL) under ice bath. Stir at room temperature for 1 hour and concentrate under reduced pressure. Adjust the pH to weak alkaline with saturated sodium bicarbonate, extract with dichloromethane (100mL ⁇ 3), wash the organic phase with saturated sodium chloride solution (100mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a brown solid Crude product 1-7 (4.8g). The crude product was directly used in the next reaction. LC-MS m/z(ESI):315.0[M+H] + .
  • Trifluoroacetic acid (1 mL) was added to a solution of 1-11 (60.0 mg) in dichloromethane (2 mL) under ice bath. Stir at room temperature for 1 hour, concentrate under reduced pressure, and the residue is subjected to high performance liquid chromatography (column: Xbridge-C18 150 x 19mm, 5um; mobile phase: ACN--H 2 O (0.1% FA); B%: 5%-10 %, 20 min) was purified to obtain the formate salt of 1 as a white solid (20.9 mg, yield 48.0%). LC-MS m/z(ESI):522.0[M+H] + .
  • Trifluoroacetamide 250.0 mg
  • cesium carbonate 380.0 mg
  • copper iodide 30.0 mg
  • (trans)-N,N'-dimethyl-1,2-cyclohexanediamine (16.0 mg) was added to a solution of 2-8 (50.0 mg) in anhydrous dioxane (8 mL), and stirred at 100°C for 16 hours under a nitrogen atmosphere.
  • Cool to room temperature add water (50 mL), extract with dichloromethane (20 mL ⁇ 3), wash the organic phase with saturated sodium chloride solution (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • Di-tert-butyl dicarbonate (11.5g), triethylamine (5.5g) and 4-dimethylaminopyridine (0.6g) were added to compound 6-methyl-1H-indole-5-carboxylic acid methyl ester ( 3.0 g) in dichloromethane (30 mL) and stirred at room temperature for 2 hours.
  • Trifluoroacetic acid (5 mL) was added to a solution of 4-3 (2.4 g) in dichloromethane (15 mL) under ice bath. Stir at room temperature for 1 hour. Concentrate under reduced pressure, adjust the pH to weak alkaline with sodium bicarbonate, extract with dichloromethane (50 ⁇ 3mL), wash the organic phase with saturated sodium chloride solution (50mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 4 -4 (1.5g), the crude product was directly used in the next reaction.
  • Trifluoroacetic acid (2 mL) was added to a solution of 5-4 (42.7 mg) in dichloromethane (6 mL) under ice bath. Stir at room temperature for 1 hour, concentrate under reduced pressure, and the residue is subjected to high performance liquid chromatography (column: Xbridge-C18 150 x 19mm, 5um; mobile phase: ACN--H 2 O (0.1% FA); B%: 5%-10 %, 20 min) to obtain the formate salt of 5 as a white solid (14.0 mg, yield 29.3%).
  • Trimethyltin hydroxide 342.0 mg was added to a solution of 6-4 (300 mg) in 1,2-dichloroethane (10 mL). Nitrogen protection Stir at 50°C for 3 hours. Add water (10mL) to dilute, extract with dichloromethane (10mL , yield 70.8%). LC-MS m/z(ESI):450.0[M+H] + .
  • N-Bromobutyrimide (187.5 mg) was added to a solution of 7-3 (150.0 mg) in 1,2-dichloroethane (3 mL). Stir at 50°C for 2 hours, cool to room temperature, wash the organic phase with saturated sodium sulfite solution (3 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain yellow solid 7-4 (180.0 mg). The crude product is directly used in the next step. reaction. LC-MS m/z(ESI): 235.0, 237.0[M+H] + .
  • trifluoromethanesulfonic acid 25 mL was added to a solution of 10-2 (10.0 g) in trifluoroacetic acid (100 mL) and anisole (45 mL) under a nitrogen atmosphere. Warm to room temperature and stir for 30 minutes, then stir at 40°C for 1 hour. Concentrate under reduced pressure, slowly pour the residue into a mixture of ice and water of sodium bicarbonate, and concentrate under reduced pressure at 60°C.
  • Benzophenone imine 440.0 mg
  • cesium carbonate 790.0 mg
  • 1,1'-binaphthyl-2,2'-bisdiphenylphosphine 150.0 mg
  • tris(dibenzylideneacetone)di Palladium 110.0 mg
  • Cool to room temperature add water (50 mL) to dilute, extract with ethyl acetate (30 mL ⁇ 3), wash the organic phase with saturated sodium chloride solution (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • N-methylimidazole (56.2mg) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (191.9mg) were added to 2-9 (50.0mg) and 98-6 (67.6 mg) in N,N-dimethylformamide solution (1 mL) and stirred at room temperature for 1 hour.
  • the reaction liquid was added dropwise to ice water, and the solid precipitated. It was filtered under reduced pressure and the filter cake was collected to obtain crude yellow solid 98-7 (50.0 mg, yield 54.0%).
  • HCT116 MTAP Deletion cells were from Pharmaron (China); HCT116 cells were from ATCC (USA); McCoy's 5A medium was purchased from Invitrogen (USA); penicillin-streptomycin and fetal calf serum were purchased from Gibco (USA); The 384-well plate was purchased from PerkinElmer Company (USA); Cell-Titer Glo reagent was purchased from Promega Company (USA).
  • Cells were cultured in strict accordance with ATCC requirements. Transfer the cell culture medium (McCoy's 5A medium + 10% fetal calf serum + 1% penicillin + streptomycin) to a 15mL centrifuge tube, centrifuge at 1000 rpm for 5 minutes. Remove the supernatant, resuspend the cells in complete culture medium, inoculate them into a culture dish at the required density, and place them in an incubator at 37°C, 95% humid air, and 5% carbon dioxide for culture. Depending on the cell growth, every 2-3 Replenish the culture medium once a day or perform passage.
  • McCoy's 5A medium + 10% fetal calf serum + 1% penicillin + streptomycin to a 15mL centrifuge tube, centrifuge at 1000 rpm for 5 minutes. Remove the supernatant, resuspend the cells in complete culture medium, inoculate them into a culture dish at the required density, and place them in an incubator at 37°C, 95%

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Abstract

提供了一类式(I)所示的PRMT5抑制剂,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,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癌症中的作用。

Description

PRMT5抑制剂
本发明要求提交于2022年8月19日的中国申请CN202211003217.9、提交于2023年4月26日的中国申请CN202310465126.5、以及提交于2023年8月9日的中国申请CN202310997144.8的优先权,将它们以其整体引入本文作为参考。
技术领域
本发明涉及一类新的PRMT5抑制剂,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PRMT5介导的疾病如癌症中的作用。
背景技术
蛋白质精氨酸甲基转移酶5(Protein arginine methyltransferase 5,PRMT5)属于二型PRMT,是一类S-腺苷甲硫氨酸(SAM)依赖性甲基转移酶,主要负责将SAM的甲基对称性地转移到组蛋白或其他蛋白质的精氨酸残基末端的胍基氮原子上。在体内,PRMT5与MEP50(methylosome protein 50)形成复合物,才能识别底物并进行定位,同时复合物形态也是PRMT5催化组蛋白2A和组蛋白4甲基转移活性所必需的。PRMT5是一种通用的转录抑制因子,可以调控基因转录和蛋白修饰的过程。同时,PRMT5在肿瘤细胞的增殖、分化、凋亡中发挥着重要功能,是极具潜力的肿瘤治疗靶点。然而,PRMT5也是正常细胞所必需的基因,PRMT5敲除和siRNA敲降研究表明,在正常组织中抑制PRMT5的活性可能引起血小板减少、不孕、骨骼肌损失、心肌肥厚等诸多毒副作用。
2016年,多个独立研究团队报道MTAP(甲硫腺苷磷酸化酶)缺失型肿瘤细胞增加对PRMT5活性的依赖。MTAP的缺失会上调细胞内MTA(甲硫腺苷)的水平,而MTA同时也是天然的PRMT5抑制剂。因此,MTAP缺失型肿瘤细胞会增加对PRMT5活性的依赖,这为靶向MTAP null肿瘤细胞,即靶向PRMT5/MTA复合物,同时不影响MTAP WT细胞提供了可能。
在研PRMT5抑制剂的作用机理包括SAM竞争性抑制剂、底物竞争性抑制剂、SAM和底物双重竞争性抑制剂及MTA协同的抑制剂。非MTA协同的PRMT5抑制剂无差别的抑制PRMT5的活性,已发现剂量限制性的血小板减少、贫血、中性粒细胞减少等毒副作用。其中,MTA协同的抑制剂靶向PRMT5/MTA复合物,有望在抑制MTAP缺失型肿瘤细胞的同时消除对MTAP WT细胞的影响,可以改善治疗窗口。
因此,开发靶向PRMT5/MTA复合物的PRMT5抑制剂将具有重要的临床应用价值,本领域对于该抑制剂存在需求。
发明内容
本发明以PRMT5/MTA复合物作为靶点,研发了一类新的小分子抑制剂,可用于治疗各种癌症。
本发明化合物靶向PRMT5/MTA复合物,是MTA协同的PRMT5抑制剂,具有优异的PRMT5/MTA抑制活性,并对PRMT5/SAM复合物具有明显的选择性。同时,本发明化合物具有良好的ADMET(吸收-分布-代谢-排泄-毒性)性质。
在一个方面,本发明提供了式(I)或(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,
L1为NH或CHRx
L2为CRxRy
其中Rx和Ry独立地选自H、D、C1-6烷基或C1-6卤代烷基;
或者CRxRy一起形成C=O、C=S或C3-6亚烷基;
或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-4亚烷基;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
或者X1、X2以及他们的取代基一起形成C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基,其任选被1、2或3个R2s取代;
X3为CR2d或N;
并且X1、X2和X3所在的环为芳香环;
R2a选自H、D、CN、ORa、NRbRc、C(O)ORa或C(O)NRbRc
R2b选自H、D、卤素、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基;
R2c选自H、D、卤素、C1-6烷基或C1-6卤代烷基;
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基;
Ar1为苯基或5-6元杂芳基,其被m个R1取代;
R1选自H、D、卤素、CN、NO2、-L-ORa、-L-SRa、-L-NRbRc、SF5、C(O)Ra、C(O)ORa、C(O)NRbRc、OC(O)Ra、NRbC(O)Rc、S(O)Ra、S(O)2Ra、S(O)ORa、S(O)2ORa、S(O)NRbRc、S(O)2NRbRc、P(O)(Ra)2、P(O)2Ra、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-10环烷基(例如C5-10环烷基)、4-10元杂环基(例如5-10元杂环基)、C6-10芳基或5-10元杂芳基,其任选被1、2或3个R1s取代;
或者相邻的两个R1以及他们连接的原子一起形成C5-6环烷基、5-6元杂环基、苯基或5-6元杂芳基,其任选地被1、2或3个R1s取代;
m=0、1、2、3、4或5;
R1s选自H、D、卤素、=O、-L-ORa、-L-SRa、-L-NRbRc、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、-L-C3-10环烷基、-L-3-10元杂环基、-L-C6-10芳基或-L-5-10元杂芳基,其任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷基-OH、-C0-6亚烷基-OC1-6烷基、C1-6烷基或C1-6卤代烷基取代;
或者孪位或相邻的两个R1s以及他们连接的原子一起形成C3-6环烷基、4-6元杂环基、苯基或5-6元杂芳基,其任选地被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;
L为化学键、C1-6亚烷基、C2-6亚烯基或C2-6亚炔基,其任选被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;
R2s选自H、D、卤素、=O、C(O)ORa、C(O)NRbRc、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;
R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C(O)Ra、C(O)ORa、C(O)NRbRc、OC(O)Ra、NRbC(O)Rc、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;
n=0、1、2、3、4、5、6或7;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-10元杂环基;
其中上述L1、L2、Rx、Ry、Ar1、R1、R2a、R2b、R2c、R2d、R1s、L、R2s、R3、R3a、R3b、Ra、Rb和Rc中的各个基团定义任选地被氘代,直至完全氘代;
条件是,当L2为C=O时,X1、X2以及他们的取代基一起形成任选被1、2或3个R2s取代的C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基。
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,例如载体、佐剂或媒介物。
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,例如选自以下靶点药物/细胞活性调节剂,包括CDK4/6抑制剂,MAT2A抑制剂,MAPK1/MAPK3抑制剂,Type I PRMT抑制剂,EGFR抑制剂,SHP2抑制剂,泛KRAS抑制剂,KRASG12C抑制剂,RAF抑制剂,MEK抑制剂,ERK抑制剂,Bcl-2抑制剂,SOS1抑制剂,PARP抑制剂,MALT1抑制剂,MALT2抑制剂,BTK抑制剂,PI3K抑制剂,AKT抑制剂,FGFR抑制剂,DNA甲基转移酶(DNMT)抑制剂,EZH1/2抑制剂,EZH2抑制剂,Menin-MLL抑制剂,IDH1抑制剂,IDH2抑制剂,IDH1/2抑制剂,化疗药物,放射疗法,STING激动剂或免疫检查点抑制剂/调节剂。
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PRMT5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PRMT5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药物组合物。
在另一个方面,本发明提供了本发明化合物或本发明药物组合物,其用于治疗和/或预防PRMT5介导的疾病。
在具体实施方案中,本发明用于治疗和/或预防癌症。在另一具体实施方案中,本发明用于治疗和/或预防以下癌症:心脏:肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤)、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤和畸胎瘤;肺:支气管癌(鳞状细胞、未分化小细胞、未分化大细胞、腺癌)、肺泡(细支气管)癌、支气管腺瘤、肉瘤、淋巴瘤、软骨瘤错构瘤、间皮瘤;胃肠道:食管(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃(癌、淋巴瘤、平滑肌肉瘤)、胰腺(导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤、血管瘤)、小肠(腺癌、淋巴瘤、类癌瘤)、卡波西肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤)、大肠(腺癌、管状腺瘤、绒毛状腺瘤、错构瘤、平滑肌瘤);泌尿生殖道:肾脏(腺癌、威尔姆氏瘤(肾母细胞瘤)、淋巴瘤、白血病)、膀胱和尿道(鳞状细胞癌、移行细胞癌、腺癌)、前列腺(腺癌、肉瘤)、睾丸(精原细胞瘤、畸胎瘤、胚胎癌、畸胎癌)、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样肿瘤、脂肪瘤);肝脏:肝细胞瘤(肝细胞癌)、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤、血管瘤;胆道:胆囊癌、壶腹癌、胆管癌;骨:成骨肉瘤(osteosarcoma)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤文氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨慢性外生骨疣(osteocartilaginous  exostoses)、良性软骨瘤、软骨母细胞瘤、纤维软骨瘤、软骨粘液纤维瘤、类骨质骨瘤和巨细胞瘤;神经系统:颅骨(骨瘤、血管瘤、肉芽肿、黄色瘤、变形性骨炎)、脑膜(脑膜瘤、脑膜肉瘤、神经胶质瘤)、脑(星形细胞瘤、髓母细胞瘤、神经胶质瘤、室管膜瘤、生殖细胞瘤(松果体瘤)、多形性胶质母细胞瘤、少突胶质细胞瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤)、脊髓神经纤维瘤、脑膜瘤、神经胶质瘤、肉瘤);妇科:子宫(子宫内膜癌)、宫颈(宫颈癌、瘤前宫颈发育不良等)、卵巢(卵巢癌、浆液性囊腺癌、粘液性囊腺癌、未分类癌)、颗粒鞘细胞瘤、支持间质细胞瘤、无性细胞瘤、恶性畸胎瘤)、外阴(鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤、黑色素瘤)、阴道(透明细胞癌、鳞状细胞癌、葡萄样肉瘤(胚胎性横纹肌肉瘤)、输卵管(癌);血液学:血液(髓性白血病(急性和慢性)、急性淋巴细胞白血病、慢性淋巴细胞性白血病、弥漫性大B细胞淋巴瘤、套细胞淋巴瘤(MCL),滤泡性淋巴瘤、骨髓增生性疾病、多发性骨髓瘤、骨髓增生异常综合征)、霍奇金病、非霍奇金淋巴瘤(恶性淋巴瘤);皮肤:恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、痣发育不良痣、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕疙瘩、牛皮癣;和肾上腺:成神经细胞瘤。
在另一具体实施方案中,本发明所述PRMT5介导的疾病选自以下癌症:恶性周围神经鞘瘤、间皮瘤、多形性胶质母细胞瘤、胰腺癌、胆管癌、前列腺癌、乳腺癌、脑癌、皮肤癌、宫颈癌、膀胱癌、星形细胞瘤、结肠直肠癌、子宫内膜癌、食道癌、胃癌、胸腺瘤、头颈癌、肝细胞癌、喉癌、肺鳞癌、肺腺癌、口腔癌、卵巢癌、肾癌和甲状腺癌以及肉瘤。
在另一具体实施方案中,本发明所述PRMT5介导的疾病选自MTAP相关癌症,例如肝细胞癌、乳腺癌、皮肤癌、膀胱癌、肝癌、胰腺癌或头颈癌。
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。
“C1-6亚烷基”是指除去C1-6烷基的另一个氢而形成的二价基团,并且可以是取代或未取代的。在一些实施方案中,C1-4亚烷基、C2-4亚烷基和C1-3亚烷基是优选的。未取代的所述亚烷基包括但不限于:亚甲基(-CH2-)、亚乙基(-CH2CH2-)、亚丙基(-CH2CH2CH2-)、亚丁基(-CH2CH2CH2CH2-)、亚戊基(-CH2CH2CH2CH2CH2-)、亚己基(-CH2CH2CH2CH2CH2CH2-),等等。示例性的取代的所述亚烷基,例如,被一个或多个烷基(甲基)取代的所述亚烷基,包括但不限于:取代的亚甲基(-CH(CH3)-、-C(CH3)2-)、取代的亚乙基(-CH(CH3)CH2-、-CH2CH(CH3)-、-C(CH3)2CH2-、-CH2C(CH3)2-)、取代的亚丙基(-CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH2CH(CH3)-、-C(CH3)2CH2CH2-、-CH2C(CH3)2CH2-、-CH2CH2C(CH3)2-),等等。
“C2-6亚烯基”是指除去C2-6烯基的另一个氢而形成的二价基团,并且可以是取代或未取代的。在一些实施方案中,C2-4亚烯基是特别优选的。示例性的未取代的所述亚烯基包括但不限于:亚乙烯基(-CH=CH-)和亚丙烯基(例如,-CH=CHCH2-、-CH2-CH=CH-)。示例性的取代的所述亚烯基,例如,被一个或多个烷基(甲基)取代的亚烯基,包括但不限于:取代的亚乙基(-C(CH3)=CH-、-CH=C(CH3)-)、取代的亚丙烯基(-C(CH3)=CHCH2-、-CH=C(CH3)CH2-、-CH=CHCH(CH3)-、-CH=CHC(CH3)2-、-CH(CH3)-CH=CH-、-C(CH3)2-CH=CH-、-CH2-C(CH3)=CH-、-CH2-CH=C(CH3)-),等等。
“C2-6亚炔基”是指除去C2-6炔基的另一个氢而形成的二价基团,并且可以是取代或未取代的。在一些实施方案中,C2-4亚炔基是特别优选的。示例性的所述亚炔基包括但不限于:亚乙炔基(-C≡C-)、取代或未取代的亚丙炔基(-C≡CCH2-),等等。
“C0-6亚烷基”是指化学键以及上述“C1-6亚烷基”,“C0-4亚烷基”是指化学键以及上述“C1-4亚烷基”。
“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。
“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,其中任选地含有1、2或3个双键或叁键。在一些实施方案中,C5-10环烷基、C3-7环烷基和C3-6环烷基是特别优选的,更优选C5-7环烷基和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。环烷基还包括其中上述环烷基环,其中任意不相邻的碳原子上的取代基相连形成桥环,一起形成共用两个或两个以上碳原子的多环烷烃。环烷基还包括其中上述环烷基环,其中同一碳原子上的取代基相连成环,一起形成共用一个碳原子的多环烷烃。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。
“C3-10亚环烷基”是指除去C3-10环烷基的另一个氢而形成的二价基团,并且可以是取代或未取代的。在一些实施方案中,C3-6亚环烷基和C3-4亚环烷基是特别优选的,尤其优选亚环丙基。
“3-10元杂环基”是指具有环碳原子和1至5个环杂原子的3至10元非芳香环系的饱和或不饱和基团,其中,每个杂原子独立地选自氮、氧、硫、硼、磷和硅,其中任选地含有1、2或3个双键或叁键。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5-10元杂环基,其为具有环碳原子和1至5个环杂原子的5至10元非芳香环系;在一些实施方案中,优选3-7元杂环基,其为具有环碳原子和1至4个环杂原子的3至7元非芳香环系;优选5-7元杂环基,其为具有环碳原子和1至3个环杂原子的5至7元非芳香环系;优选3-6元杂环基,其为具有环碳原子和1至3个环杂原子的3至6元非芳香环系;优选4-6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,其中连接点在杂环基环上,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。杂环基还包括其中上述杂环基环,其中任意不相邻的碳或氮原子上的取代基相连形成桥环,一起形成共用两个或两个以上碳或氮原子的多环杂烷烃。杂环基还包括其中上述杂环基环,其中同一碳原子上的取代基相连成环,一起形成共用一个碳原子的多环杂烷烃。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:吡唑烷基、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。杂环基还包括上述杂环基与一个环烷基、杂环基、芳基或杂芳基共享一个或两个原子,形成桥环或螺环,只要化合价允许,共享的原子可为碳或氮原子。杂环基还包括上述杂环基与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。
“5-14元杂芳基”是指具有环碳原子和1-4个环杂原子的5-14元单环或双环的4n+2芳族环体系(例如,具有以环状排列共享的6、10或14个π电子)的基团,其中每个杂原子独立地选自氮、氧和硫。在含有一个或多个氮原子的杂芳基中,只要化合价允许,连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。杂芳基还包括其中上述杂芳基环与一个或多个环烷基或杂环基稠合的环系统,而且连接点在所述杂芳基环上,在这种情况下,碳原子的数目继续表示所述杂芳基环系统中的碳原子数目。在一些实施方案中,5-10元杂芳基是优选的,其为具有环碳原子和1-4个环杂原子的5-10元单环或双环的4n+2芳族环体系。在另一些实施方案中,5-6元杂芳基是特别优选的,其为具有环碳原子和1-4个环杂原子的5-6元单环或双环的4n+2芳族环体系。示例性的含有一个杂原子的5元杂芳基包括但不限于:吡咯基、呋喃基和噻吩基。示例性的含有两个杂原子的5元杂芳基包括但不限于:咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基和异噻唑基。示例性的含有三个杂原子的5元杂芳基包括但不限于:三唑基、噁二唑基(例如,1,2,4-噁二唑基)和噻二唑基。示例性的含有四个杂原子的5元杂芳基包括但不限于:四唑基。示例性的含有一个杂原子的6元杂芳基包括但不限于:吡啶基或吡啶酮基。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。
上文定义的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基等基团除去另一个氢而形成的二价基团统称为“亚基”。环烷基、杂环基、芳基和杂芳基等成环的基团统称为“环基”。
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
术语“癌症”包括但不限于下列癌症:心脏:肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤)、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤和畸胎瘤;肺:支气管癌(鳞状细胞、未分化小细胞、未分化大细胞、腺癌)、肺泡(细支气管)癌、支气管腺瘤、肉瘤、淋巴瘤、软骨瘤错构瘤、间皮瘤;胃肠道:食管(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃(癌、淋巴瘤、平滑肌肉瘤)、胰腺(导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤、血管瘤)、小肠(腺癌、淋巴瘤、类癌瘤)、卡波西肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤)、大肠(腺癌、管状腺瘤、绒毛状腺瘤、错构瘤、平滑肌瘤);泌尿生殖道:肾脏(腺癌、威尔姆氏瘤(肾母细胞瘤)、淋巴瘤、白血病)、膀胱和尿道(鳞状细胞癌、移行细胞癌、腺癌)、前列腺(腺癌、肉瘤)、睾丸(精原细胞瘤、畸胎瘤、胚胎癌、畸胎癌)、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样肿瘤、脂肪瘤);肝脏:肝细胞瘤(肝细胞癌)、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤、血管瘤;胆道:胆囊癌、壶腹癌、胆管癌;骨:成骨肉瘤(osteosarcoma)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤文氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨慢性外生骨疣(osteocartilaginous exostoses)、良性软骨瘤、软骨母细胞瘤、纤维软骨瘤、软骨粘液纤维瘤、类骨质骨瘤和巨细胞瘤;神经系统:颅骨(骨瘤、血管瘤、肉芽肿、黄色瘤、变形性骨炎)、脑膜(脑膜瘤、脑膜肉瘤、神经胶质瘤)、脑(星形细胞瘤、髓母细胞瘤、神经胶质瘤、室管膜瘤、生殖细胞瘤(松果体瘤)、多形性胶质母细胞瘤、少突胶质细胞瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤)、脊髓神经纤维瘤、脑膜瘤、神经胶质瘤、肉瘤);妇科:子宫(子宫内膜癌)、宫颈(宫颈癌、瘤前宫颈发育不良等)、卵巢(卵巢癌、浆液性囊腺癌、粘液性囊腺癌、未分类癌)、颗粒鞘细胞瘤、支持间质细胞瘤、无性细胞瘤、恶性畸胎瘤)、外阴(鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤、黑色素瘤)、阴道(透明细胞癌、鳞状细胞癌、葡萄样肉瘤(胚胎性横纹肌肉瘤)、输卵管(癌);血液学:血液(髓性白血病(急性和慢性)、急性淋巴细胞白血病、慢性淋巴细胞性白血病、弥漫性大B细胞淋巴瘤、套细胞淋巴瘤(MCL),滤泡性淋巴瘤、骨髓增生性疾病、多发性骨髓瘤、骨髓增生异常综合征)、霍奇金病、非霍奇金淋巴瘤(恶性淋巴瘤);皮肤:恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、痣发育不良痣、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕疙瘩、牛皮癣;和肾上腺:成神经细胞瘤。
在一个实施方案中,术语“癌症”包括但不限于下列癌症:恶性周围神经鞘瘤、间皮瘤、多形性胶质母细胞瘤、胰腺癌、胆管癌、前列腺癌、乳腺癌、脑癌、皮肤癌、宫颈癌、膀胱癌、星形细胞瘤、结肠直肠癌、子宫内膜癌、食道癌、胃癌、胸腺瘤、头颈癌、肝细胞癌、喉癌、肺鳞癌、肺腺癌、口腔癌、卵巢癌、肾癌和甲状腺癌以及肉瘤。
在个一个实施方案中,术语“癌症”包括但不限于下列癌症:肝细胞癌、乳腺癌、皮肤癌、膀胱癌、肝癌、胰腺癌或头颈癌。
本文所用的术语“治疗”涉及逆转、减轻、抑制该术语适用的障碍或病症的进展或者预防之,或者这类障碍或病症的一种或多种症状。本文所用的名词“治疗”涉及动词治疗的动作,后者是如刚才所定义的。
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。
药学上可接受的碱加成盐是与金属或胺生成的,例如碱金属与碱土金属氢氧化物或有机胺。用作阳离子的金属的实例有钠、钾、镁、钙等。适合的胺的实例有N,N'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因。
酸性化合物的碱加成盐可以这样制备,按照常规方式使游离酸形式与足量所需的碱接触,生成盐。按照常规方式使盐形式与酸接触,再分离游离酸,可以使游离酸再生。游离酸形式在某些物理性质上多少不同于它们各自的盐形式,例如在极性溶剂中的溶解度,但是出于本发明的目的,盐还是等价于它们各自的游离酸。
盐可以是从无机酸制备的硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物,酸例如盐酸、硝酸、硫酸、氢溴酸、氢碘酸、磷酸等。代表性盐包括:氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、硝酸盐、乙酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘甲酸盐、甲磺酸盐、葡庚糖酸盐、乳糖酸盐、月桂基磺酸盐和羟乙磺酸盐等。盐也可以是从有机酸制备的,例如脂肪族一元与二元羧酸、苯基取代的烷酸、羟基烷酸、烷二酸、芳香族酸、脂肪族与芳香族磺酸等。代表性盐包括乙酸盐、丙酸盐、辛酸盐、异丁酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、扁桃酸盐、苯甲酸盐、氯苯甲酸盆、甲基苯甲酸盐、二硝基苯甲酸盐、萘甲酸盐、苯磺酸盐、甲苯磺酸盐、苯乙酸盐、柠檬酸盐、乳酸盐、马来酸盐、酒石酸盐、甲磺酸盐等。药学上可接受的盐可以包括基于碱金属与碱土金属的阳离子,例如钠、锂、钾、钙、镁等,以及无毒的铵、季铵和胺阳离子,包括但不限于铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。还涵盖氨基酸的盐,例如精氨酸盐、葡糖酸盐、半乳糖醛酸盐等(例如参见Berge S.M.et al.,"Pharmaceutical Salts,”J.Pharm.Sci.,1977;66:1-19,引入此作为参考)。
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。
除非另作说明,否则,本文使用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用,它降低疾病、障碍或病症的严重程度,或延迟或减缓疾病、障碍或病症的发展(“治疗性治疗”),还包括在受试者开始患有具体疾病、障碍或病症之前发生的作用(“预防性治疗”)。
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。
除非另作说明,否则,本文使用的化合物的“治疗有效量”是在治疗疾病、障碍或病症的过程中足以提供治疗益处的量,或使与疾病、障碍或病症有关的一或多种症状延迟或最小化的量。化合物的治疗有效量是指单独使用或与其它疗法联用时,治疗剂的量,它在治疗疾病、障碍或病症的过程中提供治疗益处。术语“治疗有效量”可以包括改善总体治疗、降低或避免疾病或病症的症状或病因、或增强其它治疗剂的治疗效果的量。
除非另作说明,否则,本文使用的化合物的“预防有效量”是足以预防疾病、障碍或病症的量,或足以预防与疾病、障碍或病症有关的一或多种症状的量,或防止疾病、障碍或病症复发的量。化合物的预防有效量是指单独使用或与其它药剂联用时,治疗剂的量,它在预防疾病、障碍或病症的过程中提供预防益处。术语“预防有效量”可以包括改善总体预防的量,或增强其它预防药剂的预防效果的量。
“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。
附图说明
图1和2示出了LU99CDX模型体内药效学研究的结果。
具体实施方案
本文中,“本发明化合物”指的是以下的式(I)、式(II)等化合物、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。
本文中,化合物使用标准的命名法命名。具有非对称中心的化合物,应该明白(除非另有说明)所有的光学异构体及其混合物均包含在内。此外,除非另有规定,本发明所包括的所有异构体化合物与碳碳双键可能以Z和E的形式出现。在不同的互变异构形式存在的化合物,一个所述化合物并不局限于任何特定的互变异构体,而是旨在涵盖所有的互变异构形式。
在一个实施方案中,本发明涉及式(I)或(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,
L1为NH或CHRx
L2为CRxRy
其中Rx和Ry独立地选自H、D、C1-6烷基或C1-6卤代烷基;
或者CRxRy一起形成C=O、C=S或C3-6亚烷基;
或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-4亚烷基;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
或者X1、X2以及他们的取代基一起形成C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基,其任选被1、2或3个R2s取代;
X3为CR2d或N;
并且X1、X2和X3所在的环为芳香环;
R2a选自H、D、CN、ORa、NRbRc、C(O)ORa或C(O)NRbRc
R2b选自H、D、卤素、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基;
R2c选自H、D、卤素、C1-6烷基或C1-6卤代烷基;
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基;
Ar1为苯基或5-6元杂芳基,其被m个R1取代;
R1选自H、D、卤素、CN、NO2、-L-ORa、-L-SRa、-L-NRbRc、SF5、C(O)Ra、C(O)ORa、C(O)NRbRc、OC(O)Ra、NRbC(O)Rc、S(O)Ra、S(O)2Ra、S(O)ORa、S(O)2ORa、S(O)NRbRc、S(O)2NRbRc、P(O)(Ra)2、P(O)2Ra、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-10环烷基(例如C5-10环烷基)、4-10元杂环基(例如5-10元杂环基)、C6-10芳基或5-10元杂芳基,其任选被1、2或3个R1s取代;
或者相邻的两个R1以及他们连接的原子一起形成C5-6环烷基、5-6元杂环基、苯基或5-6元杂芳基,其任选地被1、2或3个R1s取代;
m=0、1、2、3、4或5;
R1s选自H、D、卤素、=O、-L-ORa、-L-SRa、-L-NRbRc、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、-L-C3-10环烷基、-L-3-10元杂环基、-L-C6-10芳基或-L-5-10元杂芳基,其任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷基-OH、-C0-6亚烷基-OC1-6烷基、C1-6烷基或C1-6卤代烷基取代;
或者孪位或相邻的两个R1s以及他们连接的原子一起形成C3-6环烷基、4-6元杂环基、苯基或5-6元杂芳基,其任选地被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;
L为化学键、C1-6亚烷基、C2-6亚烯基或C2-6亚炔基,其任选被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;
R2s选自H、D、卤素、=O、C(O)ORa、C(O)NRbRc、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;
R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C(O)Ra、C(O)ORa、C(O)NRbRc、OC(O)Ra、NRbC(O)Rc、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;
n=0、1、2、3、4、5、6或7;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-10元杂环基;
其中上述L1、L2、Rx、Ry、Ar1、R1、R2a、R2b、R2c、R2d、R1s、L、R2s、R3、R3a、R3b、Ra、Rb和Rc中的各个基团定义任选地被氘代,直至完全氘代;
条件是,当L2为C=O时,X1、X2以及他们的取代基一起形成任选被1、2或3个R2s取代的C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基。
L1和L2
在一个实施方式中,L1为NH;在另一个实施方式中,L1为CHRx;在另一个实施方式中,L1为 NH且L2为CRxRy,优选为更优选为更优选为更优选为在另一个实施方式中,L1为CHRx且L2为CRxRy,优选为更优选为更优选为
Rx和Ry
在一个实施方式中,Rx和Ry为H;在另一个实施方式中,Rx和Ry为D;在另一个实施方式中,Rx和Ry为C1-6烷基;在另一个实施方式中,Rx和Ry为C1-6卤代烷基,优选CF3;在另一个实施方式中,CRxRy一起形成C=O;在另一个实施方式中,CRxRy一起形成C=S;在另一个实施方式中,CRxRy一起形成C3-6亚环烷基,优选亚环丙基;在另一个实施方式中,L1为CHRx且L2为CRxRy,并且两个Rx基团结合形成化学键;在另一个实施方式中,L1为CHRx且L2为CRxRy,并且两个Rx基团结合形成C1-4亚烷基,优选亚环丙基。
X1、X2和X3
在一个实施方式中,X1为C原子;在另一个实施方式中,X1为N原子;在另一个实施方式中,X1为CR2b;在另一个实施方式中,X1为NR2b;在一个实施方式中,X2为C原子;在另一个实施方式中,X2为N原子;在另一个实施方式中,X2为CR2c;在另一个实施方式中,X2为NR2c;在一个实施方式中,X3为CR2d;在另一个实施方式中,X3为N。
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在一个更具体的实施方式中,X1、X2以及他们的取代基一起形成C5-10环烷基;在另一个更具体的实施方式中,X1、X2以及他们的取代基一起形成5-10元杂环基;在另一个更具体的实施方式中,X1、X2以及他们的取代基一起形成C6-10芳基;在另一个更具体的实施方式中,X1、X2以及他们的取代基一起形成5-10元杂芳基;在另一个更具体的实施方式中,X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基;在另一个更具体的实施方式中,X1、X2以及他们的取 代基一起形成 优选为
R2a
在一个实施方式中,R2a为H;在另一个实施方式中,R2a为D;在另一个实施方式中,R2a为CN;在另一个实施方式中,R2a为ORa;在另一个实施方式中,R2a为NRbRc;在另一个实施方式中,R2a为C(O)ORa;在另一个实施方式中,R2a为C(O)NRbRc
在一个更具体的实施方式中,R2a选自H、D、CN、ORa或NRbRc;在另一个更具体的实施方式中,R2a选自ORa或NRbRc,优选为NH2
R2b
在一个实施方式中,R2b为H;在另一个实施方式中,R2b为D;在另一个实施方式中,R2b为卤素;在另一个实施方式中,R2b为C(O)ORa;在另一个实施方式中,R2b为C(O)NRbRc;在另一个实施方式中,R2b为C1-6烷基;在另一个实施方式中,R2b为C1-6卤代烷基;在另一个实施方式中,R2b为C3-10环烷基;在另一个实施方式中,R2b为3-10元杂环基。
在一个更具体的实施方式中,R2b选自H、D、卤素、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基;在另一个更具体的实施方式中,R2b选自H、D、卤素、C(O)NRbRc、C1-6烷基、C1-6卤代烷基或4-6元杂环基;在另一个更具体的实施方式中,R2b选自H、F、Cl、Br、Me、CH2CH3、C(O)NH2
R2c
在一个实施方式中,R2c为H;在另一个实施方式中,R2c为D;在另一个实施方式中,R2c为卤素;在另一个实施方式中,R2c为C1-6烷基;在另一个实施方式中,R2c为C1-6卤代烷基。
在一个更具体的实施方式中,R2c选自H或Me。
R2d
在一个实施方式中,R2d为H;在另一个实施方式中,R2d为D;在另一个实施方式中,R2d为卤素;在另一个实施方式中,R2d为CN;在另一个实施方式中,R2d为NO2;在另一个实施方式中,R2d为ORa;在另一个实施方式中,R2d为NRbRc;在另一个实施方式中,R2d为C1-6烷基;在另一个实施方式中,R2d为C1-6卤代烷基;在另一个实施方式中,R2d为C5-10环烷基;在另一个实施方式中,R2d为5-10元杂环基;在另一个实施方式中,R2d为C6-10芳基;在另一个实施方式中,R2d为5-10元杂芳基。
在一个更具体的实施方式中,R2d选自H、D、C1-6烷基或C1-6卤代烷基;在另一个更具体的实施方式中,R2d选自H或D。
Ar1
在一个实施方式中,Ar1为苯基;在另一个实施方式中,Ar1为5-6元杂芳基,优选5元杂芳基; 在另一个实施方式中,Ar1为苯基、吡啶基或噻吩基。
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在另一个实施方式中,Ar1优选其中R1s为H、Me、Et、iPr、 优选H、 在一个具体实施方式中,R1s为H;在一个具体实施方式中,R1s为Me;在一个具体实施方式中,R1s为Et;在一个具体实施方式中,R1s为iPr;在另一个具体实施方式中,R1s在一个具体实施方式中,R1s在另一个具体实施方式中,R1s在一个具体实施方式中,R1s在一个具体实施方式中,R1s在另一个具体实施方式中,R1s在另一个具体实施方式中,R1s在另一个具体实施方式中,R1s在另一个具体实施方式中,R1s在另一个具体实施方式中,R1s在另一个具体实施方式中,R1s在另一个具体实施方式中,R1s在另一个具体实施方式中,R1s在另一个具体实施方式中,R1s在另一个具体实施方式中,R1s在另一个具体实施方式中,R1s在另一个具体实施方式中,R1s在另一个具体实施方式中,R1s在另一个具体实施方式中,R1s在另一个具体实施方式中,R1s
在另一个实施方式中,Ar1
R1
在一个实施方式中,R1为H;在另一个实施方式中,R1为D;在另一个实施方式中,R1为卤素;在另一个实施方式中,R1为CN;在另一个实施方式中,R1为NO2;在另一个实施方式中,R1为-L-ORa;在另一个实施方式中,R1为-L-SRa;在另一个实施方式中,R1为-L-NRbRc;在另一个实施方式中,R1为SF5;在另一个实施方式中,R1为C(O)Ra;在另一个实施方式中,R1为C(O)ORa;在另一个实施方式中,R1为C(O)NRbRc;在另一个实施方式中,R1为OC(O)Ra;在另一个实施方式中,R1为NRbC(O)Rc;在另一个实施方式中,R1为S(O)Ra;在另一个实施方式中,R1为S(O)2Ra;在另一个实施方式中,R1为S(O)ORa;在另一个实施方式中,R1为S(O)2ORa;在另一个实施方式中,R1为S(O)NRbRc;在另一个实施方式中,R1为S(O)2NRbRc;在另一个实施方式中,R1为P(O)(ORa)2;在另一个实施方式中,R1为P(ORa)2;在另一个实施方式中,R1为C1-6烷基;在另一个实施方式中,R1为C1-6卤代烷基;在另一个实施方式中,R1为C2-6烯基;在另一个实施方式中,R1为C2-6炔基;在另一个实施方式中,R1为-L-C3-10环烷基,例如-L-C3-7环烷基;在另一个实施方式中,R1为-L-3-10元杂环基,例如-L-3-7元杂环基;在另一个实施方式中,R1为-L-C6-10芳基;在另一个实施方式中,R1为-L-5-10元杂芳基;在另一个实施方式中,相邻的两个R1以及他们连接的原子一起形成C5-6环烷基;在另一个实施方式中,相邻的两个R1以及他们连接的原子一起形成5-6元杂环基;在另一个实施方式中,相邻的两个R1以及他们连接的原子一起形成苯基;在另一个实施方式中,相邻的两个R1以及他们连接的原子一起形成5-6元杂芳基;在另一个实施方式中,R1任选被1、2或3个R1s取代。
在一个更具体的实施方式中,R1选自H、D、卤素、CN、-L-ORa、-L-SRa、-L-NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基;在另一个更具体的实施方式中,R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基;在另一个更具体的实施方式中,相邻的两个R1以及他们连接的原子一起形成C5-6环烷基、5-6元杂环基、苯基或5-6元杂芳基。
m
在一个实施方式中,m=0;在另一个实施方式中,m=1;在另一个实施方式中,m=2;在另一个实施方式中,m=3;在另一个实施方式中,m=4;在另一个实施方式中,m=5。
R1s
在一个实施方式中,R1s为H;在另一个实施方式中,R1s为D;在另一个实施方式中,R1s为卤素;在另一个实施方式中,R1s为=O;在另一个实施方式中,R1s为-L-ORa;在另一个实施方式中,R1s为-L-SRa;在另一个实施方式中,R1s为-L-NRbRc;在另一个实施方式中,R1s为C(O)ORa;在另一个实施方式中,R1s为C(O)NRbRc;在另一个实施方式中,R1s为C1-6烷基;在另一个实施方式中,R1s为C1-6卤代烷基;在另一个实施方式中,R1s为C2-6烯基;在另一个实施方式中,R1s为C2-6炔基;在另 一个实施方式中,R1s为-L-C3-10环烷基;在另一个实施方式中,R1s为-L-3-10元杂环基;在另一个实施方式中,R1s为-L-C6-10芳基;在另一个实施方式中,R1s为-L-5-10元杂芳基;在另一个实施方式中,孪位的两个R1s以及他们连接的原子一起形成C3-6环烷基、4-6元杂环基、苯基或5-6元杂芳基,优选为C3-6环烷基,优选为4-6元杂环基,优选为苯基,优选为5-6元杂芳基;在另一个实施方式中,孪位的两个R1s以及他们连接的原子一起形成的环任选地被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;在另一个实施方式中,相邻的两个R1s以及他们连接的原子一起形成C3-6环烷基、4-6元杂环基、苯基或5-6元杂芳基,优选为C3-6环烷基,优选为4-6元杂环基,优选为苯基,优选为5-6元杂芳基;在另一个实施方式中,相邻的两个R1s以及他们连接的原子一起形成的环任选地被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;在另一个实施方式中,R1s任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷基-OH、-C0-6亚烷基-OC1-6烷基、C1-6烷基或C1-6卤代烷基取代。
在一个更具体的实施方式中,R1s选自H、D、卤素、=O、-L-ORa、-L-SRa、-L-NRbRc、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、-L-C5-10环烷基、-L-5-10元杂环基、-L-C6-10芳基或-L-5-10元杂芳基;在另一个更具体的实施方式中,R1s选自H、D、卤素、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基;在另一个更具体的实施方式中,孪位或相邻的两个R1s以及他们连接的原子一起形成C3-6环烷基、4-6元杂环基、苯基或5-6元杂芳基。
L
在一个实施方式中,L为化学键;在另一个实施方式中,L为C1-6亚烷基;在另一个实施方式中,L为C2-6亚烯基;在另一个实施方式中,L为C2-6亚炔基;在另一个实施方式中,L任选被1、2或3个R取代。
R2s
在一个实施方式中,R2s为H;在另一个实施方式中,R2s为D;在另一个实施方式中,R2s为卤素;在另一个实施方式中,R2s为=O;在另一个实施方式中,R2s为C(O)ORa;在另一个实施方式中,R2s为C(O)NRbRc;在另一个实施方式中,R2s为C1-6烷基;在另一个实施方式中,R2s为C1-6卤代烷基;在另一个实施方式中,R2s为C2-6烯基;在另一个实施方式中,R2s为C2-6炔基;在另一个实施方式中,R2s为C3-10环烷基;在另一个实施方式中,R2s为3-10元杂环基;在另一个实施方式中,R2s为C6-10芳基;在另一个实施方式中,R2s为5-10元杂芳基。
在一个更具体的实施方式中,R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基。
R3、R3a和R3b
在一个实施方式中,R3为H;在另一个实施方式中,R3为D;在另一个实施方式中,R3为卤素;在另一个实施方式中,R3为ORa;在另一个实施方式中,R3为NRbRc;在另一个实施方式中,R3为C(O)Ra;在另一个实施方式中,R3为C(O)ORa;在另一个实施方式中,R3为C(O)NRbRc;在另一个实施方式中,R3为OC(O)Ra;在另一个实施方式中,R3为NRbC(O)Rc;在另一个实施方式中,R3为C1-6烷基;在另一个实施方式中,R3为C1-6卤代烷基;在另一个实施方式中,R3为C2-6烯基;在另一个实施方式中,R3为C2-6炔基;在另一个实施方式中,R3为C3-10环烷基;在另一个实施方式中,R3 为3-10元杂环基;在另一个实施方式中,R3为C6-10芳基;在另一个实施方式中,R3为5-10元杂芳基。
在一个实施方式中,R3a为H;在另一个实施方式中,R3a为D;在另一个实施方式中,R3a为卤素;在另一个实施方式中,R3a为ORa;在另一个实施方式中,R3a为NRbRc;在另一个实施方式中,R3a为C(O)Ra;在另一个实施方式中,R3a为C(O)ORa;在另一个实施方式中,R3a为C(O)NRbRc;在另一个实施方式中,R3a为OC(O)Ra;在另一个实施方式中,R3a为NRbC(O)Rc;在另一个实施方式中,R3a为C1-6烷基;在另一个实施方式中,R3a为C1-6卤代烷基;在另一个实施方式中,R3a为C2-6烯基;在另一个实施方式中,R3a为C2-6炔基;在另一个实施方式中,R3a为C3-10环烷基;在另一个实施方式中,R3a为3-10元杂环基;在另一个实施方式中,R3a为C6-10芳基;在另一个实施方式中,R3a为5-10元杂芳基。
在一个实施方式中,R3b为H;在另一个实施方式中,R3b为D;在另一个实施方式中,R3b为卤素;在另一个实施方式中,R3b为ORa;在另一个实施方式中,R3b为NRbRc;在另一个实施方式中,R3b为C(O)Ra;在另一个实施方式中,R3b为C(O)ORa;在另一个实施方式中,R3b为C(O)NRbRc;在另一个实施方式中,R3b为OC(O)Ra;在另一个实施方式中,R3b为NRbC(O)Rc;在另一个实施方式中,R3b为C1-6烷基;在另一个实施方式中,R3b为C1-6卤代烷基;在另一个实施方式中,R3b为C2-6烯基;在另一个实施方式中,R3b为C2-6炔基;在另一个实施方式中,R3b为C3-10环烷基;在另一个实施方式中,R3b为3-10元杂环基;在另一个实施方式中,R3b为C6-10芳基;在另一个实施方式中,R3b为5-10元杂芳基。
在一个更具体的实施方式中,R3选自H、D、卤素、ORa、NRbRc、C(O)Ra、C(O)ORa、C(O)NRbRc、OC(O)Ra、NRbC(O)Rc、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基;在另一个更具体的实施方式中,R3选自H、D、卤素、ORa、NRbRc、C(O)Ra、C(O)ORa、C(O)NRbRc、OC(O)Ra、NRbC(O)Rc、C1-6烷基或C1-6卤代烷基;在另一个更具体的实施方式中,R3选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基。
在一个更具体的实施方式中,R3a和R3b之一为C1-6烷基或C1-6卤代烷基,另一为H;在另一个更具体的实施方式中,R3a和R3b之一为Me,另一为H;在另一个更具体的实施方式中,R3a为H且R3b为Me。
n
在一个实施方式中,n=0;在另一个实施方式中,n=1;在另一个实施方式中,n=2;在另一个实施方式中,n=3;在另一个实施方式中,n=4;在另一个实施方式中,n=5;在另一个实施方式中,n=6;在另一个实施方式中,n=7。
Ra、Rb和Rc
在一个实施方式中,Ra、Rb和Rc独立地为H;在另一个实施方式中,Ra、Rb和Rc独立地为D;在另一个实施方式中,Ra、Rb和Rc独立地为C1-6烷基;在另一个实施方式中,Ra、Rb和Rc独立地为C1-6卤代烷基;在另一个实施方式中,Rb、Rc以及他们连接的原子一起形成5-10元杂环基,优选5-6元杂环基。
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,L1的任一技术方案或其任意组合,可以与L2、Rx、Ry、X1、X2、X3、R2a、R2b、R2c、R2d、Ar1、R1、m、R1s、L、R2s、R3、R3a、R3b、n、Ra、Rb和Rc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,本发明提供了式(I)或(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,
L1为NH或CHRx
L2为CRxRy
其中Rx和Ry独立地选自H、D、C1-6烷基或C1-6卤代烷基;
或者CRxRy一起形成C=O、C=S或C3-6亚烷基;
或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-4亚烷基;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
或者X1、X2以及他们的取代基一起形成C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基,其任选被1、2或3个R2s取代;
X3为CR2d或N;
并且X1、X2和X3所在的环为芳香环;
R2a选自H、D、CN、ORa、NRbRc、C(O)ORa或C(O)NRbRc
R2b选自H、D、卤素、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基;
R2c选自H、D、卤素、C1-6烷基或C1-6卤代烷基;
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基;
Ar1为苯基或5-6元杂芳基,其被m个R1取代;
R1选自H、D、卤素、CN、NO2、-L-ORa、-L-SRa、-L-NRbRc、SF5、C(O)Ra、C(O)ORa、C(O)NRbRc、OC(O)Ra、NRbC(O)Rc、S(O)Ra、S(O)2Ra、S(O)ORa、S(O)2ORa、S(O)NRbRc、S(O)2NRbRc、P(O)(Ra)2、P(O)2Ra、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-10环烷基(例如C5-10环烷基)、4-10元杂环基(例如5-10元杂环基)、C6-10芳基或5-10元杂芳基,其任选被1、2或3个R1s取代;
或者相邻的两个R1以及他们连接的原子一起形成C5-6环烷基、5-6元杂环基、苯基或5-6元杂芳基,其任选地被1、2或3个R1s取代;
m=0、1、2、3、4或5;
R1s选自H、D、卤素、=O、-L-ORa、-L-SRa、-L-NRbRc、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、-L-C3-10环烷基、-L-3-10元杂环基、-L-C6-10芳基或-L-5-10元杂芳基,其任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷基-OH、-C0-6亚烷基-OC1-6烷基、C1-6烷基或C1-6卤代烷基取代;
或者孪位或相邻的两个R1s以及他们连接的原子一起形成C3-6环烷基、4-6元杂环基、苯基或5-6元杂芳基,其任选地被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;
L为化学键、C1-6亚烷基、C2-6亚烯基或C2-6亚炔基,其任选被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;
R2s选自H、D、卤素、=O、C(O)ORa、C(O)NRbRc、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;
R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C(O)Ra、C(O)ORa、C(O)NRbRc、OC(O)Ra、NRbC(O)Rc、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;
n=0、1、2、3、4、5、6或7;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-10元杂环基;
其中上述L1、L2、Rx、Ry、Ar1、R1、R2a、R2b、R2c、R2d、R1s、L、R2s、R3、R3a、R3b、Ra、Rb和Rc中的各个基团定义任选地被氘代,直至完全氘代;
条件是,当L2为C=O时,X1、X2以及他们的取代基一起形成任选被1、2或3个R2s取代的C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基。
在另一更具体的实施方案中,本发明提供了上述式(I)或(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,Ar1为苯基或5元杂芳基;或者Ar1为苯基或6元杂芳基;Ar1优选为苯基、吡啶基或噻吩基;Ar1更优选为Ar1例如 例如 优选 更优选为优选其中R1s为H、Me、Et、iPr、 优选H、 更优选为
在另一更具体的实施方案中,本发明提供了上述式(I)或(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,L1为NH,L2为CRxRy;优选为更优选
在另一更具体的实施方案中,本发明提供了上述式(I)或(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,L1为CHRx,L2为 CRxRy;优选为更优选
在另一更具体的实施方案中,本发明提供了上述式(I)或(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,R1选自H、D、卤素、CN、NO2、-L-ORa、-L-SRa、-L-NRbRc、SF5、C(O)Ra、C(O)ORa、C(O)NRbRc、OC(O)Ra、NRbC(O)Rc、S(O)Ra、S(O)2Ra、S(O)ORa、S(O)2ORa、S(O)NRbRc、S(O)2NRbRc、P(O)(Ra)2、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-6环烷基、4-6元杂环基、C6-10芳基或5-10元杂芳基,其任选被1、2或3个R1s取代;优选H、D、卤素、CN、-L-ORa、-L-SRa、-L-NRbRc、SF5、S(O)Ra、S(O)2Ra、C1-6烷基、C1-6卤代烷基、C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基;优选H、D、卤素、CN、-L-ORa、-L-SRa、-L-NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基;优选选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基;优选地,相邻的两个R1以及他们连接的原子一起形成C5-6环烷基、5-6元杂环基、苯基或5-6元杂芳基。
在另一更具体的实施方案中,本发明提供了上述式(I)或(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,选自
在另一更具体的实施方案中,本发明提供了上述式(I)或(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,R2a选自H、D、CN、ORa或NRbRc;优选选自ORa或NRbRc;优选为NH2
在另一更具体的实施方案中,本发明提供了上述式(I)或(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,R2b选自H、D、卤素、C(O)NRbRc、C1-6烷基、C1-6卤代烷基或4-6元杂环基;优选选自H、F、Cl、Br、Me、CH2CH3、C(O)NH2
在另一更具体的实施方案中,本发明提供了上述式(I)或(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,R2c选自H或Me。
在另一更具体的实施方案中,本发明提供了上述式(I)或(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,X1、X2以及他们的取代基一起形成C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基;优选形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基;优选形成 优选形成更优选形成
在另一更具体的实施方案中,本发明提供了上述式(I)或(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,R2d选自H、D、C1-6烷基或C1-6卤代烷基;优选为H或D。
在另一更具体的实施方案中,本发明提供了上述式(I)或(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,R3a和R3b之一为C1-6烷基或C1-6卤代烷基,另一为H;R3a和R3b之一为Me,另一为H;优选地,R3a为H且R3b为Me。
在另一更具体的实施方案中,本发明提供了上述式(I)或(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,R3选自H、D、卤素、ORa、NRbRc、C(O)Ra、C(O)ORa、C(O)NRbRc、OC(O)Ra、NRbC(O)Rc、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基;优选选自H、D、卤素、ORa、NRbRc、C(O)Ra、C(O)ORa、C(O)NRbRc、OC(O)Ra、NRbC(O)Rc、C1-6烷基或C1-6卤代烷基;优选选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基。
在另一更具体的实施方案中,本发明提供了上述式(I)或(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,R1s选自H、D、卤素、=O、-L-ORa、-L-SRa、-L-NRbRc、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、-L-C5-10环烷基、-L-5-10元杂环基、-L-C6-10芳基或-L-5-10元杂芳基;优选选自H、D、卤素、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基;优选地,孪位或相邻的两个R1s以及他们连接的原子一起形成C3-6环烷基、4-6元杂环基、苯基或5-6元杂芳基。
在另一更具体的实施方案中,本发明提供了上述式(I)或(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,R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基。
在另一更具体的实施方案中,本发明提供了上述式(I)或(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,其具有以下结构式:
其中各基团如上文定义。
在另一更具体的实施方案中,本发明提供了上述式(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,
L1为NH或CHRx
L2为CRxRy
其中Rx和Ry独立地为H、D、C1-6烷基或C1-6卤代烷基;
或者CRxRy一起形成C3-6亚烷基;
或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-4亚烷基;
其他基团如上文定义。
在另一更具体的实施方案中,本发明提供了上述式(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,-L1-L2-选自
在另一更具体的实施方案中,本发明提供了上述式(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,
L1为NH或CHRx
L2为CRxRy
其中Rx和Ry独立地为H、D、C1-6烷基或C1-6卤代烷基;
或者CRxRy一起形成C=O、C=S或C3-6亚环烷基;
或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-4亚烷基;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
X3为CR2d或N;
并且X1、X2和X3所在的环为芳香环;
R2a选自H、D、ORa或NRbRc
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基;
R1、R1a、R1b和R1c独立地选自H、D、卤素、CN、-L-ORa、-L-SRa、-L-NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-10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、2或3个R1s取代;
或者R1a、R1b以及他们连接的原子,或者R1b、R1c以及他们连接的原子,一起形成C5-6环烷基、5-6元杂环基、苯基或5-6元杂芳基,其任选地被1、2或3个R1s取代;
m=0、1或2;
R1s选自H、D、卤素、=O、-L-ORa、-L-SRa、-L-NRbRc、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、-L-C5-10环烷基、-L-5-10元杂环基、-L-C6-10芳基或-L-5-10元杂芳基,其任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷基-OH、-C0-6亚烷基-OC1-6烷基、C1-6烷基或C1-6卤代烷基取代;
或者孪位或邻位的两个R1s以及他们连接的原子一起形成C3-6环烷基、4-6元杂环基、苯基或5-6元杂芳基,其任选地被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;
L为化学键、C1-6亚烷基、C2-6亚烯基或C2-6亚炔基,其任选被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;
R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C3-6环烷基或4-6元杂环基,优选H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
n=0、1、2、3、4、5、6或7;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-10元杂环基;
其中上述L1、L2、Rx、Ry、R1、R1a、R1b、R1c、R2a、R2d、R1s、L、R2s、R3、R3a、R3b、Ra、Rb和Rc中的各个基团定义任选地被氘代,直至完全氘代。
在另一更具体的实施方案中,本发明提供了上述式(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,
L1为NH或CHRx
L2为CRxRy
其中Rx和Ry独立地为H、D、C1-6烷基或C1-6卤代烷基;
或者CRxRy一起形成C=O或C3-6亚环烷基;
或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-3亚烷基;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
X3为CR2d或N;
并且X1、X2和X3所在的环为芳香环;
R2a选自ORa或NRbRc
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基;
R1、R1a、R1b和R1c独立地选自H、D、卤素、CN、-L-ORa、-L-SRa、-L-NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基,其任选地被1、2或3个R1s取代;
或者R1a、R1b以及他们连接的原子,或者R1b、R1c以及他们连接的原子,一起形成5-6元杂环基或5-6元杂芳基,其任选地被1、2或3个R1s取代;
m=0、1或2;
R1s选自H、D、卤素、=O、-L-ORa、-L-SRa、-L-NRbRc、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、-L-C5-10环烷基或-L-5-10元杂环基,其任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷基-OH、-C0-6亚烷基-OC1-6烷基、C1-6烷基或C1-6卤代烷基取代;
或者孪位或邻位的两个R1s以及他们连接的原子一起形成C3-6环烷基或4-6元杂环基,其任选地被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;
L为化学键或C1-6亚烷基,其任选被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代;
R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
n=0、1、2、3、4或5;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-6元杂环基。
在另一更具体的实施方案中,本发明提供了上述式(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,
L1为NH或CHRx
L2为CRxRy
其中Rx和Ry独立地为H、D、C1-6烷基或C1-6卤代烷基;
或者CRxRy一起形成C=O或C2亚环烷基;
或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-2亚烷基;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
X3为CR2d或N;
并且X1、X2和X3所在的环为芳香环;
R2a为NRbRc
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
R1、R1a、R1b和R1c独立地选自H、D、卤素、CN、-L-ORa、-L-SRa、-L-NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-6环烷基或5-6元杂环基,其任选地被1、2或3个R1s取代;
或者R1a、R1b以及他们连接的原子,或者R1b、R1c以及他们连接的原子,一起形成5-6元杂环基或5-6元杂芳基,其任选地被1、2或3个R1s取代;
m=0、1或2;
R1s选自H、D、卤素、=O、-L-ORa、-L-SRa、-L-NRbRc、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基,其任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷基-OH、-C0-6亚烷基-OC1-6烷基、C1-6烷基或C1-6卤代烷基取代;
或者孪位或邻位的两个R1s以及他们连接的原子一起形成C3-6环烷基或4-6元杂环基,其任选地被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;
L为化学键或C1-6亚烷基,其任选被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代;
R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
n=0、1、2或3;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-6元杂环基。
在另一更具体的实施方案中,本发明提供了上述式(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,
-L1-L2-选自优选
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
X3为CR2d
并且X1、X2和X3所在的环为芳香环;
R2a为NH2
R2d选自H、D、卤素、C1-6烷基或C1-6卤代烷基;
R1选自H、D、卤素、CN、C1-6烷基或C1-6卤代烷基;
R1a、R1b和R1c独立地选自H、D、卤素、CN、-L-ORa、-L-SRa、-L-NRbRc、C1-6烷基、C1-6卤代烷基、C5-6环烷基或5-6元杂环基,优选H、D、卤素、CN、-L-NRbRc、C1-6烷基、C1-6卤代烷基、C5-6环烷基或5-6元杂环基,其任选地被1、2或3个R1s取代;
或者R1a、R1b以及他们连接的原子,或者R1b、R1c以及他们连接的原子,一起形成5-6元杂环基或5-6元杂芳基,其任选地被1、2或3个R1s取代;
m=0、1或2;
R1s选自H、D、卤素、=O、-L-NRbRc、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基,其任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷基-OH、-C0-6亚烷基-OC1-6烷基、C1-6烷基或C1-6卤代烷基取代;
或者孪位或邻位的两个R1s以及他们连接的原子一起形成C3-6环烷基或4-6元杂环基,其任选地被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;
L为化学键或C1-6亚烷基,其任选被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代;
R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
R3选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
R3a和R3b之一为C1-6烷基或C1-6卤代烷基,另一为H或D;
n=0、1、2或3;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-6元杂环基;
优选地,X1、X2以及他们的取代基一起形成选自以下的基团: 优选选自 优选为
优选地,选自以下基团: 优选为 优选为
在另一更具体的实施方案中,本发明提供了上述式(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,
L1为NH;
L2为C=O;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
X3为CR2d或N;
并且X1、X2和X3所在的环为芳香环;
R2a选自ORa或NRbRc
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
R1、R1a、R1b和R1c独立地选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基或C1-6卤代烷基,其任选地被1、2或3个R1s取代;
或者R1a、R1b以及他们连接的原子,或者R1b、R1c以及他们连接的原子,一起形成5-6元杂环基或5-6元杂芳基,其任选地被1、2或3个R1s取代;
R1s选自H、D、卤素、=O、ORa、SRa、NRbRc、C(O)ORa、C(O)NRbRc、C1-6烷基或C1-6卤代烷基;
m=0、1或2;
R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
n=0、1、2、3、4、5、6或7;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-10元杂环基;
其中上述R1、R1a、R1b、R1c、R2a、R2d、R1s、R2s、R3、R3a、R3b、Ra、Rb和Rc中的各个基团定义任选地被氘代,直至完全氘代。
在另一更具体的实施方案中,本发明提供了上述式(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
L1为NH;
L2为C=O;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成
X3为CR2d
并且X1、X2和X3所在的环为芳香环;
R2a为NRbRc
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
选自以下基团: 优选
R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基或C1-6卤代烷基;
m=0、1或2;
R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
n=0、1、2、3、4、5、6或7;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-10元杂环基。
在另一更具体的实施方案中,本发明提供了上述式(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
L1为NH;
L2为C=O;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成
X3为CR2d
并且X1、X2和X3所在的环为芳香环;
R2a为NH2
R2d选自H或D;
选自以下基团: 优选
R1选自H、D、F或Me;
m=0、1或2;
R3、R3a和R3b独立地选自H、D或Me,优选地,R3b为Me;
n=0、1、2、3、4、5、6或7。
在另一更具体的实施方案中,本发明提供了上述式(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
L1为NH;
L2为C=O;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
X3为CR2d或N;
并且X1、X2和X3所在的环为芳香环;
R2a选自ORa或NRbRc
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
R1、R1a、R1b和R1c独立地选自H、D、卤素、CN、-L-ORa、-L-SRa、-L-NRbRc、SF5、C1-6烷基或C1-6卤代烷基;
或者R1a、R1b以及他们连接的原子,或者R1b、R1c以及他们连接的原子,一起形成5-6元杂环基或5-6元杂芳基;
L为化学键或C1-6亚烷基,其任选被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代;
m=0、1或2;
R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
n=0、1、2、3、4、5、6或7;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;
其中上述R1、R1a、R1b、R1c、R2a、R2d、R2s、R3、R3a、R3b、Ra、Rb和Rc中的各个基团定义任选地被氘代,直至完全氘代。
在另一更具体的实施方案中,本发明提供了上述式(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
L1为NH;
L2为C=O;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成
X3为CR2d
并且X1、X2和X3所在的环为芳香环;
R2a为NRbRc
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
选自以下基团: 优选
R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基或C1-6卤代烷基;
m=0、1或2;
R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
n=0、1、2、3、4、5、6或7;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基。
在另一更具体的实施方案中,本发明提供了上述式(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
L1为NH;
L2为C=O;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成
X3为CR2d
并且X1、X2和X3所在的环为芳香环;
R2a为NH2
R2d选自H或D;
选自以下基团: 优选
R1选自H、D、F或Me;
m=0、1或2;
R3、R3a和R3b独立地选自H、D或Me,优选地,R3b为Me;
n=0、1、2、3、4、5、6或7;
在另一更具体的实施方案中,本发明提供了上述式(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
L1为NH;
L2为C=O;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成
X3为CR2d或N;
并且X1、X2和X3所在的环为芳香环;
R2a选自ORa或NRbRc
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
R1、R1a、R1b和R1c独立地选自H、D、卤素、CN、-L-ORa、-L-SRa、-L-NRbRc、SF5、C1-6烷基或C1-6卤代烷基;
或者R1a、R1b以及他们连接的原子,或者R1b、R1c以及他们连接的原子,一起形成5-6元杂环基或5-6元杂芳基;
L为化学键或C1-6亚烷基,其任选被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代;
m=0、1或2;
R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
n=0、1、2、3、4、5、6或7;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;
其中上述R1、R1a、R1b、R1c、R2a、R2d、R3、R3a、R3b、Ra、Rb和Rc中的各个基团定义任选地被氘代,直至完全氘代。
在另一更具体的实施方案中,本发明提供了上述式(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
L1为NH;
L2为C=O;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成
X3为CR2d
并且X1、X2和X3所在的环为芳香环;
R2a为NRbRc
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
选自以下基团:
R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基或C1-6卤代烷基;
m=0、1或2;
R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
n=0、1、2、3、4、5、6或7;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基。
在另一更具体的实施方案中,本发明提供了上述式(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
L1为NH;
L2为C=O;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成
X3为CR2d
并且X1、X2和X3所在的环为芳香环;
R2a为NH2
R2d选自H或D;
选自以下基团:
R1选自H、D、F或Me;
m=0、1或2;
R3、R3a和R3b独立地选自H、D或Me,优选地,R3b为Me;
n=0、1、2、3、4、5、6或7。
在另一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
L1为NH;
L2为C=O;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代,优选5-7元杂环基或5-6元杂芳基,其任选被1、2或3个R2s取代;
X3为CR2d或N;
并且X1、X2和X3所在的环为芳香环;
R2a选自ORa或NRbRc
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基或C1-6卤代烷基;
m=0、1、2或3;
R1s选自H、D、卤素、=O、-L-ORa、-L-SRa、-L-NRbRc、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、-L-C3-6环烷基、-L-5-6元杂环基、-L-C6-10芳基或-L-5-6元杂芳基,其任选地被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代;
L为化学键或C1-6亚烷基,其任选被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代;
R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
n=0、1、2、3、4、5、6或7;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基。
在另一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
L1为NH;
L2为C=O;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成优选
X3为CR2d
并且X1、X2和X3所在的环为芳香环;
R2a为NRbRc
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基或C1-6卤代烷基;
m=0、1、2或3;
R1s为H、D、C1-6烷基、C1-6卤代烷基、
R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
n=0、1、2、3、4、5、6或7;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基。
在另一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
L1为NH;
L2为C=O;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成优选
X3为CR2d
并且X1、X2和X3所在的环为芳香环;
R2a为NH2
R2d选自H或D;
R1选自H、D、F或Me;
m=0、1、2或3;
R1s为H、Me、Et、iPr、
R3、R3a和R3b独立地选自H、D或Me,优选地,R3b为Me;
n=0、1、2、3、4、5、6或7。
在另一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,
L1为NH或CHRx
L2为CRxRy
其中Rx和Ry独立地为H、D、C1-6烷基或C1-6卤代烷基;
或者CRxRy一起形成C=O、C=S或C3-6亚环烷基;
或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-4亚烷基;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
X3为CR2d或N;
并且X1、X2和X3所在的环为芳香环;
R2a选自H、D、ORa或NRbRc
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C5-10环烷基、5-10 元杂环基、C6-10芳基或5-10元杂芳基;
R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基,其任选地被1、2或3个R1s取代;
m=0、1、2或3;
R1s选自H、D、卤素、-L-ORa、-L-SRa、-L-NRbRc、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、-L-C5-10环烷基、-L-5-10元杂环基、-L-C6-10芳基或-L-5-10元杂芳基,其任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷基-OH、-C0-6亚烷基-OC1-6烷基、C1-6烷基或C1-6卤代烷基取代;
L为化学键、C1-6亚烷基、C2-6亚烯基或C2-6亚炔基,其任选被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;
R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
n=0、1、2、3、4、5、6或7;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-10元杂环基;
其中上述L1、L2、Rx、Ry、R1、R2a、R2d、R1s、L、R2s、R3、R3a、R3b、Ra、Rb和Rc中的各个基团定义任选地被氘代,直至完全氘代。
在另一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,
L1为NH或CHRx
L2为CRxRy
其中Rx和Ry独立地为H、D、C1-6烷基或C1-6卤代烷基;
或者CRxRy一起形成C=O或C3-6亚环烷基;
或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-3亚烷基;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
X3为CR2d或N;
并且X1、X2和X3所在的环为芳香环;
R2a选自ORa或NRbRc
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基;
R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基,其任选地被1、2或3个R1s取代;
m=0、1或2;
R1s选自H、D、卤素、-L-ORa、-L-SRa、-L-NRbRc、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、-L-C5-10环烷基、-L-5-10元杂环基、-L-C6-10芳基或-L-5-10元杂芳基,其任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷 基-OH、-C0-6亚烷基-OC1-6烷基、C1-6烷基或C1-6卤代烷基取代;
L为化学键或C1-6亚烷基,其任选被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代;
R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
n=0、1、2、3、4或5;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-6元杂环基。
在另一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,
L1为NH或CHRx
L2为CRxRy
其中Rx和Ry独立地为H、D、C1-6烷基或C1-6卤代烷基;
或者CRxRy一起形成C=O或C2亚环烷基;
或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-2亚烷基;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
X3为CR2d或N;
并且X1、X2和X3所在的环为芳香环;
R2a为NRbRc
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基,其任选地被1、2或3个R1s取代;
m=0、1或2;
R1s选自H、D、卤素、=O、-L-ORa、-L-SRa、-L-NRbRc、C1-6烷基、C1-6卤代烷基、-L-C5-7环烷基、-L-5-7元杂环基或-L-5-6元杂芳基,其任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷基-OH、-C0-6亚烷基-OC1-6烷基、C1-6烷基或C1-6卤代烷基取代;
L为化学键或C1-6亚烷基,其任选被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代;
R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
n=0、1、2或3;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-6元杂环基。
在另一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,
-L1-L2-选自优选
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
X3为CR2d
并且X1、X2和X3所在的环为芳香环;
R2a为NH2
R2d选自H、D、卤素、C1-6烷基或C1-6卤代烷基;
R1选自H、D、卤素、CN、C1-6烷基或C1-6卤代烷基,其任选地被1、2或3个R1s取代;
m=0、1或2;
R1s选自H、D、卤素、=O、-L-ORa、-L-NRbRc、C1-6烷基、C1-6卤代烷基、-L-C5-7环烷基、-L-5-7元杂环基或-L-5-6元杂芳基,其任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷基-OH、-C0-6亚烷基-OC1-6烷基、C1-6烷基或C1-6卤代烷基取代;
L为化学键或C1-6亚烷基,其任选被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代;
R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
R3选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
R3a和R3b之一为C1-6烷基或C1-6卤代烷基,另一为H或D;
n=0、1、2或3;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-6元杂环基;
优选地,X1、X2以及他们的取代基一起形成选自以下的基团: 优选选自
优选地,R1s选自H、 优选为
在另一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,
L1为NH或CHRx
L2为CRxRy
其中Rx和Ry独立地为H、D、C1-6烷基或C1-6卤代烷基;
或者CRxRy一起形成C=O、C=S或C3-6亚环烷基;
或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-4亚烷基;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
X3为CR2d或N;
并且X1、X2和X3所在的环为芳香环;
R2a选自H、D、ORa或NRbRc
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基;
R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基,其任选地被1、2或3个R1s取代;
m=0、1、2或3;
m’=0、1、2、3、4、5、6、7、8或9;
R1s选自H、D、卤素、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基;
R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
R3选自H、D、卤素、C1-6烷基或C1-6卤代烷基;
n=0、1、2、3、4、5、6、7或8;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-10元杂环基;
其中上述L1、L2、Rx、Ry、R1、R2a、R2d、R1s、R2s、R3、Ra、Rb和Rc中的各个基团定义任选地被氘代,直至完全氘代。
在另一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,
L1为NH或CHRx
L2为CRxRy
其中Rx和Ry独立地为H、D、C1-6烷基或C1-6卤代烷基;
或者CRxRy一起形成C=O或C3-6亚环烷基;
或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-3亚烷基;
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
X3为CR2d或N;
并且X1、X2和X3所在的环为芳香环;
R2a选自ORa或NRbRc
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基;
R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基,其任选地被1、2或3个R1s取代;
m=0、1、2或3;
m’=0、1、2、3、4或5;
R1s选自H、D、卤素、C(O)ORa、C(O)NRbRc、C1-6烷基或C1-6卤代烷基基;
R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
R3选自H、D、卤素、C1-6烷基或C1-6卤代烷基;
n=0、1、2、3、4或5;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-6元杂环基。
在另一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,
-L1-L2-选自优选
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
X3为CR2d
并且X1、X2和X3所在的环为芳香环;
R2a为NH2
R2d选自H、D、卤素、C1-6烷基或C1-6卤代烷基;
R1选自H、D、卤素、CN、C1-6烷基或C1-6卤代烷基,其任选地被1、2或3个R1s取代;
m=0、1或2;
m’=0、1、2或3;
R1s选自H、D、卤素、C(O)ORa、C(O)NRbRc、C1-6烷基或C1-6卤代烷基基;
R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
R3选自H、D、卤素、C1-6烷基或C1-6卤代烷基;
n=0、1、2或3;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一 起形成5-6元杂环基;
优选地,X1、X2以及他们的取代基一起形成选自以下的基团: 优选选自
在另一更具体的实施方案中,本发明提供了式(Va)或(Vb)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
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
X3为CR2d或N;
并且X1、X2和X3所在的环为芳香环;
R2a选自ORa或NRbRc
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
Ar1为5-6元杂芳基,其被m个R1取代;
R1选自H、D、卤素、CN、NO2、-L-ORa、-L-SRa、-L-NRbRc、SF5、C(O)Ra、C(O)ORa、C(O)NRbRc、OC(O)Ra、NRbC(O)Rc、S(O)Ra、S(O)2Ra、S(O)ORa、S(O)2ORa、S(O)NRbRc、S(O)2NRbRc、P(O)(Ra)2、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-6环烷基、4-6元杂环基、C6-10芳基或5-10元杂芳基,其任选被1、2或3个R1s取代;
m=0、1、2、3、4或5;
或者相邻的两个R1以及他们连接的原子一起形成C5-6环烷基、5-6元杂环基、苯基或5-6元杂芳基,其任选地被1、2或3个R1s取代;
R1s选自H、D、卤素、=O、ORa、SRa、NRbRc、C1-6烷基或C1-6卤代烷基;
R3和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
n=0、1、2、3、4、5、6或7;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;
其中上述R1、R1s、R2a、R2d、R3、R3b、Ra、Rb和Rc中的各个基团定义任选地被氘代,直至完全氘代。
在另一更具体的实施方案中,本发明提供了上述式(Va)或(Vb)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
X1为C原子或N原子,其任选地被R2b取代;
X2为C原子或N原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成
X3为CR2d
并且X1、X2和X3所在的环为芳香环;
R2a为NRbRc
R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
Ar1为5-6元杂芳基,其被m个R1取代;
R1选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-6环烷基、4-6元杂环基、C6-10芳基或5-10元杂芳基,其任选被1、2或3个R1s取代;
m=0、1、2或3;
或者相邻的两个R1以及他们连接的原子一起形成C5-6环烷基、5-6元杂环基、苯基或5-6元杂芳基,其任选地被1、2或3个R1s取代;
R1s选自H、D、卤素、=O、ORa、SRa、NRbRc、C1-6烷基或C1-6卤代烷基;
R3和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
n=0、1、2、3、4、5、6或7;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基。
在另一更具体的实施方案中,本发明提供了上述式(Va)或(Vb)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
X1为C原子,其任选地被R2b取代;
X2为C原子,其任选地被R2c取代;
并且X1、X2以及他们的取代基一起形成优选
X3为CR2d
并且X1、X2和X3所在的环为芳香环;
R2a为NH2
R2d选自H或D;
Ar1为5-6元杂芳基,其被m个R1取代;优选地,Ar1选自:
R1选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-6环烷基或4-6元杂环基,其任选被1、2或3个R1s取代;
m=0、1或2;
或者相邻的两个R1以及他们连接的原子一起形成苯基或5-6元杂芳基,其任选地被1、2或3个R1s取代;
R1s选自H、D、卤素、=O、ORa、SRa、NRbRc、C1-6烷基或C1-6卤代烷基;
R3和R3b独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基;
n=0、1、2、3、4、5、6或7;
Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基。
在最具体的实施方案中,本发明提供了上述式(I)或(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,所述化合物选自以下:



在另一最具体的实施方案中,本发明提供了上述式(I)或(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,所述化合物选自以下:




在另一最具体的实施方案中,本发明提供了上述式(I)或(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,所述化合物选自以下:

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。
本发明化合物可以互变异构体形式存在。互变异构体为因分子中某一原子在两个位置迅速移动而产生的官能团异构体,互变异构体是一种特殊的官能团异构体,一对互变异构体可以互相转换,但通常以比较稳定的一种异构体为其主要的存在形式。最主要的例子为烯醇式和酮式互变异构体。
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·0.5 H2O))和多水合物(x为大于1的数,例如,二水合物(R·2 H2O)和六水合物(R·6 H2O))。
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(I)所述的那些,但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素,分别例如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如3H和14C)的那些可用于药物和/或底物组织分布测定。氚、即3H和碳-14、即14C同位素是特别优选的,因为它们容易制备和检测。进而,被更重的同位素取代,例如氘、即2H,由于代谢稳定性更高可以提供治疗上的益处,例如延长体内半衰期或减少剂量需求,因而在有些情况下可能是优选的。同位素标记的本发明式(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。
前药为任何共价键合的本发明化合物,当将这种前药给予患者时,其在体内释放母体化合物。通常通过修饰官能团来制备前药,修饰是以使得该修饰可以通过常规操作或在体内裂解产生母体化合物的方式进行的。前药包括,例如,其中羟基、氨基或巯基与任意基团键合的本发明化合物,当将其给予患者时,可以裂解形成羟基、氨基或巯基。因此,前药的代表性实例包括(但不限于)式(A)化合物的羟基、巯基和氨基官能团的乙酸酯/酰胺、甲酸酯/酰胺和苯甲酸酯/酰胺衍生物。另外,在羧酸(-COOH)的情况下,可以使用酯,例如甲酯、乙酯等。酯本身可以是有活性的和/或可以在人体体内条件下水解。合适的药学上可接受的体内可水解的酯基包括容易在人体中分解而释放母体酸或其盐的那些基团。
本发明还提供药物制剂,包含治疗有效量的式(A)化合物或其治疗学上可接受的盐和其药学上可接受的载体、稀释剂或赋形剂。所有这些形式都属于本发明。
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。
用于给予本发明化合物的合适制剂将对于本领域普通技术人员而言是显而易见的,并且包括例如片剂、丸剂、胶囊、栓剂、锭剂、糖锭剂、溶液(特别是注射(皮下、静脉内、肌内)和输注(注射剂)用溶液)、酏剂、糖浆、扁囊剂、乳液、吸入剂或可分散粉剂。一种或多种药物活性化合物的含量的范围应该是作为整体的组合物的0.1至90wt%、优选0.5至50wt%,即,其量足以实现以下指定的剂量范围。如有必要,指定的剂量可每天给药若干次。
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%)。
适应症
在MTAP缺失的肿瘤,开发MTA协同的PRMT5抑制剂可以为大量的肿瘤病人提供治疗获益。本发明中的化合物通过负调节肿瘤细胞内MTA结合的PRMT5的活性发挥治疗作用,尤其是对MTAP缺陷的细胞,或MTAP相关的各种肿瘤细胞。
在一些实施方案中,本发明所述的MTA协同的PRMT5抑制剂可以治疗多种癌症,包括但不限于肿瘤类型,例如恶性周围神经鞘瘤、间皮瘤、多形性胶质母细胞瘤、胰腺癌、胆管癌、前列腺癌、乳腺癌、脑癌、皮肤癌、宫颈癌、膀胱癌、星形细胞瘤、结肠直肠癌、子宫内膜癌、食道癌、胃癌、胸腺瘤、头颈癌、肝细胞癌、喉癌、肺鳞癌、肺腺癌、口腔癌、卵巢癌、肾癌和甲状腺癌以及肉瘤。
更具体地说,这些化合物可用于治疗:心脏:肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤等)、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤和畸胎瘤;肺:支气管癌(鳞状细胞、未分化小细胞、未分化大细胞、腺癌等)、肺泡(细支气管)癌、支气管腺瘤、肉瘤、淋巴瘤、软骨瘤错构瘤、间皮瘤;胃肠道:食管(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤等)、胃(肿瘤、淋巴瘤、平滑肌肉瘤等)、胰腺(导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤、血管瘤等)、小肠(腺癌、淋巴瘤、类癌瘤等)、卡波西肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤等)、大肠(腺 癌、管状腺瘤、绒毛状腺瘤、错构瘤、平滑肌瘤等);泌尿生殖道:肾脏(腺癌、肾母细胞瘤等)、膀胱和尿道(鳞状细胞癌,移行细胞癌,腺癌等),前列腺(腺癌,肉瘤等),睾丸(精原细胞瘤,畸胎瘤,胚胎癌,畸胎癌,绒癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样肿瘤、脂肪瘤等);肝脏:肝细胞瘤、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤、血管瘤;胆道:胆囊癌、壶腹癌、胆管癌等;骨:成骨肉瘤、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤文肉瘤、恶性淋巴瘤(网状细胞肉瘤等)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨软骨瘤(骨软骨外生骨疣)、良性软骨瘤、软骨母细胞瘤、软骨粘液纤维瘤、骨样骨瘤和骨巨细胞瘤;神经系统:颅骨(骨瘤、血管瘤、肉芽肿、黄色瘤、变形性骨炎等)、脑膜(脑膜瘤、脑膜肉瘤、神经胶质瘤等)、脑(星形细胞瘤、髓母细胞瘤、神经胶质瘤、室管膜瘤、生殖细胞瘤(松果体瘤等)、多形性胶质母细胞瘤、少突胶质细胞瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤等)、脊髓神经纤维瘤、脑膜瘤、神经胶质瘤,肉瘤等);妇科:子宫(子宫内膜癌等)、宫颈(宫颈癌、瘤前宫颈发育不良等)、卵巢(卵巢癌、浆液性囊腺癌、粘液性囊腺癌、未分类癌等)、颗粒鞘细胞瘤、支持间质细胞瘤、无性细胞瘤、恶性畸胎瘤等)、外阴(鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤、黑色素瘤等)、阴道(透明细胞癌、鳞状细胞癌、葡萄状肉瘤(胚胎性横纹肌肉瘤等)、输卵管癌等;血液学:血液(髓性白血病(急性和慢性),急性淋巴细胞白血病、慢性淋巴细胞白血病、弥漫性大B细胞淋巴瘤、套细胞淋巴瘤(MCL),滤泡性淋巴瘤、骨髓增生性疾病、多发性骨髓瘤、骨髓增生异常综合征等)、霍奇金病、非霍奇金淋巴瘤(恶性淋巴瘤)等;皮肤:恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、痣发育不良痣、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕瘤,牛皮癣等;肾上腺:神经母细胞瘤等。
联合用药
本发明所述的MTA协同的PRMT5抑制剂可以与其他药物联合治疗癌症,至少包含一种靶点药物/细胞活性调节剂,包括CDK4/6抑制剂,MAT2A抑制剂,MAPK1/MAPK3抑制剂,Type I PRMT抑制剂,EGFR抑制剂,SHP2抑制剂,泛KRAS抑制剂,KRASG12C抑制剂,RAF抑制剂,MEK抑制剂,ERK抑制剂,Bcl-2抑制剂,SOS1抑制剂,PARP抑制剂,MALT1抑制剂,MALT2抑制剂,BTK抑制剂,PI3K抑制剂,AKT抑制剂,FGFR抑制剂,DNA甲基转移酶(DNMT)抑制剂,EZH1/2抑制剂,EZH2抑制剂,Menin-MLL抑制剂,IDH1抑制剂,IDH2抑制剂,IDH1/2抑制剂,化疗药物,放射疗法,STING激动剂或免疫检查点抑制剂/调节剂等。
实施例
本文所用的原料或试剂为可购买到的或由本领域通常已知的合成方法制备。
1.实施例1的合成
1.1中间体1-1的合成
-78℃下,将1M双三甲基硅基胺基锂的四氢呋喃溶液(35mL)加入到(S)-5-甲基-2-氧代哌啶-1-甲酸叔丁酯(5.0g)的四氢呋喃溶液(100mL)中,氮气保护下,-78℃搅拌1.5小时后加入N-苯基双(三氟甲烷磺酰)亚胺(10.5g),室温搅拌12小时。向反应液中加入饱和氯化铵溶液(100mL),二氯甲烷(100mL×3)萃取,有机相用饱和氯化钠溶液(50mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=2/1)纯化,得淡黄色液体1-1(5.0g,收率61.7%)。LC-MS m/z(ESI):289.9[M-56+H]+
1.2中间体1-2的合成
将二碳酸二叔丁酯(565.0mg)加入到4-二甲胺基吡啶(6.8mg),三乙胺(112.9mg)和7-溴-1,3-二氢呋喃并[3,4-c]吡啶-4-胺(120mg)的二氯甲烷(5mL)溶液中,室温搅拌2小时。有机相用饱和氯化钠溶液(1mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=5/1-2/1)纯化,得白色固体1-2(160.0mg,收率65.6%)。LC-MS m/z(ESI):437.1,439.1[M+Na]+
1.3中间体1-3的合成
将碘化亚铜(18.1mg)、碳酸铯(200mg),反式-(1R,2R)-N,N’-二甲基-1,2-环己烷二胺(110.2mg)加入到三氟乙酰胺(71.7mg)和1-2(100.0mg)的二氧六环(5mL)溶液中。氮气保护下110℃搅拌16小时,冷却至室温,加水(10mL),乙酸乙酯(10mL×3)萃取,有机相用饱和氯化钠溶液(5mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物经硅胶柱层析(洗脱剂:二氯甲烷/乙酸乙酯=5/1-1/1)纯化,得白色固体1-3(34.0mg,收率38.7%)。LC-MS m/z(ESI):352.0[M+H]+
1.4中间体1-4的合成
将2-氨基-4-溴苯硫酚(1.0g),四氢呋喃-4-甲酸(960.0mg),五氧化二磷(1.9g)加入到多聚磷酸(6mL)溶液中,氮气保护下,100℃搅拌16小时。加氢氧化钠水溶液调pH至弱碱性,二氯甲烷(160mL)萃 取,有机相用饱和氯化钠溶液(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=10/1-5/1)纯化,得淡黄色液体1-4(680.0mg,收率46.0%)。LC-MS m/z(ESI):297.9,299.9[M+H]+
1.5中间体1-5的合成
将1-4(250.0mg),联硼酸频那醇酯(255.0mg),[1,1'-双(二苯基膦)二茂铁]二氯化钯·二氯甲烷络合物(137.0mg),乙酸钾(123.0mg)加入二氧六环(15mL)溶液中。氮气保护下,90℃搅拌16小时。减压浓缩得棕色固体粗品1-5(400.0mg),粗品直接用于下一步反应。LC-MS m/z(ESI):346.1[M+H]+
1.6中间体1-6的合成
将1-5(23.0g),1-1(10.5g),[1,1'-双(二苯基膦)二茂铁]二氯化钯·二氯甲烷络合物(4.5g),碳酸钠(5.9g)加入到二氧六环和水(V:V=3:1)的(100mL)溶液中,氮气保护下,90℃搅拌16小时。冷却至室温,减压浓缩。加入水(100mL),二氯甲烷(150mL×3)萃取,有机相用饱和氯化钠(150mL)洗涤。残余物经硅胶柱层析(洗脱剂:二氯甲烷/甲醇=20/1-10/1)纯化,得白色固体1-6(6.4g,收率55.0%)。LC-MS m/z(ESI):415.0[M+H]+
1.7中间体1-7的合成
冰浴下,将三氟乙酸(15mL)加入1-6(6.4g)的二氯甲烷(15mL)溶液中。室温搅拌1小时,减压浓缩。用饱和碳酸氢钠调pH至弱碱性,二氯甲烷(100mL×3)萃取,有机相用饱和氯化钠溶液(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得棕色固体粗品1-7(4.8g)。粗品直接用于下一步反应。LC-MS m/z(ESI):315.0[M+H]+
1.8中间体1-8的合成
冰浴下,将硼氢化钠(0.6g)加入到1-7(4.8g)的甲醇(20mL)溶液中,氮气保护下,25℃搅拌2小时。加水淬灭减压浓缩,二氯甲烷(50mL×3)萃取,有机相用饱和氯化钠(50mL)洗涤。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=10/1-3/1)纯化,得黄色固体1-8(3.0g,收率63.0%)。LC-MS m/z(ESI):317.2[M+H]+
1.9中间体1-9的合成
冰浴下,将草酰氯单乙酯(140mg)加入三乙胺(160mg)和1-8(250mg)的二氯甲烷(5mL)溶液中。室温搅拌1小时,有机相用饱和氯化钠溶液(2mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=5/1-2/1)纯化,得白色固体1-9(250.0mg,收率80.0%)。LC-MS m/z(ESI):417.2[M+H]+
1.10中间体1-10的合成
将氢氧化锂(23.0mg)加入到1-9(200.0mg)的甲醇(3mL)和水(1mL)溶液中。室温搅拌2小时,加水(5mL),用2M盐酸调节pH=6,乙酸乙酯(10mL×3)萃取,有机相用饱和氯化钠溶液(5mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,冻干得白色固体1-10(180.0mg,收率86.8%)。LC-MS m/z(ESI):389.1[M+H]+
1.11中间体1-11的合成
将T3P(123.0mg)加入N,N-二异丙基乙胺(33.0mg),1-10(50.0mg)和1-3(45.0mg)的二氯甲烷(2mL)溶液中。室温搅拌1小时,有机相用饱和氯化钠溶液(2mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=3/1-1/1)纯化,得白色固体1-11(60.0mg,收率58.1%)。LC-MS m/z(ESI):722.0[M+H]+
1.12中间体1的合成
冰浴下,将三氟乙酸(1mL)加入1-11(60.0mg)的二氯甲烷(2mL)溶液中。室温搅拌1小时,减压浓缩,残余物经高效液相色谱(柱:Xbridge-C18 150 x 19mm,5um;流动相:ACN--H2O(0.1%FA);B%:5%-10%,20min)纯化,得白色固体1的甲酸盐(20.9mg,收率48.0%)。LC-MS m/z(ESI):522.0[M+H]+1H NMR(400MHz,DMSO-d6)δppm 10.58-10.49(m,1H),8.1(d,J=8.4Hz,1H),7.93-7.73(m,1H),7.46-7.35(m,1H),6.01-5.95(m,1H),4.92-4.68(m,3H),3.97-3.94(m,2H),3.52-3.48(m,1H),2.32-2.30(m,1H),2.04-2.02(m,3H),1.88-1.71(m,5H),1.35-1.33(m,1H),1.05-1.04(m,1H).
2.实施例2的合成
2.1中间体2-1的合成
将联硼酸频那醇酯(2.2g),[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.7g),乙酸钾(1.5g)加入到1-(3-溴苯基)-4-甲基-哌嗪(2.0g)的二氧六环(20mL)溶液中。氮气保护下,90℃搅拌16小时。冷却至室温,减压浓缩得棕色固体粗品2-1(4.0g),产物不经纯化直接进行下一步反应。LC-MS m/z(ESI):303.1[M+H]+
2.2中间体2-2的合成
将1-1(1.0g),碳酸钠(0.6g),[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.5g),加入到粗品2-1(2.0g)的二氧六环(10mL)溶液中,氮气保护下90℃搅拌16小时。冷却至室温,加入水(50mL),乙酸乙酯(30mL×3)萃取,合并的有机相用饱和氯化钠溶液(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=10/1–5/1)纯化,得透明油状物2-2(600.0mg,收率60%)。LC-MS m/z(ESI):372.2[M+H]+
2.3中间体2-3的合成
氮气氛围下,将三氟乙酸(2mL)加入到2-2(600mg)的二氯甲烷(6mL)溶液中,室温搅拌1小时,加入碳酸氢钠水溶液(10mL),二氯甲烷(30mL×3)萃取,合并的有机相用饱和氯化钠溶液(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得黄色油状物粗品2-3(550.0mg),产物不经纯化直接进行下一步反应。LC-MS m/z(ESI):272.3[M+H]+
2.4中间体2-4的合成
氮气氛围下,分批将硼氢化钠(100.0mg)加入到2-3(550mg)的甲醇(10mL)溶液中,室温搅拌2小时。加入水(50mL),乙酸乙酯(30mL×3)萃取,合并的有机相用饱和氯化钠溶液(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=10/1–1/1)纯化,得透明油状物2-4(170.0mg,收率34.0%)。LC-MS m/z(ESI):274.2[M+H]+
2.5中间体2-5的合成
0℃氮气氛围下,将氢化钠(2.0g)加到4-溴-7-氯-1H-吡唑并[3,4-C]吡啶(3.0g)的N,N-二甲基甲酰胺(30mL)溶液中,搅拌1小时,将碘甲烷(375.0mg)滴加到反应溶液中,升至室温,搅拌2小时,加入水(50mL),乙酸乙酯(20mL×3)萃取,有机相用饱和氯化钠溶液(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=10/1–2/1)纯化,得白色固体2-5(1.9g,收率61.9%)。LC-MS m/z(ESI):245.9,247.8[M+H]+
2.6中间体2-6的合成
氮气氛围下,将碳酸钠(1.6g),对氨基苯甲醚(1.6g)加到2-5(1.9g)的N-甲基吡咯烷酮溶液(20mL)中,130℃搅拌2小时,加入水(60mL),乙酸乙酯(20mL×3)萃取,有机相用饱和氯化钠溶液(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(石油醚/乙酸乙酯=10/1–2/1)纯化,得白色固体2-6(1.6g,收率60.4%)。LC-MS m/z(ESI):346.9,348.9[M+H]+
2.7中间体2-7的合成
氮气氛围下,将2-6(1.6g)加入到三氟乙酸(20mL)中,60℃搅拌16小时,加入碳酸氢钠水溶液(60mL),乙酸乙酯(20mL×3)萃取,有机相用饱和氯化钠溶液(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=10/1–1/1)纯化,得白色固体2-7(800.0mg,收率76.9%)。LC-MS m/z(ESI):227.0,229.1[M+H]+
2.8中间体2-8的合成
氮气氛围下,将三乙胺(1.5g),4-二甲氨基吡啶(80.0mg),二碳酸二叔丁酯(1.9g)加到2-7(800.0mg)的二氯甲烷溶液(20mL)中,室温搅拌2小时,加入水(60mL),二氯甲烷(20mL×3)萃取,有机相用饱和氯化钠溶液(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=10/1–3/1)纯化,得白色固体2-8(900.0mg,收率59.6%)。LC-MS m/z(ESI):449.0,451.0[M+Na]+
2.9中间体2-9的合成
将三氟乙酰胺(250.0mg),碳酸铯(380.0mg),碘化亚铜(30.0mg)和(反式)-N,N'-二甲基-1,2-环己二胺(16.0mg)加入到2-8(50.0mg)的无水二氧六环(8mL)溶液中,氮气氛围下,100℃搅拌16小时。冷却至室温,加入水(50mL),二氯甲烷萃取(20mL×3),有机相用饱和氯化钠溶液(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:二氯甲烷/甲醇=20/1)纯化,得黄色固体2-9(120.0mg,收率56.3%)。LC-MS m/z(ESI):364.2[M+H]+
2.10中间体2-10的合成
0℃,氮气氛围下,将草酰氯单乙酯(45.0mg)滴加到三乙胺(35.0mg)和2-9(110.0mg)的无水二氯甲烷(5mL)溶液中,搅拌1小时。升至室温,加入水(20mL),二氯甲烷萃取(10mL×3),有机相用饱和氯化钠溶液(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:二氯甲烷/甲醇=50/1)纯化,得黄色固体2-10(110.0mg,收率72.3%)。LC-MS m/z(ESI):464.0[M+H]+
2.11中间体2-11的合成
0℃,氮气氛围下,将三甲基铝(0.1mL,2M正己烷溶液)滴加到2-4(20.0mg)的三氯甲烷(1mL) 溶液中,搅拌0.5小时,加入2-10(30.0mg),80℃搅拌16小时。冷却至室温,加入水(10mL),二氯甲烷萃取(10mL×3),有机相用饱和氯化钠溶液(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到黄色固体粗品2-11(20.0mg),产物不经纯化直接进行下一步反应。LC-MS m/z(ESI):591.4[M-100+H]+
2.12中间体2的合成
氮气氛围下,将三氟乙酸(1mL)加入到粗品2-11(20.0mg)二氯甲烷(1mL)中,室温搅拌1小时。减压浓缩,残余物经高效液相色谱(柱:Gemini 5u C18 150 x 21.2mm;流动相:[水(0.05%NH3)-ACN];B%:2%-10%,10min)纯化,得白色固体2(7.0mg,两步产率22.5%)。LC-MS m/z(ESI):491.1[M+H]+1H NMR(400MHz,MeOD-d4)δppm 8.15-8.04(m,1H),7.90-7.73(m,1H),7.34(t,J=7.8Hz,1H),7.08-6.90(m,3H),5.70-5.30(m,1H),4.43-4.32(m,3H),3.65-3.08(m,9H),2.95(s,3H),2.27(s,2H),1.93(d,J=48.8Hz,3H),1.45(d,J=13.4Hz,1H),1.16(d,J=7.2Hz,3H).
3.实施例3的合成
3.1中间体3-1的合成
将二碳酸二叔丁酯(1442.1mg)加入到4-二甲胺基吡啶(64.6mg),三乙胺(802.4mg)和4-硝基异喹啉-1-胺(500.0mg)的二氯甲烷(8mL)溶液中,室温搅拌1小时。有机相用饱和氯化钠溶液(5mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=1/1-2/3)纯化,得白色固体3-1(830.0mg,收率72.5%)。LC-MS m/z(ESI):412.0[M+Na]+
3.2中间体3-2的合成
氮气保护下,将钯碳(88.5mg)加入到3-1(810.0mg)的甲醇(10mL)溶液中。氢气球通氢气,25℃搅拌4小时。过滤,滤液减压浓缩,得类白色固体粗品3-2(600.0mg)。LC-MS m/z(ESI):360.0[M+H]+
3.3中间体3-3的合成
氮气保护下,将二氧化铂(73.3mg)加入到3-2(580.0mg)和乙酸(48.5mg)的甲醇(8mL)溶液中。氢气球通氢气,25℃搅拌16小时。过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:二氯甲烷/甲 醇=12/1-10/1)纯化,得类白色固体3-3(500.0mg,收率76.7%)。LC-MS m/z(ESI):364.1[M+H]+
3.4中间体3-4的合成
将2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲鎓六氟磷酸盐(75.3mg)加入N,N-二异丙基乙胺(42.7mg),3-3(60.0mg)和1-10(70.6mg)的N,N-二甲基甲酰胺(2mL)溶液中。室温搅拌2小时。加入冰水(20mL),乙酸乙酯(10*3mL)萃取,有机相用饱和氯化钠溶液(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物经硅胶柱层析(洗脱剂:二氯甲烷/甲醇=10/1-8/1)纯化,得浅白色半固体3-4(35.0mg,收率30.0%)。LC-MS m/z(ESI):734.1[M+H]+
3.5化合物3的合成
冰浴下,将HCl的1,4-二氧六环溶液(4M,2mL)加入3-4(30.0mg)中。室温搅拌4小时,减压浓缩,残余物经高效液相色谱(柱:Xbridge-C18 150×19mm,5um;流动相:ACN--H2O(0.1%FA);B%:10%-40%,20min)纯化,得白色固体3的甲酸盐(9.0mg,收率39.1%)。LC-MS m/z(ESI):534.1[M+H]+1H NMR(400MHz,DMSO-d6)δppm 10.11-9.98(m,1H),8.08(d,J=8.4Hz,1H),7.96-7.86(m,1H),7.69-7.58(m,1H),7.54-7.35(m,1H),5.65(t,J=26.8Hz,3H),3.95(d,J=11.8Hz,2H),3.56-3.46(m,3H),2.40-2.28(m,3H),2.27-2.15(m,2H),2.09-1.99(m,3H),1.98-1.53(m,9H),1.49-1.32(m,2H),1.11-1.02(m,3H).
4.实施例4的合成
4.1中间体4-1的合成
将二碳酸二叔丁酯(11.5g),三乙胺(5.5g)和4-二甲氨基吡啶(0.6g)加入到化合物6-甲基-1H-吲哚-5-羧酸甲酯(3.0g)的二氯甲烷(30mL)溶液中,室温搅拌2小时。加入水(200mL),二氯甲烷(100mL×3)萃取,有机相用饱和氯化钠(50mL)溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=5/1)纯化得无色油状物4-1(5.5g,收率89.2%)。LC-MS m/z(ESI):449.0[2M+H]+
4.2中间体4-2的合成
-78℃,氮气氛围下,将双三甲基硅基胺基锂(30mL,1M)的四氢呋喃溶液加入到4-1(5.5g)四氢呋喃(60mL)溶液中,-78℃搅拌1.5小时,加入N-苯基双(三氟甲烷磺酰)亚胺(13.5g),室温搅拌12小时。加入饱和氯化铵溶液(5mL)淬灭,加入水(100mL),乙酸乙酯(50mL×3)萃取,有机相用饱和氯化钠溶液(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=20/1)纯化得无色油状物4-2(6.5g,收率70.2%)。LC-MS m/z(ESI):289.9[M-56+H]+
4.3中间体4-3的合成
将[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(2.3g),碳酸钠(3.3g)和4-2(6.5g)加入到5-苯并噻唑频哪醇硼酸酯(4.0g)的二氧六环和水(60mL,v/v=3:1)溶液中,氮气保护下,90℃搅拌16小时。冷却至室温,减压浓缩,加入水(100mL),乙酸乙酯(50×3mL)萃取,有机相用饱和氯化钠(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=5/1)纯化得白色固体4-3(2.4g,收率45.5%)。LC-MS m/z(ESI):331.0[M+H]+
4.4中间体4-4的合成
冰浴下,将三氟乙酸(5mL)加入4-3(2.4g)的二氯甲烷(15mL)溶液中。室温搅拌1小时。减压浓缩,碳酸氢钠调pH至弱碱性,二氯甲烷(50×3mL)萃取,有机相用饱和氯化钠溶液(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩得4-4(1.5g),粗品直接用于下一步反应。LC-MS m/z(ESI):231.0[M+H]+
4.5中间体4-5的合成
冰浴下,将硼氢化钠(600.0mg)加入到4-4(1.5g)的甲醇(20mL)溶液中,0℃搅拌2小时,加水(100mL),二氯甲烷(3×80mL)萃取,有机相用饱和氯化钠溶液(50mL)洗涤。残余物经硅胶柱层析(洗脱剂:二氯甲烷/甲醇=10/1)纯化得白色固体4-5(1.4g,两步收率83.3%)。LC-MS m/z(ESI):233.1[M+H]+
4.6中间体4-6的合成
冰浴下,将草酰氯单甲酯(630.0mg)滴加到三乙胺(440.0mg)和4-5(1.0g)的二氯甲烷(15mL)溶液中,室温搅拌2小时。加水(50mL),二氯甲烷(30mL×3)萃取,有机相用饱和氯化钠溶液(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=5/1-1/1)纯化得无色油状物4-6(1.1g,收率75.4%)。LC-MS m/z(ESI):319.0[M+H]+
4.7中间体4-7的合成
将氢氧化锂(170.0mg)加入到4-6(1.1g)的甲醇和水的混合溶液(20mL,v/v=1:1)中,室温搅拌2小时。盐酸(1M)调至酸性,二氯甲烷(30mL×3)萃取,有机相用饱和氯化钠溶液(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得白色固体4-7(950.0mg),粗品直接用于下一步反应。LC-MS m/z(ESI):305.0[M+H]+
4.8中间体4-8的合成
将N,N,N,N-四甲基氯甲脒六氟磷酸盐(370.0mg)和N-甲基咪唑(110.0mg)加入到4-7(200.0mg)和2-9(240.0mg)的乙腈(6mL)溶液中,室温搅拌5小时。加水(40mL),乙酸乙酯(20mL×3mL)萃取,有机相用饱和氯化钠溶液(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:二氯甲烷/甲醇=20/1-10/1)纯化得黄色固体4-8(300.0mg,收率56.6%)。LC-MS m/z(ESI):650.0[M+H]+
4.9化合物4的合成
将化合物4-8(300.0mg)加入到1,4-二氧六环的盐酸(6mL,4M)溶液中,室温搅拌1小时。反应液减压浓缩,加入水(10mL),用饱和碳酸氢钠溶液调节pH至弱碱性,二氯甲烷(10mL×3)萃取,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物经硅胶柱层析(洗脱剂:二氯甲烷/甲醇=20/1-10/1)纯化得黄色固体(250.0mg),经SFC(柱:CHIRALPAK AS-H 250mm×20mm,5μm;流动相:40%IPA(0.2%NH4OH))拆分得白色固体(ee=80%,65.0mg,RT=6.08min),再经高效液相色谱(柱:Gemini 5u C18 150 x 21.2mm;mobile phase:[water(FA)-ACN];B%:2%-20%,15min)纯化得白色固体4 (ee=100%,56.0mg,产率33.1%)。LC-MS m/z(ESI):449.9[M+H]+1H NMR(400MHz,DMSO-d6)δppm 10.92-10.74(m,1H),9.48-9.36(m,1H),8.25-8.16(m,1H),8.15-8.03(m,1H),7.99-7.85(m,1H),7.86-7.72(m,1H),7.60-7.43(m,1H),6.36-6.16(m,2H),5.89-5.22(m,1H),4.32-4.22(m,3H),3.54-3.36(m,2H),2.47-2.03(m,2H),1.99-1.66(m,2H),1.40-1.30(m,1H),1.08(d,J=4.0Hz,3H).
5.实施例5的合成
5.1中间体5-1的合成
将3-1(2.6g),[(2-二-环己基膦基-3,6-二甲氧基-2′,4′,6′-三异丙基-1,1′-联苯基)-2-(2′-氨基-1,1′-联苯基)]甲磺酸钯(II)甲磺酸酯(469.4mg)和2-(二环己基膦)-3,6-二甲氧基-2′,4′,6′-三异丙基-1,1′-联苯(138.8mg)加入到1-氨基环丙烷-1-羧酸甲酯(357.4mg)的1,4-二氧六环(50mL)溶液中。氮气保护下,100℃搅拌8小时。冷却至室温,向反应液中加入水(50mL),用乙酸乙酯(30mLx3)萃取,有机相用饱和氯化钠溶液(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=1/1)纯化得淡黄色固体5-1(220.0mg,收率20.1%)。LC-MS m/z(ESI):422.1[M+H]+
5.2中间体5-2的合成
将氢氧化锂(65.8mg),加入到5-1(220.0mg)的四氢呋喃和水(10mL,V/V=5/1)溶液中。40℃搅拌5小时。减压浓缩,残余物经高效液相色谱(柱:Daisogel-C18 30 x 250mm,10um;流动相:ACN--H2O(0.1%FA);B%:5%-60%,80min)纯化得淡黄色固体5-2(120.0mg,收率74.6%)。LC-MS m/z(ESI):308.2[M+H]+
5.3中间体5-3的合成
将5-2(40.0mg),N,N-二异丙基乙胺(50.4mg),2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(99.1mg)加入到1-8(41.2mg)的N,N-二甲基甲酰胺(5mL)溶液中。氮气保护下,室温搅拌2小时。加入水(10mL),用乙酸乙酯(5mLx3)萃取,有机相用饱和氯化钠溶液(5mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=1/2)纯化得淡黄色固体5-3(42.7mg,收率54.2%)。LC-MS m/z(ESI):606.2[M+H]+
5.4化合物5的合成
冰浴下,将三氟乙酸(2mL)加入到5-4(42.7mg)的二氯甲烷(6mL)溶液中。室温搅拌1小时,减压浓缩,残余物经高效液相色谱(柱:Xbridge-C18 150 x 19mm,5um;流动相:ACN--H2O(0.1%FA);B%:5%-10%,20min)纯化得白色固体5的甲酸盐(14.0mg,收率29.3%)。LC-MS m/z(ESI):506.1[M+H]+1H NMR(400MHz,DMSO-d6)δppm 7.89-7.73(m,1H),7.66-7.53(m,1H),7.22(s,1H),7.05-6.94(m,1H),6.20-5.66(m,5H),4.08(d,J=12.6Hz,1H),3.96-3.94(m,2H),3.52-3.47(m,3H),2.29-2.19(m,1H),2.02-1.97(m,6H),1.84-1.75(m,3H),1.64-1.57(m,1H),1.38-1.23(m,3H),1.19-1.14(m,1H),0.98-0.77(m,5H).
6.实施例6的合成
6.1中间体6-1的合成
将二碳酸二叔丁酯(18.0g),三乙胺(13.0g),4-二甲氨基吡啶(0.8g)加入到2-氨基-3-甲基-5-硝基吡啶(5.0g)的二氯甲烷(50mL)溶液中,室温搅拌3小时,乙酸乙酯萃取(100mL x 3),有机相用饱和氯化钠溶液(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=5/1)纯化得白色固体6-1(10.0g,收率86.9%)。LC-MS m/z(ESI):376.1[M+Na]+
6.2中间体6-2的合成
将10%钯碳(2.0g)加入到化合物6-1(10.0g)的甲醇(100mL)溶液中,氢气置换3次,室温搅拌2小时。过滤,滤液减压浓缩得淡黄色固体6-2(9.2g),未经纯化直接用于下一步反应。LC-MS m/z(ESI):324.2[M+H]+
6.3中间体6-3的合成
将3,3,3-三氟丙酮酸乙酯(780.0mg)和无水对甲苯磺酸(54.0mg)加入到6-2(1.0g)的无水甲苯(20mL)溶液中。氮气保护下100℃搅拌15小时。冷却至室温,减压浓缩得淡黄色固体6-3(1.8g),未经纯化直接用于下一步反应。LC-MS m/z(ESI):476.0[M+H]+
6.4中间体6-4的合成
氮气氛围下,将氰基硼氢化钠(125.0mg)加入到粗品6-3(1.8g)的乙酸(20mL)溶液中,室温搅拌1小时。加入水(20mL)稀释,乙酸乙酯萃取(10mL x 3),有机相用饱和氯化钠溶液(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=3/1-1/1)纯化得白色固体6-4(300mg,收率20.4%)。LC-MS m/z(ESI):478.3[M+H]+
6.5中间体6-5的合成
将三甲基氢氧化锡(342.0mg)加入到6-4(300mg)的1,2-二氯乙烷(10mL)溶液中。氮气保护 下50℃搅拌3小时。加入水(10mL)稀释,二氯甲烷萃取(10mL x 3),有机相用饱和氯化钠溶液(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得黄色固体6-5(200mg,收率70.8%)。LC-MS m/z(ESI):450.0[M+H]+
6.6中间体6-6的合成
将化合物1-8(50.0mg)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(80.0mg)加入到6-5(50mg)的N,N-二甲基甲酰胺(5mL)溶液中。室温搅拌3小时。加入水(20mL),乙酸乙酯(20mL×3)萃取,有机相用饱和氯化钠溶液(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:二氯甲烷/甲醇=30/1)纯化得白色固体6-6(12.0mg,收率14%)。LC-MS m/z(ESI):748.2[M+H]+
6.7化合物6的合成
冰浴下,将三氟乙酸(0.5mL)加入6-6(14.0mg)的二氯甲烷(2mL)溶液中,室温搅拌2小时。减压浓缩,残余物经高效液相色谱(柱:Xbridge-C18 150 x 19mm,5um;流动相:ACN--H2O(0.05%FA);B%:5%-60%,35min)纯化得白色固体6的甲酸盐(1.4mg,收率14.1%)。LC-MS m/z(ESI):548.2[M+H]+1H NMR(400MHz,MeOD-d4)δppm 7.72-7.60(m,2H),7.45(d,J=2.8Hz,1H),7.10(s,1H),6.61(s,1H),5.74(s,1H),4.50(s,2H),4.02-3.89(m,2H),3.63(s,1H),3.59-3.45(m,2H),3.39-3.24(m,1H),2.16(s,2H),2.07-1.88(m,7H),1.68(s,2H),1.28(s,1H),1.01(s,3H).
7.实施例7的合成
7.1中间体7-1的合成
0℃下,将双三甲基硅基胺基锂的四氢呋喃溶液(77.8mL,1M)加入到2-胺基-4-氯-吡啶(5.0g) 的四氢呋喃(50mL)溶液中,搅拌0.5小时,将二碳酸二叔丁酯(10.2g)慢慢加入,混合物室温搅拌2小时,加水(50mL),乙酸乙酯(60mL×3)萃取,有机相用饱和氯化钠溶液(50mL)洗涤。无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=2/1-1/1)纯化得白色固体7-1(6.0g,收率60.7%)。LC-MS m/z(ESI):173.0[M-56+H]+
7.2中间体7-2的合成
-78℃下,将正丁基锂的四氢呋喃溶液(4.4mL,2.4M)加入到7-1(1.0g)的四氢呋喃溶液(10mL)中,氮气保护下,-78℃搅拌0.5小时后加入N,N-二甲基甲酰胺(1.6g),室温搅拌1小时。向反应液中加入饱和氯化铵溶液(10mL),乙酸乙酯(15mL×3)萃取,有机相用饱和氯化钠溶液(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=1/2)纯化得黄色固体7-2(270.0mg,收率20.5%)。LC-MS m/z(ESI):156.9[M-100+H]+
7.3中间体7-3的合成
冰浴下,将三氟乙酸(600.0mg)加入7-2(270.0mg)的二氯甲烷(3mL)溶液中。室温搅拌1小时,减压浓缩。用饱和碳酸氢钠溶液调pH至弱碱性,二氯甲烷(10mL×3)萃取,有机相用饱和氯化钠溶液(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得黄色固体粗品7-3(180.0mg),粗品直接用于下一步反应。LC-MS m/z(ESI):157.0[M+H]+
7.4中间体7-4的合成
将N-溴代丁亚酰二胺(187.5mg)加入7-3(150.0mg)的1,2-二氯乙烷(3mL)溶液中。50℃搅拌2小时,冷却至室温,有机相用饱和亚硫酸钠溶液(3mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得黄色固体7-4(180.0mg),粗品直接用于下一步反应。LC-MS m/z(ESI):235.0,237.0[M+H]+
7.5中间体7-5的合成
将水合肼(171.9mg)加入7-4(160.0mg)的二甲基亚砜(2mL)溶液中。120℃搅拌2小时,冷却至室温,加水(5mL),乙酸乙酯(5mL×3)萃取,有机相用饱和氯化钠溶液(5mL)洗涤。无水硫酸钠干燥,过滤,滤液减压浓缩后加入二氯甲烷(2mL),过滤得黄色固体7-5(60.0mg,收率35.2%)。LC-MS m/z(ESI):213.0,215.0[M+H]+
7.6中间体7-6的合成
氮气保护下0℃将偶氮二甲酸二异丙酯(142.3mg)加入到7-5(100.0mg),三苯基膦(160.0mg)和甲醇(30.0mg)的四氢呋喃(2mL)溶液中,室温搅拌16小时,加入水(5mL),乙酸乙酯(5mL×3)萃取,有机相用饱和氯化钠溶液(5mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物经硅胶柱层析(洗脱剂:二氯甲烷/乙酸乙酯=1/2)纯化得白色固体7-6(70.0mg,收率59.1%)。LC-MS m/z(ESI):226.9,228.9[M+H]+
7.7中间体7-7的合成
将二碳酸二叔丁酯(148.0mg)加入到7-6(70mg),三乙胺(62.3mg)和4-二甲氨基吡啶(3.7mg)的二氯甲烷(2mL)溶液中,室温搅拌3小时。减压浓缩,残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=1/1)纯化得白色固体7-7(100.0mg,收率89.2%)。LC-MS m/z(ESI):427.0,429.0[M+H]+
7.8中间体7-8的合成
将7-7(150.0mg),二苯甲酮亚胺(127.2mg),三(二亚卞基丙酮)二钯(32.1mg),1,1'-联苯-2,2'-双二苯膦(32.7mg),碳酸铯(228.7mg)加入甲苯(10mL)溶液中。氮气保护下,110℃搅拌16小时。过滤,减压浓缩,残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=1/3)纯化得黄色固体7-8(100.0mg,收率48.6%)。LC-MS m/z(ESI):528.3[M+H]+
7.9中间体7-9的合成
0℃下,将盐酸(1mL,2M)溶液加入到7-8(90.0mg)的四氢呋喃溶液(2mL)中,0℃搅拌1小时,减压浓缩后冻干得黄色固体7-9(20.0mg),粗品未经纯化直接用于下一步反应。LC-MS m/z(ESI):264.1[M+H]+
7.10中间体7-10的合成
将N-甲基咪唑(123.0mg)加入7-9(20.0mg)和1-10(32.4mg),四甲基氯代脲六氟磷酸酯(42.6mg)的乙腈(2mL)溶液中。室温搅拌2小时,加入水(5mL),乙酸乙酯(5mL×3)萃取,有机相用饱和氯化钠溶液(5mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物经硅胶柱层析(洗脱剂:二氯甲烷/甲醇=15/1)纯化得黄色固体7-10(15.0mg,收率15.5%)。LC-MS m/z(ESI):634.2[M+H]+
7.11化合物7-11的合成
冰浴下,将HCl的二氧六环溶液(2mL,4M)加入7-10(15.0mg)的二氧六环(1mL)溶液中。室温搅拌1小时,减压浓缩,残余物经高效液相色谱(柱:Xbridge-C18 150×19mm,5um;流动相:ACN--H2O(0.1%FA);B%:5%-10%,20min)纯化得白色固体7的甲酸盐(4.3mg,收率42.8%)。LC-MS m/z(ESI):534.0[M+H]+1H NMR(400MHz,CD3OD)δppm 8.18-8.12(m,1H),7.98-7.73(m,2H),7.53-7.31(m,2H),5.85-5.75(m,1H),4.16-4.08(m,2H),4.05-4.02(m,2H),3.96-3.94(m,1H),3.62-3.55(m,2H),3.43-3.36(m,1H),2.35-2.26(m,2H),2.20-1.90(m,6H),1.49-1.26(m,3H),1.18-1.13(m,3H).
8.实施例8的合成
8.1中间体8-1的合成
0℃下,将浓硝酸(1.0mL)加入到[2,6]萘啶-1-氨基(1.0g)的浓硫酸(20mL)溶液中,搅拌16小时。反应液缓慢倒入饱和碳酸氢钠溶液中,调节pH=8。过滤,滤饼干燥后得黄色固体8-1(1.0g,收率75.75%)。LC-MS m/z(ESI):191.1[M+H]+
8.2中间体8-2的合成
0℃下,将氢化钠(336.8mg,60%wt)加入到8-1(1.0g)的四氢呋喃溶液(500mL)中,搅拌0.5 小时,加入二碳酸二叔丁酯(10.2g),室温搅拌1小时。加入饱和氯化铵溶液(10mL),无水硫酸钠干燥,过滤,滤液减压浓缩,残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=2/1)纯化得黄色固体8-2(1.0g,收率65.5%)。LC-MS m/z(ESI):291.1[M+H]+
8.3中间体8-3的合成
将还原铁粉(1.9g)加入8-2(1.0g)和氯化铵(900.0mg)的乙醇和水(30mL,V/V=1:9)混合溶液中。50℃搅拌8小时,加入水(20mL),乙酸乙酯(30mL×3)萃取,有机相用饱和氯化钠溶液(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物经硅胶柱层析(洗脱剂:二氯甲烷/甲醇=20/1)纯化得黄色油状物体8-3(600.0mg,收率66.9%)。LC-MS m/z(ESI):261.2[M+H]+
8.4中间体8-4的合成
将N-甲基咪唑(50.4mg)加入8-3(80.0mg)和1-10(131.3mg),四甲基氯代脲六氟磷酸酯(258.6mg)的乙腈(2mL)溶液中。室温搅拌2小时,加入水(5mL),乙酸乙酯(5mL×3)萃取,有机相用饱和氯化钠溶液(5mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=1/1)纯化得黄色油状物体8-4(150.0mg,收率69.6%)。LC-MS m/z(ESI):631.0[M+H]+
8.5化合物8的合成
冰浴下,将三氟乙酸(1mL)加入8-4(130.0mg)的二氧甲烷(2mL)溶液中。室温搅拌1小时,饱和碳酸钠溶液调节pH=8,二氯甲烷(5mL×3)萃取,减压浓缩,残余物经高效液相色谱(柱:Xbridge-C18 150×19mm,5um;流动相:ACN--H2O(0.1%FA);B%:5%-10%,20min)纯化得黄色固体8的甲酸盐(60mg,收率52.1%)。LC-MS m/z(ESI):531.0[M+H]+1H NMR(400MHz,DMSO-d6)δppm10.77-10.70(m,1H),8.63-8.29(m,2H),8.12-8.06(m,2H),7.97-7.84(m,2H),7.50-7.40(m,1H),7.29-7.24(m,2H),5.80-5.76(m,1H),3.96-3.94(m,2H),3.59-3.47(m,4H),2.06-1.94(m,4H),1.87-1.75(m,4H),1.46-1.37(m,2H),1.15-1.08(m,3H),
9.实施例9的合成
9.1中间体9-1的合成
将2-氯-4-溴嘧啶(100.0mg)加入到1-8(196.9mg)的乙二醇单甲醚(5mL)溶液中,125℃下搅拌3小时。加入水(10mL),二氯甲烷(10mL×3)萃取,有机相用饱和氯化钠溶液(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:二氯甲烷/甲醇=20/1)纯化得白色固体9-1(60.0mg,收率25.7%)。LC-MS m/z(ESI):429.0[M+H]+
9.2中间体9-2的合成
将联硼酸频那醇酯(235.0mg),醋酸钾(298.2mg)加入3-1(300.0mg)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(126.2mg)的1,4-二氧六环(15mL)溶液中,90℃搅拌16小时。冷却至室温,加入水(30mL),二氯甲烷(30mL×3)萃取,有机相用饱和氯化钠溶液(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:二氯甲烷/甲醇=20/1)纯化得白色固体9-2(250.0mg,收率74.2%)。LC-MS m/z(ESI):435.2[M+H]+
9.3化合物9的合成
将[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(22.8mg),碳酸铯(91.2mg)加入9-1(21.0mg)和9-2(72.9mg)的1,4-二氧六环(5mL)和水(1mL)的混合溶液中,90℃搅拌16小时。冷却至室温,加入水(20mL),二氯甲烷(15mL×3)萃取,有机相用饱和氯化钠溶液(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经高效液相色谱(柱:Xbridge-C18 150×19mm,5um;流动相:ACN--H2O(0.1%TFA);B%:5%-10%,20min)纯化得白色固体9的三氟乙酸盐(1.4mg,收率5.6%)。LC-MS m/z(ESI):501.2[M+H]+1H NMR(400MHz,CD3OD)δppm 8.62(d,J=4.0Hz,1H),8.11(d,J=8.0Hz,1H),8.03(s,1H),7.94(d,J=8.0Hz,1H),7.81(s,1H),7.40(dd,J=4.0,8.0Hz,1H),6.57(d,J=8.0Hz,1H),5.80-5.77(m,1H),4.20-4.17(m,1H),4.05-4.02(m,2H),3.59-3.55(m,3H),3.39-3.35(m,1H),2.38-2.32(m,2H),2.14(s,3H),1.99-1.96(m,2H),1.93-1.90(m,4H),1.11(d,J=8.0Hz,3H).
10.实施例10的合成
10.1中间体10-1的合成
0℃,氮气氛围下,将2-溴-5-羟基吡嗪(10.0g)的N,N-二甲基甲酰胺(30mL)和四氢呋喃(30mL)溶液缓慢滴加到氢化钠(2.7g,60%wt)的N,N-二甲基甲酰胺(30mL)溶液中,0℃搅拌30分钟,加入4-甲氧基苄氯(10.0g)的四氢呋喃(30mL)溶液,缓慢升至室温搅拌16小时。冷却至0℃,滴加饱和氯化铵溶液(10mL)淬灭,加水(500mL)稀释,乙酸乙酯(100mL×3)萃取,有机相用饱和氯化钠溶液(50mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=3/1-2/1)纯化得白色固体10-1(11.0g,收率65.5%)。LC-MS m/z(ESI):316.9,318.9[M+Na]+
10.2中间体10-2的合成
0℃,氮气氛围下,将对甲基苯磺酰甲基异腈(8.9g)和10-1(12.2g)的四氢呋喃(60mL)溶液缓慢滴加到氢化钠(2.3g,60%wt)的四氢呋喃(60mL)溶液中,0℃搅拌30分钟,升至室温搅拌1小时。冷却至0℃,滴加饱和氯化铵溶液(5mL)淬灭,加水(500mL)稀释,乙酸乙酯(100mL×3)萃取,有机相用饱和氯化钠溶液(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=2/3-1/4)纯化得白色固体10-2(10.0g,收率72.4%)。LC-MS m/z(ESI):333.9,335.9[M+H]+
10.3中间体10-3的合成
0℃,氮气氛围下,将三氟甲磺酸(25mL)加入到10-2(10.0g)的三氟乙酸(100mL)和苯甲醚(45mL)溶液中。升至室温搅拌30分钟,40℃搅拌1小时。减压浓缩,缓慢将残余物倒入碳酸氢钠的冰水混合物中,60℃减压浓缩,残余物用二氯甲烷和甲醇(200mL,V/V=10:1)打浆,过滤,滤 液减压浓缩,残余物经硅胶柱层析(洗脱剂:二氯甲烷/甲醇=100/5-100/6)纯化得白色固体10-3(4.5g,收率71.4%)。LC-MS m/z(ESI):213.9,215.9[M+H]+
10.4中间体10-4的合成
将4-甲氧基苄胺(4.6g),1,8-二氮杂环[5,4,0]十一烯-7(6.8g)和苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(14.8g)加入到10-3(4.5g)的无水乙腈(80mL)溶液中,80℃搅拌16小时。冷却至室温,减压浓缩,加水(100mL)稀释,乙酸乙酯(50mL×3)萃取,有机相用饱和氯化钠溶液(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=3/1-1/1)纯化得淡黄色固体10-4(6.0g,收率85.7%)。LC-MS m/z(ESI):333.1,335.0[M+H]+
10.5中间体10-5的合成
将10-4(5.0g)加入到三氟乙酸(50mL)中,80℃搅拌16小时。冷却至室温,减压浓缩,残余物用碳酸氢钠溶液调pH至弱碱性,乙酸乙酯(50mL×3)萃取,有机相用饱和氯化钠溶液(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物经硅胶柱层析(洗脱剂:二氯甲烷/甲醇=100/3)纯化得得黄色固体10-5(2.3g,收率71.8%)。LC-MS m/z(ESI):213.0,214.9[M+H]+
10.6中间体10-6的合成
将二碳酸二叔丁酯(5.9g),三乙胺(3.2g),4-二甲氨基吡啶(0.3g)加入到10-5(2.3g)的二氯甲烷(30mL)溶液中,室温搅拌16小时。加入二氯甲烷(100mL),饱和氯化钠溶液(50mL)洗涤,有机相用无水硫酸钠干燥,过滤,反应液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=3/1)纯化得黄色固体10-6(2.5g,收率54.3%)。LC-MS m/z(ESI):412.9,414.9[M+H]+
10.7中间体10-7的合成
将二苯甲酮亚胺(440.0mg),碳酸铯(790.0mg),1,1'-联萘-2,2'-双二苯膦(150.0mg)和三(二亚苄基丙酮)二钯(110.0mg)加入到10-6(500.0mg)的无水甲苯(20mL)溶液中,氮气保护下,100℃搅拌16小时。冷却至室温,加水(50mL)稀释,乙酸乙酯(30mL×3)萃取,有机相用饱和氯化钠溶液(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=4/1-3/1)纯化得黄色固体10-7(500.0mg,收率80.3%)。LC-MS m/z(ESI):514.1[M+H]+
10.8中间体10-8的合成
将盐酸(5mL,2M)加入到10-7(500.0mg)的甲醇(5mL)溶液中,室温搅拌30分钟。用饱和碳酸氢钠溶液调pH至弱碱性,乙酸乙酯(30mL×3)萃取,有机相用饱和氯化钠溶液(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:二氯甲烷/甲醇=100/31-100/3)纯化得类白色固体10-8(300.0mg,收率88.3%)。LC-MS m/z(ESI):350.2[M+H]+
10.9中间体10-9的合成
将草酰氯单甲酯(83.0mg),三乙胺(80.0mg)加入到10-8(200.0mg)的二氯甲烷(5mL)溶液中,室温搅拌3小时。加水(10mL)稀释,乙酸乙酯(20mL×3)萃取,有机相用饱和氯化钠溶液(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=1/1)纯化得类白色固体10-9(100.0mg,收率40.2%)。LC-MS m/z(ESI):436.1[M+H]+
10.10化合物10的合成
0℃,氮气氛围下,将三甲基铝(0.25mL,1M正己烷溶液)滴加到1-8(28.0mg)的无水甲苯(2mL)溶液中,0℃搅拌0.5小时,加入10-9(30.0mg),100℃搅拌16小时。冷却至室温,减压浓缩,加入饱和碳酸氢钠溶液(10mL)和水(20mL),二氯甲烷萃取(10mL×3),有机相用饱和氯化钠溶 液(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物经高效液相色谱(柱:Xbridge-C18150×19mm,5um;流动相:ACN--H2O(0.1%FA);B%:5%-30%,14min)纯化得白色固体10的甲酸盐(1.0mg,收率2.8%)。LC-MS m/z(ESI):520.2[M+H]+1H NMR(400MHz,MeOD-d4)δppm 8.28-8.22(m,1H),8.03-7.99(m,1H),7.96(s,1H),7.92-7.85(m,1H),7.51-7.42(m,1H),7.07-7.01(m,1H),5.37-5.32(m,1H),4.08-4.01(m,2H),3.66-3.56(m,2H),2.41-2.33(m,1H),2.22-2.16(m,1H),2.15-2.07(m,2H),2.06-1.92(m,4H),1.64-1.56(m,1H),1.53-1.46(m,1H),1.31-1.26(m,3H),1.21-1.14(m,2H).
11.实施例98的合成
11.1中间体98-1的合成
将三苯基膦(22.3mg),碳酸钾(718.3mg)加入到双三苯基磷二氯化钯(36.5mg),联硼酸频那醇酯(659.9mg)和1-1(600.0mg)的二氧六环溶液(20mL)中。氮气保护下90℃搅拌3小时。反应液冷却至室温,将反应液过滤,滤液减压浓缩,残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=20/1-2/1)纯化得白色油状98-1(525.0mg,收率93.5%)。LC-MS m/z(ESI):346.2[M+Na]+
11.2中间体98-2的合成
将98-1(813.8mg),四三苯基膦钯(241.7mg)和氢氧化钾(352.1mg)加入到1-溴-4-[(二氟甲基)硫烷基]苯(500.0mg)的1,4二氧六环和水混合溶液(22mL,v/v=10:1)中。氮气保护下70℃下搅拌1小时。向反应液中加入水(10mL),用二氯甲烷(10mLⅹ3)萃取,合并有机相,有机相用饱和氯化钠溶液(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物经硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=10/1)纯化得白色固体98-2(330.0mg,收率44.3%)。LC-MS m/z(ESI):300.0[M-55]+
11.3中间体98-3的合成
将98-2(330.0mg)加入到三氟乙酸和二氯甲烷混合溶液(6mL,v/v=2:1)中。氮气保护下室温下搅拌1小时。反应液未经纯化直接进行下一步反应。LC-MS m/z(ESI):256.2[M+H]+
11.4中间体98-4的合成
氮气保护下0℃,将硼氢化钠(170.4mg)加入到98-3(230.0mg)的甲醇溶液(5mL)中,搅拌1小时。向反应液中加入水(50mL),用二氯甲烷(50mLⅹ3)萃取,合并有机相,有机相用饱和氯化钠溶液(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得粗品黄色油状98-4(230.0mg,收率99.2%)。产物未经纯化直接进行下一步反应。LC-MS m/z(ESI):258.1[M+H]+
11.5中间体98-5的合成
0℃下,将草酰氯单乙酯(305.1mg)加入到三乙胺(271.3mg)和98-4(230.0mg)的二氯甲烷溶液(1.0mL)中。反应液升至室温,氮气保护下搅拌1小时。向反应液中加入水(10mL),用二氯甲烷(10mLⅹ3)萃取,合并有机相,有机相用饱和氯化钠溶液(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得粗品黄色油状物98-5(100.0mg,收率93.9%)。LC-MS m/z(ESI):358.1[M+H]+
11.6中间体98-6的合成
将氢氧化锂一水合物(352.2mg)加入到98-5(300.0mg)的甲醇和水混合溶液(4.0mL,v/v=3:1)中。氮气保护下室温搅拌1小时。向反应液中加入(10mL)水,滴加盐酸(1M)至反应液pH为5~6,水相经反相经碳十八柱(洗脱剂:0.1%FA/乙腈=50%)纯化后冻干得白色固体98-6的甲酸盐(180.0mg,收率65.1%)。LC-MS m/z(ESI):330.0[M+H]+
11.7中间体98-7的合成
将N-甲基咪唑(56.2mg)和N,N,N',N'-四甲基氯甲脒六氟磷酸盐(191.9mg)加入到2-9(50.0mg)和98-6(67.6mg)的N,N-二甲基甲酰胺溶液(1mL)中,室温搅拌1小时。将反应液滴加到冰水中,固体析出,减压抽滤,收集滤饼得粗品黄色固体98-7(50.0mg,收率54.0%)。LC-MS m/z(ESI):675.2[M+H]+
11-8化合物98的合成
将98-7(50.0mg)加入到HCl的二氧六环溶液(2mL,4M)中,氮气保护下,常温搅拌1小时。反应液减压浓缩,残余物经高效液相色谱(柱:Xbridge-C18 150×19mm,5um;流动相:ACN--H2O(0.1%FA);B%:20%-95%,9.5min)纯化得白色固体98的甲酸盐(14.1mg,收率40.2%)。LC-MS m/z(ESI):475.0[M+H]+1H NMR(400MHz,DMSO-d6,80℃)δ10.48(s,1H),7.79-7.90(m,2H),7.63-7.61(m,2H),7.54-7.40(m,3H),5.99(s,2H),5.55(s,1H),4.27(s,3H),3.14-3.10(m,2H),2.25-2.06(m,2H),1.72(s,1H),1.68-1.65(m,1H),1.26-1.24(m,1H),1.05(d,J=7.0Hz,3H)。
如下列表化合物,通过实施例1,2,98相同合成策略进行合成:

















实验例1:细胞抗增殖实验方法
1.1材料与细胞
HCT116MTAP Deletion细胞来源于Pharmaron(中国);HCT116细胞来源于ATCC(美国);McCoy's5A培养基购于Invitrogen公司(美国);青霉素-链霉素和胎牛血清购于Gibco公司(美国);384孔板购于PerkinElmer公司(美国);Cell-Titer Glo试剂购于Promega公司(美国)。
1.2化合物储存
化合物溶解:所有化合物使用二甲基亚砜(DMSO)溶解后储存。在室温干燥的条件下短期保存3个月或者-20℃长期保存。
1.3细胞培养及传代
细胞严格按照ATCC要求进行培养。将细胞培养基(McCoy's 5A培养基+10%胎牛血清+1%青霉素+链霉素)转移至15mL离心管中,1000rpm,离心5min。去除上清,用完全培养基重悬细胞,按所需密度接种于培养皿中,置于37℃,95%的潮湿空气,5%二氧化碳的培养箱中培养,视细胞生长情况每2-3天补一次培养液或进行传代。
1.4细胞增殖活性检测
细胞在培养皿中的汇合度达到90%左右时,用PBS清洗细胞两次后,使用胰蛋白酶将细胞处理成单细胞,进行细胞计数,每孔40μl接种于384孔板(50个细胞/孔),置于37℃,5%二氧化碳条件下平衡10-15min。利用Echo550将化合物打入384孔板中,设置day0_cell和阴性对照(0.1%DMSO),每个化合物10个梯度,3倍稀释,双复孔,DMSO含量0.1%。将384孔板置于细胞培养箱中培养10天。
后将40μl细胞增殖检测试剂(CTG)加入到384孔板中并震板混匀,后将384孔板置于37℃,5%二氧化碳的条件下避光孵育30分钟。通过多功能酶标仪Envision进行读数。化合物抑制率百分比的计算公式如下:抑制率百分比=100-(信号值药物处理组-信号值day0_cell)/(信号值阴性对照组-信号值day0_cell)×100。根据不同药物浓度及其所对应的抑制率,使用GraphPad 8.0软件进行GI50曲线绘制,分析数据,得出最终GI50值。结果见表1,其中GI50≤0.1μM为A,0.1μM<GI50≤1μM为B,1μM<GI50≤10μM为C,10μM<GI50为D。
表1本发明化合物的测试结果


另外,本发明化合物还具有针对突变型HCT116细胞的选择性,例如化合物33和34对HCT116MTAP  Deletion的GI50为≤0.1μM,但对HCT116的GI50为1-10μM,选择性超过300倍。代表性化合物的选择性数据如表2所示:
表2代表性化合物的选择性数据

实验例2:细胞SDMA In-cell western实验方法
2.1材料与细胞
HCT116MTAP Deletion细胞来源于Horizon;HCT116细胞来源于ATCC;RPMI-1640培养基购于ATCC公司(美国);青霉素-链霉素购于Gibco公司(美国);胎牛血清购于ExCell公司;96孔板购于Corning公司(美国);Symmetric Di-Methyl Arginine Motif[sdme-RG]抗体购于CST(美国);IRDye 800CW Goat anti-Rabbit IgG二抗购于LI-COR(美国),CellTag 700stain购于LI-COR(美国)。
2.2化合物储存
化合物溶解:所有化合物使用二甲基亚砜(DMSO)溶解后储存。-20℃长期保存。
2.3细胞培养及传代
细胞严格按照ATCC要求进行培养。将细胞培养基(RPMI-1640培养基+10%血清+1%青霉素+链霉素)转移至15mL离心管中,1000rpm,离心5min。去除上清,用完全培养基重悬细胞,按所需密度接种于培养皿中,置于37℃,95%的潮湿空气,5%二氧化碳的培养箱中培养,视细胞生长情况每2-3天补一次培养液或进行传代。
2.4 SDMA In-cell western实验
细胞在培养皿中的汇合度达到90%左右时,用PBS清洗细胞两次后,用胰酶消化细胞,每孔100μL接种于96孔板(800/孔),在37℃,5%CO2培养箱中培养过夜。将50μL 3x终浓度的化合物加入细胞培养板中,每个化合物10个梯度,3倍稀释,双复孔,DMSO终浓度0.5%,在37℃,5%CO2培养箱中培养96小时。
每孔加入150μL 8%多聚甲醛,常温孵育15分钟。弃上清,PBS洗板,每孔加入200μL新制备的1x Permeabilization buffer,室温孵育30分钟。弃上清,每孔加入200μL 1x Blocking buffer,室温孵育2小时。弃上清,每孔加入50μL一抗(CST,1x Incubation buffer 1:500稀释),4℃过夜。弃上清,每孔加入250μL 1x Washing buffer,清洗三次。每孔加入50μL二抗(IRDye 800CW Goat anti-Rabbit IgG和CellTag 700染料,Incubation buffer 1:800和1:500稀释),室温孵育1小时。弃上清,1x Washing buffer洗板。使用Licor Odyssey CLX检测信号。化合物抑制率百分比的计算公式如下:抑制率百分比=100-(信号值药物处理组-信号值背景值)/(信号值0.5%DMSO处理组-信号值背景值)×100。根据不同药物浓度及其所对应的抑制率,使用GraphPad 8.0软件进行IC50曲线绘制,分析数据,得出最终IC50值。结果见表3,其中IC50≤0.1μM为A,0.1μM<IC50≤1μM为B,1μM<IC50≤10μM为C。
表3细胞SDMA抑制活性
实验例3 LU99 CDX模型体内药效学研究
3.1实验材料:LU99细胞来源于JCRB(日本);RPMI-1640和0.25%胰酶-EDTA购自Gibco(美国);胎牛血清购自东岭(中国);PBS购自Hyclone(美国);青霉素-链霉素购于美仑生物(中国);Matrigel基质胶购于Corning(美国)。
3.2动物信息:BALB/c Nude小鼠,雌性,6-8周龄,体重18-22克,动物购自北京维通利华实验 动物技术有限公司,将小鼠饲养在SPF级环境中,每个笼位单独送排风,所有动物都可以自由获取标准认证的商业实验室饮食和自由饮水。
3.3实验方法:
3.3.1细胞培养:人大细胞肺癌细胞LU99体外单层培养,培养条件为RPMI-1640培养基中加10%胎牛血清,37℃5%CO2孵箱培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞数量到达要求时,收取细胞,计数。
3.3.2细胞接种:将0.2mL(5×106个)LU99细胞(加基质胶,体积比为1:1)细胞皮下接种于每只小鼠的右后背,肿瘤平均体积达到约150mm3时,依据肿瘤体积和动物体重采用随机分层分组方法开始分组给药。
3.3.3给药:化合物14的给药剂量为30mpk,PO,每天一次给药(QD)×3周。每组6只小鼠。
3.3.4肿瘤测量和实验指标:
每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为:V=0.5a×b2,a和b分别表示肿瘤的长径和短径。每周两次测量小鼠体重。
化合物的抑瘤疗效用肿瘤生长抑制率TGI(%)来评价。
TGI(%)=[(1-(某处理组给药结束时平均瘤体积-该处理组开始给药时平均瘤体积))/(溶剂对照组治疗结束时平均瘤体积-溶剂对照组开始治疗时平均瘤体积)]×100%。
实验结果见图1和图2。实验过程中无小鼠发病或死亡。

Claims (48)

  1. 式(I)或(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,
    L1为NH或CHRx
    L2为CRxRy
    其中Rx和Ry独立地选自H、D、C1-6烷基或C1-6卤代烷基;
    或者CRxRy一起形成C=O、C=S或C3-6亚烷基;
    或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-4亚烷基;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    或者X1、X2以及他们的取代基一起形成C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基,其任选被1、2或3个R2s取代;
    X3为CR2d或N;
    并且X1、X2和X3所在的环为芳香环;
    R2a选自H、D、CN、ORa、NRbRc、C(O)ORa或C(O)NRbRc
    R2b选自H、D、卤素、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基;
    R2c选自H、D、卤素、C1-6烷基或C1-6卤代烷基;
    R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基;
    Ar1为苯基或5-6元杂芳基,其被m个R1取代;
    R1选自H、D、卤素、CN、NO2、-L-ORa、-L-SRa、-L-NRbRc、SF5、C(O)Ra、C(O)ORa、C(O)NRbRc、OC(O)Ra、NRbC(O)Rc、S(O)Ra、S(O)2Ra、S(O)ORa、S(O)2ORa、S(O)NRbRc、S(O)2NRbRc、P(O)(Ra)2、P(O)2Ra、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-10环烷基(例如C5-10环烷基)、4-10元杂环基(例如5-10元杂环基)、C6-10芳基或5-10元杂芳基,其任选被1、2或3个R1s取代;
    或者相邻的两个R1以及他们连接的原子一起形成C5-6环烷基、5-6元杂环基、苯基或5-6元杂芳基,其任选地被1、2或3个R1s取代;
    m=0、1、2、3、4或5;
    R1s选自H、D、卤素、=O、-L-ORa、-L-SRa、-L-NRbRc、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、-L-C3-10环烷基、-L-3-10元杂环基、-L-C6-10芳基或-L-5-10元杂芳基,其任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷基-OH、-C0-6亚烷基-OC1-6烷基、C1-6烷基或C1-6卤代烷基取代;
    或者孪位或相邻的两个R1s以及他们连接的原子一起形成C3-6环烷基、4-6元杂环基、苯基或5-6元杂芳基,其任选地被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔 基的基团取代;
    L为化学键、C1-6亚烷基、C2-6亚烯基或C2-6亚炔基,其任选被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;
    R2s选自H、D、卤素、=O、C(O)ORa、C(O)NRbRc、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;
    R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C(O)Ra、C(O)ORa、C(O)NRbRc、OC(O)Ra、NRbC(O)Rc、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;
    n=0、1、2、3、4、5、6或7;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-10元杂环基;
    其中上述L1、L2、Rx、Ry、Ar1、R1、R2a、R2b、R2c、R2d、R1s、L、R2s、R3、R3a、R3b、Ra、Rb和Rc中的各个基团定义任选地被氘代,直至完全氘代;
    条件是,当L2为C=O时,X1、X2以及他们的取代基一起形成任选被1、2或3个R2s取代的C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基。
  2. 权利要求1的式(I)或(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,Ar1为苯基或5元杂芳基;或者Ar1为苯基或6元杂芳基;Ar1优选为苯基、吡啶基或噻吩基;Ar1更优选为Ar1例如 例如 优选 更优选为优选其中R1s为H、Me、Et、iPr、 优选H、 更优选为
  3. 权利要求1或2的式(I)或(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,L1和L2
  4. 权利要求1-3中任一项的式(I)或(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,R1选自H、D、卤素、CN、NO2、-L-ORa、-L-SRa、-L-NRbRc、SF5、C(O)Ra、C(O)ORa、C(O)NRbRc、OC(O)Ra、NRbC(O)Rc、S(O)Ra、S(O)2Ra、S(O)ORa、S(O)2ORa、S(O)NRbRc、S(O)2NRbRc、P(O)(Ra)2、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-6环烷基、4-6元杂环基、C6-10芳基或5-10元杂芳基,其任选被1、2或3个R1s取代;优选H、D、卤素、CN、-L-ORa、-L-SRa、-L-NRbRc、SF5、S(O)Ra、S(O)2Ra、C1-6烷基、C1-6卤代烷基、C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基;优选H、D、卤素、CN、-L-ORa、-L-SRa、-L-NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基;优选选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基;优选地,相邻的两个R1以及他们连接的原子一起形成C5-6环烷基、5-6元杂环基、苯基或5-6元杂芳基。
  5. 权利要求1-4中任一项的式(I)或(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,选自
  6. 权利要求1-5中任一项的式(I)或(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,R2a选自H、D、CN、ORa或NRbRc;优选选自ORa或NRbRc;优选为NH2
  7. 权利要求1-6中任一项的式(I)或(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,X1、X2以及他们的取代基一起形成C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基;优选形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基;优选形成 优选形成更优选形成
  8. 权利要求1-7中任一项的式(I)或(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,R2d选自H、D、C1-6烷基或C1-6卤代烷基;优选为H或D。
  9. 权利要求1-8中任一项的式(I)或(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,R3a和R3b之一为C1-6烷基或C1-6卤代烷基,另一为H;R3a和R3b之一为Me,另一为H;优选地,R3a为H且R3b为Me。
  10. 权利要求1-9中任一项的式(I)或(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,R1s选自H、D、卤素、=O、-L-ORa、-L-SRa、-L-NRbRc、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、-L-C3-10环烷基(优选-L-C5-10环烷基)、-L-5-10元杂环基、-L-C6-10芳基或-L-5-10元杂芳基;优选选自H、D、卤素、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基;优选地,孪位或相邻的两个R1s以及他们连接的原子一起形成C3-6环烷基、4-6元杂环基、苯基或5-6元杂芳基。
  11. 权利要求1-10中任一项的式(I)或(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,R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基。
  12. 权利要求1-11中任一项的式(I)或(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,其具有以下结构式:
    其中各基团如权利要求1-11定义。
  13. 权利要求12的式(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,
    L1为NH或CHRx
    L2为CRxRy
    其中Rx和Ry独立地为H、D、C1-6烷基或C1-6卤代烷基;
    或者CRxRy一起形成C=O、C=S或C3-6亚环烷基;
    或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-4亚烷基;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
    X3为CR2d或N;
    并且X1、X2和X3所在的环为芳香环;
    R2a选自H、D、ORa或NRbRc
    R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基;
    R1、R1a、R1b和R1c独立地选自H、D、卤素、CN、-L-ORa、-L-SRa、-L-NRbRc、SF5、S(O)Ra、S(O)2Ra、C1-6烷基、C1-6卤代烷基、C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基,优选H、 D、卤素、CN、-L-ORa、-L-SRa、-L-NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-10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、2或3个R1s取代;
    或者R1a、R1b以及他们连接的原子,或者R1b、R1c以及他们连接的原子,一起形成C5-6环烷基、5-6元杂环基、苯基或5-6元杂芳基,其任选地被1、2或3个R1s取代;
    m=0、1或2;
    R1s选自H、D、卤素、=O、-L-ORa、-L-SRa、-L-NRbRc、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、-L-C5-10环烷基、-L-5-10元杂环基、-L-C6-10芳基或-L-5-10元杂芳基,其任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷基-OH、-C0-6亚烷基-OC1-6烷基、C1-6烷基或C1-6卤代烷基取代;
    或者孪位或邻位的两个R1s以及他们连接的原子一起形成C3-6环烷基、4-6元杂环基、苯基或5-6元杂芳基,其任选地被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;
    L为化学键、C1-6亚烷基、C2-6亚烯基或C2-6亚炔基,其任选被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;
    R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
    R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C3-6环烷基或4-6元杂环基,优选H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    n=0、1、2、3、4、5、6或7;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-10元杂环基;
    其中上述L1、L2、Rx、Ry、R1、R1a、R1b、R1c、R2a、R2d、R1s、L、R2s、R3、R3a、R3b、Ra、Rb和Rc中的各个基团定义任选地被氘代,直至完全氘代。
  14. 权利要求13的式(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,
    L1为NH或CHRx
    L2为CRxRy
    其中Rx和Ry独立地为H、D、C1-6烷基或C1-6卤代烷基;
    或者CRxRy一起形成C=O或C3-6亚环烷基;
    或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-3亚烷基;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
    X3为CR2d或N;
    并且X1、X2和X3所在的环为芳香环;
    R2a选自ORa或NRbRc
    R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基;
    R1、R1a、R1b和R1c独立地选自H、D、卤素、CN、-L-ORa、-L-SRa、-L-NRbRc、SF5、C1-6烷基、 C1-6卤代烷基、C5-7环烷基或5-7元杂环基,其任选地被1、2或3个R1s取代;
    或者R1a、R1b以及他们连接的原子,或者R1b、R1c以及他们连接的原子,一起形成5-6元杂环基或5-6元杂芳基,其任选地被1、2或3个R1s取代;
    m=0、1或2;
    R1s选自H、D、卤素、=O、-L-ORa、-L-SRa、-L-NRbRc、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、-L-C5-10环烷基或-L-5-10元杂环基,其任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷基-OH、-C0-6亚烷基-OC1-6烷基、C1-6烷基或C1-6卤代烷基取代;
    或者孪位或邻位的两个R1s以及他们连接的原子一起形成C3-6环烷基或4-6元杂环基,其任选地被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;
    L为化学键或C1-6亚烷基,其任选被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代;
    R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
    R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    n=0、1、2、3、4或5;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-6元杂环基。
  15. 权利要求13的式(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,
    L1为NH或CHRx
    L2为CRxRy
    其中Rx和Ry独立地为H、D、C1-6烷基或C1-6卤代烷基;
    或者CRxRy一起形成C=O或C2亚环烷基;
    或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-2亚烷基;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
    X3为CR2d或N;
    并且X1、X2和X3所在的环为芳香环;
    R2a为NRbRc
    R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    R1、R1a、R1b和R1c独立地选自H、D、卤素、CN、-L-ORa、-L-SRa、-L-NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-6环烷基或5-6元杂环基,其任选地被1、2或3个R1s取代;
    或者R1a、R1b以及他们连接的原子,或者R1b、R1c以及他们连接的原子,一起形成5-6元杂环基或5-6元杂芳基,其任选地被1、2或3个R1s取代;
    m=0、1或2;
    R1s选自H、D、卤素、=O、-L-ORa、-L-SRa、-L-NRbRc、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基,其任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6 烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷基-OH、-C0-6亚烷基-OC1-6烷基、C1-6烷基或C1-6卤代烷基取代;
    或者孪位或邻位的两个R1s以及他们连接的原子一起形成C3-6环烷基或4-6元杂环基,其任选地被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;
    L为化学键或C1-6亚烷基,其任选被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代;
    R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
    R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    n=0、1、2或3;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-6元杂环基。
  16. 权利要求13的式(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,
    -L1-L2-选自优选
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
    X3为CR2d
    并且X1、X2和X3所在的环为芳香环;
    R2a为NH2
    R2d选自H、D、卤素、C1-6烷基或C1-6卤代烷基;
    R1选自H、D、卤素、CN、C1-6烷基或C1-6卤代烷基;
    R1a、R1b和R1c独立地选自H、D、卤素、CN、-L-ORa、-L-SRa、-L-NRbRc、C1-6烷基、C1-6卤代烷基、C5-6环烷基或5-6元杂环基,优选H、D、卤素、CN、-L-NRbRc、C1-6烷基、C1-6卤代烷基、C5-6环烷基或5-6元杂环基,其任选地被1、2或3个R1s取代;
    或者R1a、R1b以及他们连接的原子,或者R1b、R1c以及他们连接的原子,一起形成5-6元杂环基或5-6元杂芳基,其任选地被1、2或3个R1s取代;
    m=0、1或2;
    R1s选自H、D、卤素、=O、-L-NRbRc、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基,其任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷基-OH、-C0-6亚烷基-OC1-6烷基、C1-6烷基或C1-6卤代烷基取代;
    或者孪位或邻位的两个R1s以及他们连接的原子一起形成C3-6环烷基或4-6元杂环基,其任选地被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;
    L为化学键或C1-6亚烷基,其任选被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代;
    R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
    R3选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    R3a和R3b之一为C1-6烷基或C1-6卤代烷基,另一为H或D;
    n=0、1、2或3;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-6元杂环基;
    优选地,X1、X2以及他们的取代基一起形成选自以下的基团: 优选选自 优选为
    优选地,选自以下基团: 优选为 优选为
  17. 权利要求12的式(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,
    L1为NH;
    L2为C=O;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
    X3为CR2d或N;
    并且X1、X2和X3所在的环为芳香环;
    R2a选自ORa或NRbRc
    R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
    R1、R1a、R1b和R1c独立地选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基或C1-6卤代烷基,其任选地被1、2或3个R1s取代;
    或者R1a、R1b以及他们连接的原子,或者R1b、R1c以及他们连接的原子,一起形成5-6元杂环基或5-6元杂芳基,其任选地被1、2或3个R1s取代;
    R1s选自H、D、卤素、=O、ORa、SRa、NRbRc、C(O)ORa、C(O)NRbRc、C1-6烷基或C1-6卤代烷基;
    m=0、1或2;
    R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    n=0、1、2、3、4、5、6或7;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-10元杂环基;
    其中上述R1、R1a、R1b、R1c、R2a、R2d、R1s、R2s、R3、R3a、R3b、Ra、Rb和Rc中的各个基团定义任选地被氘代,直至完全氘代。
  18. 权利要求17的式(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
    L1为NH;
    L2为C=O;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成
    X3为CR2d
    并且X1、X2和X3所在的环为芳香环;
    R2a为NRbRc
    R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    选自以下基团: 优选
    R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基或C1-6卤代烷基;
    m=0、1或2;
    R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    n=0、1、2、3、4、5、6或7;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-10元杂环基。
  19. 权利要求17的式(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
    L1为NH;
    L2为C=O;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成
    X3为CR2d
    并且X1、X2和X3所在的环为芳香环;
    R2a为NH2
    R2d选自H或D;
    选自以下基团: 优选
    R1选自H、D、F或Me;
    m=0、1或2;
    R3、R3a和R3b独立地选自H、D或Me,优选地,R3b为Me;
    n=0、1、2、3、4、5、6或7。
  20. 权利要求12的式(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
    L1为NH;
    L2为C=O;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
    X3为CR2d或N;
    并且X1、X2和X3所在的环为芳香环;
    R2a选自ORa或NRbRc
    R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
    R1、R1a、R1b和R1c独立地选自H、D、卤素、CN、-L-ORa、-L-SRa、-L-NRbRc、SF5、C1-6烷基或C1-6卤代烷基;
    或者R1a、R1b以及他们连接的原子,或者R1b、R1c以及他们连接的原子,一起形成5-6元杂环基或5-6元杂芳基;
    L为化学键或C1-6亚烷基,其任选被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代;
    m=0、1或2;
    R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    n=0、1、2、3、4、5、6或7;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;
    其中上述R1、R1a、R1b、R1c、R2a、R2d、R2s、R3、R3a、R3b、Ra、Rb和Rc中的各个基团定义任选地被氘代,直至完全氘代。
  21. 权利要求20的式(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
    L1为NH;
    L2为C=O;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成
    X3为CR2d
    并且X1、X2和X3所在的环为芳香环;
    R2a为NRbRc
    R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    选自以下基团: 优选
    R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基或C1-6卤代烷基;
    m=0、1或2;
    R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    n=0、1、2、3、4、5、6或7;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基。
  22. 权利要求20的式(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
    L1为NH;
    L2为C=O;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成
    X3为CR2d
    并且X1、X2和X3所在的环为芳香环;
    R2a为NH2
    R2d选自H或D;
    选自以下基团: 优选
    R1选自H、D、F或Me;
    m=0、1或2;
    R3、R3a和R3b独立地选自H、D或Me,优选地,R3b为Me;
    n=0、1、2、3、4、5、6或7。
  23. 权利要求12的式(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
    L1为NH;
    L2为C=O;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成
    X3为CR2d或N;
    并且X1、X2和X3所在的环为芳香环;
    R2a选自ORa或NRbRc
    R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    R1、R1a、R1b和R1c独立地选自H、D、卤素、CN、-L-ORa、-L-SRa、-L-NRbRc、SF5、C1-6烷基或C1-6卤代烷基;
    或者R1a、R1b以及他们连接的原子,或者R1b、R1c以及他们连接的原子,一起形成5-6元杂环基或5-6元杂芳基;
    L为化学键或C1-6亚烷基,其任选被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代;
    m=0、1或2;
    R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    n=0、1、2、3、4、5、6或7;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;
    其中上述R1、R1a、R1b、R1c、R2a、R2d、R3、R3a、R3b、Ra、Rb和Rc中的各个基团定义任选地被氘代,直至完全氘代。
  24. 权利要求23的式(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
    L1为NH;
    L2为C=O;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成
    X3为CR2d
    并且X1、X2和X3所在的环为芳香环;
    R2a为NRbRc
    R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    选自以下基团:
    R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基或C1-6卤代烷基;
    m=0、1或2;
    R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    n=0、1、2、3、4、5、6或7;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基。
  25. 权利要求23的式(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
    L1为NH;
    L2为C=O;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成
    X3为CR2d
    并且X1、X2和X3所在的环为芳香环;
    R2a为NH2
    R2d选自H或D;
    选自以下基团:
    R1选自H、D、F或Me;
    m=0、1或2;
    R3、R3a和R3b独立地选自H、D或Me,优选地,R3b为Me;
    n=0、1、2、3、4、5、6或7。
  26. 权利要求12的式(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
    L1为NH;
    L2为C=O;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代,优选5-7元杂环基或5-6元杂芳基,其任选被1、2或3个R2s取代;
    X3为CR2d或N;
    并且X1、X2和X3所在的环为芳香环;
    R2a选自ORa或NRbRc
    R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
    R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基或C1-6卤代烷基;
    m=0、1、2或3;
    R1s选自H、D、卤素、=O、-L-ORa、-L-SRa、-L-NRbRc、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、-L-C3-6环烷基、-L-5-6元杂环基、-L-C6-10芳基或-L-5-6元杂芳基,其任选地被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代;
    L为化学键或C1-6亚烷基,其任选被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代;
    R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    n=0、1、2、3、4、5、6或7;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基。
  27. 权利要求26的式(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
    L1为NH;
    L2为C=O;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成优选
    X3为CR2d
    并且X1、X2和X3所在的环为芳香环;
    R2a为NRbRc
    R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基或C1-6卤代烷基;
    m=0、1、2或3;
    R1s为H、D、C1-6烷基、C1-6卤代烷基、
    R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    n=0、1、2、3、4、5、6或7;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基。
  28. 权利要求26的式(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
    L1为NH;
    L2为C=O;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成优选
    X3为CR2d
    并且X1、X2和X3所在的环为芳香环;
    R2a为NH2
    R2d选自H或D;
    R1选自H、D、F或Me;
    m=0、1、2或3;
    R1s为H、Me、Et、iPr、
    R3、R3a和R3b独立地选自H、D或Me,优选地,R3b为Me;
    n=0、1、2、3、4、5、6或7。
  29. 权利要求12的式(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,
    L1为NH或CHRx
    L2为CRxRy
    其中Rx和Ry独立地为H、D、C1-6烷基或C1-6卤代烷基;
    或者CRxRy一起形成C=O、C=S或C3-6亚环烷基;
    或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-4亚烷基;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
    X3为CR2d或N;
    并且X1、X2和X3所在的环为芳香环;
    R2a选自H、D、ORa或NRbRc
    R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基;
    R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基,其任选地被1、2或3个R1s取代;
    m=0、1、2或3;
    R1s选自H、D、卤素、-L-ORa、-L-SRa、-L-NRbRc、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、-L-C5-10环烷基、-L-5-10元杂环基、-L-C6-10芳基或-L-5-10元杂芳基,其任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷基-OH、-C0-6亚烷基-OC1-6烷基、C1-6烷基或C1-6卤代烷基取代;
    L为化学键、C1-6亚烷基、C2-6亚烯基或C2-6亚炔基,其任选被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代;
    R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
    R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    n=0、1、2、3、4、5、6或7;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-10元杂环基;
    其中上述L1、L2、Rx、Ry、R1、R2a、R2d、R1s、L、R2s、R3、R3a、R3b、Ra、Rb和Rc中的各个基团定义任选地被氘代,直至完全氘代。
  30. 权利要求29的式(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,
    L1为NH或CHRx
    L2为CRxRy
    其中Rx和Ry独立地为H、D、C1-6烷基或C1-6卤代烷基;
    或者CRxRy一起形成C=O或C3-6亚环烷基;
    或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-3亚烷基;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
    X3为CR2d或N;
    并且X1、X2和X3所在的环为芳香环;
    R2a选自ORa或NRbRc
    R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基;
    R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基,其任选地被1、2或3个R1s取代;
    m=0、1或2;
    R1s选自H、D、卤素、-L-ORa、-L-SRa、-L-NRbRc、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、-L-C5-10环烷基、-L-5-10元杂环基、-L-C6-10芳基或-L-5-10元杂芳基,其任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷基-OH、-C0-6亚烷基-OC1-6烷基、C1-6烷基或C1-6卤代烷基取代;
    L为化学键或C1-6亚烷基,其任选被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代;
    R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
    R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    n=0、1、2、3、4或5;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-6元杂环基。
  31. 权利要求29的式(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,
    L1为NH或CHRx
    L2为CRxRy
    其中Rx和Ry独立地为H、D、C1-6烷基或C1-6卤代烷基;
    或者CRxRy一起形成C=O或C2亚环烷基;
    或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-2亚烷基;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
    X3为CR2d或N;
    并且X1、X2和X3所在的环为芳香环;
    R2a为NRbRc
    R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基,其任选地被1、2或3个R1s取代;
    m=0、1或2;
    R1s选自H、D、卤素、=O、-L-ORa、-L-SRa、-L-NRbRc、C1-6烷基、C1-6卤代烷基、-L-C5-7环烷基、-L-5-7元杂环基或-L-5-6元杂芳基,其任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷基-OH、-C0-6亚烷基-OC1-6烷基、C1-6 烷基或C1-6卤代烷基取代;
    L为化学键或C1-6亚烷基,其任选被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代;
    R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
    R3、R3a和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    n=0、1、2或3;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-6元杂环基。
  32. 权利要求29的式(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,
    -L1-L2-选自优选
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
    X3为CR2d
    并且X1、X2和X3所在的环为芳香环;
    R2a为NH2
    R2d选自H、D、卤素、C1-6烷基或C1-6卤代烷基;
    R1选自H、D、卤素、CN、C1-6烷基或C1-6卤代烷基,其任选地被1、2或3个R1s取代;
    m=0、1或2;
    R1s选自H、D、卤素、=O、-L-ORa、-L-NRbRc、C1-6烷基、C1-6卤代烷基、-L-C5-7环烷基、-L-5-7元杂环基或-L-5-6元杂芳基,其任选被1、2或3个H、D、卤素、=O、-C0-6亚烷基-NH2、-C0-6亚烷基-NH(C1-6烷基)、-C0-6亚烷基-N(C1-6烷基)2、-C0-6亚烷基-OH、-C0-6亚烷基-OC1-6烷基、C1-6烷基或C1-6卤代烷基取代;
    L为化学键或C1-6亚烷基,其任选被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代;
    R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
    R3选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    R3a和R3b之一为C1-6烷基或C1-6卤代烷基,另一为H或D;
    n=0、1、2或3;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-6元杂环基;
    优选地,X1、X2以及他们的取代基一起形成选自以下的基团: 优选选自
    优选地,R1s选自H、 优选为
  33. 权利要求12的式(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,
    L1为NH或CHRx
    L2为CRxRy
    其中Rx和Ry独立地为H、D、C1-6烷基或C1-6卤代烷基;
    或者CRxRy一起形成C=O、C=S或C3-6亚环烷基;
    或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-4亚烷基;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
    X3为CR2d或N;
    并且X1、X2和X3所在的环为芳香环;
    R2a选自H、D、ORa或NRbRc
    R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基;
    R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基,其任选地被1、2或3个R1s取代;
    m=0、1、2或3;
    m’=0、1、2、3、4、5、6、7、8或9;
    R1s选自H、D、卤素、C(O)ORa、C(O)NRbRc、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基;
    R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
    R3选自H、D、卤素、C1-6烷基或C1-6卤代烷基;
    n=0、1、2、3、4、5、6、7或8;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-10元杂环基;
    其中上述L1、L2、Rx、Ry、R1、R2a、R2d、R1s、R2s、R3、Ra、Rb和Rc中的各个基团定义任选地被氘代,直至完全氘代。
  34. 权利要求33的式(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,
    L1为NH或CHRx
    L2为CRxRy
    其中Rx和Ry独立地为H、D、C1-6烷基或C1-6卤代烷基;
    或者CRxRy一起形成C=O或C3-6亚环烷基;
    或者当L1为CHRx、L2为CRxRy时,两个Rx基团可以结合形成化学键或C1-3亚烷基;
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
    X3为CR2d或N;
    并且X1、X2和X3所在的环为芳香环;
    R2a选自ORa或NRbRc
    R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基;
    R1选自H、D、卤素、CN、ORa、SRa、NRbRc、SF5、C1-6烷基、C1-6卤代烷基、C5-7环烷基或5-7元杂环基,其任选地被1、2或3个R1s取代;
    m=0、1、2或3;
    m’=0、1、2、3、4或5;
    R1s选自H、D、卤素、C(O)ORa、C(O)NRbRc、C1-6烷基或C1-6卤代烷基基;
    R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
    R3选自H、D、卤素、C1-6烷基或C1-6卤代烷基;
    n=0、1、2、3、4或5;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-6元杂环基。
  35. 权利要求33的式(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,
    -L1-L2-选自优选
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任 选被1、2或3个R2s取代;
    X3为CR2d
    并且X1、X2和X3所在的环为芳香环;
    R2a为NH2
    R2d选自H、D、卤素、C1-6烷基或C1-6卤代烷基;
    R1选自H、D、卤素、CN、C1-6烷基或C1-6卤代烷基,其任选地被1、2或3个R1s取代;
    m=0、1或2;
    m’=0、1、2或3;
    R1s选自H、D、卤素、C(O)ORa、C(O)NRbRc、C1-6烷基或C1-6卤代烷基基;
    R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
    R3选自H、D、卤素、C1-6烷基或C1-6卤代烷基;
    n=0、1、2或3;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;或者Rb、Rc以及他们连接的原子一起形成5-6元杂环基;
    优选地,X1、X2以及他们的取代基一起形成选自以下的基团: 优选选自
  36. 权利要求12的式(Va)或(Vb)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
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基,其任选被1、2或3个R2s取代;
    X3为CR2d或N;
    并且X1、X2和X3所在的环为芳香环;
    R2a选自ORa或NRbRc
    R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    R2s选自H、D、卤素、=O、C1-6烷基或C1-6卤代烷基;
    Ar1为5-6元杂芳基,其被m个R1取代;
    R1选自H、D、卤素、CN、NO2、-L-ORa、-L-SRa、-L-NRbRc、SF5、C(O)Ra、C(O)ORa、C(O)NRbRc、OC(O)Ra、NRbC(O)Rc、S(O)Ra、S(O)2Ra、S(O)ORa、S(O)2ORa、S(O)NRbRc、S(O)2NRbRc、P(O)(Ra)2、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-6环烷基、4-6元杂环基、C6-10芳基或5-10元杂芳基,其任选被1、2或3个R1s取代;
    m=0、1、2、3、4或5;
    或者相邻的两个R1以及他们连接的原子一起形成C5-6环烷基、5-6元杂环基、苯基或5-6元杂芳 基,其任选地被1、2或3个R1s取代;
    R1s选自H、D、卤素、=O、ORa、SRa、NRbRc、C1-6烷基或C1-6卤代烷基;
    R3和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    n=0、1、2、3、4、5、6或7;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基;
    其中上述R1、R1s、R2a、R2d、R3、R3b、Ra、Rb和Rc中的各个基团定义任选地被氘代,直至完全氘代。
  37. 权利要求36的式(Va)或(Vb)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
    X1为C原子或N原子,其任选地被R2b取代;
    X2为C原子或N原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成
    X3为CR2d
    并且X1、X2和X3所在的环为芳香环;
    R2a为NRbRc
    R2d选自H、D、卤素、CN、NO2、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    Ar1为5-6元杂芳基,其被m个R1取代;
    R1选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-6环烷基、4-6元杂环基、C6-10芳基或5-10元杂芳基,其任选被1、2或3个R1s取代;
    m=0、1、2或3;
    或者相邻的两个R1以及他们连接的原子一起形成C5-6环烷基、5-6元杂环基、苯基或5-6元杂芳基,其任选地被1、2或3个R1s取代;
    R1s选自H、D、卤素、=O、ORa、SRa、NRbRc、C1-6烷基或C1-6卤代烷基;
    R3和R3b独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基;
    n=0、1、2、3、4、5、6或7;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基。
  38. 权利要求36的式(Va)或(Vb)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
    X1为C原子,其任选地被R2b取代;
    X2为C原子,其任选地被R2c取代;
    并且X1、X2以及他们的取代基一起形成优选
    X3为CR2d
    并且X1、X2和X3所在的环为芳香环;
    R2a为NH2
    R2d选自H或D;
    Ar1为5-6元杂芳基,其被m个R1取代;优选地,Ar1选自:
    R1选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-6环烷基或4-6元杂环基,其任选被1、2或3个R1s取代;
    m=0、1或2;
    或者相邻的两个R1以及他们连接的原子一起形成苯基或5-6元杂芳基,其任选地被1、2或3个R1s取代;
    R1s选自H、D、卤素、=O、ORa、SRa、NRbRc、C1-6烷基或C1-6卤代烷基;
    R3和R3b独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基;
    n=0、1、2、3、4、5、6或7;
    Ra、Rb和Rc独立地选自H、D、C1-6烷基或C1-6卤代烷基。
  39. 权利要求1的式(I)或(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,所述化合物选自实施例1-104的化合物。
  40. 药物组合物,其包含权利要求1-39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。
  41. 权利要求40的药物组合物,其中所述其它治疗剂选自以下靶点药物/细胞活性调节剂,包括CDK4/6抑制剂,MAT2A抑制剂,MAPK1/MAPK3抑制剂,Type I PRMT抑制剂,EGFR抑制剂,SHP2抑制剂,泛KRAS抑制剂,KRASG12C抑制剂,RAF抑制剂,MEK抑制剂,ERK抑制剂,Bcl-2抑制剂,SOS1抑制剂,PARP抑制剂,MALT1抑制剂,MALT2抑制剂,BTK抑制剂,PI3K抑制剂,AKT抑制剂,FGFR抑制剂,DNA甲基转移酶(DNMT)抑制剂,EZH1/2抑制剂,EZH2抑制剂,Menin-MLL抑制剂,IDH1抑制剂,IDH2抑制剂,IDH1/2抑制剂,化疗药物,放射疗法,STING激动剂或免疫检查点抑制剂/调节剂。
  42. 权利要求1-39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PRMT5介导的疾病的药物中的用途。
  43. 一种在受试者中治疗或预防PRMT5介导的疾病的方法,包括向所述受试者给药权利要求1-39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40或41的药物组合物。
  44. 权利要求1-39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40或41的药物组合物,其用于治疗或预防PRMT5介导的疾病。
  45. 权利要求42的用途或权利要求43的方法或权利要求44的化合物或药物组合物的用途,其中所述疾病为癌症。
  46. 权利要求42的用途或权利要求43的方法或权利要求44的化合物或药物组合物的用途,其中所述PRMT5介导的疾病选自以下癌症:心脏:肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤)、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤和畸胎瘤;肺:支气管癌(鳞状细胞、未分化小细胞、未分化大细胞、腺癌)、肺泡(细支气管)癌、支气管腺瘤、肉瘤、淋巴瘤、软骨瘤错构瘤、间皮瘤;胃肠道:食管(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃(癌、淋巴瘤、平滑肌肉瘤)、胰腺(导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤、血管瘤)、小肠(腺癌、淋巴瘤、类癌瘤)、卡波西肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤)、大肠(腺癌、管状腺瘤、绒毛状腺瘤、错构瘤、平滑肌瘤);泌尿生殖道:肾脏(腺癌、威尔姆氏瘤(肾母细胞瘤)、淋巴瘤、白血病)、膀胱和尿道(鳞状细胞癌、移行细胞癌、腺癌)、前列腺(腺癌、肉瘤)、睾丸(精原细胞瘤、畸胎瘤、胚胎癌、畸胎癌)、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样肿瘤、脂肪瘤);肝脏:肝细胞瘤(肝细胞癌)、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤、血管瘤;胆道:胆囊癌、壶腹癌、胆管癌;骨:成骨肉瘤(osteosarcoma)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤文氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨慢性外生骨疣(osteocartilaginous exostoses)、良性软骨瘤、软骨母细胞瘤、纤维软骨瘤、软骨粘液纤维瘤、类骨质骨瘤和巨细胞瘤;神经系统:颅骨(骨瘤、血管瘤、肉芽肿、黄色瘤、变形性骨炎)、脑膜(脑膜瘤、脑膜肉瘤、神经胶质瘤)、脑(星形细胞瘤、髓母细胞瘤、神经胶质瘤、室管膜瘤、生殖细胞瘤(松果体瘤)、多形性胶质母细胞瘤、少突胶质细胞瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤)、脊髓神经纤维瘤、脑膜瘤、神经胶质瘤、肉瘤);妇科:子宫(子宫内膜癌)、宫颈(宫颈癌、瘤前宫颈发育不良等)、卵巢(卵巢癌、浆液性囊腺癌、粘液性囊腺癌、未分类癌)、颗粒鞘细胞瘤、支持间质细胞瘤、无性细胞瘤、恶性畸胎瘤)、外阴(鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤、黑色素瘤)、阴道(透明细胞癌、鳞状细胞癌、葡萄样肉瘤(胚胎性横纹肌肉瘤)、输卵管(癌);血液学:血液(髓性白血病(急性和慢性)、急性淋巴细胞白血病、慢性淋巴细胞性白血病、弥漫性大B细胞淋巴瘤、套细胞淋巴瘤(MCL),滤泡性淋巴瘤、骨髓增生性疾病、多发性骨髓瘤、骨髓增生异常综合征)、霍奇金病、非霍奇金淋巴瘤(恶性淋巴瘤);皮肤:恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、痣发育不良痣、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕疙瘩、牛皮癣;和肾上腺:成神经细胞瘤。
  47. 权利要求42的用途或权利要求43的方法或权利要求44的化合物或药物组合物的用途,其中所述PRMT5介导的疾病选自以下癌症:恶性周围神经鞘瘤、间皮瘤、多形性胶质母细胞瘤、胰腺 癌、胆管癌、前列腺癌、乳腺癌、脑癌、皮肤癌、宫颈癌、膀胱癌、星形细胞瘤、结肠直肠癌、子宫内膜癌、食道癌、胃癌、胸腺瘤、头颈癌、肝细胞癌、喉癌、肺鳞癌、肺腺癌、口腔癌、卵巢癌、肾癌和甲状腺癌以及肉瘤。
  48. 权利要求42的用途或权利要求43的方法或权利要求44的化合物或药物组合物的用途,其中所述PRMT5介导的疾病选自MTAP相关癌症,例如肝细胞癌、乳腺癌、皮肤癌、膀胱癌、肝癌、胰腺癌或头颈癌。
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