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WO2024222677A1 - Wrn抑制剂 - Google Patents

Wrn抑制剂 Download PDF

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Publication number
WO2024222677A1
WO2024222677A1 PCT/CN2024/089315 CN2024089315W WO2024222677A1 WO 2024222677 A1 WO2024222677 A1 WO 2024222677A1 CN 2024089315 W CN2024089315 W CN 2024089315W WO 2024222677 A1 WO2024222677 A1 WO 2024222677A1
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Prior art keywords
alkyl
ring
haloalkyl
cycloalkyl
compound
Prior art date
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PCT/CN2024/089315
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English (en)
French (fr)
Inventor
刘彬
高峰
郭永起
景连栋
吴勇勇
李治中
吴卓
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Puhe Biopharma Co Ltd
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Puhe Biopharma Co Ltd
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Priority to CN202480011392.3A priority Critical patent/CN120981458A/zh
Publication of WO2024222677A1 publication Critical patent/WO2024222677A1/zh
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicine, and in particular relates to a WRN inhibitor.
  • MMR Abnormal DNA mismatch repair
  • MSI microsatellite instability
  • MSI-H High microsatellite instability
  • colorectal cancer including colorectal cancer, gastric cancer, endometrial cancer, and ovarian cancer (Nature, 2019, 568, 551-556), among which colorectal cancer (15%) and gastric cancer (22%) have the highest mutation rates.
  • immunotherapy PD-1/PD-L1 currently has very good therapeutic effects in multiple tumors, such as pembrolizumab, which greatly improves the median progression-free survival (PFS) in patients with advanced colorectal cancer with MSI-H compared to chemotherapy, and has been approved by the FDA as a first-line therapy (N. Engl. J. Med. 2020, 383, 2207-2218), there are still many MSI-H tumor patients who cannot benefit from it.
  • the 2022 ASCO conference reported that in the Phase 2 CheckMate 142 (NCT02060188) clinical trial: the dual immunotherapy PD-1+CTLA-4 (nivolumab+ipilimumab) was used to treat patients with metastatic colorectal cancer. Regardless of whether the patients were in first-line treatment or second-line treatment, more than half of the tumor patients would relapse after 4 years of follow-up, so new treatments are urgently needed.
  • Synthetic lethality means that in tumor cells, the inactivation of any single gene in the two genes has no obvious effect on the survival of tumor cells, but the simultaneous inactivation of the two genes can lead to the death of tumor cells (Nat. Rev. Drug Discov. 2020, 19, 23-38; Cancer Discov. 2021, 11, 1626-1635).
  • Synthetic lethal targeted drugs generally produce a good therapeutic safety window, while also increasing the development accessibility of certain targets with high mutation rates but difficult to drug.
  • PARP1/2 inhibitors such as Olaparib, Rucaparib, Niraparib, etc. These drugs have achieved excellent therapeutic effects in the treatment of BRCA1/2 mutant ovarian cancer, breast cancer, etc. and have been approved for marketing one after another (Nat. Rev.
  • the present invention provides a novel WRN inhibitor, wherein the compound of the present invention has a good inhibitory effect on WRN DNA unwinding, has a good anti-proliferation effect on MSI-H tumor cells, and has no inhibitory effect on microsatellite stable (MSS) tumor cells.
  • MSS microsatellite stable
  • the present invention provides a compound of formula (A), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:
  • Ring B or Ring C is a 5-6 membered heteroaryl or a 5-6 membered heterocyclic group, and at least one ring exists;
  • Y is selected from CH or N;
  • R 1 is selected from 5-12 membered heteroaryl or 5-12 membered heterocyclyl; said R 1 may be substituted by 1, 2 or 3 R x ;
  • R2 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio or C3-6 cycloalkyl;
  • R 3 is independently selected from H, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl; or two R 3 are connected to the carbon atom where they are located to form a 3-6 membered spiro ring or bridged ring;
  • R 4 is independently selected from H, halogen, CN, SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylthio, C 3-6 cycloalkyl or 4-10 membered heterocyclyl;
  • Ring A is present or absent, and ring A is selected from a 5-6 membered heteroaryl group or a 5-7 membered heterocyclic group;
  • R 5 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 3-6 cycloalkyl;
  • Rx is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, CN, NH 2 , -C(O)R a , -C(O)OR a , -(CH 2 ) p -OR a , -P(O)-(R a ) 2 or -S(O) 2 -R a ;
  • R a is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl
  • n 0, 1, 2 or 3;
  • n is selected from 0, 1 or 2;
  • p is selected from 0, 1 or 2.
  • Ring B and Ring C are present.
  • Y is N.
  • M 1 and M 2 are each independently selected from CH or N.
  • M 1 and M 2 form a monomer
  • M 3 , M 4 and M 5 are each independently selected from CH, O, S or N, and M 3 , M 4 and M 5 contain at least one N atom
  • Y is selected from CH or N.
  • M1 and M2 are each independently selected from CH or N. In some embodiments, for Wherein R 5 is H or C 1-6 alkyl.
  • R 1 is selected from a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, a 5-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, a 7-12 membered bicyclic heteroaryl containing 1 or 2 or 3 or 4 heteroatoms selected from oxygen, nitrogen and sulfur, or a 7-12 membered bicyclic heterocyclyl containing 1 or 2 or 3 or 4 heteroatoms selected from oxygen, nitrogen and sulfur, each of which may be substituted by 1, 2 or 3 R x selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy , CN, NH 2 , -C(O)R a , -C(O)OR a , -(CH 2 ) p -OR a , -P(O)-(R a ) 2 or -S(O) 2 -R a
  • R 1 is selected from The R 1 may be substituted by 1, 2 or 3 R x , wherein R x is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, CN, NH 2 , -C(O)R a , -C(O)OR a , -(CH 2 )p-OR a , -P(O)-(R a ) 2 or -S(O) 2 -R a .
  • R 1 is selected from In some embodiments, R is selected from
  • R 2 is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R 2 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • R 3 is selected from H or C 1-6 alkyl. In some embodiments, R 3 is C 1-6 alkyl. In some embodiments, R 3 is methyl, ethyl or propyl.
  • Ring A is absent.
  • R 4a , R 4b and R 4c are independently selected from H, halogen, CN, SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylthio or C 3-6 cycloalkyl.
  • R 4a is halogen or C 1-6 haloalkyl
  • R 4b is halogen or C 1-6 alkyl.
  • R 4a is C 1-6 haloalkyl
  • R 4b is halogen.
  • R 4a is selected from H, halogen, CN, SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylthio or C 3-6 cycloalkyl, wherein Ring A is a 5- or 6-membered heteroaryl or heterocyclic group, each of which contains 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur.
  • R 4a is selected from halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylthio or C 3-6 cycloalkyl
  • ring A is In some embodiments, R 4a is C 1-4 haloalkyl. In some embodiments, R 4a is trifluoromethyl.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:
  • M 1 and M 2 are each independently selected from CH or N. When one of M 1 or M 2 is selected from N, M 1 and M 2 form a monomer;
  • M 3 , M 4 and M 5 are each independently selected from CH, O, S or N, and M 3 , M 4 and M 5 contain at least one N atom;
  • Y is selected from CH or N;
  • R 1 is selected from 5-12 membered heteroaryl or 5-12 membered heterocyclyl; said R 1 may be substituted by 1, 2 or 3 R x ;
  • R2 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio or C3-6 cycloalkyl;
  • R 3 is independently selected from H, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl; or two R 3 are connected to the carbon atom where they are located to form a 3-6 membered spiro ring or bridged ring;
  • R4 is independently selected from H, halogen, CN, SF5 , C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylthio, C3-6 cycloalkyl or 4-10 membered heterocyclyl;
  • Ring A is present or absent, and ring A is selected from a 5-6 membered heteroaryl group or a 5-7 membered heterocyclic group;
  • R 5 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 3-6 cycloalkyl;
  • Rx is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, CN, NH 2 , -C(O)R a , -C(O)OR a , -(CH 2 ) p -OR a , -P(O)-(R a ) 2 or -S(O) 2 -R a ;
  • R a is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl
  • n 0, 1, 2 or 3;
  • n is selected from 0, 1 or 2.
  • the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:
  • R 1 is selected from 5-12 membered heteroaryl or 5-12 membered heterocyclyl; said R 1 may be substituted by 1, 2 or 3 Rx;
  • R2 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio or C3-6 cycloalkyl;
  • R 3 is independently selected from H, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl; or two R 3 are connected to the carbon atom where they are located to form a 3-6 membered spiro ring or bridged ring;
  • R4 is independently selected from H, halogen, CN, SF5 , C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylthio, C3-6 cycloalkyl or 4-10 membered heterocyclyl:
  • Ring A is present or absent, and ring A is selected from a 5-6 membered heteroaryl group or a 5-7 membered heterocyclic group;
  • R 5 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 3-6 cycloalkyl;
  • Rx is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, CN, NH 2 , -C(O)R a , -C(O)OR a , -(CH 2 ) p -OR a , -P(O)-(R a ) 2 or -S(O) 2 -R a ;
  • R a is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl
  • n 0, 1, 2 or 3;
  • n is selected from 0, 1 or 2.
  • the present invention provides a compound of formula (III) or formula (IV), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:
  • M 1 and M 2 are each independently selected from CH or N;
  • R 1 is selected from 5-12 membered heteroaryl or 5-12 membered heterocyclyl; said R 1 may be substituted by 1, 2 or 3 Rx;
  • R2 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio or C3-6 cycloalkyl;
  • R 3 is independently selected from H, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl; or two R 3 are connected to the carbon atom where they are located to form a 3-6 membered spiro ring or bridged ring;
  • R4 is independently selected from H, halogen, CN, SF5 , C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylthio, C3-6 cycloalkyl or 4-10 membered heterocyclyl;
  • Ring A is present or absent, and ring A is selected from a 5-6 membered heteroaryl group or a 5-7 membered heterocyclic group;
  • R5 is selected from H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio or C3-6 cycloalkyl;
  • Rx is selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, CN, NH2, -C(O) Ra , -C(O) ORa , -( CH2 ) p - ORa , -P (O)-( Ra ) 2 or -S (O) 2 - Ra ;
  • R a is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl
  • n 0, 1, 2 or 3;
  • n is selected from 0, 1 or 2.
  • the present invention relates to a compound of formula (II), (III) or (IV), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:
  • R 1 is selected from The R 1 may be substituted by 1, 2 or 3 Rx;
  • R2 is selected from methyl, ethyl, trifluoroethyl, methylthio or cyclopropyl;
  • R 3 is independently selected from H, F, CN, methyl, ethyl, trifluoromethyl, cyclopropyl; or two R 3 are connected to the carbon atom where they are located to form a cyclopropyl or cyclobutyl group;
  • R 4 is independently selected from H, F, Cl, Br, CN, SF 5 , methyl, ethyl, trifluoromethyl, difluoromethyl, methylthio or cyclopropyl;
  • Ring A is present or absent, and ring A is selected from a 5-6 membered heteroaryl group or a 5-7 membered heterocyclic group;
  • R 5 is selected from H, F, Cl, methyl, ethyl, trifluoromethyl, methoxy, methylthio or cyclopropyl;
  • Rx is selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, CN, NH2, -C(O) Ra , -C(O) ORa , -( CH2 ) p - ORa , -P (O)-( Ra ) 2 or -S (O) 2 - Ra ;
  • R a is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl
  • n 0, 1, 2 or 3;
  • n is selected from 0, 1 or 2.
  • the present invention provides a compound of formula (III-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:
  • M1 is selected from CH or N;
  • R 1 is selected from The R 1 may be substituted by 1, 2 or 3 Rx;
  • R2 is selected from H, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, methylthio or cyclopropyl;
  • R 4 is independently selected from H, halogen, CN, SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylthio, C 3-6 cycloalkyl or 4-10 membered heterocyclyl:
  • Ring A is selected from 5-6 membered heteroaryl or Ring A is absent;
  • R 5 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 3-6 cycloalkyl;
  • Rx is selected from H, methyl, trifluoromethyl, methoxy, CN, NH2 , -C(O)Me, -C(O)OMe, -( CH2 )-OH or -S(O) 2- Me;
  • n is selected from 0, 1, 2 or 3.
  • M1 is N.
  • R 1 is It may be substituted by 1, 2 or 3 Rx. In some embodiments, R1 is
  • R 2 is methyl or ethyl. In some embodiments, R 2 is ethyl.
  • Ring A is absent.
  • R 4a is halogen or C 1-6 haloalkyl
  • R 4b is halogen or C 1-6 alkyl.
  • R 4a is C 1-6 haloalkyl
  • R 4b is halogen.
  • R5 is H.
  • the present invention provides a compound of formula (IV-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:
  • R 1 is selected from The R 1 may be substituted by 1, 2 or 3 Rx;
  • R2 is selected from H, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, methylthio or cyclopropyl;
  • R 4 is independently selected from H, halogen, CN, SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylthio, C 3-6 cycloalkyl or 4-10 membered heterocyclyl;
  • Ring A is selected from 5-6 membered heteroaryl or Ring A is absent;
  • R 5 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 3-6 cycloalkyl;
  • Rx is selected from H, methyl, trifluoromethyl, methoxy, CN, NH2 , -C(O)Me, -C(O)OMe, -( CH2 )-OH or -S(O) 2- Me;
  • n is selected from 0, 1, 2 or 3.
  • R 1 is It may be substituted by 1, 2 or 3 Rx. In some embodiments, R1 is
  • R 2 is methyl or ethyl. In some embodiments, R 2 is ethyl.
  • R 4 is independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl, and in some embodiments, m is 2.
  • Ring A is absent.
  • R 4a is halogen or C 1-6 haloalkyl
  • R 4b is halogen or C 1-6 alkyl.
  • R 4a is C 1-6 haloalkyl
  • R 4b is halogen.
  • the present invention provides the following compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, and optionally a pharmaceutically acceptable excipient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, which may also contain another therapeutic agent.
  • the present invention provides the use of a compound of the present invention in the preparation of a medicament for treating and/or preventing a WRN-mediated disease.
  • the present invention provides a method for treating and/or preventing a WRN-mediated disease in a subject, comprising administering to the subject a compound or composition of the present invention.
  • the present invention provides a compound of the present invention or a composition of the present invention for use in the treatment and/or prevention of a WRN-mediated disease.
  • the disease treated by the present invention includes a cancer selected from the group consisting of colorectal cancer (e.g., colon cancer, rectal cancer, large intestine adenocarcinoma), gastric cancer (e.g., gastric adenocarcinoma), or lung cancer (e.g., bronchial carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, lung squamous cell carcinoma).
  • colorectal cancer e.g., colon cancer, rectal cancer, large intestine adenocarcinoma
  • gastric cancer e.g., gastric adenocarcinoma
  • lung cancer e.g., bronchial carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, lung squamous cell carcinoma.
  • 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 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 include: methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3), n-butyl (C 4 ), tert-butyl (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).
  • An alkyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • alkyl abbreviations include: Me ( -CH3 ), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3 ) , or i - Bu ( -CH2CH ( CH3 ) 2 ) .
  • C2-6 alkenyl refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C2-4 alkenyl is preferred. Examples of C2-6 alkenyl include: vinyl ( C2 ), 1-propenyl ( C3 ), 2-propenyl ( C3 ), 1-butenyl ( C4 ), 2-butenyl ( C4 ), butadienyl ( C4 ), pentenyl ( C5 ), pentadienyl ( C5 ), hexenyl ( C6 ), and the like.
  • C2-6 alkenyl also includes heteroalkenyl groups, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus).
  • the alkenyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
  • C 2-6 alkynyl refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 alkynyl is preferred. Examples of C 2-6 alkynyl include, but are not limited to, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), pentynyl (C 5 ), hexynyl (C 6 ), and the like.
  • 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).
  • Alkynyl 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 1-6 alkylene refers to a divalent group formed by removing another hydrogen of a C 1-6 alkyl group, and may be substituted or unsubstituted. In some embodiments, C 1-4 alkylene, C 2-4 alkylene, and C 1-3 alkylene are preferred.
  • the unsubstituted alkylene includes, but is not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene (-CH 2 CH 2 CH 2 CH 2 -), pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -), and the like.
  • substituted alkylene groups for example, substituted alkylene groups with one or more alkyl(methyl) groups, include, but are not limited to, substituted methylene groups (—CH(CH 3 )—, —C(CH 3 ) 2 —), substituted ethylene groups (—CH(CH 3 )CH 2 —, —CH 2 CH(CH 3 )—, —C(CH 3 ) 2 CH 2 —, —CH 2 C(CH 3 ) 2 —), substituted propylene groups (—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 — ) , and the like.
  • substituted methylene groups —CH(CH 3 )—, —C(CH 3 ) 2 —
  • substituted ethylene groups —CH(CH 3 )
  • alkenylene groups substituted with one or more alkyl(methyl) groups include, but are not limited to, substituted ethylene groups (—C(CH 3 ) ⁇ CH—, —CH ⁇ C(CH 3 )—), substituted propenylene groups (—C(CH 3 ) ⁇ CHCH 2 —, —CH ⁇ C(CH 3 )CH 2 — , —CH ⁇ CHCH ( CH 3 )—, —CH ⁇ CHC(CH 3 ) 2 —, —CH(CH 3 )—CH ⁇ CH—, —C(CH 3 ) 2 —CH ⁇ CH—, —CH 2 —C(CH 3 ) ⁇ CH—, —CH 2 —CH ⁇ C(CH 3 )—), and the like.
  • C 2-6 alkynylene refers to a divalent group formed by removing another hydrogen of a 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.
  • 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” substituted by one or more halogen groups.
  • C 1-4 haloalkyl is particularly preferred, more preferably C 1-2 haloalkyl.
  • Exemplary haloalkyls 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, and the like.
  • the haloalkyl group may be substituted at any available attachment point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 1-6 alkoxy refers to a -OR group wherein R is a C 1-6 alkyl group as defined above. C 1-4 alkoxy is preferred.
  • C 1-6 haloalkoxy refers to a "C 1-6 alkoxy” group which is substituted with one or more halogen groups. In some embodiments, a C 1-4 haloalkoxyalkyl group is particularly preferred, and a C 1-2 haloalkoxyalkyl group is more preferred.
  • C3-10 cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms.
  • C4-10 cycloalkyl, C5-10 cycloalkyl, C4-7 cycloalkyl, C3-7 cycloalkyl, C3-6 cycloalkyl, C3-5 cycloalkyl and C3-4 cycloalkyl are particularly preferred, more preferably C5-6 cycloalkyl.
  • Cycloalkyl also includes a ring system in which the above 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 a case, the number of carbons continues to represent the number of carbons in the cycloalkyl system.
  • Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ) , cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), etc.
  • the cycloalkyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • 3--12 membered heterocyclyl refers to a group of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon.
  • the point of attachment may be a carbon or nitrogen atom as long as the valence permits.
  • a 5-12 membered heterocyclyl is preferably a 3-10 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, a 3-10 membered heterocyclyl is preferably a 3-10 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, a 4-10 membered heterocyclyl is preferably a 4-10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, a 5-10 membered heterocyclyl is preferably a 5-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 5-8 membered heterocyclyl is preferably a 5-8 membered non-aromatic ring having ring carbon atoms and 1 to 5 ring heteroatoms.
  • 3-7 membered heterocyclyl is preferably a 3-7 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; 3-6 membered heterocyclyl is preferably a 3-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; 4-7 membered heterocyclyl is preferably a 4-7 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; 4-6 membered heterocyclyl is preferably a 4-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; 5-6 membered heterocyclyl is more preferably a 5-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; 3-5 membered heterocyclyl is more preferably a 3-5 membered non-aromatic ring
  • the heterocyclyl may contain an unsaturated double bond, but the heterocyclyl itself is not aromatic.
  • Heterocyclyl also includes a ring system in which the above heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or a ring system in which the above heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such a case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system.
  • Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl.
  • Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidine, oxirane, and thiorenyl.
  • Exemplary 5-membered heterocyclyls containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.
  • Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, dihydropyranyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazinyl.
  • Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thianyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrobenzopyranyl, tetrahydropyranopyridinyl, and the like.
  • the heterocyclyl group may be optionally substituted with one or more substituents, for example, 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 or 10 ⁇ electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms.
  • the aryl group has six ring carbon atoms ("C 6 aryl”; e.g., phenyl).
  • the aryl group has ten ring carbon atoms ("C 10 aryl”; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl).
  • Aryl also includes ring systems in which the above aryl ring is fused to one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system.
  • the aryl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • 5-14 membered heteroaryl refers to a group of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, 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 valence permits.
  • Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings.
  • Heteroaryl also includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system.
  • 5-12 membered heteroaryl is preferred, which is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system with ring carbon atoms and 1-4 ring heteroatoms; in some embodiments, 5-10 membered heteroaryl is preferred, which is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system with ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5-10 membered heteroaryl is preferred, which is a 6-10 membered monocyclic or bicyclic 4n+2 aromatic ring system with ring carbon atoms and 1-4 ring heteroatoms.
  • 5-9 membered heteroaryl is preferred, which is a 5-9 membered monocyclic or bicyclic 4n+2 aromatic ring system with ring carbon atoms and 1-4 ring heteroatoms.
  • 5-6 membered heteroaryls 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 heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl.
  • Exemplary 5 membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5 membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl.
  • Exemplary 5 membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl.
  • Exemplary 6 membered heteroaryls containing one heteroatom include, but are not limited to, pyridinyl.
  • Exemplary 6 membered heteroaryls containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryls containing three or four heteroatoms include, but are not limited to, triazine and tetrazine, respectively.
  • Exemplary 7-membered heteroaryls containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxacycloheptatrienyl, and thiacycloheptatrienyl.
  • Exemplary 5,6-bicyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl.
  • Exemplary 6,6-bicyclic heteroaryls include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • a heteroaryl group can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • Cycloalkylene is a divalent group formed by removing another hydrogen from the above-defined “cycloalkyl”, “heterocyclyl”, “aryl” or “heteroaryl”, and may be substituted or unsubstituted.
  • C 5-7 cycloalkylene refers to a divalent group formed by removing another hydrogen from C 5-7 cycloalkyl
  • 5-8 membered heterocyclylene refers to a divalent group formed by removing another hydrogen from 5-8 membered heterocyclyl
  • C 6-10 arylene refers to a divalent group formed by removing another hydrogen from C 6-10 aryl
  • 5-6 membered heteroarylene refers to a divalent group formed by removing another hydrogen from 5-6 membered heteroaryl.
  • Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups and the like as defined herein are optionally substituted groups.
  • each of Raa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two Ra groups combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
  • each of R cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R cc groups combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups;
  • Each of R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups;
  • Each of Rff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two Rff groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 Rgg groups:
  • pharmaceutically acceptable salt refers to those carboxylates, amino acid addition salts of the compounds of the present invention which are suitable for use in contact with patient tissues within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the present invention.
  • Subjects for administration include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and/or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms "human,” “patient,” and “subject” are used interchangeably herein.
  • the "effective amount" of a compound refers to an amount sufficient to cause a target biological response.
  • the effective amount of the compounds of the invention may vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject.
  • An effective amount includes a therapeutically effective amount and a prophylactically effective amount.
  • Combination and related terms refer to the simultaneous or sequential administration of the compounds of the invention and other therapeutic agents.
  • the compounds of the invention can be administered simultaneously or sequentially with the other therapeutic agents in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agents in a single unit dosage form.
  • compound of the present invention refers to a compound of the following formula (A) (including sub-general formulae, such as formula (I), (II), (III) or formula (IV), a pharmaceutically acceptable salt, enantiomer, diastereoisomer or isotopic variant thereof, and a mixture thereof.
  • the compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and/or diastereoisomeric forms.
  • the compounds of the present invention may be individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.
  • 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 preferred isomers may be prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • the compounds of the present invention may also exist as tautomers.
  • a compound is not limited to any specific tautomer, but is intended to encompass all tautomeric forms.
  • the present invention also includes isotopically labeled compounds (isotopic variants), which are equivalent to those described in formula (A), but one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature.
  • isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H , 3H , 13C , 11C , 14C, 15N , 18O , 17O , 31P , 32P , 35S , 18F and 36Cl , respectively.
  • Isotopically labeled compounds of the invention such as those into which radioactive isotopes (e.g., 3 H and 14 C) are introduced, can be used in drug and/or substrate tissue distribution assays. Tritium, i.e., 3 H, and carbon-14, i.e., 14 C isotopes are particularly preferred because they are easy to prepare and detect.
  • Isotopically labeled compounds of the invention of formula (A) and their prodrugs can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents when performing the processes disclosed in the following flows and/or the Examples and Preparations.
  • deuterium (D or 2H) is a stable isotope of hydrogen that exists at a natural abundance of 0.015 mol%.
  • deuterated refers to a group or compound in which one or more hydrogen atoms H are replaced by D.
  • deuterated compounds include deuterated compounds.
  • “Deuterated compound” refers to a compound in which one or more hydrogens bonded to carbon are replaced by one or more deuteriums.
  • “deuterated” refers to a chemical structure or organic group in which one or more hydrogens bonded to carbon are replaced by one or more deuteriums, for example, “deuterated alkyl”, “deuterated cycloalkyl”, “deuterated heterocycloalkyl”, “deuterated aryl”, etc.
  • “deuterated alkyl” refers to an alkyl group defined in the present application, in which at least one hydrogen atom bonded to carbon is replaced by deuterium.
  • deuterated alkyl at least one carbon atom is bonded to one deuterium; one carbon atom can be bonded to multiple deuteriums; and multiple carbon atoms in an alkyl group can also be bonded to deuterium.
  • deuterated methyl includes methyl-d3, in which three hydrogen atoms are replaced by deuterium; it also includes monodeuterated methyl and dideuterated methyl.
  • deuterated piperazinyl means that one or more hydrogen atoms on the piperazinyl group are replaced by deuterium, including all 8 hydrogen atoms replaced by deuterium.
  • the compounds of the present invention include deuterated compounds.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of a compound of the present invention.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention.
  • the pharmaceutical composition comprises a preventive effective amount of a compound of the present invention.
  • the pharmaceutically acceptable excipient used in the present invention refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the composition of the present invention include (but are not limited to) ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glyco
  • the present invention also includes a kit (e.g., a pharmaceutical package).
  • the kit provided may include a compound of the invention, other therapeutic agents, and a first and second container (e.g., a vial, an ampoule, a bottle, a syringe, and/or a dispersible package or other suitable container) containing the compound of the invention and other therapeutic agents.
  • the kit provided may also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the invention and/or other therapeutic agents.
  • the compound of the invention and other therapeutic agents provided in the first container and the second container are combined to form a unit dosage form.
  • composition provided by the invention can be administered by many ways, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other modes of administration.
  • parenteral administration used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial cavity administration, intrasternal administration, intrathecal administration, intralesional administration and intracranial injection or infusion technology.
  • an effective amount of the compounds provided herein is administered.
  • the amount of the compound actually administered can be determined by a physician according to the relevant circumstances, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the compounds provided herein are administered to a subject at risk of developing the condition, typically on the advice of a physician and under the supervision of a physician, at dosage levels as described above.
  • Subjects at risk of developing a particular condition typically include subjects with a family history of the condition, or subjects who have been identified by genetic testing or screening as being particularly susceptible to developing the condition. Those subjects who were affected.
  • Chronic administration refers to administration of a compound or a pharmaceutical composition thereof over a long period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration may continue indefinitely, e.g., for the rest of the subject's life.
  • chronic administration is intended to provide a constant level of the compound in the blood over a long period of time, e.g., within a therapeutic window.
  • the pharmaceutical composition can be administered by push injection, for example, in order to increase the concentration of the compound in the blood to an effective level.
  • the push dose depends on the target systemic level of the active component through the body, for example, the intramuscular or subcutaneous push dose slowly releases the active component, and the push delivered directly to the vein (for example, by IV intravenous drip) can be delivered more quickly, so that the concentration of the active component in the blood is quickly increased to an effective level.
  • the pharmaceutical composition can be given in a continuous infusion form, for example, by IV intravenous drip, so as to provide a steady-state concentration of the active component in the subject's body.
  • the pharmaceutical composition of the push dose can be first given, and then continuous infusion.
  • Oral compositions can be in the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, in order to facilitate accurate dosing, the composition is provided in unit dosage form.
  • unit dosage form refers to a physical discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined amount of active substances suitable for producing the desired therapeutic effect and a suitable pharmaceutical excipient.
  • Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions.
  • the compound is usually a relatively small component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), and the remainder is various carriers or excipients and processing aids useful for forming the desired administration form.
  • a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides about 0.01 to about 20 mg/kg of the compound of the invention, and preferred doses each provide about 0.1 to about 10 mg/kg, especially 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 about 0.5 to about 15% by weight.
  • the injected dosage level is in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour.
  • a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be given.
  • the maximum total dose cannot exceed about 2 g/day.
  • Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier and buffers, suspending and dispersing agents, colorants, flavoring agents, etc.
  • Solid forms may include, for example, any of the following components, or compounds of a similar nature: binders, such as microcrystalline cellulose, tragacanth, or gelatin; excipients, such as starch or lactose, disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring.
  • binders such as microcrystalline cellulose, tragacanth, or gelatin
  • excipients such as starch or lactose, disintegrants, such as alginic acid, Primogel, or corn starch
  • lubricants such as magnesium ste
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound is typically a minor component, often about 0.05 to 10% by weight, and the remainder is an injectable excipient, etc.
  • transdermal compositions are formulated as topical ointments or creams containing active ingredients.
  • the active ingredient When formulated as an ointment, the active ingredient is typically combined with a paraffin or water-miscible ointment base.
  • the active ingredient can be formulated as an ointment together with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art and typically include other components for enhancing the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by the invention.
  • transdermal administration may be achieved using patches of the reservoir or porous membrane type, or a variety of solid matrices.
  • the compounds of the invention may also be administered in a sustained release form or from a sustained release delivery system.
  • Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention.
  • the formulation comprises water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are ⁇ -, ⁇ - and ⁇ -cyclodextrins composed of 6, 7 and 8 ⁇ -1,4-linked glucose units, respectively, which optionally include one or more substituents on the linked sugar moiety, including but not limited to: methylated, hydroxyalkylated, acylated and sulfoalkyl ether substitutions.
  • the cyclodextrin is a sulfoalkyl ether ⁇ -cyclodextrin, for example, sulfobutyl ether ⁇ -cyclodextrin, also known as Captisol. See, for example, U.S.5,376,645.
  • the formulation includes hexapropyl- ⁇ -cyclodextrin (e.g., in water, 10-50%).
  • the reagents used in the present invention are commercial reagents purchased directly or synthesized by common methods well known in the art.
  • PE petroleum ether
  • EA ethyl acetate
  • MeOH methanol
  • DCM dichloromethane
  • DCE dichloroethane
  • CH 3 CN acetonitrile
  • 1,4-dioxane 1,4-dioxane
  • DMSO dimethyl sulfoxide
  • HFIP hexafluoroisopropanol
  • DMF N,N-dimethylformamide
  • Hex n-hexane
  • IPA isopropanol
  • NMP N-methylpyrrolidone
  • NMO N-methylmorpholine-N-oxide
  • TEA triethylamine
  • DIEA diisopropylethylamine
  • CuI cuprous iodide
  • CuCN cuprous cyanide
  • triphosgene triphosgene
  • p-TsOH p-toluenesulfonic acid
  • T 3 P 1-propylphosphoric acid
  • MSI-H microsatellite instability-high
  • MSI-L microsatellite instability-low
  • MSS microsatellite stable.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Steps Dissolve the raw material ethyl acetoacetate a1-1 (9.0 g, 69.2 mmol) and 5-bromo-1-H-3-amino 1,2,4-triazole a1-2 (11.3 g, 69.2 mmol) in 90 mL of ethanol, slowly add polyphosphoric acid PPA (8.0 g, 69.2 mmol), add dropwise, heat to 80°C and react for 12 hours, cool to room temperature, and evaporate the solvent under reduced pressure.
  • PPA polyphosphoric acid
  • Step 1 Dissolve the raw material a5-1 (24.0 g, 134 mmol) and tert-butyl piperazine-1-carboxylate (25.0 g, 134 mmol) in 240 mL of acetonitrile, slowly add TEA (40.8 g, 403 mmol), and heat to 60°C for 16 hours, cool to room temperature, and evaporate the solvent under reduced pressure. Pour the reaction solution into 100 mL of ice water, extract with dichloromethane, dry with anhydrous sodium sulfate, concentrate, and separate the crude product by column chromatography (PE/EA, 9/1) to obtain a yellow oil a5-2 (24 g), yield: 54%. LCMS ESI-MS m/z: 329 [M+H] + .
  • Step 2 Dissolve the intermediate a5-2 (22.2 g, 67.6 mmol) and 5-bromo-1-H-3-amino 1,2,4-triazole a1-2 (11.0 g, 67.6 mmol) in 200 mL of ethanol, slowly add polyphosphoric acid PPA (7.8 g, 67.6 mmol), and heat to 80°C for 12 hours, cool to room temperature, and remove the solvent under reduced pressure.
  • PPA polyphosphoric acid
  • Steps Dissolve the intermediate a1 (7.5 g, 30.9 mmol) and the raw material a2-1 (10.1 g, 37.0 mmol) in 75 mL NMP, slowly add DIEA (12.0 g, 92.6 mmol), and heat to 50°C for 16 hours, cool to room temperature, and stop the reaction. Pour the reaction solution into 100 mL ice water, extract with dichloromethane, dry with anhydrous sodium sulfate, and concentrate.
  • Steps: Dissolve the intermediate a5 (1.1 g, 2.57 mmol) and the raw material a2-1 (1.1 g, 3.86 mmol) in 11 mL NMP, slowly add DIEA (1.0 g, 7.72 mmol), and heat to 70°C for 12 hours, cool to room temperature, and stop the reaction. Pour the reaction solution into 50 mL ice water, extract with dichloromethane, dry with anhydrous sodium sulfate, concentrate, and separate the crude product by flash reverse column chromatography (chromatographic column: C18; CH 3 CN/H 2 O 5/1) to obtain a yellow solid a6 (996 mg), yield: 58%. LCMS ESI-MS m/z: 662[M+H] + .
  • Step 1 Under nitrogen protection, the raw material 4,6-dichloro-5-methoxypyrimidine b1-1 (20.0 g, 111 mmol), the raw material methylboric acid (7.0 g, 117 mmol) and potassium phosphate (59.2 g, 279 mmol) were dissolved in 120 mL DME, and the catalyst Pd(dppf)Cl 2 (4.6 g, 5.6 mmol) was added. The mixture was heated to 85°C for 12 hours, the reaction was stopped, and the mixture was filtered.
  • Step 2 Under carbon monoxide atmosphere, the intermediate b1-2 (6.0 g, 37.0 mmol) and TEA (7.66 g, 75.0 mmol) were dissolved in 90 mL of methanol, and the catalyst Pd(dppf)Cl 2 (1.85 g, 2.3 mmol) was added. The mixture was heated to 100°C under CO (20 atm) for 12 hours, and the reaction was stopped and filtered.
  • Step 3 Dissolve the intermediate b1-3 (3.0 g, 16.5 mmol) in 15 mL HBr aqueous solution (40%), heat to 40°C and react for 10 hours, then stop the reaction. Add HI (15 mL) to the reaction solution, continue to react at 40°C for 6 hours, and remove the solvent under reduced pressure. Adjust the pH of the crude product to about 8 with NaOH aqueous solution (1N), then adjust the pH to about 3 with concentrated hydrochloric acid, and remove the solvent under reduced pressure. The crude product is separated by flash reverse column chromatography (chromatographic column: C18; CH 3 CN/H 2 O, 1/1) to obtain a yellow solid b1 (1.5 g), yield: 59%. LCMS ESI-MS m/z: 155[M+H] + .
  • Step 1 In an ice bath, under nitrogen protection, the raw material b2-1 (500 mg, 3.81 mmol) was dissolved in 10 mL of tetrahydrofuran, and NBS (679 mg, 3.81 mmol) was added. The mixture was reacted at room temperature for 0.5 hours, the reaction was stopped, and filtered. Saturated sodium bicarbonate aqueous solution was added to the reaction solution to adjust the pH to about 8, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (PE/EA, 10/1) to obtain a yellow oil b2-2 (540 mg), yield: 63%. LCMS ESI-MS m/z: 224 [M+H] + .
  • Step 2 Under nitrogen protection, the intermediate b2-2 (510 mg, 2.28 mmol) of the previous step was dissolved in 3 mL of diethyl carbonate DMC, and CH 3 ONa (185 mg, 3.42 mmol) was added. The mixture was heated to 125°C for reaction for 0.5 hours and cooled to room temperature. 20 mL of ice water was added to the reaction solution, extracted with methyl tert-butyl ether, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (PE/EA, 1/1) to obtain a yellow oil b2-3 (300 mg), with a yield of 64%. LCMS ESI-MS m/z: 205 [M+H] + .
  • Step 3 -78°C, under nitrogen protection, the intermediate b2-3 (300 mg, 1.46 mmol) of the previous step was dissolved in 6 mL of anhydrous tetrahydrofuran, and nBuLi (2.5 M, 1.47 mL) was added dropwise. After the addition was completed, stirring was continued for 1 hour. Isopropyl alcohol pinacol borate (327 mg, 1.75 mmol) was added to the reaction solution, and the reaction was continued at -78°C for 1 hour.
  • Step 1 In an ice bath, under nitrogen protection, the raw material 5-bromo-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid methyl ester b3-1 (600 mg, 2.35 mmol) and NaH (70 mg, 2.82 mmol) were dissolved in 12 mL DMF, SEM-Cl (570 mg, 3.52 mmol) was added, and the mixture was reacted at room temperature for 3 hours to stop the reaction.
  • Step 2 Under nitrogen protection, the intermediate b3-2 (500 mg, 1.29 mmol) and diboronic acid pinacol ester (490 mg, 1.95 mmol) were dissolved in 13 mL 1,4-dioxane, KOAc (380 mg, 3.89 mmol) and catalyst Pd(dppf)Cl 2 .DCM (110 mg, 0.13 mmol) were added, and the mixture was heated to 120°C for 5 hours, cooled to room temperature, and filtered. The filter cake was washed and dried to obtain a brown solid b3 (400 mg), with a yield of 71%.
  • Step 1 In an ice bath, under nitrogen protection, the intermediate b3 (400 mg, 0.92 mmol) was dissolved in a mixed solution of 5 mL tetrahydrofuran and water (v/v, 1/1), sodium borate (210 mg, 1.38 mmol) was added, and the mixed solution was reacted at room temperature for 3 hours to stop the reaction. 20 mL of ice water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a brown oil b4-1 (100 mg), yield: 40%. LCMS ESI-MS m/z: 323 [M+H] + .
  • Step 2 Under nitrogen protection, the intermediate b4-1 (100 mg, 0.31 mmol) of the previous step was dissolved in a mixed solution of 3 mL of tetrahydrofuran and water (v/v, 1/1), and NaOH (25 mg, 0.62 mmol) was added. The mixture was reacted at room temperature for 2 hours, and the reaction was stopped. The solvent was evaporated under reduced pressure. 10 mL of water was added to the mixture, and the pH was adjusted to about 4 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated.
  • Step 1 Under nitrogen protection, the raw material 4,6-dichloro-5-methoxypyrimidine b1-1 (5.0 g, 27.9 mmol), the raw material b6-1 (9.2 g, 27.9 mmol) and CuI (50 mg, 0.28 mmol) were dissolved in 5 mL DME, and the catalyst Pd(PPh 3 ) 4 (320 mg, 0.28 mmol) was added. The mixed solution was heated to 85° C. for 1 hour, the reaction was stopped, and filtered.
  • Step 2 Under carbon monoxide atmosphere, the intermediate b6-2 (3.0 g, 16.4 mmol) and TEA (3.3 g, 32.9 mmol) were dissolved in 60 mL of methanol, and the catalyst Pd(dppf)Cl 2 (1.2 g, 1.64 mmol) was added. The mixture was heated to 100°C under CO (30 atm) for 4 hours, the reaction was stopped, and the mixture was filtered. The solvent was evaporated under reduced pressure, and the crude product was separated by column chromatography (PE/EA, 4/1) to obtain a yellow solid b6-3 (1.45 g), with a yield of 43%. LCMS ESI-MS m/z: 207 [M+H] + .
  • Step 3 Under nitrogen protection, the intermediate b6-3 (1.4 g, 6.79 mmol) and TEA (7.0 mL) were dissolved in 7 mL DMA, and the catalyst CuI (130 mg, 0.68 mmol) was added. The mixture was heated to 105 ° C for 2 hours, the reaction was stopped, and filtered. 30 mL of water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (PE/EA, 1/1) to obtain yellow solid b6-4 (150 mg), yield: 11%. LCMS ESI-MS m/z: 207 [M+H] + .
  • Step 4 Dissolve the intermediate b6-4 (150 mg, 0.73 mmol) in a mixed solution of 3 mL of methanol and water (v/v, 1/1), add NaOH (58 mg, 1.5 mmol), react at room temperature for 2 hours, and stop the reaction. Add 2 M dilute hydrochloric acid to the reaction solution to adjust the pH to about 6, and evaporate the solvent under reduced pressure.
  • the crude product was separated by flash reverse column chromatography (chromatographic column: C18; CH 3 CN/H 2 O, 3/2) to obtain a white solid b6 (110 mg), yield: 79%.
  • Step 1 In an ice bath, under nitrogen protection, the raw material b7-1 (11.0 g, 59.3 mmol) was dissolved in 115 mL of acetonitrile, and NBS (10.5 g, 59.3 mmol) was added. The mixed solution was reacted for 1 hour in an ice bath, the reaction was stopped, and filtered. 300 mL of water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (PE/EA, 1/1) to obtain yellow solid b7-2 (9.0 g), yield: 91%. LCMS ESI-MS m/z: 245 [M+H] + .
  • Step 2 Under nitrogen protection, the intermediate b7-2 (10.0 g, 40.8 mmol) of the previous step was dissolved in a mixed solution of 150 mL of acetic acid and tetrahydrofuran (v/v, 2/1), and NIS (13.8 g, 61.2 mmol) was added. The mixed solution was reacted at 35°C for 12 hours, the reaction was stopped, and filtered. 300 mL of water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (PE/EA, 1/2) to obtain yellow solid b7-3 (8.0 g), yield: 53%. LCMS ESI-MS m/z: 371 [M+H] + .
  • Step 3 Under nitrogen protection, the intermediate b7-3 (8.0 g, 21.6 mmol), K 3 PO 4 (13.7 g, 64.70 mmol) and the raw material b7-4 (8.5 g, 43.1 mmol) were dissolved in 100 mL of isopropanol, and the catalyst Pd(OAc) 2 (500 mg, 2.16 mmol) and the ligand RuPhos (1.0 g, 2.16 mmol) were added. The mixed solution was reacted at room temperature for 14 hours, the reaction was stopped, and the mixture was filtered.
  • the catalyst Pd(OAc) 2 500 mg, 2.16 mmol
  • RuPhos 1.0 g, 2.16 mmol
  • Step 4 Dissolve the intermediate b7-5 (5.3 g, 15.4 mmol) in 53 mL of methanol, add concentrated hydrochloric acid (11 mL), and react the mixture at 40 ° C for 12 hours to stop the reaction.
  • the solvent was evaporated under reduced pressure, and a saturated sodium bicarbonate aqueous solution was added to the reaction solution to adjust the pH to about 7, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated.
  • the crude product was separated by flash column chromatography (PE/EA, 1/2) to obtain a yellow solid b7-6 (2.0 g), with a yield of 48%.
  • Step 5 In an ice bath, under nitrogen protection, the intermediate b7-6 (2.0 g, 7.43 mmol) and NaH (200 mg, 8.92 mmol) of the previous step were dissolved in 32 mL of DMF, and SEM-Cl (1.9 g, 11.2 mmol) was added. The mixture was reacted at room temperature for 3 hours to stop the reaction. 100 mL of ice water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash reverse column chromatography (chromatographic column: C18; CH 3 CN/H 2 O, 1/1) to obtain yellow oil b7-7 (1.2 g), yield: 40%. LCMS ESI-MS m/z: 399 [M+H] + .
  • Step 6 Under nitrogen protection, the intermediate b7-7 (1.2 g, 3.0 mmol) and biboronic acid pinacol ester (1.1 g, 4.5 mmol) were dissolved in 24 mL 1,4-dioxane, KOAc (900 mg, 9.02 mmol) and catalyst Pd(dppf)Cl 2 .DCM (210 mg, 0.30 mmol) were added, and the mixture was heated to 100°C for 2 hours, cooled to room temperature, and filtered. The solvent was evaporated under reduced pressure to obtain a brown oil b7-8 (1.0 g). LCMS ESI-MS m/z: 447 [M+H] + .
  • Step 7 In an ice bath, under nitrogen protection, the intermediate b7-8 (1.0 g, 2.24 mmol) of the previous step was dissolved in a mixed solution of 12 mL of tetrahydrofuran and water (v/v, 1/1), sodium borate (310 mg, 3.38 mmol) was added, and the mixed solution was reacted at 50°C for 3 hours to stop the reaction. 50 mL of ice water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE/EA, 1/1) to obtain a yellow solid b7-9 (100 mg), yield: 13%. LCMS ESI-MS m/z: 337 [M+H] + .
  • Step 8 Under nitrogen protection, the intermediate b7-9 (100 mg, 0.30 mmol) of the previous step was dissolved in a mixed solution of 3 mL of tetrahydrofuran and water (v/v, 2/1), and NaOH (25 mg, 0.62 mmol) was added. The mixture was reacted for 2 hours at room temperature, and the reaction was stopped. The solvent was evaporated under reduced pressure. 10 mL of water was added to the mixture, and the pH was adjusted to about 4 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated.
  • Step 1 Under nitrogen protection, intermediate a4 (210 mg, 0.3 mmol) and TEA (114 mg, 1.1 mmol) were dissolved in 2 mL DMSO, and raw material c1-1 (371 mg, 1.9 mmol) was added. The mixture was heated to 85°C for 12 hours to stop the reaction.
  • Step 2 Dissolve the intermediate c1-1 (120 mg, 0.2 mmol) and trifluoroacetic acid (0.5 mL) in 2 mL of dichloromethane, react at room temperature for 2 hours, and stop the reaction. Evaporate the solvent under reduced pressure, and separate the crude product by HPLC preparative chromatography (chromatographic column: WelFlash C18-I, 20-40 um, 40 g; mobile phase A: water (10 mmol/L NH 4 HCO 3 ) mobile phase B: acetonitrile; flow rate: 50 mL/min; retention time: 9 min) to obtain white solid c1 (80 mg), yield: 78%.
  • Step 1 Dissolve the intermediate a6 (996 mg, 1.5 mmol) in 10 mL of dichloromethane, add 0.5 mL of trifluoroacetic acid, and react the mixture at room temperature for 1 hour to stop the reaction. Add 20 mL of water to the reaction solution, adjust the pH to about 9 with a saturated sodium bicarbonate aqueous solution, extract with dichloromethane, dry with anhydrous sodium sulfate, and concentrate to obtain a yellow solid c5-2 (694 mg), yield: 82%.
  • Step 2 Dissolve the intermediate c5-2 (494 mg, 0.88 mmol) and DIEA (567 mg, 4.4 mmol) in 5 mL of dichloromethane, add the raw material 3-hydroxy-2-pyridinecarbonyl chloride c5-1 (277 mg, 1.76 mmol), react at room temperature for 2 hours, and stop the reaction. The solvent was evaporated under reduced pressure, and the crude product was separated by flash column chromatography (chromatographic column: WelFlash C18-I, 20-40um, 130g; mobile phase A: water, mobile phase B: acetonitrile; flow rate: 60 mL/min; retention time: 14 min) to obtain a yellow solid c5 (360 mg), yield: 60%. LCMS ESI-MS m/z: 683 [M+H] + .
  • DIEA 138 mg, 1.06 mmol
  • intermediate c5-2 120 mg, 0.21 mmol
  • Step 1 Under nitrogen protection, intermediate a5 (2.5 g, 5.85 mmol), raw material a3-1 (1.2 g, 5.85 mmol) and sodium carbonate (1.9 g, 17.5 mmol) were dissolved in 50 mL of a mixed solution of 1,4-dioxane and water (v/v, 1/1), and catalyst Pd(dppf)Cl 2 (400 mg, 0.59 mmol) was added. The mixture was heated to 100° C. and reacted for 12 hours. The reaction was stopped and filtered.
  • Step 2 Dissolve the intermediate c7-1 (1.5 g, 3.48 mmol) and the raw material ethyl bromoacetate c7-2 (0.8 g, 4.88 mmol) in 25 mL 1,4-dioxane, slowly add DIEA (1.4 g, 10.5 mmol), and heat to 80°C for 4 hours, cool to room temperature, and stop the reaction. Pour the reaction solution into 100 mL ice water, extract with dichloromethane, dry with anhydrous sodium sulfate, and concentrate.
  • Step 3 Dissolve the intermediate c7-3 (1.2 g, 2.32 mmol) in a mixed solution of 18 mL tetrahydrofuran and water (v/v, 2/1), slowly add NAOH aqueous solution (3.5 mL, 1 M), dropwise, react at room temperature for 1 hour, and stop the reaction.
  • Step 1 Under nitrogen protection, the raw material d1-1 (2.0 g, 7.40 mmol) and methylhydrazine sulfate (1.1 g, 7.40 mmol) were dissolved in 40 mL of ethanol, acetic acid (100 mg, 0.14 mmol) was added, and the mixture was heated to 80 ° C for 2 hours, the reaction was stopped, and the mixture was evaporated under reduced pressure. Solvent. Saturated sodium bicarbonate aqueous solution was added to the mixed solution to adjust the pH to about 8, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oil d1-2 (2.5 g), yield: 89%. LCMS ESI-MS m/z: 297 [M+H] + .
  • Step 2 Under nitrogen protection, the intermediate d1-2 (2.5 g, 8.38 mmol) and potassium phosphate (1.78 g, 8.39 mmol) of the previous step were dissolved in 38 mL DMSO, and the catalyst CuI (160 mg, 0.83 mmol) was added. The mixture was heated to 100 ° C for 3 hours, the reaction was stopped, and filtered.
  • Step 3 -78°C, under nitrogen protection, the intermediate d1-3 (130 mg, 0.59 mmol) of the previous step was dissolved in 2.5 mL of anhydrous tetrahydrofuran, and n-BuLi (0.28 mL, 2.5 M) was slowly added. After the addition was complete, the mixture was stirred at -78°C for 1 hour. 2-isopropoxyboronic acid pinacol ester (134 mg, 1.23 mmol) was added to the reaction solution, and stirring was continued for 30 minutes to stop the reaction.
  • the first step under nitrogen protection, the raw material 1-bromo-2-fluoro-4-iodobenzene d8-1 (1.95 g, 6.5 mmol) and the raw material d8-2 (2.32 g, 7.8 mmol) were dissolved in 40 mL of acetonitrile, potassium tert-butoxide (2.2 g, 19.4 mmol) was added, and the mixture was heated to 50 ° C for 6 hours, the reaction was stopped, and filtered.
  • Step 2 Dissolve the intermediate d8-3 (2.22 g, 5.15 mmol) in 133 mL of chlorobenzene, add polyphosphoric acid PPA (2.37 g, 20.6 mmol), heat the mixture to 130°C for 5 hours, stop the reaction, and cool to room temperature. Add 100 mL of ice water to the reaction solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, concentrate, and separate the crude product by flash reverse column chromatography (chromatographic column: C18; CH 3 CN/H 2 O, 9/10) to obtain yellow oil d8-4 (1.05 g), yield: 60%.
  • PPA polyphosphoric acid
  • Step 3 Under nitrogen protection, the intermediate d8-4 (1.05 g, 3.1 mmol) and the raw material d8-5 (1.95 g, 9.3 mmol) of the previous step were dissolved in 21 mL DMF, and the catalyst CuI (290 mg, 1.55 mmol) and HMPA (2.39 g, 13.3 mmol) were added. The mixture was heated to 100 ° C for 2 hours, the reaction was stopped, and filtered.
  • Step 4 Under nitrogen protection, the intermediate d8-6 (0.8 g, 2.85 mmol) and the raw material diphenyl ketone imine (1.03 g, 5.69 mmol) were dissolved in 16 mL of toluene, and catalyst Pd(OAc) 2 (60 mg, 0.28 mmol), ligand BINAP (0.35 g, 0.57 mmol) and cesium carbonate (1.85 g, 5.69 mmol) were added. The mixed solution was heated to 110°C for 2 hours, the reaction was stopped, and filtered. 60 mL of water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a crude mixture.
  • Step 1 Under CO 2 (20 atm), the raw material d9-1 (2.5 g, 15.7 mmol) and TEA (21.8 mL, 157 mmol) were dissolved in 50 mL of methanol, and the catalyst Pd(dppf)Cl 2 (1.2 g, 1.57 mmol) was added. The mixture was heated to 80°C for 12 hours, the reaction was stopped, and the mixture was filtered.
  • Step 2 Dissolve the intermediate d9-2 (900 mg, 4.91 mmol) and chloroacetaldehyde (771 mg, 9.8 mmol) in 18 mL of ethanol, heat the mixture to 80°C for 5 hours, stop the reaction, and cool to room temperature.
  • Step 3 Under nitrogen protection, the intermediate d9-3 (200 mg, 0.97 mmol) of the previous step was dissolved in 4 mL of dichloromethane, and BBr 3 (1.93 mL, 1.93 mmol) was added. The mixture was reacted at room temperature for 12 hours, the reaction was stopped, and the mixture was filtered. 20 mL of water was added to the reaction solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to obtain a crude mixture. The mixture was dissolved in 3 mL of tetrahydrofuran, 2N aqueous NAOH solution (1 mL) was added, reacted at room temperature for 1 hour, and the reaction was stopped.
  • Step 1 Under nitrogen protection, the raw materials NBS (3.81 g, 21.4 mmol) and AIBN (200 mg, 1.22 mmol) were dissolved in 40 mL of carbon tetrachloride, the mixed solution was heated to 80 ° C, and the raw material d10-1 (3.0 g, 21.4 mmol) was added dropwise to the reaction solution. After the addition was completed, the reaction was continued for 5 hours, the reaction was stopped, and the reaction was filtered.
  • NBS 3.81 g, 21.4 mmol
  • AIBN 200 mg, 1.22 mmol
  • Step 2 The intermediate d10-2 (2.5 g, 11.4 mmol) and the raw material d10-3 (3.05 g, 12.5 mmol) of the previous step were dissolved in 18 mL of DMF, and KI (189 mg, 1.1 mmol) and K 2 CO 3 (2.36 g, 17.1 mmol) were added. The mixture was heated to 50°C for 3 hours, the reaction was stopped, and the mixture was cooled to room temperature.
  • Step 3 -70°C, under nitrogen protection, the intermediate d10-4 (2.11 g, 5.54 mmol) of the previous step was dissolved in 40 mL of anhydrous tetrahydrofuran, and LiHMDS (15.51 mL, 15.51 mmol) was added. The mixture continued to react for 1 hour, the reaction was stopped, and the temperature was raised to room temperature. 20 mL of water was added to the reaction solution, and the pH was adjusted to about 6 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by chromatography (PE/EA, 1/5) to obtain a yellow oil d10-5 (951 mg), with a yield of 89%. LCMS ESI-MS m/z: 194 [M+H] + .
  • Step 4 The intermediate d10-5 (903 mg, 4.68 mmol) of the previous step was dissolved in a mixed solution of 12 mL of tetrahydrofuran and water (v/v, 2/1), and LiOH (280 mg, 11.7 mmol) was added. The mixed solution was heated to 50°C for 4 hours to stop the reaction. 20 mL of water was added to the reaction solution, and the pH was adjusted to about 3 with dilute hydrochloric acid. The solid was precipitated, filtered, and the filter cake was dried to obtain a white solid d10 (265 mg), with a yield of 32%. LCMS ESI-MS m/z: 180 [M+H] + .
  • Step 1 Under hydrogen protection (1 atm), the intermediate d10-5 (800 mg, 4.14 mmol) and Pd/C (320 mg, 40% wt) were dissolved in 16 mL of ethanol, mixed and reacted at room temperature for 2 hours, the reaction was stopped, and filtered. The solvent was evaporated under reduced pressure to obtain a white solid d11-1 (707 mg), yield: 88%. LCMS ESI-MS m/z: 196 [M+H] + .
  • Step 2 Dissolve the intermediate d11-1 (700 mg, 3.58 mmol) in a mixed solution of 10 mL tetrahydrofuran and water (v/v, 3/1), add LiOH (215 mg, 9.0 mmol), heat the mixed solution to 50°C for 4 hours, and stop the reaction. Add 20 mL of water to the reaction solution, adjust the pH to about 3 with dilute hydrochloric acid, precipitate the solid, filter, and dry the filter cake to obtain a white solid d11 (485 mg), yield: 75%.
  • Step 1 Under carbon monoxide protection, the raw material d12-1 (1.0 g, 6.26 mmol) and methanol (3.0 mL) were dissolved in 10 mL DMF, and catalyst Pd(dppf)Cl 2 (0.9 g, 1.25 mmol) and TEA (3.0 mL) were added. The mixed solution was heated to 120°C under carbon monoxide (30 atm) for 12 hours, the reaction was stopped, and the mixture was filtered.
  • Step 2 Dissolve the intermediate d12-2 (500 mg, 2.73 mmol) and the raw material chloroacetaldehyde (642 mg, 8.2 mmol) in 10 mL of tert-butyl alcohol, heat the mixture to 90 °C and react for 12 hours, stop the reaction, and cool to room temperature. Add 50 mL of ice water to the reaction solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash reverse column chromatography (chromatographic column: C18; CH 3 CN/H 2 O, 2/1) to obtain a yellow solid d12-3 (200 mg), yield: 35%. LCMS ESI-MS m/z: 208 [M+H] + .
  • Step 3 Dissolve the intermediate d12-3 (190 mg, 0.91 mmol) in a mixed solution of 4 mL tetrahydrofuran and water (v/v, 3/1), add NaOH (73 mg, 1.8 mmol), and react the mixed solution at room temperature for 1 hour to stop the reaction. Add 10 mL of water to the reaction solution, adjust the pH to about 3 with dilute hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, concentrate, and separate the crude product by flash reverse column chromatography (chromatographic column: C18; CH 3 CN/H 2 O, 2/1) to obtain a white solid d12 (100 mg), yield: 56%.
  • Step 1 Dissolve the raw material d13-1 (5.0 g, 17.7 mmol) and ethanol (50 mL) in 100 mL of concentrated HBr, add KSCN (5.2 g, 53.2 mmol), heat the mixture to 100°C for 2 hours, and stop the reaction. Evaporate the solvent under reduced pressure, add 100 mL of water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and separate the crude product by flash reverse column chromatography (chromatographic column: C18; CH 3 CN/H 2 O, 2/1) to obtain a brown solid d13-2 (1.1 g), yield: 24%.
  • Step 2 Under nitrogen protection, the intermediate d13-2 (1.1 g, 4.22 mmol) and the raw material iPrONO (1.49 g, 12.7 mmol) were dissolved in 17 mL of anhydrous tetrahydrofuran, and DMSO (0.3 g, 3.38 mmol) was added. The mixture was heated to 50°C for 12 hours, the reaction was stopped, and the mixture was cooled to room temperature.
  • Step 3 Under carbon monoxide protection, the intermediate d13-3 (460 mg, 1.87 mmol) and TEA (380 mg, 3.75 mmol) of the previous step were dissolved in 10 mL of methanol, and the catalyst Pd(dppf)Cl 2 (137 mg, 0.18 mmol) was added. The mixed solution was heated to 100°C under carbon monoxide (30 atm) for 12 hours, the reaction was stopped, and the mixture was filtered. The solvent was evaporated under reduced pressure, 100 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a brown solid d13-4 (525 mg). LCMS ESI-MS m/z: 225 [M+H] + .
  • Step 4 The intermediate d13-4 (525 mg, 2.34 mmol) of the previous step was dissolved in a mixed solution of 10 mL of tetrahydrofuran and water (v/v, 7/3), and NaOH (187 mg, 4.8 mmol) was added. The mixed solution was reacted at room temperature for 1 hour to stop the reaction. 10 mL of water was added to the reaction solution, and the pH was adjusted to about 6 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated.
  • Step 1 Under nitrogen protection, the raw material 2-bromo-5-trifluoromethylphenol d18-1 (5.0 g, 20.75 mmol) and potassium carbonate (8.6 g, 62.2 mmol) were dissolved in 100 mL DMF, and the raw material d18-2 (12.3 g, 62.2 mmol) was added dropwise. The mixture was heated to 80 ° C for 12 hours, the reaction was stopped, and filtered. 250 mL of water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (PE/EA, 20/1) to obtain a yellow oil d18-3 (6.0 g), with a yield of 81%.
  • PE/EA column chromatography
  • Step 2 Dissolve the intermediate d18-3 (6.0 g, 16.8 mmol) and polyphosphoric acid (30 g, 261 mmol) in 72 mL of toluene, heat the mixture to 120°C and react for 5 hours to stop the reaction. Add 100 mL of water to the reaction solution, adjust the pH to about 8 with ammonia water, extract with methyl tert-butyl ether, dry with anhydrous sodium sulfate, concentrate, and separate by column chromatography (PE/EA, 20/1) to obtain a yellow oil d18-4 (1.0 g), with a yield of 23%.
  • PE/EA column chromatography
  • Step 3 Under nitrogen protection, the intermediate d18-4 (1.0 g, 3.77 mmol) and the raw material diphenyl ketone imine (1.4 g, 7.55 mmol) were dissolved in 20 mL of toluene, and the catalyst Pd(OAc) 2 (80 mg, 0.38 mmol), the ligand BINAP (0.5 g, 0.8 mmol) and Cesium carbonate (2.5 g, 7.55 mmol), the mixture was heated to 110 ° C and reacted for 2 hours, the reaction was stopped and filtered. 100 mL of water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a crude mixture.
  • the catalyst Pd(OAc) 2 80 mg, 0.38 mmol
  • the ligand BINAP 0.5 g, 0.8 mmol
  • Cesium carbonate 2.5 g, 7.55 mmol
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Step 1 In an ice bath, under nitrogen protection, the intermediate b4 (70 mg, 0.22 mmol) and 1-chloro-N, N, 2-trimethylpropyl-1-en-1-amine (61 mg, 0.45 mmol) were dissolved in 2 mL of dichloromethane and stirred for 1 hour in an ice bath. The intermediate c2 (129 mg, 0.23 mmol) and DIEA (88 mg, 0.68 mmol) were added to the reaction solution, and the mixture was reacted at room temperature for 2 hours to stop the reaction.
  • Step 2 In an ice bath, under nitrogen protection, the compound P1-1 (40 mg, 0.05 mmol) and trifluoroacetic acid (0.4 mL) were dissolved in 1 mL of dichloromethane, stirred at room temperature for 2 hours, and the solvent was evaporated under reduced pressure. The mixture was dissolved in 1 mL of dichloromethane again, and DMEDA (0.08 mL) was added. The reaction solution was reacted at room temperature for 8 hours, and the reaction was stopped.
  • the compound P1-1 40 mg, 0.05 mmol
  • trifluoroacetic acid 0.4 mL
  • Step 1 In an ice bath, under nitrogen protection, the intermediate b4 (602 mg, 1.95 mmol) and 1-chloro-N, N, 2-trimethylpropyl-1-en-1-amine (261 mg, 1.95 mmol) were dissolved in 12 mL of dichloromethane and stirred for 1 hour in an ice bath.
  • the intermediate c5-2 550 mg, 0.98 mmol
  • DIEA 379 mg, 2.9 mmol
  • Step 2 In an ice bath, under nitrogen protection, the compound P3-1 (300 mg, 0.35 mmol) and trifluoroacetic acid (3.0 mL) were dissolved in 3 mL of dichloromethane, stirred at room temperature for 2 hours, and the solvent was evaporated under reduced pressure. The mixture was dissolved in 3 mL of dichloromethane again, and DMEDA (0.08 mL) was added. The reaction solution was reacted at room temperature for 8 hours, and the reaction was stopped. The solvent was evaporated under reduced pressure, and the crude product was separated by flash reverse column chromatography (chromatographic column: C18; CH 3 CN/H 2 O, 4/5) to obtain a yellow oil P3-2 (150 mg), with a yield of 59%. LCMS ESI-MS m/z: 722 [M+H] + .
  • Step 3 Under nitrogen protection, the intermediate P3-2 (34 mg, 0.05 mmol) and the intermediate d7 (23 mg, 0.09 mmol) of the previous step were dissolved in a mixed solution of 1 mL DMF and water (3/1), and catalyst Pd(dppf)Cl 2 (60 mg, 0.28 mmol) and potassium phosphate (30 mg, 0.14 mmol) were added. The mixed solution was heated to 70°C for 2 hours, the reaction was stopped, and filtered. 5 mL of water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a crude mixture.
  • catalyst Pd(dppf)Cl 2 60 mg, 0.28 mmol
  • potassium phosphate 30 mg, 0.14 mmol
  • Step 1 Under nitrogen protection, intermediate c23 (100 mg, 0.12 mmol) and morpholine (51 mg, 0.59 mmol) were dissolved in 2 mL DMSO, KOAc (69 mg, 0.70 mmol) was added, and the temperature was raised to 120°C for reaction for 5 hours to stop the reaction. 20 mL of water was added to the reaction solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash reverse column chromatography (chromatographic column: C18; CH 3 CN/H 2 O, 4/5) to obtain yellow solid P10-1 (60 mg), yield: 60%. LCMS ESI-MS m/z: 859 [M+H] + .
  • Step 2 In an ice bath, under nitrogen protection, the compound P10-1 (60 mg, 0.07 mmol) and trifluoroacetic acid (1.0 mL) were dissolved in 1 mL of dichloromethane, stirred at room temperature for 2 hours, and the solvent was evaporated under reduced pressure. The mixture was dissolved in 1 mL of dichloromethane again, and DMEDA (0.12 mL) was added. The reaction solution was reacted at room temperature for 8 hours, and the reaction was stopped.
  • the compound P10-1 60 mg, 0.07 mmol
  • trifluoroacetic acid 1.0 mL
  • Step 1 Under nitrogen protection, intermediate c2 (687 mg, 1.21 mmol) and 1-chloro-N, N, 2-trimethylpropyl-1-en-1-amine (161 mg, 1.2 mmol) were dissolved in 3 mL of dichloromethane and stirred for 1 hour under ice bath. Intermediate d11 (110 mg, 0.60 mmol) and DIEA (392 mg, 3.0 mmol) were added to the reaction solution, and the mixture was reacted at room temperature for 2 hours to stop the reaction.
  • Step 1 Under nitrogen protection, intermediate c2 (563 mg, 1.0 mmol), DIEA (428 mg, 3.32 mmol) and intermediate d13 (131 mg, 0.66 mmol) were dissolved in 3 mL of acetonitrile. EDCI (254 mg, 1.32 mmol) and HOAt (180 mg, 1.33 mmol) were added to the reaction solution, and the mixture was reacted at room temperature for 3 hours to stop the reaction.
  • Step 2 Under nitrogen protection, the compound P16-1 (88 mg, 0.45 mmol) and LiCl (76 mg, 1.8 mmol) were dissolved in 2 mL DMF. The mixture was heated to 150°C for 13 hours and the reaction was stopped.
  • Step 1 Under nitrogen protection, intermediate c7 (150 mg, 0.31 mmol), DIEA (238 mg, 1.84 mmol) and intermediate d18 (74 mg, 0.37 mmol) were dissolved in 5 mL of dichloromethane and stirred for 5 minutes under ice bath. T 3 P (110 mg, 0.60 mmol) and DMAP (113 mg, 0.92 mmol) were added to the reaction solution, and the mixture was reacted at room temperature for 12 hours to stop the reaction.
  • Step 2 Dissolve the compound P18-1 (162 mg, 0.24 mmol) in 1 mL of 1,4-dioxane and stir for 5 minutes under ice bath. Add 1,4-dioxane solution of HCl (2 M, 3.3 mL) to the reaction solution, and react the mixture at room temperature for 1 hour to stop the reaction. Evaporate the solvent under reduced pressure to obtain a brown solid P18-2 (162 mg).
  • Step 3 Under nitrogen protection, the compound P18-2 (162 mg, 0.28 mmol), DIEA (238 mg, 1.84 mmol) and intermediate b4 (175 mg, 0.57 mmol) were dissolved in 4 mL of dichloromethane and stirred for 5 minutes under ice bath. 1-Chloro-N, N, 2-trimethylpropyl-1-en-1-amine (76 mg, 0.56 mmol) was added to the reaction solution, and the mixture was reacted at room temperature for 2 hours to stop the reaction.
  • Step 4 Dissolve the compound P18-3 (93 mg, 0.11 mmol) in a mixed solution of 2 mL trifluoroacetic acid and dichloromethane (v/v, 1/1), react for 2 hours under ice bath, and remove the solvent under reduced pressure. Dissolve the mixture in 1 mL dichloromethane, add ethylenediamine EDA (1.0 mL) to the reaction solution, and continue to react at room temperature for 1 hour to stop the reaction.
  • EDA ethylenediamine
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • test compound was dissolved in DMSO and diluted 4 times (10 ⁇ M final concentration as the starting concentration). 0.2 ⁇ L of the test compound solution was added to a 384-well plate, and 10 ⁇ L (2X) WRN enzyme solution was added. After incubation in the dark for 30 minutes, 10 ⁇ L of substrate detection solution containing double-stranded DNA was added to initiate the reaction (DNA length 19 bp, 3′ and 5′ labeled TAMRA and BHQ2, respectively), and incubated at room temperature for 60 minutes. The inhibitory activity (IC 50 ) for WRN enzyme was calculated based on the changes in fluorescence Ex530/Em590 of the blank group (DMSO) and the compound group.
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • the molecules of the present invention were tested for their anti-proliferative activity against MSI-H tumor cells.
  • MSI unstable SW48 colorectal cancer cells were cultured in RMI1640 medium containing 10% FBS and 1% penicillin-streptomycin, placed in a 37°C, 5% CO 2 constant temperature incubator, and 40 ⁇ L of cell suspension was added to each well of a 384-well microplate. 40 nL of compounds of different concentrations were added to each well using Echo, and placed in a 37°C, 5% CO 2 constant temperature incubator for 5 days. 40 ⁇ L of CTG solution (Promega, CatNo. G7573) was added to each well and placed in a 37°C, 5% CO 2 constant temperature incubator incubated in the dark for 30 minutes. The luminescence value was read using an Envision multifunctional microplate reader (Perkin Elmer, catalog number Envision 2104). The light signal was proportional to the amount of ATP in the system, and the ATP content directly characterized the number of viable cells in the system.
  • control molecule A1 was synthesized
  • control molecule P11b has no inhibitory effect on SW48 cells, while the molecules of the present invention such as P13, P14, P15, P16, P26 and the like have significant inhibitory effects, indicating that different ring structures significantly affect the anti-proliferation effect.
  • Embodiment 5 is a diagrammatic representation of Embodiment 5:
  • the molecules of the present invention were tested for their antiproliferative activity against MSS tumor cells.
  • the HT-29 colorectal cancer cells of MSS were cultured in McCoy's 5A medium containing 10% FBS and 1% penicillin-streptomycin, placed in a 37°C, 5% CO 2 constant temperature incubator, and 40 ⁇ L of cell suspension was added to each well of a 384-well microplate. 40 nL of compounds of different concentrations were added to each well using Echo, and placed in a 37°C, 5% CO 2 constant temperature incubator for 5 days. 40 ⁇ L of CTG solution (Promega, Cat No. G7573) was added to each well and placed in a 37°C, 5% CO 2 constant temperature incubator incubated in the dark for 30 minutes. The luminescence value was read using an Envision multifunctional microplate reader (Perkin Elmer, catalog number Envision 2104). The light signal was proportional to the amount of ATP in the system, and the ATP content directly characterized the number of viable cells in the system.
  • Table 2.2 2D antiproliferative effects of compounds on MSS colon cancer HT-29 cell line
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • liver microsome stability test of the compound is as follows:
  • the compounds of the present invention were subjected to a liver microsome stability test.
  • the compounds to be tested were co-incubated with liver microsomes of different species with or without the addition of NADPH.
  • the final concentration of the compounds to be tested in the test system was 1 ⁇ M, the final concentration of NADPH was 1 mM, and the final concentration of liver microsomes was 0.5 mg/mL.
  • the compound concentrations in the incubation supernatant at different time points within 60 minutes were detected and pharmacokinetic parameters (e.g., clearance Cl int ) were calculated.
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • CD1 female mice were used as test animals and the drug was administered orally/intravenously (oral dosage was 10 mg/kg, intravenous dosage was 2 mg/kg).
  • mice in each oral group (solvent: 10% H ⁇ -CD-pH7.4), 3 mice in each intravenous group.
  • Use LC/MS/MS method to determine the blood concentration of plasma after oral and intravenous administration of mice, and the collected data are calculated by AB Sciex QTRAP 6500 software.
  • the experimental results are as follows:

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Abstract

本发明提供了一种式(A)化合物作为WRN抑制剂，化合物或其药学上可接受的盐、同位素变体、互变异构体或立体异构体。本发明还提供了包含所述化合物的药物组合物，及其在治疗癌症中的用途。

Description

WRN抑制剂 技术领域
本发明属于医药领域，具体涉及WRN抑制剂。
背景技术
DNA错配修复(MMR)异常会导致DNA核苷酸重复区的高度突变(缺失或插入)，这种突变被称为微卫星(MSI)。高度的微卫星不稳定(MSI-H)会诱导肿瘤的发生，包括结直肠癌、胃癌，子宫内膜癌以及卵巢癌等(Nature，2019，568，551-556)，其中结直肠癌(15％)和胃癌(22％)的突变比例最高。尽管免疫疗法PD-1/PD-L1目前在多个肿瘤中产生了非常好的治疗效果，如pembrolizumab(帕博丽珠单抗)在MSI-H的晚期结直肠癌患者中相比化疗大大提高了中位无进展生存期(PFS)，并被FDA获批一线疗法(N.Engl.J.Med.2020，383，2207-2218)，但目前仍有很多MSI-H肿瘤患者并不能从中获益。此外，2022年ASCO会议报道，临床2期CheckMate 142(NCT02060188)试验中：采用双免疫疗法PD-1+CTLA-4(nivolumab+ipilimumab)治疗转移性直结肠癌患者，不论患者处于一线治疗还是经过二线治疗，4年的随访时间后，仍超过一半的肿瘤患者会复发，因此迫切开发需要新的治疗手段。
合成致死是指在肿瘤细胞中，两个基因中任一单一基因的失活对肿瘤细胞的存活没有明显影响，但两个基因的同时失活可以导致肿瘤细胞的死亡(Nat.Rev.Drug Discov.2020，19，23-38；Cancer Discov.2021，11，1626-1635)。合成致死靶向药物一般可以产生良好的治疗安全窗，同时也增加了某些高突变率但很难成药的靶点的开发可及性。当前，合成致死最成功的案例是PARP1/2抑制剂例如Olaparib、Rucaparib、Niraparib等，这些药物在BRCA1/2突变卵巢癌、乳腺癌等的治疗中获得了优异的疗效并已经相继获批上市(Nat.Rev.Drug Discov.2020，19，711-736；Nat.Rev.Clin.Oncol.2020，17，136-137)。在2019年，Adam J.Bass等人连续在Nature发文证明Werner解旋酶(WRN)是MSI-H肿瘤的合成致死靶标(Nature，2019，568，551-556；Nature，2019，586，292-298)。将WRN整体敲除或将WRN的螺旋酶进行K557M突变(螺旋酶功能丢失)均诱导MSI-H的肿瘤细胞发生周期阻滞、凋亡。不仅如此，Mathew J.Garnett等人也发现，即使MSI-H患者的肿瘤细胞经过化疗、免疫疗法后耐药，仍能通过抑制WRN来进一步抑制肿瘤生长(Cancer Discov.2021，11，1923-1937)。
尽管在WRN研究方面取得了进展，目前仍未有被批准的WRN抑制剂来治疗MSI-H相关的癌症。本发明提供的结构新颖的WRN抑制剂有望解决临床所需。
发明内容
本发明提供了一种结构新颖的WRN抑制剂，本发明的化合物表现出对WRN解旋DNA具有良好抑制效果；对MSI-H肿瘤细胞具有良好抗增殖效果；并且对微卫星稳定(MSS)肿瘤细胞无抑制效果。
在另一个方面，本发明提供了如下式(A)化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体：
其中，
环B或环C为5-6元杂芳基或5-6元杂环基，至少有一个环存在；
Y选自CH或N；
R1选自5-12元杂芳基或5-12元杂环基；所述R1可以被1个、2个或3个Rx取代；
R2选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C3-6环烷基；
R3独立地选自H、卤素、CN、C1-6烷基、C1-6卤代烷基或C3-6环烷基；或者两个R3连接其所在碳原子形成3-6元螺环或桥环；
R4独立地选自H、卤素、CN、SF5、C1-6烷基、C1-6卤代烷基、C1-6烷硫基、C3-6环烷基或4-10元杂环基；
环A存在或不存在，环A选自5-6元杂芳基或5-7元杂环基；
R5选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C3-6环烷基；
Rx选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、CN、NH2、-C(O)Ra、-C(O)ORa、-(CH2)p-ORa、-P(O)-(Ra)2或-S(O)2-Ra；
Ra选自H、C1-6烷基或C3-6环烷基；
m选自0、1、2或3；
n选自0、1或2；
p选自0、1或2。
在一些实施方案中，环B和环C中只有一个环存在。
在一些实施方案中，Y为N。
在一些实施方案中，为其中M1，M2各自独立地选自CH或N，当M1或M2其中之一选自为N时，M1和M2形成单建；M3，M4和M5各自独立地选自CH、O、S或N，且M3，M4和M5至少含有一个N原子；Y选自CH或N。
在一些实施方案中，为其中M1和M2各自独立地选自CH或N。在一些实施方案中，为 其中R5为H或C1-6烷基。
在一些实施方案中，R1选自含有1或2个选自氧、氮和硫的杂原子的5-6元单环杂芳基、含有1或2个选自氧、氮和硫的杂原子的5-6元单环杂环基、含有1或2或3或4个选自氧、氮和硫的杂原子的7-12元二环杂芳基，或含有1或2或3或4个选自氧、氮和硫的杂原子的7-12元二环杂环基，其各自可以被1个、2个或3个Rx取代，Rx选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、CN、NH2、-C(O)Ra、-C(O)ORa、-(CH2)p-ORa、-P(O)-(Ra)2或-S(O)2-Ra。在一些实施方案中，R1选自 所述R1可以被1个、2个或3个Rx取代，Rx选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、CN、NH2、-C(O)Ra、-C(O)ORa、-(CH2)p-ORa、-P(O)-(Ra)2或-S(O)2-Ra。在一些实施方案中，R1选自 在一些实施方案中，R1选自
在一些实施方案中，R2选自C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4烷硫基、环丙基、环丁基、环戊基和环己基。在一些实施方案中，R2选自甲基、乙基、丙基、异丙基、正丁基、异丁基或叔丁基。
在一些实施方案中，R3选自H或C1-6烷基。在一些实施方案中，R3为C1-6烷基。在一些实施方案中，R3为甲基、乙基或丙基。
在一些实施方案中，环A不存在。
在一些实施方案中，为其中R4a、R4b和R4c独立地选自H、卤素、CN、SF5、C1-6烷基、C1-6卤代烷基、C1-6烷硫基或C3-6环烷基。在一些实施方案中，为其中R4a为卤素或C1-6卤代烷基，以及R4b为卤素或C1-6烷基。在一些实施方案中，为其中R4a为C1-6卤代烷基，以及R4b为卤素。在一些实施方案中，为
在一些实施方案中，为其中R4a选自H、卤素、CN、SF5、C1-6烷基、C1-6卤代烷基、C1-6烷硫基或C3-6环烷基，其中环A为5或6元杂芳基或杂环基，其各自含有1或2个选自氧、氮和硫的杂原子。在一些实施方案中，为其中R4a选自卤素、CN、C1-6烷基、C1-6卤代烷基、C1-6烷硫基或C3-6环烷基，环A为 在一些实施方案中，R4a为C1-4卤代烷基。在一些实施方案中，R4a为三氟甲基。
在另一个方面，本发明提供了如下式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体：
其中，
M1，M2各自独立地选自CH或N，当M1或M2其中之一选自为N时，M1和M2形成单建；
M3，M4和M5各自独立地选自CH、O、S或N，且M3，M4和M5至少含有一个N原子；
Y选自CH或N；
R1选自5-12元杂芳基或5-12元杂环基；所述R1可以被1个、2个或3个Rx取代；
R2选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C3-6环烷基；
R3独立地选自H、卤素、CN、C1-6烷基、C1-6卤代烷基或C3-6环烷基；或者两个R3连接其所在碳原子形成3-6元螺环或桥环；
R4独立地选自H、卤素、CN、SF5、C1-6烷基、C1-6卤代烷基、C1-6烷硫基、C3-6环烷基或4-10元杂环基；
环A存在或不存在，环A选自5-6元杂芳基或5-7元杂环基；
R5选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C3-6环烷基；
Rx选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、CN、NH2、-C(O)Ra、-C(O)ORa、-(CH2)p-ORa、-P(O)-(Ra)2或-S(O)2-Ra；
Ra选自H、C1-6烷基或C3-6环烷基；
m选自0、1、2或3；
n选自0、1或2。
在另一个方面，本发明提供了式(II)化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体：
其中，
R1选自5-12元杂芳基或5-12元杂环基；所述R1可以被1个、2个或3个Rx取代；
R2选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C3-6环烷基；
R3独立地选自H、卤素、CN、C1-6烷基、C1-6卤代烷基或C3-6环烷基；或者两个R3连接其所在碳原子形成3-6元螺环或桥环；
R4独立地选自H、卤素、CN、SF5、C1-6烷基、C1-6卤代烷基、C1-6烷硫基、C3-6环烷基或4-10元杂环基：
环A存在或不存在，环A选自5-6元杂芳基或5-7元杂环基；
R5选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C3-6环烷基；
Rx选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、CN、NH2、-C(O)Ra、-C(O)ORa、-(CH2)p-ORa、-P(O)-(Ra)2或-S(O)2-Ra；
Ra选自H、C1-6烷基或C3-6环烷基；
m选自0、1、2或3；
n选自0、1或2。
在另一个方面，本发明提供了式(III)或式(IV)化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体：
其中，
M1，M2各自独立地选自CH或N；
R1选自5-12元杂芳基或5-12元杂环基；所述R1可以被1个、2个或3个Rx取代；
R2选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C3-6环烷基；
R3独立地选自H、卤素、CN、C1-6烷基、C1-6卤代烷基或C3-6环烷基；或者两个R3连接其所在碳原子形成3-6元螺环或桥环；
R4独立地选自H、卤素、CN、SF5、C1-6烷基、C1-6卤代烷基、C1-6烷硫基、C3-6环烷基或4-10元杂环基；
环A存在或不存在，环A选自5-6元杂芳基或5-7元杂环基；
R5选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C3-6环烷基；
Rx选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、CN、NH2、-C(O)Ra、-C(O)ORa、-(CH2)p-ORa、-P(O)-(Ra)2或-S(O)2-Ra；
Ra选自H、C1-6烷基或C3-6环烷基；
m选自0、1、2或3；
n选自0、1或2。
在另一个更具体的实施方案中，本发明涉及式(II)、(III)或(IV)化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体：
其中，R1选自 所述R1可以被1个、2个或3个Rx取代；
R2选自甲基、乙基、三氟乙基、甲硫基或环丙基；
R3独立地选自H、F、CN、甲基、乙基、三氟甲基、环丙基；或者两个R3连接其所在碳原子形成环丙基或环丁基；
R4独立地选自H、F、Cl、Br、CN、SF5、甲基、乙基、三氟甲基、二氟甲基、甲硫基或环丙基；
环A存在或不存在，环A选自5-6元杂芳基或5-7元杂环基；
R5选自H、F、Cl、甲基、乙基、三氟甲基、甲氧基、甲硫基或环丙基；
Rx选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、CN、NH2、-C(O)Ra、-C(O)ORa、-(CH2)p-ORa、-P(O)-(Ra)2或-S(O)2-Ra；
Ra选自H、C1-6烷基或C3-6环烷基；
m选自0、1、2或3；
n选自0、1或2。
在另一个方面，本发明提供了式(III-1)化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体：
其中，
M1选自CH或N；
R1选自所述R1可以被1个、2个或3个Rx取代；
R2选自H、甲基、乙基、三氟甲基、三氟乙基、甲氧基、甲硫基或环丙基；
R4独立地选自H、卤素、CN、SF5、C1-6烷基、C1-6卤代烷基、C1-6烷硫基、C3-6环烷基或4-10元杂环基：
环A选自5-6元杂芳基或环A不存在；
R5选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C3-6环烷基；
Rx选自H、甲基、三氟甲基、甲氧基、CN、NH2、-C(O)Me、-C(O)OMe、-(CH2)-OH或-S(O)2-Me；
m选自0、1、2或3。
在一些实施方案中，M1为N。
在一些实施方案中，R1为其可以被1个、2个或3个Rx取代。在一些实施方案中，R1为
在一些实施方案中，R2为甲基或乙基。在一些实施方案中，R2为乙基。
在一些实施方案中，环A不存在。
在一些实施方案中，为其中R4a为卤素或C1-6卤代烷基，以及R4b为卤素或C1-6烷基。在一些实施方案中，为其中R4a为C1-6卤代烷基，以及R4b为卤素。在一些实施方案中，为
在一些实施方案中，R5为H。
在另一个方面，本发明提供了式(IV-1)化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体：
其中，
R1选自所述R1可以被1个、2个或3个Rx取代；
R2选自H、甲基、乙基、三氟甲基、三氟乙基、甲氧基、甲硫基或环丙基；
R4独立地选自H、卤素、CN、SF5、C1-6烷基、C1-6卤代烷基、C1-6烷硫基、C3-6环烷基或4-10元杂环基；
环A选自5-6元杂芳基或环A不存在；
R5选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C3-6环烷基；
Rx选自H、甲基、三氟甲基、甲氧基、CN、NH2、-C(O)Me、-C(O)OMe、-(CH2)-OH或-S(O)2-Me；
m选自0、1、2或3。
在一些实施方案中，R1为其可以被1个、2个或3个Rx取代。在一些实施方案中，R1为
在一些实施方案中，R2为甲基或乙基。在一些实施方案中，R2为乙基。
在一些实施方案中，R4独立地选自H、卤素、C1-6烷基或C1-6卤代烷基，以及在一些实施方案中，m为2。
在一些实施方案中，环A不存在。
在一些实施方案中，为其中R4a为卤素或C1-6卤代烷基，以及R4b为卤素或C1-6烷基。在一些实施方案中，为其中R4a为C1-6卤代烷基，以及R4b为卤素。在一些实施方案中，为
在另一个方面，本发明提供了如下化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体：


在另一个方面，本发明提供了一种药物组合物，所述药物组合物含有本发明化合物，和任选地药学上可接受的赋形剂。
在另一个方面，本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物，其还含有其它治疗剂。
在另一个方面，本发明提供了本发明化合物在制备用于治疗和/或预防WRN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WRN介导的疾病的方法，包括向所述受试者给药本发明化合物或本发明组合物。
在另一个方面，本发明提供了本发明化合物或本发明组合物，其用于治疗和/或预防WRN介导的疾病。
在具体实施方案中，本发明治疗的疾病包括选自以下的癌症：结肠直肠癌(例如结肠癌、直肠癌、大肠腺癌)、胃癌(如胃腺癌)或肺癌(如支气管癌、小细胞肺癌(SCLC)、非小细胞肺癌(NSCLC)、肺腺癌、肺鳞癌。
由随后的具体实施方案、实施例和权利要求，本发明的其它目的和优点将对于本领域技术人员显而易见。
具体实施方案
相关定义
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。
“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。
因此，“C1-6卤代烷基”是指上述“C1-6烷基”，其被一个或多个卤素基团取代。在一些实施方案中，C1-4卤代烷基是特别优选的，更优选C1-2卤代烷基。示例性的所述卤代烷基包括但不限于：-CF3、-CH2F、-CHF2、-CHFCH2F、-CH2CHF2、-CF2CF3、-CCl3、-CH2Cl、-CHCl2、2，2，2-三氟-1，1-二甲基-乙基，等等。卤代烷基基团可以在任何可用的连接点上被取代，例如，1至5个取代基、1至3个取代基或1个取代基。
“C1-6烷氧基”是指-OR基团，其中R为上文定义的C1-6烷基。C1-4烷氧基是优选的。
“C1-6卤代烷氧基”是指“C1-6烷氧基”，其被一个或多个卤素基团取代。在一些实施方案中，C1-4卤代烷氧烷基是特别优选的，更优选C1-2卤代烷氧烷基。
“C3-10环烷基”是指具有3至10个环碳原子和零个杂原子的非芳香环烃基团。在一些实施方案中，C4-10环烷基、C5-10环烷基、C4-7环烷基、C3-7环烷基、C3-6环烷基、C3-5环烷基和C3-4环烷基是特别优选的，更优选C5-6环烷基。环烷基还包括其中上述环烷基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在环烷基环上，且在这样的情况中，碳的数目继续表示环烷基体系中的碳的数目。示例性的所述环烷基包括但不限于：环丙基(C3)、环丙烯基(C3)、环丁基(C4)、环丁烯基(C4)、环戊基(C5)、环戊烯基(C5)、环己基(C6)、环己烯基(C6)、环已二烯基(C6)、环庚基(C7)、环庚烯基(C7)、环庚二烯基(C7)、环庚三烯基(C7)，等等。环烷基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“3-12元杂环基”是指具有环碳原子和1至5个环杂原子的3至12元非芳香环系的基团，其中，每个杂原子独立地选自氮、氧、硫、硼、磷和硅。在包含一个或多个氮原子的杂环基中，只要化合价允许，连接点可为碳或氮原子。在一些实施方案中，优选5-12元杂环基，其为具有环碳原子和1至3个环杂原子的3至10元非芳香环系；在一些实施方案中，优选3-10元杂环基，其为具有环碳原子和1至3个环杂原子的3至10元非芳香环系；在一些实施方案中，优选4-10元杂环基，其为具有环碳原子和1至4个环杂原子的4至10元非芳香环系；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5-8元杂环基，其为具有环碳原子和1至5个环杂原子的5至8元非芳香环系；在一些实施方案中，优选3-7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3-6元杂环基，其为具有环碳原子和1至3个环杂原子的3至6元非芳香环系；优选4-7元杂环基，其为具有环碳原子和1至3个环杂原子的4至7元非芳香环系；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；更优选3-5元杂环基，其为具有环碳原子和1至3个环杂原子的3至5元非芳香环系。在一些实施方案中，杂环基可以含有不饱和双键，但是杂环基本身并非是芳香性的。杂环基还包括其中上述杂环基环与一个或多个环烷基稠合的环体系，其中连接点在环烷基环上，或其中上述杂环基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在杂环基环上；且在这样的情况下，环成员的数目继续表示在杂环基环体系中环成员的数目。示例性的包含一个杂原子的3元杂环基包括但不限于：氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基(thiorenyl)。示例性的含有一个杂原子的4元杂环基包括但不限于：氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基。示例性的含有一个杂原子的5元杂环基包括但不限于：四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、吡咯烷基、二氢吡咯基和吡咯基-2，5-二酮。示例性的包含两个杂原子的5元杂环基包括但不限于：二氧杂环戊烷基、氧硫杂环戊烷基(oxasulfuranyl)、二硫杂环戊烷基(disulfuranyl)和噁唑烷-2-酮。示例性的包含三个杂原子的5元杂环基包括但不限于：三唑啉基、噁二唑啉基和噻二唑啉基。示例性的包含一个杂原子的6元杂环基包括但不限于：哌啶基、二氢吡喃基、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、四氢苯并吡喃基、四氢吡喃并吡啶基，等等。杂环基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“C6-10芳基”是指具有6-10个环碳原子和零个杂原子的单环或多环的(例如，双环)4n+2芳族环体系(例如，具有以环状排列共享的6或10个π电子)的基团。在一些实施方案中，芳基具有六个环碳原子(“C6芳基”；例如，苯基)。在一些实施方案中，芳基具有十个环碳原子(“C10芳基”；例如，萘基，例如，1-萘基和2-萘基)。芳基还包括其中上述芳基环与一个或多个环烷基或杂环基稠合的环系统，而且连接点在所述芳基环上，在这种情况下，碳原子的数目继续表示所述芳基环系统中的碳原子数目。芳基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“5-14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，5-12元杂芳基是优选的，其为具有环碳原子和1-4个环杂原子的5-10元单环或双环的4n+2芳族环体系；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6-10元单环或双环的4n+2芳族环体系。在一些实施方案中，5-9元杂芳基是优选的，其为具有环碳原子和1-4个环杂原子的5-9元单环或双环的4n+2芳族环体系。在另一些实施方案中，5-6元杂芳基是特别优选的，其为具有环碳原子和1-4个环杂原子的5-6元单环或双环的4n+2芳族环体系。示例性的含有一个杂原子的5元杂芳基包括但不限于：吡咯基、呋喃基和噻吩基。示例性的含有两个杂原子的5元杂芳基包括但不限于：咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基和异噻唑基。示例性的含有三个杂原子的5元杂芳基包括但不限于：三唑基、噁二唑基(例如，1，2，4-噁二唑基)和噻二唑基。示例性的含有四个杂原子的5元杂芳基包括但不限于：四唑基。示例性的含有一个杂原子的6元杂芳基包括但不限于：吡啶基。示例性的含有两个杂原子的6元杂芳基包括但不限于：哒嗪基、嘧啶基和吡嗪基。示例性的含有三个或四个杂原子的6元杂芳基分别包括但不限于：三嗪基和四嗪基。示例性的含有一个杂原子的7元杂芳基包括但不限于：氮杂环庚三烯基、氧杂环庚三烯基和硫杂环庚三烯基。示例性的5，6-双环杂芳基包括但不限于：吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基和嘌呤基。示例性的6，6-双环杂芳基包括但不限于：萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。杂芳基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“亚环烷基”、“亚杂环基”、“亚芳基”或“亚杂芳基”为上述定义的“环烷基”、“杂环基”、“芳基”或“杂芳基”除去另一个氢而形成的二价基团，并且可以是取代或未取代的。例如，“C5-7亚环烷基”是指去除C5-7环烷基的另一个氢而形成的二价基团，“5-8元亚杂环基”是指去除5-8元杂环基的另一个氢而形成的二价基团，“C6-10亚芳基”是指去除C6-10芳基的另一个氢而形成的二价基团，“5-6元亚杂芳基”是指去除5-6元杂芳基的另一个氢而形成的二价基团。
本文定义的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基等为任选取代的基团。
示例性的碳原子上的取代基包括但不局限于：卤素、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-ORaa、-ON(Rbb)2、-N(Rbb)2、-N(Rbb)3 +X-、-N(ORcc)Rbb、-SH、-SRaa、-SSRcc、-C(＝O)Raa、-CO2H、-CHO、-C(ORcc)2、-CO2Raa、-OC(＝O)Raa、-OCO2Raa、-C(＝O)N(Rbb)2、-OC(＝O)N(Rbb)2、-NRbbC(＝O)Raa、-NRbbCO2Raa、-NRbbC(＝O)N(Rbb)2、-C(＝NRbb)Raa、-C(＝NRbb)ORaa、-OC(＝NRbb)Raa、- OC(＝NRbb)ORaa、-C(＝NRbb)N(Rbb)2、-OC(＝NRbb)N(Rbb)2、-NRbbC(＝NRbb)N(Rbb)2、-C(＝O)NRbbSO2Raa、-NRbbSO2Raa、-SO2N(Rbb)2、-SO2Raa、-SO2ORaa、-OSO2Raa、-S(＝O)Raa、-OS(＝O)Raa、-Si(Raa)3、-OSi(Raa)3、-C(＝S)N(Rbb)2、-C(＝O)SRaa、-C(＝S)SRaa、-SC(＝S)SRaa、-SC(＝O)SRaa、-OC(＝O)SRaa、-SC(＝O)ORaa、-SC(＝O)Raa、-P(＝O)2Raa、-OP(＝O)2Raa、-P(＝O)(Raa)2、-OP(＝O)(Raa)2、-OP(＝O)(ORcc)2、-P(＝O)2N(Rbb)2、-OP(＝O)2N(Rbb)2、-P(＝O)(NRbb)2、-OP(＝O)(NRbb)2、-NRbbP(＝O)(ORcc)2、-NRbbP(＝O)(NRbb)2、-P(Rcc)2、-P(Rcc)3、-OP(Rcc)2、-OP(Rcc)3、-B(Raa)2、-B(ORcc)2、-BRaa(ORcc)、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代；
或者在碳原子上的两个偕氢被基团＝O、＝S、＝NN(Rbb)2、＝NNRbbC(＝O)Raa、＝NNRbbC(＝O)ORaa、＝NNRbbS(＝O)2Raa、＝NRbb或＝NORcc取代；
Raa的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个Raa基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代；
Rbb的每个独立地选自：氢、-OH、-ORaa、-N(Rcc)2、-CN、-C(＝O)Raa、-C(＝O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(＝NRcc)ORaa、-C(＝NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(＝S)N(Rcc)2、-C(＝O)SRcc、-C(＝S)SRcc、-P(＝O)2Raa、-P(＝O)(Raa)2、-P(＝O)2N(Rcc)2、-P(＝O)(NRcc)2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个Rbb基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代；
Rcc的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个Rcc基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代；
Rdd的每个独立地选自：卤素、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-ORee、-ON(Rff)2、-N(Rff)2，、-N(Rff)3 +X-、-N(ORee)Rff、-SH、-SRee、-SSRee、-C(＝O)Ree、-CO2H、-CO2Ree、-OC(＝O)Ree、-OCO2Ree、-C(＝O)N(Rff)2、-OC(＝O)N(Rff)2、-NRffC(＝O)Ree、-NRffCO2Ree、-NRffC(＝O)N(Rff)2、-C(＝NRff)ORee、-OC(＝NRff)Ree、-OC(＝NRff)ORee、-C(＝NRff)N(Rff)2、-OC(＝NRff)N(Rff)2、-NRffC(＝NRff)N(Rff)2、-NRffSO2Ree、-SO2N(Rff)2、-SO2Ree、-SO2ORee、-OSO2Ree、-S(＝O)Ree、-Si(Ree)3、-OSi(Ree)3、-C(＝S)N(Rff)2、-C(＝O)SRee、-C(＝S)SRee、-SC(＝S)SRee、-P(＝O)2Ree、-P(＝O)(Ree)2、-OP(＝O)(Ree)2、-OP(＝O)(ORee)2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代，或者两个偕Rdd取代基可结合以形成＝O或＝S；
Ree的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、芳基、杂环基和杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代；
Rff的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个Rff基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代：
Rgg的每个独立地是：卤素、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-OC1-6烷基、-ON(C1-6烷基)2、-N(C1-6烷基)2、-N(C1-6烷基)3 +X-、-NH(C1-6烷基)2 +X-、-NH2(C1-6烷基)+X-、-NH3 +X-、-N(OC1-6烷基)(C1-6烷基)、-N(OH)(C1-6烷基)、-NH(OH)、-SH、-SC1-6烷基、-SS(C1-6烷基)、-C(＝O)(C1-6烷基)、-CO2H、-CO2(C1-6烷基)、-OC(＝O)(C1-6烷基)、-OCO2(C1-6烷基)、-C(＝O)NH2、-C(＝O)N(C1-6烷基)2、-OC(＝O)NH(C1-6烷基)、-NHC(＝O)(C1-6烷基)、-N(C1-6烷基)C(＝O)(C1-6烷基)、-NHCO2(C1-6烷基)、-NHC(＝O)N(C1-6烷基)2、-NHC(＝O)NH(C1-6烷基)、-NHC(＝O)NH2、-C(＝NH)O(C1-6烷基)、-OC(＝NH)(C1-6烷基)、-OC(＝NH)OC1-6烷基、-C(＝NH)N(C1-6烷基)2、-C(＝NH)NH(C1-6烷基)、-C(＝NH)NH2、-OC(＝NH)N(C1-6烷基)2、-OC(NH)NH(C1-6烷基)、-OC(NH)NH2、-NHC(NH)N(C1-6烷 基)2、-NHC(＝NH)NH2、-NHSO2(C1-6烷基)、-SO2N(C1-6烷基)2、-SO2NH(C1-6烷基)、-SO2NH2、-SO2C1- 6烷基、-SO2OC1-6烷基、-OSO2C1-6烷基、-SOC1-6烷基、-Si(C1-6烷基)3、-OSi(C1-6烷基)3、-C(＝S)N(C1-6烷基)2、C(＝S)NH(C1-6烷基)、C(＝S)NH2、-C(＝O)S(C1-6烷基)、-C(＝S)SC1-6烷基、-SC(＝S)SC1-6烷基、-P(＝O)2(C1-6烷基)、-P(＝O)(C1-6烷基)2、-OP(＝O)(C1-6烷基)2、-OP(＝O)(OC1-6烷基)2、C1-6烷基、C1-6卤代烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、C3-C7杂环基、C5-C10杂芳基；或者两个偕Rgg取代基可结合形成＝O或＝S；其中，X-为反离子。
示例性的氮原子上取代基包括但不局限于：氢、-OH、-ORaa、-N(Rcc)2、-CN、-C(＝O)Raa、-C(＝O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(＝NRbb)Raa、-C(＝NRcc)ORaa、-C(＝NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(＝S)N(Rcc)2、-C(＝O)SRcc、-C(＝S)SRcc、-P(＝O)2Raa、-P(＝O)(Raa)2、-P(＝O)2N(Rcc)2、-P(＝O)(NRcc)2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者连接至氮原子的两个Rcc基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代，且其中Raa、Rbb、Rcc和Rdd如上所述。
其它定义
本文所用的术语“药学上可接受的盐”表示本发明化合物的那些羧酸盐、氨基酸加成盐，它们在可靠的医学判断范围内适用于与患者组织接触，不会产生不恰当的毒性、刺激作用、变态反应等，与合理的益处/风险比相称，就它们的预期应用而言是有效的，包括(可能的话)本发明化合物的两性离子形式。
给药的“受试者”包括但不限于：人(即，任何年龄组的男性或女性，例如，儿科受试者(例如，婴儿、儿童、青少年)或成人受试者(例如，年轻的成人、中年的成人或年长的成人))和/或非人的动物，例如，哺乳动物，例如，灵长类(例如，食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中，受试者是人。在一些实施方案中，受试者是非人动物。本文可互换使用术语“人”、“患者”和“受试者”。
“疾病”、“障碍”和“病症”在本文中可互换地使用。
通常，化合物的“有效量”是指足以引起目标生物反应的数量。正如本领域普通技术人员所理解的那样，本发明化合物的有效量可以根据下列因素而改变：例如，生物学目标、化合物的药代动力学、所治疗的疾病、给药模式以及受试者的年龄健康情况和症状。有效量包括治疗有效量和预防有效量。
“组合”以及相关术语是指同时或依次给药本发明化合物和其它治疗剂。例如，本发明化合物可以与其它治疗剂以分开的单位剂型同时或依次给药，或与其它治疗剂一起在单一单位剂型中同时给药。
本文中，“本发明化合物”指的是以下的式(A)化合物(包括子通式，例如式(I)、(II)、(III)或式(IV)，其药学上可接受的盐、对映异构体、非对映异构体或同位素变体，以及它们的混合物。
本发明化合物可包括一个或多个不对称中心，且因此可以存在多种立体异构体形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋体混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。
本发明化合物还可能以互变异构体存在。在不同的互变异构形式存在的化合物，一个所述化合物并不局限于任何特定的互变异构体，而是旨在涵盖所有的互变异构形式。
本发明还包括同位素标记的化合物(同位素变体)，它们等同于式(A)所述的那些，但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些 同位素标记的本发明化合物、例如引入放射性同位素(例如3H和14C)的那些可用于药物和/或底物组织分布测定。氚、即3H和碳-14、即14C同位素是特别优选的，因为它们容易制备和检测。进而，被更重的同位素取代，例如氘、即2H，由于代谢稳定性更高可以提供治疗上的益处，例如延长体内半衰期或减少剂量需求，因而在有些情况下可能是优选的。同位素标记的本发明式(A)化合物及其前体药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。
术语“氘(D或2H)”是氢的稳定同位素，其以0.015摩尔％的天然丰度存在。术语“氘代”是指基团或化合物中一个或多个氢原子H被D替代。
本发明的同位素变体包括氘代化合物。“氘代合物”是指一个或多个与碳键合的氢被一个或多个氘取代的化合物。同样，“氘代”是指一个或多个与碳键合的氢被一个或多个氘取代的化学结构或有机基团，例如，“氘代烷基”，“氘代环烷基”，“氘代杂环烷基”，“氘代芳基”等。例如，“氘代烷基”是指本申请所定义的烷基基团，其中至少有一个与碳键合的氢原子被氘取代。在氘代烷基中，至少有一个碳原子与一个氘键合；一个碳原子可键合多个氘；烷基基团中的多个碳原子也可键合氘。例如，氘代甲基包括甲基-d3，其中三个氢原子被氘替代；亦包括一氘代甲基和二氘代甲基。例如，氘代哌嗪基是指哌嗪基上一个或多个氢原子被氘替代，包括8个氢原子全被氘替代。在一些实施方案中，本发明的化合物包括氘代化合物。
药物组合物和试剂盒
在另一方面，本发明提供了药物组合物，其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中，所述药物组合物包含有效量的本发明化合物。在一些实施方案中，所述药物组合物包含治疗有效量的本发明化合物。在一些实施方案中，所述药物组合物包含预防有效量的本发明化合物。
用于本发明的药学上可接受的赋形剂是指不会破坏一起调配的化合物的药理学活性的无毒载剂、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载剂、佐剂或媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。
本发明还包括试剂盒(例如，药物包装)。所提供的试剂盒可以包括本发明化合物、其它治疗剂，以及含有本发明化合物、其它治疗剂的第一和第二容器(例如，小瓶、安瓿瓶、瓶、注射器和/或可分散包装或其它合适的容器)。在一些实施方案中，提供的试剂盒还可以任选包括第三容器，其含有用于稀释或悬浮本发明化合物和/或其它治疗剂的药用赋形剂。在一些实施方案中，提供在第一容器和第二容器中的本发明化合物和其它治疗剂组合形成一个单位剂型。
给药
本发明提供的药物组合物可以通过许多途径给药，包括但不限于：口服给药、肠胃外给药、吸入给药、局部给药、直肠给药、鼻腔给药、口腔给药、阴道给药、通过植入剂给药或其它给药方式。例如，本文使用的肠胃外给药包括皮下给药、皮内给药、静脉内给药、肌肉内给药、关节内给药、动脉内给药、滑膜腔内给药、胸骨内给药、脑脊髓膜内给药、病灶内给药、和颅内的注射或输液技术。
通常，给予有效量的本文所提供的化合物。按照有关情况，包括所治疗的病症、选择的给药途径、实际给予的化合物、个体患者的年龄、体重和响应、患者症状的严重程度，等等，可以由医生确定实际上给予的化合物的量。
当用于预防本发明所述病症时，给予处于形成所述病症危险之中的受试者本文所提供的化合物，典型地基于医生的建议并在医生监督下给药，剂量水平如上所述。处于形成具体病症的危险之中的受试者，通常包括具有所述病症的家族史的受试者，或通过遗传试验或筛选确定尤其对形成所述病症敏 感的那些受试者。
还可以长期给予本文所提供的药物组合物(“长期给药”)。长期给药是指在长时间内给予化合物或其药物组合物，例如，3个月、6个月、1年、2年、3年、5年等等，或者可无限期地持续给药，例如，受试者的余生。在一些实施方案中，长期给药意欲在长时间内在血液中提供所述化合物的恒定水平，例如，在治疗窗内。
可以使用各种给药方法，进一步递送本发明的药物组合物。例如，在一些实施方案中，可以推注给药药物组合物，例如，为了使化合物在血液中的浓度提高至有效水平。推注剂量取决于通过身体的活性组分的目标全身性水平，例如，肌内或皮下的推注剂量使活性组分缓慢释放，而直接递送至静脉的推注(例如，通过IV静脉滴注)能够更加快速地递送，使得活性组分在血液中的浓度快速升高至有效水平。在其它实施方案中，可以以持续输液形式给予药物组合物，例如，通过IV静脉滴注，从而在受试者身体中提供稳态浓度的活性组分。此外，在其它实施方案中，可以首先给予推注剂量的药物组合物，而后持续输液。
口服组合物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而，更通常，为了便于精确地剂量给药，以单位剂量形式提供所述组合物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位，每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适药学赋形剂。典型的单位剂量形式包括液体组合物的预装填的、预先测量的安瓿或注射器，或者在固体组合物情况下的丸剂、片剂、胶囊剂等。在这种组合物中，所述化合物通常为较少的组分(约0.1至约50重量％，或优选约1至约40重量％)，剩余部分为对于形成所需给药形式有用的各种载体或赋形剂以及加工助剂。
对于口服剂量，代表性的方案是，每天一个至五个口服剂量，尤其是两个至四个口服剂量，典型地是三个口服剂量。使用这些剂量给药模式，每个剂量提供大约0.01至大约20mg/kg的本发明化合物，优选的剂量各自提供大约0.1至大约10mg/kg，尤其是大约1至大约5mg/kg。
为了提供与使用注射剂量类似的血液水平，或比使用注射剂量更低的血液水平，通常选择透皮剂量，数量为大约0.01至大约20％重量，优选大约0.1至大约20％重量，优选大约0.1至大约10％重量，且更优选大约0.5至大约15％重量。
从大约1至大约120小时，尤其是24至96小时，注射剂量水平在大约0.1mg/kg/小时至至少10mg/kg/小时的范围。为了获得足够的稳定状态水平，还可以给予大约0.1mg/kg至大约10mg/kg或更多的预载推注。对于40至80kg的人类患者来说，最大总剂量不能超过大约2g/天。
适于口服给药的液体形式可包括合适的水性或非水载体以及缓冲剂、悬浮剂和分散剂、着色剂、调味剂，等等。固体形式可包括，例如，任何下列组份，或具有类似性质的化合物：粘合剂，例如，微晶纤维素、黄著胶或明胶；赋形剂，例如，淀粉或乳糖，崩解剂，例如，褐藻酸、Primogel或玉米淀粉；润滑剂，例如，硬脂酸镁；助流剂，例如，胶体二氧化硅；甜味剂，例如，蔗糖或糖精；或调味剂，例如，薄荷、水杨酸甲酯或橙味调味剂。
可注射的组合物典型地基于可注射用的无菌盐水或磷酸盐缓冲盐水，或本领域中已知的其它可注射的赋形剂。如前所述，在这种组合物中，活性化合物典型地为较少的组分，经常为约0.05至10％重量，剩余部分为可注射的赋形剂等。
典型地将透皮组合物配制为含有活性组分的局部软膏剂或乳膏剂。当配制为软膏剂时，活性组分典型地与石蜡或可与水混溶的软膏基质组合。或者，活性组分可与例如水包油型乳膏基质一起配制为乳膏剂。这种透皮制剂是本领域中公知的，且通常包括用于提升活性组分或制剂的稳定的皮肤渗透的其它组份。所有这种已知的透皮制剂和组份包括在本发明提供的范围内。
本发明化合物还可通过经皮装置给予。因此，经皮给药可使用贮存器(reservoir)或多孔膜类型、或者多种固体基质的贴剂实现。
用于口服给予、注射或局部给予的组合物的上述组份仅仅是代表性的。其它材料以及加工技术等阐述于Remington′s Pharmaceutical Sciences，17th edition，1985，Mack Publishing Company，Easton，Pennsylvania的第8部分中，本文以引用的方式引入该文献。
本发明化合物还可以以持续释放形式给予，或从持续释放给药系统中给予。代表性的持续释放材料的描述可在Remington′s Pharmaceutical Sciences中找到。
本发明还涉及本发明化合物的药学上可接受的制剂。在一个实施方案中，所述制剂包含水。在另一个实施方案中，所述制剂包含环糊精衍生物。最常见的环糊精为分别由6、7和8个α-1，4-连接的葡萄糖单元组成的α-、β-和γ-环糊精，其在连接的糖部分上任选包括一个或多个取代基，其包括但不限于：甲基化的、羟基烷基化的、酰化的和磺烷基醚取代。在一些实施方案中，所述环糊精为磺烷基醚β-环糊精，例如，磺丁基醚β-环糊精，也称作Captisol。参见，例如，U.S.5,376,645。在一些实施方案中，所述制剂包括六丙基-β-环糊精(例如，在水中，10-50％)。
实施例
本发明所采用的试剂为直接购买的商业化试剂或经本领域熟知的常用方法合成。
常用缩略词注释：
PE＝石油醚；EA＝乙酸乙酯；MeOH＝甲醇；DCM＝二氯甲烷；DCE＝二氯乙烷；CH3CN＝乙腈；1，4-dioxane＝1，4-二氧六环；DMSO＝二甲基亚砜；HFIP＝六氟异丙醇；DMF＝N，N-二甲基甲酰胺；Hex＝正己烷；IPA＝异丙醇；NMP＝N-甲基吡咯烷酮；NMO＝N-甲基吗啉-N-氧化物；TEA＝三乙胺；DIEA＝二异丙基乙基胺；CuI＝碘化亚铜；CuCN＝氰化亚铜；triphosgene＝三光气；p-TsOH＝对甲苯磺酸；T3P＝1-丙基磷酸环酐；TsN3＝对甲苯磺酰基叠氮；PPA＝多聚磷酸；SEM-Cl＝2-(三甲硅烷基)乙氧甲基氯；DMC＝碳酸二乙酯；DMEDA＝N，N′-二甲基乙二胺；AIBN＝偶氮二异丁腈；DMC＝碳酸二乙酯；NBS＝N-溴代琥珀酰亚胺；TBS-Cl＝叔丁基二甲基氯硅烷；LDA＝二异丙基氨基锂；HMPA＝六甲基磷酰三胺；HATU＝2-(7-氮杂苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸盐；DMA＝N，N-二甲基乙酰胺；EDCI＝碳二亚胺盐酸盐；HOAT＝1-羟基-7-氮杂苯并三氮唑；EDA＝乙二胺。
MSI-H＝微卫星高度不稳定；MSI-L＝微卫星低度不稳定；MSS＝微卫星稳定。
实施例1：
关键中间体的制备
中间体a1的制备
步骤：将原料乙酰乙酸乙酯a1-1(9.0g，69.2mmol)和5-溴-1-H-3-氨基1，2，4-三氮唑a1-2(11.3g，69.2mmol)溶于90mL乙醇中，缓慢加入多聚磷酸PPA(8.0g，69.2mmol)，滴毕，升温至80℃下反应12小时，冷却至室温，减压蒸除溶剂。将反应液中倒入100mL冰水中，饱和碳酸氢钠水溶液调节pH至8左右，二氯甲烷萃取，无水硫酸钠干燥，浓缩，得到白色固体a1(7.5g)，收率：45％。LCMS ESI-MS m/z：243[M+H]+。
中间体a5，a7-a13的制备
第一步：将原料a5-1(24.0g，134mmol)和哌嗪-1-甲酸叔丁酯(25.0g，134mmol)溶于240mL乙腈中，缓慢加入TEA(40.8g，403mmol)，滴毕，升温至60℃下反应16小时，冷却至室温，减压蒸除溶剂。将反应液中倒入100mL冰水中，，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经柱层析分离(PE/EA，9/1)，得到黄色油状物a5-2(24g)，收率：54％。LCMS ESI-MS m/z：329[M+H]+。
第二步：将上步中间体a5-2(22.2g，67.6mmol)和5-溴-1-H-3-氨基1，2，4-三氮唑a1-2(11.0g，67.6mmol)溶于200mL乙醇中，缓慢加入多聚磷酸PPA(7.8g，67.6mmol)，滴毕，升温至80℃下反应12小时，冷却至室温，减压蒸除溶剂。将反应液中倒入100mL冰水中，饱和碳酸氢钠水溶液调节pH至8左右，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经柱层析分离(PE/EA，3/1)，得到黄色固体a5(4.4g)，收率：15％。LCMS ESI-MS m/z：427[M+H]+。
参照中间体a1或a5的合成路线，采用类似的原料/类似物，合成如下目标中间体。
中间体a2，a6，a14-a32的制备
步骤：将中间体a1(7.5g，30.9mmol)和原料a2-1(10.1g，37.0mmol)溶于75mLNMP中，缓慢加入DIEA(12.0g，92.6mmol)，滴毕，升温至50℃下反应16小时，冷却至室温，停止反应。将反应液中倒入100mL冰水中，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经HPLC制备色谱分离(色谱柱：XSelect Prep OBD C18 Column，30*150mm，5μm；流动相A：水(10mmol/L NH4HCO3)，流动相B：乙腈；流速：90mL/min；保留时间：3min)，得到黄色固体a2(5.2g)，收率：35％)。LCMS ESI-MS m/z：478[M+H]+。
步骤：将中间体a5(1.1g，2.57mmol)和原料a2-1(1.1g，3。86mmol)溶于11mLNMP中，缓慢加入DIEA(1.0g，7.72mmol)，滴毕，升温至70℃下反应12小时，冷却至室温，停止反应。将反应液中倒入50mL冰水中，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O＝5/1)，得到黄色固体a6(996mg)，收率：58％。LCMS ESI-MS m/z：662[M+H]+。
参照中间体a2或a6的合成路线，采用类似的原料/类似物，合成如下目标中间体。
[以类似的杂芳基NH2为原料，与氯乙酰氯反应，合成a2-1类似物]

中间体a3的制备
步骤：氮气保护下，将中间体a2(5.0g，10.4mmol)、原料a3-1(2.9g，13.6mmol)和碳酸钠(3.3g，31.3mmol)溶于50mL 1，4-二氧六环和水的混合溶液中(v/v，4/1)，加入催化剂Pd(dppf)Cl2(900mg，1.0mmol)，混合液升温至100℃下反应2小时，停止反应，过滤。向反应液中加入100mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经HPLC制备色谱分离(色谱柱：WelFlash C18-I，20-40μm，330g；流动相A水：(10mmol/LNH4HCO3)，流动相B：乙腈；流速：80mL/min；保留时间：12min)，得到黄色固体a3(2.6g)，收率：52％。LCMS ESI-MS m/z：482[M+H]+。
中间体a4的制备
步骤：将中间体a3(2.4g，5.0mmol)溶于25mL DMF中，加入NBS(1.8g，10.0mmol)，混合液室温下反应2小时，停止反应，过滤。向反应液中加入100mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经HPLC制备色谱分离(色谱柱：C18-I，20-40μm，330g；流动相A水：(10mmol/L NH4HCO3)，流动相B：乙腈；流速：90mL/min；保留时间：11min)，得到白色固体a4(1.6g)，收率：57％。LCMS ESI-MS m/z：560[M+H]+。
中间体b1的制备
第一步：氮气保护下，将原料4，6-二氯-5-甲氧基嘧啶b1-1(20.0g，111mmol)、原料甲基硼酸(7.0g，117mmol)和磷酸钾(59.2g，279mmol)溶于120mL DME中，加入催化剂Pd(dppf)Cl2(4.6g，5.6mmol)，混合液升温至85℃下反应12小时，停止反应，过滤。向反应液中加入100mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析色谱分离(PE/EA，10/1)，得到白色固体b1-2(6.0g)，收 率：34％。LCMS ESI-MS m/z：159[M+H]+。
第二步：一氧化碳氛围下，将上步中间体b1-2(6.0g，37.0mmol)和TEA(7.66g，75.0mmol)溶于90mL甲醇中，加入催化剂Pd(dppf)Cl2(1.85g，2.3mmol)，混合液在CO(20atm)下，升温至100℃下反应12小时，停止反应，过滤。减压蒸除溶剂，粗品经HPLC制备色谱分离(色谱柱：WelFlash C18-I，20-40um，120g；流动相A：水(10mmol/L NH4HCO3)流动相B：乙腈；流速：60mL/min)，得到白色固体b1-3(5.0g)，收率：73％。LCMS ESI-MS m/z：183[M+H]+。
第三步：将上步中间体b1-3(3.0g，16.5mmol)溶于15mL HBr水溶液中(40％)，升温至40℃下反应10小时，停止反应。向反应液中加入HI(15mL)，继续在40℃下反应6小时，减压蒸除溶剂。将粗品用NaOH水溶液(1N)调节pH至8左右，随后再用浓盐酸调节pH至3左右，减压蒸除溶剂。粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，1/1)，得到黄色固体b1(1.5g)，收率：59％。LCMS ESI-MS m/z：155[M+H]+。
中间体b2的制备
第一步：冰浴，氮气保护下，将原料b2-1(500mg，3.81mmol)溶于10mL四氢呋喃中，加入NBS(679mg，3.81mmol)，混合液在室温下反应0.5小时，停止反应，过滤。向反应液中加入饱和碳酸氢钠水溶液调节pH至8左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析色谱分离(PE/EA，10/1)，得到黄色油状物b2-2(540mg)，收率：63％。LCMS ESI-MS m/z：224[M+H]+。
第二步：氮气保护下，将上步中间体b2-2(510mg，2.28mmol)溶于3mL碳酸二乙酯DMC中，加入CH3ONa(185mg，3.42mmol)，混合液升温至125℃下反应0.5小时，冷却至室温。向反应液中加入20mL冰水，甲基叔丁基醚萃取，无水硫酸钠干燥，浓缩，粗品经柱层析色谱分离(PE/EA，1/1)，得到黄色油状物b2-3(300mg)，收率：64％。LCMS ESI-MS m/z：205[M+H]+。
第三步：-78℃，氮气保护下，将上步中间体b2-3(300mg，1.46mmol)溶于6mL无水四氢呋喃中，滴加nBuLi(2.5M，1.47mL)，滴毕，继续搅拌1小时。向反应液中加入异丙醇频哪醇硼酸酯(327mg，1.75mmol)，继续在-78℃下反应1小时。将混合物用饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，得到黄色油状物b2(300mg)，收率：81％。LCMS ESI-MS m/z：253[M+H]+。
中间体b3的制备
第一步：冰浴，氮气保护下，将原料5-溴-1H-吡咯[2，3-b]并吡啶-6-甲酸甲酯b3-1(600mg，2.35mmol)和NaH(70mg，2.82mmol)溶于12mL DMF中，加入SEM-Cl(570mg，3.52mmol)，混合液在室温下反应3小时，停止反应。向反应液中加入100mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，7/10)，得到黄色固体b3-2(500mg)，收率：55％。LCMS ESI-MS m/z：385[M+H]+。
第二步：氮气保护下，将上步中间体b3-2(500mg，1.29mmol)和联硼酸频那醇酯(490mg，1.95mmol)溶于13mL 1，4-二氧六环中，加入KOAc(380mg，3.89mmol)和催化剂Pd(dppf)Cl2.DCM(110mg，0.13mmol)，混合液升温至120℃下反应5小时，冷却至室温，过滤。滤饼洗涤干燥，得到棕色固体b3(400mg)，收率：71％。LCMS ESI-MS m/z：433[M+H]+。
中间体b4，b5的制备
第一步：冰浴，氮气保护下，将中间体b3(400mg，0.92mmol)溶于5mL四氢呋喃和水的混合溶液中(v/v，1/1)，加入硼酸钠(210mg，1.38mmol)，混合液在室温下反应3小时，停止反应。向反应液中加入20mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，得到棕色油状物b4-1(100mg)，收率：40％。LCMS ESI-MS m/z：323[M+H]+。
第二步：氮气保护下，将上步中间体b4-1(100mg，0.31mmol)溶于3mL四氢呋喃和水的混合溶液中(v/v，1/1)，加入NaOH(25mg，0.62mmol)，室温下反应2小时，停止反应，减压蒸除溶剂。向混合物中加入10mL水，稀盐酸调节pH至4左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析分离(色谱柱：C18；CH3CN/H2O，1/1)，得到黄色固体b4(70mg)，收率：73％。LCMS ESI-MS m/z：309[M+H]+。
参照中间体b4的合成路线，采用类似的原料/类似物，合成如下目标中间体。
中间体b6的制备
第一步：氮气保护下，将原料4，6-二氯-5-甲氧基嘧啶b1-1(5.0g，27.9mmol)、原料b6-1(9.2g，27.9mmol)和CuI(50mg，0.28mmol)溶于5mL DME中，加入催化剂Pd(PPh3)4(320mg，0.28mmol)，混合液升温至85℃下反应1小时，停止反应，过滤。向反应液中加入30mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析色谱分离(PE/EA，9/1)，得到黄色固体b6-2(3.0g)，收率：59％。LCMS ESI-MS m/z：183[M+H]+。
第二步：一氧化碳氛围下，将上步中间体b6-2(3.0g，16.4mmol)和TEA(3.3g，32.9mmol)溶于60mL甲醇中，加入催化剂Pd(dppf)Cl2(1.2g，1.64mmol)，混合液在CO(30atm)下，升温至100℃下反应4小时，停止反应，过滤。减压蒸除溶剂，粗品经柱层析色谱分离(PE/EA，4/1)，得到黄色固体b6-3(1.45g)，收率：43％。LCMS ESI-MS m/z：207[M+H]+。
第三步：氮气保护下，将上步中间体b6-3(1.4g，6.79mmol)和TEA(7.0mL)溶于7mL DMA中，加入催化剂CuI(130mg，0.68mmol)，混合液升温至105℃下反应2小时，停止反应，过滤。向反应液中加入30mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析色谱分离(PE/EA，1/1)，得到黄色固体b6-4(150mg)，收率：11％。LCMS ESI-MS m/z：207[M+H]+。
第四步：将上步中间体b6-4(150mg，0.73mmol)溶于3mL甲醇和水的混合溶液中(v/v，1/1)，加入NaOH(58mg，1.5mmol)，室温下反应2小时，停止反应。向反应液中加入2M浓度稀盐酸调节pH至6左右，减压蒸除溶剂。粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，3/2)，得到白色固体b6(110mg)，收率：79％。LCMS ESI-MS m/z：193[M+H]+。
中间体b7的制备
第一步：冰浴，氮气保护下，将原料b7-1(11.0g，59.3mmol)溶于115mL乙腈中，加入NBS(10.5g，59.3mmol)，混合液在冰浴下反应1小时，停止反应，过滤。向反应液中加入300mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析色谱分离(PE/EA，1/1)，得到黄色固体b7-2(9.0g)，收率：91％。LCMS ESI-MS m/z：245[M+H]+。
第二步：氮气保护下，将上步中间体b7-2(10.0g，40.8mmol)溶于150mL乙酸和四氢呋喃的混合溶液中(v/v，2/1)，加入NIS(13.8g，61.2mmol)，混合液在35℃下反应12小时，停止反应，过滤。向反应液中加入300mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析色谱分离(PE/EA，1/2)，得到黄色固体b7-3(8.0g)，收率：53％。LCMS ESI-MS m/z：371[M+H]+。
第三步：氮气保护下，将上步中间体b7-3(8.0g，21.6mmol)、K3PO4(13.7g，64.70mmol)和原料b7-4(8.5g，43.1mmol)溶于100mL异丙醇中，加入催化剂Pd(OAc)2(500mg，2.16mmol)和配体RuPhos(1.0g，2.16mmol)，混合液在室温下反应14小时，停止反应，过滤。减压蒸除溶剂，粗品经柱层析色谱分离(PE/EA，1/1)，得到黄色固体b7-5(5.3g)，收率：72％。LCMS ESI-MS m/z：343[M+H]+。
第四步：将上步中间体b7-5(5.3g，15.4mmol)溶于53mL甲醇中，加入浓盐酸(11mL)，混合液在40℃下反应12小时，停止反应。减压蒸除溶剂，向反应液中加入饱和碳酸氢钠水溶液调节pH至7左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。粗品经flash柱层析色谱分离(PE/EA，1/2)，得到黄色固体b7-6(2.0g)，收率：48％。LCMS ESI-MS m/z：269[M+H]+。
第五步：冰浴，氮气保护下，将上步中间体b7-6(2.0g，7.43mmol)和NaH(200mg，8.92mmol)溶于32mL DMF中，加入SEM-Cl(1.9g，11.2mmol)，混合液在室温下反应3小时，停止反应。向反应液中加入100mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，1/1)，得到黄色油状物b7-7(1.2g)，收率：40％。LCMS ESI-MS m/z：399[M+H]+。
第六步：氮气保护下，将上步中间体b7-7(1.2g，3.0mmol)和联硼酸频那醇酯(1.1g，4.5mmol)溶于24mL 1，4-二氧六环中，加入KOAc(900mg，9.02mmol)和催化剂Pd(dppf)Cl2.DCM(210mg，0.30mmol)，混合液升温至100℃下反应2小时，冷却至室温，过滤。减压蒸除溶剂，得到棕色油状物b7-8(1.0g)。LCMS ESI-MS m/z：447[M+H]+。
第七步：冰浴，氮气保护下，将上步中间体b7-8(1.0g，2.24mmol)溶于12mL四氢呋喃和水的混合溶液中(v/v，1/1)，加入硼酸钠(310mg，3.38mmol)，混合液在50℃下反应3小时，停止反应。向反应液中加入50mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩。粗品经柱层析色谱分离(PE/EA，1/1)，得到黄色固体b7-9(100mg)，收率：13％。LCMS ESI-MS m/z：337[M+H]+。
第八步：氮气保护下，将上步中间体b7-9(100mg，0.30mmol)溶于3mL四氢呋喃和水的混合溶液中(v/v，2/1)，加入NaOH(25mg，0.62mmol)，室温下反应2小时，停止反应，减压蒸除溶剂。向混合物中加入10mL水，稀盐酸调节pH至4左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析分离(色谱柱：C18；CH3CN/H2O，1/1)，得到黄色固体b7(37mg)，收率：39％。LCMS ESI-MS m/z：323[M+H]+。
中间体c1-c4，c16-c22的制备
第一步：氮气保护下，将中间体a4(210mg，0.3mmol)和TEA(114mg，1.1mmol)溶于2mL DMSO中，加入原料c1-1(371mg，1.9mmol)，混合液升温至85℃下反应12小时，停止反应。向反应液中加入100mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经HPLC色谱分离(色谱柱：WelFlash C18-I，20-40μm，180g；流动相A：水(10mmol/L NH4HCO3)，流动相B：乙腈；流速：70mL/min；保留时间：12min)，得到白色固体c1-2(120mg)，收率：47％。LCMS ESI-MS m/z：678[M+H]+。
第二步：将上步中间体c1-1(120mg，0.2mmol)和三氟乙酸(0.5mL)溶于2mL二氯甲烷中，室温下反应2小时，停止反应。减压蒸除溶剂，粗品经HPLC制备色谱分离(色谱柱：WelFlash C18-I，20-40um，40g；流动相A：水(10mmol/L NH4HCO3)流动相B：乙腈；流速：50mL/min；保留时间：9min)，得到白色固体c1(80mg)，收率：78％。LCMS ESI-MS m/z：578[M+H]+。
参照中间体c1的合成路线，采用类似的原料/类似物，合成如下目标中间体。
参照中间体c1的合成路线，采用类似的原料/类似物，合成如下目标中间体。

中间体c5-c6，c12-c15，c23的制备
第一步：将中间体a6(996mg，1.5mmol)溶于10mL二氯甲烷中，滴加0.5mL三氟乙酸，混合液室温下反应1小时，停止反应。向反应液中加入20mL水，饱和碳酸氢钠水溶液调节pH至9左右，二氯甲烷萃取，无水硫酸钠干燥，浓缩，得到黄色固体c5-2(694mg)，收率：82％。LCMS ESI-MS m/z：562[M+H]+。
第二步：将上步中间体c5-2(494mg，0.88mmol)和DIEA(567mg，4.4mmol)溶于5mL二氯甲烷中，加入原料3-羟基-2-吡啶甲酰氯c5-1(277mg，1.76mmol)，室温下反应2小时，停止反应。减压蒸除溶剂，粗品经flash柱层析色谱分离(色谱柱：WelFlash C18-I，20-40um，130g；流动相A：水，流动相B：乙腈；流速：60mL/min；保留时间：14min)，得到黄色固体c5(360mg)，收率：60％。LCMS ESI-MS m/z：683[M+H]+。
步骤：冰浴，氮气保护下，将中间体b1(49mg，0.32mmol)和1-氯-N，N，2-三甲基丙基-1-烯基-1-胺(43mg，0.32mmol)溶于2mL二氯甲烷中，冰浴下搅拌1小时。向反应液加入DIEA(138mg，1.06mmol)和中间体c5-2(120mg，0.21mmol)，室温下反应1小时，停止反应。向反应液中加入15mL水，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，4/5)，得到淡黄色固体c6(45mg)，收率：30％。LCMS ESI-MS m/z：698[M+H]+。
参照中间体c5或c6的合成路线，采用类似的原料/类似物，合成如下目标中间体。
中间体c7-c11的制备
第一步：氮气保护下，将中间体a5(2.5g，5.85mmol)、原料a3-1(1.2g，5.85mmol)和碳酸钠(1.9g，17.5mmol)溶于50mL 1，4-二氧六环和水的混合溶液中(v/v，1/1)，加入催化剂Pd(dppf)Cl2(400mg，0.59mmol)，混合液升温至100℃下反应12小时，停止反应，过滤。向反应液中加入100mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经HPLC制备色谱分离(色谱柱：WelFlash C18-I，20-40μm，330g；流动相A水：(10mmol/L NH4HCO3)，流动相B：乙腈；流速：40mL/min；保留时间：16min)，得到黄色油状物c7-1(1.5g)，收率：58％。LCMS ESI-MS m/z：431[M+H]+。
第二步：将上步中间体c7-1(1.5g，3.48mmol)和原料溴乙酸乙酯c7-2(0.8g，4.88mmol)溶于25mL 1，4-二氧六环中，缓慢加入DIEA(1.4g，10.5mmol)，滴毕，升温至80℃下反应4小时，冷却至室温，停止反应。将反应液中倒入100mL冰水中，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经HPLC制备色谱分离(色谱柱：XSelect Prep OBD C18 Column，30*150mm，5μm；流动相A：水(10mmol/L NH4HCO3)，流动相B：乙腈；流速：40mL/min；保留时间：16min)，得到黄色固体c7-3(1.4g)，收率：78％。LCMS ESI-MS m/z：517[M+H]+。
第三步：将上步中间体c7-3(1.2g，2.32mmol)溶于18mL四氢呋喃和水的混合溶液中(v/v，2/1)，缓慢加入NAOH水溶液(3.5mL，1M)，滴毕，室温下反应1小时，停止反应。将反应液用稀盐酸调节pH至4左右，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经HPLC制备色谱分离(色谱柱：XSelect Prep OBD C18，30*150mm，5μm；流动相A：水，流动相B：乙腈；流速：40mL/min；保留时间：16min)，得到黄色固体c7(900mg)，收率：92％。LCMS ESI-MS m/z：489[M+H]+。
参照中间体c7的合成路线，采用类似的原料/类似物，合成如下目标中间体。
中间体d1-d7的制备
第一步：氮气保护下，将原料d1-1(2.0g，7.40mmol)、甲基肼硫酸盐(1.1g，7.40mmol)溶于40mL乙醇中，加入醋酸(100mg，0.14mmol)，混合液升温至80℃下反应2小时，停止反应，减压蒸除 溶剂。向混合液中加入饱和碳酸氢钠水溶液调节pH至8左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，得到黄色油状物d1-2(2.5g)，收率：89％。LCMS ESI-MS m/z：297[M+H]+。
第二步：氮气保护下，将上步中间体d1-2(2.5g，8.38mmol)和磷酸钾(1.78g，8.39mmol)溶于38mL DMSO中，加入催化剂CuI(160mg，0.83mmol)，混合液升温至100℃下反应3小时，停止反应，过滤。向反应液中加入100mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经HPLC制备色谱分离(色谱柱：WelFlash C18-I，20-40μm，330g；流动相A水：(0.1％TFA)，流动相B：乙腈；流速：40mL/min；保留时间：12min)，得到白色固体d1-3(130mg)，收率：7％。LCMS ESI-MS m/z：217[M+H]+。
第三步：-78℃，氮气保护下，将上步中间体d1-3(130mg，0.59mmol)溶于2.5mL无水四氢呋喃中，缓慢加入n-BuLi(0.28mL，2.5M)，滴毕，在-78℃下搅拌1小时。向反应液中加入2-异丙氧基硼酸频哪醇酯(134mg，1.23mmol)，继续搅拌30分钟，停止反应。将向反应液加入饱和氯化铵水溶液10mL，乙酸乙酯，无水硫酸钠干燥，浓缩，得到黄色油状物d1(110mg)，收率：70％。LCMS ESI-MS m/z：265[M+H]+。
参照中间体d1的合成路线，采用类似的原料/类似物，合成如下目标中间体。
中间体d8，d15的制备
第一步：氮气保护下，将原料1-溴-2氟-4-碘苯d8-1(1.95g，6.5mmol)和原料d8-2(2.32g，7.8mmol)溶于40mL乙腈中，加入叔丁醇钾(2.2g，19.4mmol)，混合液升温至50℃下反应6小时，停止反应，过滤。向反应液中加入100mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析色谱分离(PE/EA，20/1)，得到黄色油状物d8-3(2.22g)，收率：79％。
第二步：将上步中间体d8-3(2.22g，5.15mmol)溶于133mL氯苯中，加入多聚磷酸PPA(2.37g，20.6mmol)，混合液升温至130℃下反应5小时，停止反应，冷却至室温。将反应液中加入100mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18； CH3CN/H2O，9/10)，得到黄色油状物d8-4(1.05g)，收率：60％。
第三步：氮气保护下，将上步中间体d8-4(1.05g，3.1mmol)和原料d8-5(1.95g，9.3mmol)溶于21mLDMF中，加入催化剂CuI(290mg，1.55mmol)和HMPA(2.39g，13.3mmol)，混合液升温至100℃下反应2小时，停止反应，过滤。向反应液中加入60mL水，甲基叔丁基醚萃取，无水硫酸钠干燥，浓缩，粗品经柱层析色谱分离(PE/EA，100/1)，得到黄色固体d8-6(0.8g)，收率：92％。
第四步：氮气保护下，将上步中间体d8-6(0.8g，2.85mmol)和原料二苯基甲酮亚胺(1.03g，5.69mmol)溶于16mL甲苯中，加入催化剂Pd(OAc)2(60mg，0.28mmol)、配体BINAP(0.35g，0.57mmol)和碳酸铯(1.85g，5.69mmol)，混合液升温至110℃下反应2小时，停止反应，过滤。向反应液中加入60mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，得到粗品混合物。将混合物溶于4mL四氢呋喃中，加入2M浓度的氯化氢的四氢呋喃溶液(16mL)，室温下反应1小时，停止反应。向反应液中加入饱和碳酸氢钠水溶液调节pH至8左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，10/7)，得到黄色固体d8(0.5g)，收率：81％。LCMS ESI-MS m/z：218[M+H]+。
参照中间体d8的合成路线，采用类似的原料/类似物，合成如下目标中间体。
中间体d9的制备
第一步：CO2(20atm)下，将原料d9-1(2.5g，15.7mmol)和TEA(21.8mL，157mmol)溶于50mL甲醇中，加入催化剂Pd(dppf)Cl2(1.2g，1.57mmol)，混合液升温至80℃下反应12小时，停止反应，过滤。减压蒸除溶剂，向反应液中加入100mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，3/10)，得到黄色固体d9-2(900mg)，收率：31％。LCMS ESI-MS m/z：184[M+H]+。
第二步：将上步中间体d9-2(900mg，4.91mmol)和氯乙醛(771mg，9.8mmol)溶于18mL乙醇中，混合液升温至80℃下反应5小时，停止反应，冷却至室温。将反应液中加入100mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经ASFC色谱分离(色谱柱：DAICEL DCpak P4VP 3*25cm，5μm；流动相：CO2，流动相B：MeOH(0.1％甲酸)；流速：60mL/min；d9-3保留时间(min)：3.41；d9-4保留时间(min)：5.94)。d9-3(300mg)，收率：30％；d9-4(150mg)，收率：15％。
第三步：氮气保护下，将上步中间体d9-3(200mg，0.97mmol)溶于4mL二氯甲烷中，加入BBr3(1.93mL，1.93mmol)，混合液室温下反应12小时，停止反应，过滤。向反应液中加入20mL水，二氯甲烷萃取，无水硫酸钠干燥，浓缩，得到粗品混合物。将混合物溶于3mL四氢呋喃中，加入2N浓度的NAOH水溶液(1mL)，室温下反应1小时，停止反应。向反应液中加入稀盐酸调节pH至6左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，得到黄色固体d9(40mg)，收率：23％。LCMS ESI-MS m/z：180[M+H]+。
中间体d10的制备
第一步：氮气保护下，将原料NBS(3.81g，21.4mmol)和AIBN(200mg，1.22mmol)溶于40mL四氯化碳中，混合液升温至80℃，向反应液滴加原料d10-1(3.0g，21.4mmol)，滴毕，继续反应5小时，停止反应，过滤。减压蒸除溶剂，向反应液中加入100mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析色谱分离(PE/EA，1/10)，得到黄色油状物d10-2(4.09g)，收率：87％。
第二步：将上步中间体d10-2(2.5g，11.4mmol)和原料d10-3(3.05g，12.5mmol)溶于18mL DMF中，加入KI(189mg，1.1mmol)和K2CO3(2.36g，17.1mmol)，混合液升温至50℃下反应3小时，停止反应，冷却至室温。将反应液中加入100mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经层析色谱分离(PE/EA，1/4)，得到黄色油状物d10-4(3.77g)，收率：87％。LCMS ESI-MS m/z：382[M+H]+。
第三步：-70℃，氮气保护下，将上步中间体d10-4(2.11g，5.54mmol)溶于40mL无水四氢呋喃中，加入LiHMDS(15.51mL，15.51mmol)，混合液继续反应1小时，停止反应，升温至室温。向反应液中加入20mL水，稀盐酸调节pH至6左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经层析色谱分离(PE/EA，1/5)，得到黄色油状物d10-5(951mg)，收率：89％。LCMS ESI-MS m/z：194[M+H]+。
第四步：将上步中间体d10-5(903mg，4.68mmol)溶于12mL四氢呋喃和水的混合溶液中(v/v，2/1)，加入LiOH(280mg，11.7mmol)，混合液升温至50℃反应4小时，停止反应。向反应液中加入20mL水，稀盐酸调节pH至3左右，析出固体，过滤，滤饼干燥，得到白色固体d10(265mg)，收率：32％。LCMS ESI-MS m/z：180[M+H]+。
中间体d11的制备
第一步：氢气保护下(1atm)，将中间体d10-5(800mg，4.14mmol)和Pd/C(320mg，40％w.t.)溶于16mL乙醇中，混合室温下反应2小时，停止反应，过滤。减压蒸除溶剂，得到白色固体d11-1(707mg)，收率：88％。LCMS ESI-MS m/z：196[M+H]+。
第二步：将上步中间体d11-1(700mg，3.58mmol)溶于10mL四氢呋喃和水的混合溶液中(v/v，3/1)，加入LiOH(215mg，9.0mmol)，混合液升温至50℃反应4小时，停止反应。向反应液中加入20mL水，稀盐酸调节pH至3左右，析出固体，过滤，滤饼干燥，得到白色固体d11(485mg)，收率：75％。LCMS ESI-MS m/z：182[M+H]+。
中间体d12的制备
第一步：一氧化碳保护下，将原料d12-1(1.0g，6.26mmol)和甲醇(3.0mL)溶于10mL DMF中，加入催化剂Pd(dppf)Cl2(0.9g，1.25mmol)和TEA(3.0mL)，混合液在一氧化碳(30atm)下，升温至120℃反应12小时，停止反应，过滤。减压蒸除溶剂，向反应液中加入100mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，2/1)，得到黄色固体d12-2(500mg)，收率：44％。LCMS ESI-MS m/z：184[M+H]+。
第二步：将上步中间体d12-2(500mg，2.73mmol)和原料氯乙醛(642mg，8.2mmol)溶于10mL叔丁醇中，混合液升温至90℃下反应12小时，停止反应，冷却至室温。将反应液中加入50mL冰水， 乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，2/1)，得到黄色固体d12-3(200mg)，收率：35％。LCMS ESI-MS m/z：208[M+H]+。
第三步：将上步中间体d12-3(190mg，0.91mmol)溶于4mL四氢呋喃和水的混合溶液中(v/v，3/1)，加入NaOH(73mg，1.8mmol)，混合液室温下反应1小时，停止反应。向反应液中加入10mL水，稀盐酸调节pH至3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，2/1)，得到白色固体d12(100mg)，收率：56％。LCMS ESI-MS m/z：194[M+H]+。
中间体d13的制备
第一步：将原料d13-1(5.0g，17.7mmol)和乙醇(50mL)溶于100mL浓HBr中，加入KSCN(5.2g，53.2mmol)，混合液升温至100℃反应2小时，停止反应。减压蒸除溶剂，向反应液中加入100mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，2/1)，得到棕色固体d13-2(1.1g)，收率：24％。LCMS ESI-MS m/z：260[M+H]+。
第二步：氮气保护下，将上步中间体d13-2(1.1g，4.22mmol)和原料iPrONO(1.49g，12.7mmol)溶于17mL无水四氢呋喃中，加入DMSO(0.3g，3.38mmol)，混合液升温至50℃下反应12小时，停止反应，冷却至室温。将反应液中加入50mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，2/1)，得到黄色固体d13-3(460mg)，收率：44％。LCMS ESI-MS m/z：245[M+H]+。
第三步：一氧化碳保护下，将上步中间体d13-3(460mg，1.87mmol)和TEA(380mg，3.75mmol)溶于10mL甲醇中，加入催化剂Pd(dppf)Cl2(137mg，0.18mmol)，混合液在一氧化碳(30atm)下，升温至100℃反应12小时，停止反应，过滤。减压蒸除溶剂，向反应液中加入100mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，得到棕色固体d13-4(525mg)。LCMS ESI-MS m/z：225[M+H]+。
第四步：将上步中间体d13-4(525mg，2.34mmol)溶于10mL四氢呋喃和水的混合溶液中(v/v，7/3)，加入NaOH(187mg，4.8mmol)，混合液室温下反应1小时，停止反应。向反应液中加入10mL水，稀盐酸调节pH至6左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，2/1)，得到黄色固体d13(230mg)，收率：50％。LCMS ESI-MS m/z：211[M+H]+。
中间体d18-d19的制备
第一步：氮气保护下，将原料2-溴-5-三氟甲基苯酚d18-1(5.0g，20.75mmol)和碳酸钾(8.6g，62.2mmol)溶于100mL DMF中，逐滴加入原料d18-2(12.3g，62.2mmol)，混合液升温至80℃下反应12小时，停止反应，过滤。向反应液中加入250mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析色谱分离(PE/EA，20/1)，得到黄色油状物d18-3(6.0g)，收率：81％。
第二步：将上步中间体d18-3(6.0g，16.8mmol)和多聚磷酸(30g，261mmol)溶于72mL甲苯中，混合液升温至120℃下反应5小时，停止反应。向反应液中加入100mL水，氨水调节pH至8左右，甲基叔丁基醚萃取，无水硫酸钠干燥，浓缩，经柱层析色谱分离(PE/EA，20/1)，得到黄色油状物d18-4(1.0g)，收率：23％。
第三步：氮气保护下，将上步中间体d18-4(1.0g，3.77mmol)和原料二苯基甲酮亚胺(1.4g，7.55mmol)溶于20mL甲苯中，加入催化剂Pd(OAc)2(80mg，0.38mmol)、配体BINAP(0.5g，0.8mmol)和 碳酸铯(2.5g，7.55mmol)，混合液升温至110℃下反应2小时，停止反应，过滤。向反应液中加入100mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，得到粗品混合物。将混合物溶于5mL四氢呋喃中，加入2M浓度的氯化氢的四氢呋喃溶液(20mL)，室温下反应1小时，停止反应。向反应液中加入饱和碳酸氢钠水溶液调节pH至8左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，1/1)，得到黄色固体d18(150mg)，收率：20％。LCMS ESI-MS m/z：202[M+H]+。
参照中间体d18的合成路线，采用类似的原料/类似物，合成如下目标中间体。
中间体d20的制备
步骤：-78℃，氮气保护下，将原料7-氨基苯并呋喃d20-1(600mg，4.13mmol)溶于14mL无水二氯甲烷中，加入提前配置的液Br2溶液(0.7g，4.13mmol，DCM 11mL)，混合液于-78℃下反应1小时，停止反应。向反应液中加入20mL饱和硫代硫酸钠水溶液，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，1/1)，得到黄色油状物d20(200mg)，收率：23％。LCMS ESI-MS m/z：212[M+H]+。
实施例2：
目标分子P1-P2，P5-P9，P22-P23的制备
第一步：冰浴，氮气保护下，将中间体b4(70mg，0.22mmol)和1-氯-N，N，2-三甲基丙基-1-烯-1-胺(61mg，0.45mmol)溶于2mL二氯甲烷中，冰浴下搅拌1小时。向反应液加入中间体c2(129mg，0.23mmol)和DIEA(88mg，0.68mmol)，混合液在室温下反应2小时，停止反应。向反应液中加入10mL水，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，7/10)，得到黄色固体P1-1(40mg)，收率：21％。LCMS ESI-MS m/z：856[M+H]+。
第二步：冰浴，氮气保护下，将上步化合物P1-1(40mg，0.05mmol)和三氟乙酸(0.4mL)溶于1mL二氯甲烷中，室温下搅拌2小时，减压蒸除溶剂。将混合物再次溶解于1mL二氯甲烷中，加入DMEDA(0.08mL)，反应液在室温下反应8小时，停止反应。减压蒸除溶剂，粗品经HPLC色谱分离(色谱柱：XBridge Prep Shield RP18 OBD Column，19*250mm，5μm；流动相A：水(10mmol/L NH4HCO3)，流动相B：CH3CN；流速：25mL/min mL/min；G保留时间(min)：9.6)，得到白色固体P1(12mg)，收率：35％。LCMS ESI-MS m/z：726[M+H]+。
1H NMR(300MHz，DMSO-d6) δ11.46(s，1H)，10.25(s，1H)，9.62(s，1H)，8.06(d，J＝8.6Hz，1H)，7.96(d，J＝2.1Hz，1H)，7.71(dd，J＝8.7，2.1Hz，1H)，7.46(t，J＝2.9Hz，1H)，7.41(s，1H)，6.83(dd，J＝3.2，1.7Hz，1H)，6.33(dd，J＝3.3，1.7Hz，1H)，5.31(s，2H)，4.57(s，1H)，4.25(d，J＝2.9Hz，2H)，3.84-3.76(m， 2H)，3.55(d，J＝39.2Hz，4H)，3.25(d，J＝13.1Hz，2H)，2.98(d，J＝9.8Hz，3H)，2.81(d，J＝11.1Hz，1H)，2.61(d，J＝10.9Hz，1H)，1.19(t，J＝7.5Hz，3H).
参照化合物P1的合成路线，采用类似的原料/中间体(如中间体b5，b7，c16-c22，d10等)，合成如下目标分子。

目标分子P3-P4，P24的制备
第一步：冰浴，氮气保护下，将中间体b4(602mg，1.95mmol)和1-氯-N，N，2-三甲基丙基-1-烯-1-胺(261mg，1.95mmol)溶于12mL二氯甲烷中，冰浴下搅拌1小时。向反应液加入中间体c5-2(550mg，0.98mmol)和DIEA(379mg，2.9mmol)，混合液在室温下反应2小时，停止反应。向反应液中加入50mL水，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，4/5)，得到黄色油状物P3-1(400mg)，收率：48％。LCMS ESI-MS m/z：852[M+H]+。
第二步：冰浴，氮气保护下，将上步化合物P3-1(300mg，0.35mmol)和三氟乙酸(3.0mL)溶于3mL二氯甲烷中，室温下搅拌2小时，减压蒸除溶剂。将混合物再次溶解于3mL二氯甲烷中，加入DMEDA(0.08mL)，反应液在室温下反应8小时，停止反应。减压蒸除溶剂，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，4/5)，得到黄色油状物P3-2(150mg)，收率：59％。LCMS ESI-MS m/z：722[M+H]+。
第三步：氮气保护下，将上步中间体P3-2(34mg，0.05mmol)和中间体d7(23mg，0.09mmol)溶于1mL DMF和水的混合溶液中(3/1)，加入催化剂Pd(dppf)Cl2(60mg，0.28mmol)和磷酸钾(30mg，0.14mmol)，混合液升温至70℃下反应2小时，停止反应，过滤。向反应液中加入5mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，得到粗品混合物。粗品经HPLC色谱分离(色谱柱：Xselect CSH Prep C18 OBD Colum，19*250nm，5μm；流动相A：水(0.1％三氟乙酸)，流动相B：MeOH；流速：25mL/min；保留时间(min)：12.4)，得到白色固体P3(4.4mg)，收率：3％。LCMS ESI-MS m/z：757[M+H]+。1H NMR(300MHz，DMSO-d6)δ 11.47(s，1H)，10.37(s，1H)，9.63(s，1H)，8.29(s，1H)，8.10-7.88(m，2H)，7.71(dd，J＝8.8，2.1Hz，1H)，7.51-7.44(m，1H)，7.41(s，1H)，6.33(dd，J＝3.4，1.8Hz，1H)，6.28(t，J＝5.9Hz，1H)，5.36(s，2H)，4.78(d，J＝5.5Hz，2H)，4.60(d，J＝12.2Hz，1H)，3.51(t，J＝12.3Hz，3H)，3.24(s，1H)，3.01(s，3H)，2.83(d，J＝11.1Hz，1H)，2.63(d，J＝10.3Hz，1H)，1.23(s，3H).
参照化合物P3的合成路线，采用类似的原料/中间体(如中间体b2，b7)，合成如下目标分子。

目标分子P10的制备
第一步：氮气保护下，将中间体c23(100mg，0.12mmol)和吗啉(51mg，0.59mmol)溶于2mL DMSO中，加入KOAc(69mg，0.70mmol)，升温至120℃下反应5小时，停止反应。向反应液加入20mL水，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，4/5)，得到黄色固体P10-1(60mg)，收率：60％。LCMS ESI-MS m/z：859[M+H]+。
第二步：冰浴，氮气保护下，将上步化合物P10-1(60mg，0.07mmol)和三氟乙酸(1.0mL)溶于1mL二氯甲烷中，室温下搅拌2小时，减压蒸除溶剂。将混合物再次溶解于1mL二氯甲烷中，加入DMEDA(0.12mL)，反应液在室温下反应8小时，停止反应。减压蒸除溶剂，粗品经HPLC色谱分离(色谱柱：XSelectPrep OBD C18 Column，30*150mm，5μm；流动相A：水(0.1％甲酸)，流动相B：乙腈；流速：60mL/min；保留时间(min)：9.9)，得到白色固体P10(6.1mg)，收率：11％。LCMS ESI-MS m/z：729[M+H]+。1H NMR(300MHz，DMSO-d6)δ11.46(s，1H)，10.35(s，1H)，9.60(s，1H)，8.04(d，J＝8.6Hz，1H)，7.97(d，J＝2.1Hz，1H)，7.72(dd，J＝8.9，2.2Hz，1H)，7.49-7.43(m，1H)，7.40(s，1H)，6.33(dd，J＝3.4，1.8Hz，1H)，5.22(s，2H)，4.57(d，J＝12.2Hz，1H)，3.66(t，J＝4.8Hz，4H)，3.50(t，J＝13.3Hz，3H)，3.42-3.37(m，4H)，3.23(d，J＝12.9Hz，1H)，2.95(s，3H)，2.77(d，J＝13.4Hz，1H)，2.58(s，1H)，1.16(t，J＝7.4Hz，3H).
目标分子P11-P15，P17的制备
第一步：氮气保护下，将中间体c2(687mg，1.21mmol)和1-氯-N，N，2-三甲基丙基-1-烯-1-胺(161mg，1.2mmol)溶于3mL二氯甲烷中，冰浴下搅拌1小时。向反应液加入中间体d11(110mg，0.60mmol)和DIEA(392mg，3.0mmol)，混合液在室温下反应2小时，停止反应。向反应液中加入10mL水，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，1/1)，得到白色固体P13(19mg)，收率：4％。LCMS ESI-MS m/z：729[M+H]+。
1H NMR(300MHz，DMSO-d6)δ11.01(s，1H)，10.39(s，1H)，8.07(d，J＝8.6Hz，1H)，7.98(d，J＝2.1Hz，1H)，7.78-7.66(m，2H)，6.84(s，1H)，5.33(s，2H)，4.66(t，J＝8.8Hz，3H)，4.26(d，J＝3.0Hz，3H)，3.81 (t，J＝5.5Hz，2H)，3.51(t，J＝11.0Hz，2H)，3.33(s，3H)，3.20(t，J＝8.9Hz，2H)，3.00(d，J＝7.8Hz，3H)，2.74(s，2H)，1.20(t，J＝7.4Hz，3H).
参照化合物P13的合成路线，采用类似的原料/中间体(如中间体b6，d9-d12，c20)，合成如下目标分子。
目标分子P16的制备
第一步：氮气保护下，将中间体c2(563mg，1.0mmol)、DIEA(428mg，3.32mmol)和中间体d13(131mg，0.66mmol)溶于3mL乙腈中。向反应液加入EDCI(254mg，1.32mmol)和HOAt(180mg，1.33mmol)，混合液在室温下反应3小时，停止反应。向反应液中加入10mL水，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，2/1)，得到黄色固体P16-1(96mg)，收率：19％。LCMS ESI-MS m/z：758[M+H]+。
第二步：氮气保护下，将上步化合物P16-1(88mg，0.45mmol)和LiCl(76mg，1.8mmol)溶于2mL DMF中。混合液升温至150℃下反应13小时，停止反应。向反应液中加入10mL水，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经HPLC制备色谱分离(色谱柱：Xselect CSH F-Phenyl OBD Column 30*150mm 5μmn；流动相A：水(0.1％甲酸)，流动相B：乙腈；流速：60mL/min；保留时间：9.55min)，得到淡黄色固体P16(11mg)，收率：3％。LCMS ESI-MS m/z：744[M+H]+。
1H NMR(400MHz，DMSO-d6)δ9.51(s，1H)，8.06(d，J＝8.6Hz，1H)，7.92(d，J＝36.3Hz，2H)，7.71(d，J＝8.6Hz，1H)，6.83(s，1H)，5.32(s，2H)，4.57(d，J＝12.4Hz，1H)，4.25(s，2H)，3.80(t，J＝5.6Hz，2H)，3.54(s，2H)，3.30(dd，J＝21.8，12.7Hz，3H)，2.99(d，J＝11.0Hz，3H)，2.82(d，J＝11.3Hz，1H)，1.20(q，J＝9.5，7.7Hz，3H).
目标分子P18-P21，P25-P27的制备
第一步：氮气保护下，将中间体c7(150mg，0.31mmol)、DIEA(238mg，1.84mmol)和中间体d18(74mg，0.37mmol)溶于5mL二氯甲烷中，冰浴下搅拌5分钟。向反应液加入T3P(110mg，0.60mmol)和DMAP(113mg，0.92mmol)，混合液在室温下反应12小时，停止反应。向反应液中加入30mL水，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，2/1)，得到黄色固体P18-1(162mg)，收率：79％。LCMS ESI-MS m/z：672[M+H]+。
第二步：将上步化合物P18-1(162mg，0.24mmol)溶于1mL 1，4-二氧六环中，冰浴下搅拌5分钟。向反应液加入HCl的1，4-二氧六环溶液(2M，3.3mL)，混合液在室温下反应1小时，停止反应。减压蒸除溶剂，得到棕色固体P18-2(162mg)。LCMS ESI-MS m/z：572[M+H]+。
第三步：氮气保护下，将上步化合物P18-2(162mg，0.28mmol)、DIEA(238mg，1.84mmol)和中间体b4(175mg，0.57mmol)溶于4mL二氯甲烷中，冰浴下搅拌5分钟。向反应液加入1-氯-N，N，2-三甲基丙基-1-烯-1-胺(76mg，0.56mmol)，混合液在室温下反应2小时，停止反应。向反应液中加入30mL水，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(色谱柱：C18；CH3CN/H2O，2/1)，得到黄色固体P18-3(94mg)，两步收率：38％。LCMS ESI-MS m/z：862[M+H]+。
第四步：将上步化合物P18-3(93mg，0.11mmol)溶于2mL三氟乙酸和二氯甲烷的混合溶液中(v/v，1/1)，冰浴下反应2小时，减压蒸除溶剂。将混合物溶于1mL二氯甲烷中，向反应液加入乙二胺EDA(1.0mL)，混合液继续在室温下反应1小时，停止反应。向反应液中加入10mL水，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经HPLC制备色谱分离(色谱柱：Xbridge Prep phenyl OBD Colum，19*250nm，5μm；流动相A：水(0.1％甲酸)，流动相B：乙腈；流速：25mL/min；保留时间：11.2min)，得到白色固体P18(13.5mg)，收率：16％。LCMS ESI-MS m/z：732[M+H]+。
1H NMR(300MHz，DMSO-d6)δ 11.47(s，1H)，9.67(s，1H)，8.36(d，J＝2.2Hz，1H)，8.06(d，J＝8.3Hz，1H)，7.61(d，J＝8.5Hz，1H)，7.49-7.38(m，2H)，7.14(q，J＝1.8Hz，1H)，6.81(t，J＝2.3Hz，1H)，6.33(dd，J＝3.4，1.6Hz，1H)，5.37(s，2H)，4.59(d，J＝12.4Hz，1H)，4.24(q，J＝2.7Hz，2H)，3.80(t，J＝5.5Hz，2H)，3.57(t，J＝10.6Hz，2H)，3.51(s，1H)，3.47(s，1H)，3.36(s，1H)，3.24(s，1H)，3.09-2.89(m，3H)，2.82(d，J＝11.0Hz，1H)，2.62(d，J＝10.5Hz，1H)，1.20(q，J＝7.4，6.4Hz，3H).
参照化合物P18的合成路线，采用类似的原料/中间体(如中间体d10，d20，c8)，合成如下目标分子。

实施例3：
测试本发明分子对于WRN解旋酶水解DNA双链的活性(表1)。
准备待测工作液和缓冲液，待测化合物以DMSO溶解4倍稀释(10μM终浓度作为起始浓度)。将0.2μL待测化合物溶液加入到384孔板中，加入10μL(2X)WRN酶溶液，避光孵育30分钟后，加入10μL含有双链DNA的底物检测液来起始反应(DNA长度19bp，3′和5′分别标记TAMRA和BHQ2)，在室温下孵育60分钟。根据空白组(DMSO)和化合物组的荧Ex530/Em590变化来计算对于WRN酶的抑制活力(IC50)。
计算公式：Y＝下平台信号+(上平台信号-下平台信号)/(1+10^((LogIC50-X)×希尔斜率))
X：化合物浓度log值
Y：抑制率(％)
表1.化合物对于WRN酶的解旋抑制效果
Unwinding＝解旋
以上结果表明，本发明分子对于WRN解旋DNA具有良好抑制效果，有望通过抑制WRN解旋酶活性来达到较好的肿瘤抑制效果。
实施例4：
测试本发明分子对于MSI-H肿瘤细胞的抗增殖活性。
微卫星不稳定MSI-H的肿瘤细胞，其增殖对于WRN抑制剂敏感；微卫星稳定MSS的肿瘤细胞，其增殖对于WRN抑制剂不敏感。通过测试两者的活性，显示本发明分子在细胞层面的对于WRN的抑制和合成致死效果。
将MSI不稳定的SW48结直肠癌细胞培养于包含10％FBS和1％青链霉素的RMI1640培养基中，置于37℃，5％CO2恒温培养箱培养，在384孔微板中每孔加入40μL细胞悬液。使用Echo在每孔中加入40nL不同浓度的化合物，置于37℃，5％CO2恒温培养箱培养5天。在每孔中加入40μL的CTG溶液(Promega，CatNo.G7573)，置于37℃，5％CO2恒温培养箱避光温孵30分钟。用Envision多功能酶标仪(Perkin Elmer，目录号Envision 2104)读取发光值，光信号和体系中ATP量成正比，而ATP的含量直接表征体系中的活细胞数。
IC50值计算：
Y＝下平台信号+(上平台信号-下平台信号)/(1+10^((LogIC50-X)×希尔斜率))
X：化合物浓度log值
Y：抑制率(％)
表2.1：化合物对于MSI-H的肠癌SW48细胞系的2D抗增殖效果
N.D.＝未测试
参照WO2022249060，合成如下对照分子A1
以上结果表明，本发明分子对于MSI-H肿瘤细胞具有良好抗增殖效果，有望通过抑制WRN解旋酶活性来达到较好的肿瘤抑制效果。
以上结果还表明：对照分子P11b对于SW48细胞已经完全无抑制效果，而本发明分子如P13，P14，P15，P16，P26等分子具有显著的抑制效果；表明不同的并环结构，显著影响抗增殖效果。
实施例5：
测试本发明分子对于MSS肿瘤细胞的抗增殖活性。
将MSS的HT-29结直肠癌细胞培养于包含10％FBS和1％青链霉素的McCoy′s5A培养基中，置于37℃，5％CO2恒温培养箱培养，在384孔微板中每孔加入40μL细胞悬液。使用Echo在每孔中加入40nL不同浓度的化合物，置于37℃，5％CO2恒温培养箱培养5天。在每孔中加入40μL的CTG溶液(Promega，Cat No.G7573)，置于37℃，5％CO2恒温培养箱避光温孵30分钟。用Envision多功能酶标仪(Perkin Elmer，目录号Envision 2104)读取发光值，光信号和体系中ATP量成正比，而ATP的含量直接表征体系中的活细胞数。
IC50值计算：
Y＝下平台信号+(上平台信号-下平台信号)/(1+10^((LogIC50-X)×希尔斜率))
X：化合物浓度log值
Y：抑制率(％)
表2.2：化合物对于MSS的肠癌HT-29细胞系的2D抗增殖效果
N.D.＝未测试
以上结果表明，本发明分子对于MSS肿瘤细胞无抑制效果，体现了本发明分子的对于WRN选择性抑制带来的高选择性。
实施例6：
化合物的肝微粒体稳定性实验。具体如下：
对本发明化合物进行肝微粒体稳定性试验研究，将待测化合物在加入或不加入NADPH情况下与不同种属的肝微粒体进行共孵育，试验体系中待测化合物终浓度为1μM，NADPH终浓度为1mM，肝微粒体终浓度为0.5mg/mL。检测60分钟内不同时间点孵育上清中的化合物浓度并计算药代动力学参数(例如清除率Clint)。
该结果表明本发明分子具有较好的代谢稳定性(尤其在人体中，具有较好的代谢稳定性，且化合物P13，P14和P25的代谢更稳定)。
表3：化合物对于人的体外肝微粒体稳定性实验结果

实施例7：
小鼠药代动力学评价实验
以CD1雌性小鼠为受试动物，口服/静脉给药(口服给药量为10mg/kg，静脉为2mg/kg)。
实验方案：口服组每组3只(溶媒：10％Hβ-CD-pH7.4)，静脉组每组三只。口服：收集给药前(0h)和给药后(0.25，0.5，1，2，4，8，24h)的血浆样品；静脉：收集给药前(0h)和给药后(0.083，0.25，0.5，1，2，4，8，24h)的血浆样品；用LC/MS/MS法分别测定小鼠口服和静脉给药后的血浆的血液浓度，采集的数据用AB Sciex QTRAP 6500软件计算，实验结果如下：
表4：化合物在小鼠体内的PK结果
以上实验结果表明，本发明化合物具有良好的口服吸收效果，相比对照分子A1，口服吸收更优，具有较高的体内暴露量，有望带来更高的治疗效果。

Claims (26)

  1. 式(A)化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体：
    其中，
    环B或环C为5-6元杂芳基或5-6元杂环基，至少有一个环存在；
    Y选自CH或N；
    R1选自5-12元杂芳基或5-12元杂环基；所述R1可以被1个、2个或3个Rx取代；
    R2选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C3-6环烷基；
    R3独立地选自H、D、卤素、CN、C1-6烷基、C1-6卤代烷基或C3-6环烷基；或者两个R3连接其所在碳原子形成3-6元螺环或桥环；
    R4独立地选自H、卤素、CN、SF5、C1-6烷基、C1-6卤代烷基、C1-6烷硫基、C3-6环烷基或4-10元杂环基；
    环A存在或不存在，环A选自5-6元杂芳基或5-7元杂环基；
    R5选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C3-6环烷基；
    Rx选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、CN、NH2、-C(O)Ra、-C(O)ORa、-(CH2)p-ORa、-P(O)-(Ra)2或-S(O)2-Ra；
    Ra选自H、C1-6烷基或C3-6环烷基；
    m选自0、1、2或3；
    n选自0、1或2；
    p选自0、1或2。
  2. 权利要求1的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体，其中环B和环C中只有一个环存在。
  3. 权利要求1或2的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体，其中Y为N。
  4. 权利要求1-3中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体，其中为其中M1，M2各自独立地选自CH或N，当M1或M2其中之一选自为N时，M1和M2形成单建；M3，M4和M5各自独立地选自CH、O、S或N，且M3，M4和M5至少含有一个N原子；Y选自CH或N。
  5. 权利要求4的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体，其中为其中M1和M2各自独立地选自CH或N。
  6. 权利要求4的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体，其中为其中R5为H或C1-6烷基。
  7. 权利要求1-6中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体，其中R1选自含有1或2个选自氧、氮和硫的杂原子的5-6元单环杂芳基、含有1或2个选自氧、氮和硫的杂原子的5-6元单环杂环基、含有1或2或3或4个选自氧、氮和硫的杂原子的7-12元二环杂芳基，或含有1或2或3或4个选自氧、氮和硫的杂原子的7-12元二环杂环基，其各自可以被1个、2个或3个Rx取代，Rx选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、CN、NH2、-C(O)Ra、-C(O)ORa、-(CH2)p-ORa、-P(O)-(Ra)2或-S(O)2-Ra，其中Ra选自H、C1-6烷基或C3-6环烷基。
  8. 权利要求7的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体，其中R1选自 所述R1可以被1个、2个或3个Rx取代，Rx选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、CN、NH2、-C(O)Ra、-C(O)ORa、-(CH2)p-ORa、-P(O)-(Ra)2或-S(O)2-Ra。
  9. 权利要求1-8中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体，其中R2选自C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4烷硫基、环丙基、环丁基、环戊基和环己基。
  10. 权利要求9的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体，其中R2选自甲基、乙基、丙基、异丙基、正丁基、异丁基或叔丁基。
  11. 权利要求1-10中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体，其中R3选自H或C1-6烷基。
  12. 权利要求1-11中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体，其中环A不存在，以及为其中R4a、R4b和R4c独立地选自H、卤素、CN、SF5、C1-6烷基、C1-6卤代烷基、C1-6烷硫基或C3-6环烷基。
  13. 权利要求12的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体，其中环A不存在，以及为其中R4a为卤素或C1-6卤代烷基，以及R4b 为卤素或C1-6烷基。
  14. 权利要求1-11中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体，其中为其中R4a选自H、卤素、CN、SF5、C1-6烷基、C1-6卤代烷基、C1-6烷硫基或C3-6环烷基，其中环A为5或6元杂芳基或杂环基，其各自含有1或2个选自氧、氮和硫的杂原子。
  15. 权利要求14的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体，其中为其中R4a选自卤素、CN、C1-6烷基、C1-6卤代烷基、C1-6烷硫基或C3-6环烷基，环A为
  16. 权利要求1的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体，其具有式(I)结构：
    其中，
    M1，M2各自独立地选自CH或N，当M1或M2其中之一选自为N时，M1和M2形成单建；
    M3，M4和M5各自独立地选自CH、O、S或N，且M3，M4和M5至少含有一个N原子；
    Y选自CH或N；
    R1选自5-12元杂芳基或5-12元杂环基；所述R1可以被1个、2个或3个Rx取代；
    R2选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C3-6环烷基；
    R3独立地选自H、卤素、CN、C1-6烷基、C1-6卤代烷基或C3-6环烷基；或者两个R3连接其所在碳原子形成3-6元螺环或桥环；
    R4独立地选自H、卤素、CN、SF5、C1-6烷基、C1-6卤代烷基、C1-6烷硫基、C3-6环烷基或4-10元杂环基；
    环A存在或不存在，环A选自5-6元杂芳基或5-7元杂环基；
    R5选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C3-6环烷基；
    Rx选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、CN、NH2、-C(O)Ra、-C(O)ORa、-(CH2)p-ORa、-P(O)-(Ra)2或-S(O)2-Ra；
    Ra选自H、C1-6烷基或C3-6环烷基；
    m选自0、1、2或3；
    n选自0、1或2。
  17. 权利要求16的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体，其为式(II)的化合物：
    其中，
    R1选自5-12元杂芳基或5-12元杂环基；所述R1可以被1个、2个或3个Rx取代；
    R2选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C3-6环烷基；
    R3独立地选自H、卤素、CN、C1-6烷基、C1-6卤代烷基或C3-6环烷基；或者两个R3连接其所在碳原子形成3-6元螺环或桥环；
    R4独立地选自H、卤素、CN、SF5、C1-6烷基、C1-6卤代烷基、C1-6烷硫基、C3-6环烷基或4-10元杂环基；
    环A存在或不存在，环A选自5-6元杂芳基或5-7元杂环基；
    R5选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C3-6环烷基；
    Rx选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、CN、NH2、-C(O)Ra、-C(O)ORa、-(CH2)p-ORa、-P(O)-(Ra)2或-S(O)2-Ra；
    Ra选自H、C1-6烷基或C3-6环烷基；
    m选自0、1、2或3；
    n选自0、1或2。
  18. 权利要求1的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体，其具有式(III)、式(IV)结构：
    其中，
    M1，M2各自独立地选自CH或N；
    R1选自5-12元杂芳基或5-12元杂环基；所述R1可以被1个、2个或3个Rx取代；
    R2选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C3-6环烷基；
    R3独立地选自H、卤素、CN、C1-6烷基、C1-6卤代烷基或C3-6环烷基；或者两个R3连接其所在碳原子形成3-6元螺环或桥环；
    R4独立地选自H、卤素、CN、SF5、C1-6烷基、C1-6卤代烷基、C1-6烷硫基、C3-6环烷基或4-10元杂环基；
    环A存在或不存在，环A选自5-6元杂芳基或5-7元杂环基；
    R5选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C3-6环烷基；
    Rx选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、CN、NH2、-C(O)Ra、-C(O)ORa、-(CH2)p-ORa、-P(O)-(Ra)2或-S(O)2-Ra；
    Ra选自H、C1-6烷基或C3-6环烷基；
    m选自0、1、2或3；
    n选自0、1或2。
  19. 权利要求18的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体：
    其中，
    R1选自 所述R1可以被1个、2个或3个Rx取代；
    R2选自甲基、乙基、三氟乙基、甲硫基或环丙基；
    R3独立地选自H、F、CN、甲基、乙基、三氟甲基、环丙基；或者两个R3连接其所在碳原子形成环丙基或环丁基；
    R4独立地选自H、F、Cl、Br、CN、SF5、甲基、乙基、三氟甲基、二氟甲基、甲硫基或环丙基；
    环A存在或不存在，环A选自5-6元杂芳基或5-7元杂环基；
    R5选自H、F、Cl、甲基、乙基、三氟甲基、甲氧基、甲硫基或环丙基；
    Rx选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、CN、NH2、-C(O)Ra、-C(O)ORa、-(CH2)p-ORa、-P(O)-(Ra)2或-S(O)2-Ra；
    Ra选自H、C1-6烷基或C3-6环烷基；
    m选自0、1、2或3：
    n选自0、1或2。
  20. 权利要求18的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体，其具有式(III-1)结构：
    其中，
    M1选自CH或N；
    R1选自所述R1可以被1个、2个或3个Rx取代；
    R2选自H、甲基、乙基、三氟甲基、三氟乙基、甲氧基、甲硫基或环丙基；
    R4独立地选自H、卤素、CN、SF5、C1-6烷基、C1-6卤代烷基、C1-6烷硫基、C3-6环烷基或4-10元杂环基；
    环A选自5-6元杂芳基或环A不存在；
    R5选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C3-6环烷基；
    Rx选自H、甲基、三氟甲基、甲氧基、CN、NH2、-C(O)Me、-C(O)OMe、-(CH2)-OH或-S(O)2-Me；
    m选自0、1、2或3。
  21. 权利要求18的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体，其具有式(IV-1)结构：
    其中，
    R1选自所述R1可以被1个、2个或3个Rx取代；
    R2选自H、甲基、乙基、三氟甲基、三氟乙基、甲氧基、甲硫基或环丙基；
    R4独立地选自H、卤素、CN、SF5、C1-6烷基、C1-6卤代烷基、C1-6烷硫基、C3-6环烷基或4-10元杂环基；
    环A选自5-6元杂芳基或环A不存在；
    R5选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C3-6环烷基；
    Rx选自H、甲基、三氟甲基、甲氧基、CN、NH2、-C(O)Me、-C(O)OMe、-(CH2)-OH或-S(O)2-Me；
    m选自0、1、2或3。
  22. 权利要求21的化合物，或其药学上可接受的盐、同位素变体、互变异构体或立体异构体：
    其中，
    R1选自所述R1可以被1个、2个或3个Rx取代；
    R2选自H、甲基、乙基、三氟甲基、三氟乙基、甲氧基、甲硫基或环丙基；
    R4独立地选自H、Cl、Br、CN、SF5、甲基、乙基、三氟甲基、二氟甲基或环丙基；
    环A选自或环A不存在；
    R5选自H、Cl、F、甲基、三氟甲基、甲氧基、甲硫基或环丙基；
    Rx选自H、甲基、三氟甲基、甲氧基、CN、NH2、-C(O)Me、-C(O)OMe、-(CH2)-OH或-S(O)2-Me；
    m选自0、1、2或3。
  23. 化合物，或其互变异构体、立体异构体，其中所述化合物选自：


  24. 药物组合物，其含有权利要求1-23中任一项的化合物，或其药学上可接受的盐、互变异构体、立体异构体或同位素变体，和药学上可接受的赋形剂；优选地，其还含有其它治疗剂。
  25. 权利要求1-23中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体或同位素变体或权利要求24的药物组合物在制备用于治疗和/或预防WRN介导的疾病的药物中的用途。
  26. 权利要求25的化合物或组合物的用途，其中所述WRN介导的疾病为癌症，所述癌症选自：结肠直肠癌(例如结肠癌、直肠癌、大肠腺癌)、胃癌(如胃腺癌)或肺癌(如支气管癌、小细胞肺癌(SCLC)、非小细胞肺癌(NSCLC)、肺腺癌、肺鳞癌)。
PCT/CN2024/089315 2023-04-25 2024-04-23 Wrn抑制剂 Pending WO2024222677A1 (zh)

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US12344609B2 (en) 2023-06-08 2025-07-01 Nimbus Wadjet, Inc. WRN inhibitors
WO2025152750A1 (zh) * 2024-01-17 2025-07-24 成都微芯药业有限公司 双杂环wrn抑制剂、其制备方法及其应用
WO2025152932A1 (zh) * 2024-01-15 2025-07-24 上海齐鲁制药研究中心有限公司 一种三唑并嘧啶类衍生物、其制备方法和应用
WO2025161791A1 (zh) * 2024-02-01 2025-08-07 福石生物科技(合肥)有限公司 作为wrn抑制剂的螺环衍生物及其应用
WO2025215527A2 (en) 2024-04-10 2025-10-16 Novartis Ag Pharmaceutical combinations and uses thereof

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WO2022249060A1 (en) * 2021-05-26 2022-12-01 Novartis Ag Triazolo-pyrimidine analogues for treating diseases connected to the inhibiton of werner syndrome recq helicase (wrn)
WO2024105553A1 (en) * 2022-11-16 2024-05-23 Novartis Ag Bicyclic heterocycles and their use as wrn inhibitors

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WO2022249060A1 (en) * 2021-05-26 2022-12-01 Novartis Ag Triazolo-pyrimidine analogues for treating diseases connected to the inhibiton of werner syndrome recq helicase (wrn)
WO2024105553A1 (en) * 2022-11-16 2024-05-23 Novartis Ag Bicyclic heterocycles and their use as wrn inhibitors

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12344609B2 (en) 2023-06-08 2025-07-01 Nimbus Wadjet, Inc. WRN inhibitors
US12421233B2 (en) 2023-06-08 2025-09-23 Nimbus Wadjet, Inc. WRN inhibitors
WO2025152932A1 (zh) * 2024-01-15 2025-07-24 上海齐鲁制药研究中心有限公司 一种三唑并嘧啶类衍生物、其制备方法和应用
WO2025152750A1 (zh) * 2024-01-17 2025-07-24 成都微芯药业有限公司 双杂环wrn抑制剂、其制备方法及其应用
WO2025161791A1 (zh) * 2024-02-01 2025-08-07 福石生物科技(合肥)有限公司 作为wrn抑制剂的螺环衍生物及其应用
WO2025215527A2 (en) 2024-04-10 2025-10-16 Novartis Ag Pharmaceutical combinations and uses thereof

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