WO2024032597A1 - 具有sting抑制作用的酰胺类化合物及其药物组合物和用途 - Google Patents

具有sting抑制作用的酰胺类化合物及其药物组合物和用途 Download PDF

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WO2024032597A1
WO2024032597A1 PCT/CN2023/111702 CN2023111702W WO2024032597A1 WO 2024032597 A1 WO2024032597 A1 WO 2024032597A1 CN 2023111702 W CN2023111702 W CN 2023111702W WO 2024032597 A1 WO2024032597 A1 WO 2024032597A1
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membered
ring
alkyl
optionally substituted
cycloalkyl
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PCT/CN2023/111702
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French (fr)
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贺川
翟文强
赵梦婷
刘东舟
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杭州中美华东制药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
    • C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings

Definitions

  • the present application relates to compounds with interferon gene stimulator (STING) inhibitory effects or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, metabolites, isotope-labeled compounds or Prodrugs, pharmaceutical compositions containing the same, and their use for preventing and/or treating diseases associated with abnormal expression of STING.
  • STING interferon gene stimulator
  • Stimulator of interferon genes also known as transmembrane protein 173, regulatory activator of interferon regulatory factor 3, and endoplasmic reticulum interferon-stimulating protein, is mainly expressed in human macrophages. , T lymphocytes, dendritic cells, endothelial cells, epithelial cells and fibroblasts, etc. on the rough endoplasmic reticulum, mitochondria and outer membranes of microsomes.
  • cGAS cyclic GMP-AMP synthase nucleotide nucleotide
  • Ligand-bound STING is transported to the Golgi apparatus and initiates a cascade of downstream signals, including recruitment of serine/threonine protein kinase (TBK1), phosphorylation of interferon-regulated transcription factor (IRF3) and nuclear factor kappa B (NF- ⁇ B ), and produces type I interferon and pro-inflammatory cytokines, such as interleukin 6 (IL-6), tumor necrosis factor ⁇ (TNF ⁇ ), etc.
  • TNK1 serine/threonine protein kinase
  • IRF3 interferon-regulated transcription factor
  • NF- ⁇ B nuclear factor kappa B
  • type I interferon and pro-inflammatory cytokines such as interleukin 6 (IL-6), tumor necrosis factor ⁇ (TNF ⁇ ), etc.
  • STING plays an important pivotal role in the innate immune response triggered by viral, bacterial and parasitic infections, the body's tumor immune process and the cell autophagy process; it regulates protein synthesis and IFN expression plays a key role in multiple immune links of the body.
  • Many viruses can interact with signaling proteins on the cGAS-STING pathway, thereby stimulating the body to produce interferons in varying amounts from the normal immune response, causing virus proliferation or autoimmune diseases; tumor cell proliferation can cause antigens to be raised STING is activated in cells, thereby activating the adaptive immune process mediated by T cells and exerting anti-tumor effects.
  • STING agonists cyclic dinucleotide (CDN) derivatives and non-nucleotide small molecules
  • STING inhibitors covalent inhibitors and non-covalent inhibition. agents, in addition to some STING indirect regulators whose mechanisms have not been elucidated.
  • the invention provides a compound represented by the following formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof , which is selected from:
  • L 0 is selected from single bond, -NH-, -CH 2 -, -S(O) 1-2 -, -C(O)-;
  • L 1 is selected from -C-, -S-, S(O)-;
  • L 2 is selected from the group consisting of single bonds, -CH 2 -, -O-, -S(O) 0-2 - and -NH-, wherein -CH 2 - and -NH- are optionally substituted by R a 1 ⁇ 3 times;
  • Ring A is selected from C 3 to 10 saturated or partially unsaturated monocyclic or bicyclic cycloalkyl groups, 3 to 10 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic groups, C 6 to 10 aryl groups, and 5 to 10 membered aryl groups.
  • X is selected from CR a R b , NR a , O, S and S(O) 2 ;
  • Y 1 , Y 2 , Y 3 are independently selected from -CH 2 -, -NH-, -O-, -S-; the H in -CH 2 - and -NH- is as long as the chemical valency allows. optionally substituted 1 or 2 times by R 1 ;
  • Z is selected from -CH 2 -, -NH-; the hydrogen in -CH 2 - and -NH- can be optionally substituted 1 or 2 times by R 1 if the valency allows;
  • R 1 is selected from H, CN, OH, halogen, C 1 ⁇ 6 alkyl, 3 ⁇ 6 membered cycloalkyl, 3 ⁇ 6 membered heterocycloalkyl, phenyl, 5 ⁇ 6 membered heteroaryl, C 1 ⁇ 6 alkoxy, O-3 ⁇ 6-membered cycloalkyl, O-3 ⁇ 6-membered heterocycloalkyl, O-phenyl, O-5 ⁇ 6-membered heteroaryl, -C(O)-OC 1 ⁇ 6 alkyl; the C 1-6 alkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl can be optionally substituted by R a 1 ⁇ 3 times;
  • R 2 is selected from H, N(R b ) 2 , CN, C(O), S(O) 0-2 , halogen, C 1-3 alkyl, C 1-3 alkoxy; the C 1 ⁇ 3 alkyl and C 1 ⁇ 3 alkoxy groups may be optionally substituted 1 to 3 times by R a ;
  • R 3 is selected from H, C 1 to 6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, CH 2 -OC 1 to 6 alkyl, CH 2 -NH-C 1 to 6 alkyl base, CH 2 -3 to 6-membered cycloalkyl, CH 2 -3 to 6-membered heterocycloalkyl; the C 1-6 alkyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl
  • the group can be optionally substituted 1 to 3 times by R a ;
  • R 3 is optionally connected to the ring atom of ring A to form a C 3 to 7 saturated or partially unsaturated monocyclic cyclic hydrocarbon group, a 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclic group, phenyl, or 5- or 6-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted 1 to 3 times by R a ;
  • R 4 is selected from H, CN, C 1 to 6 alkyl, 3 to 7 membered cycloalkyl, 3 to 7 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, C 1 to 3 alkylene -3 to 7-membered cycloalkyl, C 1 to 3 alkylene-3 to 7-membered heterocycloalkyl, C 1 to 3 alkylene-phenyl, C 1 to 3 alkylene-5 to 6-membered hetero Aryl; the C 1-6 alkyl, 3-7-membered cycloalkyl, 3-7-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl can optionally be substituted 1 ⁇ by R b 3 times;
  • p is selected from 1, 2 and 3;
  • q is selected from 0, 1, 2 and 3;
  • R a is independently selected from H, F, Cl, and C 1 to 3 alkyl
  • R b is independently selected from H, F, Cl, Br, I, NH 2 , OH, C 1-3 alkyl, C 1-3 alkoxy and CN, the C 1 ⁇ 3 alkyl and C 1 ⁇ 3
  • the alkoxy group is optionally substituted 1 to 3 times by halogen.
  • the present invention provides compounds represented by the following formula I' or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, metabolites, isotopically labeled compounds or precursors thereof. Medicine, selected from:
  • R 5 is selected from H, CN, C 1 to 6 alkyl, C 1 to 6 alkoxy, 3 to 7 membered cycloalkyl, 3 to 7 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl , CH 2 -OC 1 ⁇ 6 alkyl, CH 2 -NH-C 1 ⁇ 6 alkyl, CH 2 -3 ⁇ 6 membered cycloalkyl, CH 2 -3 ⁇ 6 membered heterocycloalkyl, CH 2 -benzene base, CH 2 -5-6-membered heteroaryl; the C 1-6 alkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl Optionally substituted 1 to 3 times by R b ;
  • R 5 can further form a 5 to 7-membered ring together with the ring atoms of ring A, the 5 to 7-membered ring can be optionally substituted 1 to 3 times by R a , and the 5 to 7-membered ring can be carbon Ring, heterocycle, aromatic ring, heteroaromatic ring;
  • n 0, 1, 2 and 3.
  • L 0 is selected from single bond, -NH-, -CH 2 -, -C(O)-.
  • L 1 is selected from -C-, -S(O)-.
  • L 2 is selected from single bond, -CH 2 -, -O-, -S(O)-, -NH-; the -CH 2 - and -NH- can optionally be R a is substituted 1 to 3 times.
  • L 0 is selected from single bond, -NH-, -C(O)-.
  • the Y 1 , Y 2 and Y 3 are each independently selected from CH 2 , CH, NH, N, O and S, wherein the CH 2 , CH and NH are under the condition that the chemical valency allows. Optionally substituted 1 or 2 times by R1 .
  • the Z is selected from CH 2 , CH, NH and N, wherein the CH 2 , CH and NH are optionally substituted 1 or 2 times by R 1 if the chemical valency allows.
  • each of Y 1 , Y 2 , Y 3 and Z is CH; or one N among Y 1 , Y 2 , Y 3 and Z, and the rest are CH.
  • the structural unit Partially selected from:
  • the X is selected from NR a , O, S and S(O) 2 .
  • the R 1 is selected from H, N(R b ) 2 , CN, OH, halogen, C 1 to 3 alkyl, C 1 to 3 alkoxy, C 3 to 6 cycloalkyl , 3 to 6-membered heterocycloalkyl, phenyl, 5 or 6-membered heteroaryl, -OC 3 to 6 -membered heterocycloalkyl, -O-3 to 6-membered heterocycloalkyl, -O-phenyl, -O -5 or 6-membered heteroaryl, -C(O)-OC 1 ⁇ 3 alkyl and -C(O)-NR a R b , where The C 1 to 3 alkyl group, C 1 to 3 alkoxy group, C 3 to 6 cycloalkyl group, 3 to 6 membered heterocycloalkyl group, phenyl and 5 to 6 membered heteroaryl group are optionally substituted by R a 1 to 3 times; wherein R
  • the R 1 is selected from H, NH 2 , -NH(C 1 ⁇ 3 alkyl), -N(C 1 ⁇ 3 alkyl) 2 , CN, OH, F, Cl, Br , C 1 to 3 alkyl group, C 1 to 3 haloalkyl group, C 1 to 3 alkoxy group, 3 to 6 membered heterocycloalkyl group, 5 or 6 membered heteroaryl group, -OC 3 to 6 cycloalkyl group, - O-phenyl, -C(O)-OC 1 ⁇ 3 alkyl, -C(O)-NH 2 , -C(O)-NH(C 1 ⁇ 3 alkyl), -C(O)-N (C 1-3 alkyl) 2 , wherein the C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally substituted 1 to 3 by R a Second-rate.
  • the R 1 is selected from NH 2 , CN, OH, F, Cl, Br, CH 3 , CH 2 CH 3 , CH(CH 3 )CH 3 , CF 3 , methoxy, - C(O)OCH 3 , -C(O)-N(CH 3 ) 2 , cyclopropyl, Cyclopropyloxy, phenoxy.
  • R 1 is selected from H, F, Cl, Br, CH 3 , CH 2 CH 3 , CH(CH 3 )CH 3 , OCH 3 , OH, C(O)OCH 3 ,
  • the R 1 may be optionally substituted 1 to 3 times by R a .
  • the R 1 is selected from CN, OH, F, Cl, CF 3 and methoxy.
  • the structural unit Partially selected from:
  • the ring A is selected from the group consisting of C 3-6 saturated or partially unsaturated monocyclic cyclic hydrocarbon groups, C 8-10 saturated or partially unsaturated bicyclic cyclic hydrocarbon groups, 3-6 membered saturated or partially unsaturated bicyclic cyclic hydrocarbon groups.
  • Ring A is selected from the group consisting of pyridine, imidazole, pyridazine, oxazole, isoxazole, benzene ring, thiazole, pyrimidine, pyrazine, quinoline, isoquinoline, benzimidazole, imidazopyridine and Naphthyridine; wherein, the ring A may be optionally substituted 1 to 3 times by R2 .
  • ring A is selected from Wherein, the ring A may be optionally substituted 1 to 3 times by R2 .
  • ring A is selected from Wherein, the ring A may be optionally substituted 1 to 3 times by R2 .
  • the ring A is selected from the group consisting of C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered monocyclic heterocycloalkenyl, 8-10 membered bicyclic heterocycloalkenyl , phenyl, 5- or 6-membered heteroaryl with 1, 2, 3 or 4 nitrogen heteroatoms and 0 or 1 oxygen or sulfur heteroatom (such as pyridine, imidazole, pyridazine, oxazole, isoxazole, Thiazole, pyrimidine, pyrazine) and 8-10 membered bicyclic heteroaryl groups with 1, 2, 3, 4, 5 or 6 nitrogen heteroatoms and 0 or 1 oxygen or sulfur heteroatoms (such as quinoline, isoquinoline phosphine, benzimidazole, imidazopyridine and naphthyridine).
  • the ring A is selected from: Wherein: one of the bonds identified by the letters "a” and “b” as shown is connected to L 0 and the other is connected to L 1 ;
  • X a and X g are each independently selected from CH 2 , O, S and NH;
  • the ring A is selected from Wherein: one of the bonds identified by the letters "a” and “b” as shown is connected to L 0 and the other is connected to L 1 ;
  • X a and X g are each independently selected from CH 2 , O, S and NH;
  • the R 2 is selected from H, NH 2 , CN, F, Cl, methyl, ethyl, -CH 2 F, -CHF 2 , -CH 2 CH 2 F, -CH 2 - OH, methoxy.
  • the R 2 is selected from H, F, Cl, cyano, oxo, and CH 3 .
  • said L 1 is selected from C and S(O).
  • R 3 is selected from H, CH 3 , CH 2 CH 3 , CH(CH 3 )CH 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 3 , CH 2 OCH 3 , CH 2 NHCH 3 ,
  • the R 3 may be optionally substituted 1 to 3 times by R a .
  • the R 3 is selected from H, CH 3 , -CH 2 CH 3 , -CH(CH 3 )CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 OCH 3 , -CH 2 NHCH 3 .
  • the 5- to 6-membered ring when R 3 further forms a 5- to 6-membered ring together with the ring atoms of ring A, the 5- to 6-membered ring is selected from Wherein, the 5-6 membered ring may be optionally substituted 1-3 times by R a .
  • the L 2 is selected from a single bond, -CH 2 -, -O- and S(O), wherein the -CH 2 - is optionally substituted 1 to 3 times by R a .
  • R 4 is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 )CH 2 CH 3 , CH 2 CH 2 CH(CH 3 )CH 3 , CH(CH 3 )CH 3 , C(CH 3 ) 3 , CN, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, phenyl, methyl-cyclo Butyl, methyl-cyclohexyl, methyl-cycloheptyl, methyl-phenyl, piperidine, pyridine, pyrimidine, pyrazine, pyrazole; the R 4 can be optionally substituted 1 to 3 by R b Second-rate.
  • the R 4 is selected from C 1 to 4 haloalkyl, C 3 to 7 cycloalkyl, 3 to 7 membered heterocycloalkyl, -CH 2 -C 3 to 7 cycloalkyl, - CH 2 -phenyl, -CH 2 -5 to 6-membered heteroaryl and -CH 2 -C(O)-3 to 7-membered heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl optionally substituted 1 to 3 times by R b , wherein R b is independently selected from F, Cl, CN, and methyl or ethyl substituted 1 to 3 times by F or Cl.
  • the R 4 is selected from H, CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH ( CH 3 )CH 2 CH 3 , -CH 2 CH 2 CH(CH 3 )CH 3 , -CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CF 3 , -CH(CH 3 )CF 3 , -CH 2 CH 2 CH 2 CF 3 , -CH(CH 3 )CF 3 , -CH 2 CH 2 CH 2 CF 3 ,
  • the R 4 is selected from -CH 2 CF 3 and
  • R 5 is selected from H, CN, CH 3 , CH 2 CH 3 , CH(CH 3 )CH 3 , CH 2 CH 2 CH 3 , C(CH 3 ) 3 , CH 2 CH 2 CH 2 CH 3 , CN, Phenyl, CH 2 OCH 3 , CH 2 NHCH 3 , Piperidine, pyridine, pyrimidine; the R 3 can be optionally substituted 1 to 3 times by R a .
  • the 5-6 membered ring when R 5 is further combined with the ring atoms of ring A to form a 5-6 membered ring, the 5-6 membered ring is selected from Wherein, the 5-6 membered ring may be optionally substituted 1-3 times by R a .
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:
  • rings A, R 1 , R 2 , R 3 , R 4 , L 2 , q and m are as defined above.
  • the present invention provides compounds according to the present invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers thereof A conformer, solvate, metabolite, isotopically labeled compound or prodrug, wherein the compound is selected from:
  • the present invention provides a compound according to the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein the compound is selected from since:
  • the present invention provides a compound according to the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein the compound is selected from since:
  • stereoisomers of compounds of the invention are configurational isomers.
  • the configurational isomers are cis-trans isomers (cis-/trans-isomers), also known as geometric isomers (E-/Z-isomers).
  • the configurational isomers are enantiomers.
  • the configurational isomers are diastereoenantiomers.
  • the compounds of the invention are racemic.
  • Pharmaceutically acceptable salts of the present invention include acid addition salts and base salts.
  • a pharmaceutically acceptable salt of a compound of the invention is, for example, but not limited to, a formate salt.
  • the pharmaceutically acceptable salts of the present invention may exist in unsolvated and solvated forms.
  • compositions and methods of treatment are provided.
  • compositions which comprise compounds of the present invention (including compounds of Formula I-A and Formula I), or pharmaceutically acceptable salts, esters, stereoisomers, and tautomers thereof. isotopically labeled compounds or prodrugs, and pharmaceutically acceptable carriers.
  • the compounds of the present invention and their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, metabolites, isotopically labeled compounds or prodrugs can be used alone or in combination with at least one used in combination with other therapeutic agents.
  • the present invention also provides pharmaceutical compositions, which contain the compounds of the present invention as described above or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, metabolites, isotopically labeled compounds or prodrugs, and one or more other therapeutically active ingredients.
  • the application provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof, or
  • the pharmaceutical composition of the present invention is used as a medicine.
  • the application provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof, or
  • the pharmaceutical composition of the present invention is used as a STING inhibitor.
  • the application provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof, or Use of the pharmaceutical composition of the present invention in the preparation of drugs as STING inhibitors.
  • the STING inhibitor or drug is used to treat and/or prevent tumors and/or cancer.
  • the compound of the present invention is a STING inhibitor and has excellent STING receptor inhibitory activity. These STING inhibitor compounds are capable of treating and/or preventing STING-mediated diseases or conditions and related diseases or conditions.
  • the application provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof, or the Use of the pharmaceutical composition of the invention in the preparation of medicaments for the prevention and/or treatment of STING-mediated diseases or disorders and related diseases or disorders.
  • the application provides methods for preventing and/or treating STING-mediated diseases or conditions and related diseases or conditions in an individual, comprising administering to the individual a therapeutically effective amount of a compound of the invention or a pharmaceutical thereof.
  • a compound of the invention or a pharmaceutical thereof.
  • the STING-mediated disease or disorder is tumor and/or cancer.
  • the tumors and/or cancers include, but are not limited to, melanoma, thyroid cancer, head and neck cancer, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer , non-small cell lung cancer, small cell lung cancer, colorectal adenoma, sarcoma, intestinal stromal tumor, gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, small intestine cancer, renal cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma , mesothelioma, lymphoma, leukemia, myelodysplastic syndrome, multiple myeloma, plasmacytoma, neuroblastoma, retinoblastoma and germinoma.
  • the STING-mediated disease or disorder is a central nervous system, peripheral nervous system, and autonomic nervous system disease or disorder.
  • the central nervous system, peripheral nervous system, and autonomic nervous system diseases or conditions include, but are not limited to, epileptiform aphasia, encephalomyelitis, macular degeneration, Alpers disease, agenesis of the corpus callosum, Icardi syndrome syndrome, alternating hemiplegia, Alzheimer's disease, vascular dementia, amyotrophic lateral sclerosis, arachnoid cyst, arachnoiditis, Asperger's syndrome, ataxia teleectasias, attention deficit hyperactivity disorder disorders, autism, autonomic nervous system dysfunction, muscular atrophy, benign intracranial hypertension, Binswanger's disease, cerebral atrophy, cerebral gigantism, cerebral arteriosclerosis, chorea, chronic inflammatory demyelinating polyneuropathy, Congenital facial palsy, corticobasal degeneration,
  • the STING-mediated disease or disorder is a STING-related disorder, including but not limited to type I interferonopathy, Aicardi-Goutines syndrome (AGS), lupus, rheumatoid arthritis.
  • STING-related disorder including but not limited to type I interferonopathy, Aicardi-Goutines syndrome (AGS), lupus, rheumatoid arthritis.
  • the STING-mediated disease or disorder is an autoimmune disease, including but not limited to rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Crohn's disease (CD), inflammation Inflammatory bowel disease (IBD), ulcerative colitis (UC), autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, Adoptive cell therapy for the treatment of induced colitis, irritable bowel syndrome, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis.
  • autoimmune disease including but not limited to rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Crohn's disease (CD), inflammation Inflammatory bowel disease (IBD), ulcerative colitis (UC), autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, co
  • the STING-mediated diseases or disorders and related diseases or disorders include, but are not limited to Indicated in: melanoma, thyroid tumor, head and neck cancer, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, colorectal adenoma, sarcoma, Intestinal stromal tumor, gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, small bowel cancer, kidney cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, mesothelioma, lymphoma, leukemia, myelodysplastic syndrome, multiple Myeloma, plasmacytoma, neuroblastoma, retinoblastoma, and germ cell tumors.
  • the STING-mediated diseases or disorders and related diseases or disorders include, but are not limited to: encephalomyelitis, macular degeneration, Alzheimer's disease, vascular dementia, arachnoiditis, autonomic nervous function disorders, muscular atrophy, cerebral atrophy, chorea, dystonia, giant cell arteritis, hemifacial spasm, herpes zoster, Huntington's disease, myasthenia gravis, Parkinson's disease, locked-in syndrome, lumbar disc disease, migraine, Multiple sclerosis.
  • the STING-mediated diseases or disorders and related diseases or disorders include, but are not limited to: rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Crohn's disease, inflammatory bowel disease , ulcerative colitis, autoimmune colitis, irritable bowel syndrome, scleroderma, and psoriasis.
  • the STING-mediated diseases or disorders and related diseases or disorders include, but are not limited to: psoriasis, psoriatic arthritis, contact dermatitis, atopic dermatitis, vitiligo, rheumatoid joints inflammatory bowel disease, systemic lupus erythematosus, type I diabetes, multiple sclerosis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, autoimmune colitis, irritable bowel syndrome, scleroderma, asthma, renal insufficiency Glomerulonephritis, periodontal disease, cycloplanitis, transplant rejection, neurodegenerative diseases, obesity, hypertension, encephalomyelitis, macular degeneration, Alzheimer's disease, vascular dementia, arachnoiditis , autonomic dysfunction, muscular atrophy, cerebral atrophy, chorea, dystonia, giant cell arteritis, hemifacial spasm, herpes zoster, Huntington'
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient, or vehicle with which a therapeutic agent is administered and which, within the scope of sound medical judgment, is suitable for contact human and/or other animal tissue without undue toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • treating means reversing, alleviating, inhibiting the disorder or condition to which such term is applied, or the progression of one or more symptoms of such disorder or condition.
  • prevention means preventing the development of the disorder or condition to which such term is applied or one or more symptoms of such disorder or condition.
  • “Individual” as used herein includes humans or non-human animals.
  • Exemplary human subjects include human subjects (referred to as patients) suffering from a disease, such as those described herein, or normal subjects.
  • non-human animals include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (such as sheep, dogs , cats, cows, pigs, etc.).
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use with human and animal tissue. Exposure use without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, including acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , and salts of organic acids such as glucuronic acid.
  • Certain specific compounds of the present invention contain both basic and acidic functional
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the term “isomer” is intended to include stereoisomers, geometric isomers, cis-trans isomers, enantiomers, optical isomers, diastereomers and tautomers isomer.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers isomer, the (D)-isomer, the (L)-isomer, as well as their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to the present invention. within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” refers to the inability of the double bonds or single bonds of the carbon atoms in the ring to rotate freely.
  • diastereomer refers to stereoisomers whose molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules.
  • wedge-shaped solid line keys and wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center
  • using straight solid line keys and straight dotted keys Represent the relative configuration of the three-dimensional center with a wavy line
  • wedge-shaped solid line key or wedge-shaped dotted key or use tilde Represents a straight solid line key or straight dotted key
  • the terms "enriched in an isomer,”"enantiomericallyenriched,””enriched in an enantiomer,” or “enantiomerically enriched” refer to one of the isomers or enantiomers.
  • the content of the enantiomer is less than 100%, and the isomer or enantiomer contains The amount is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than Equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • isomeric excess or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.
  • Optically active (R)- and (S)-isomers as well as D- and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then the salt is formed by conventional methods known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally combined with chemical derivatization methods (e.g., generation of amino groups from amines). formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable of.
  • oxygen it means that two hydrogen atoms are replaced.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievability.
  • any variable e.g., R
  • its definition in each instance is independent.
  • said group may optionally be substituted by up to two R's, with independent options for R in each case.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • the substituent can be bonded to any atom in the ring, e.g., structural unit It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • the substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom thereof.
  • a pyridyl group as a substituent can be bonded through any one of the pyridine rings. The carbon atom is attached to the substituted group.
  • the direction of attachment is arbitrary.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • connection mode of the chemical bond is non-positioned and there are H atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will be reduced correspondingly with the number of connected chemical bonds and become the corresponding valence. group.
  • the chemical bond connecting the site to other groups can be a straight solid line bond straight dashed key or wavy lines express.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.
  • the number of atoms in a ring is usually defined as the number of ring members.
  • a "5- to 7-membered ring” refers to a “ring” with 5 to 7 atoms arranged around it.
  • halo means fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, and the like.
  • Preferred halogen atoms as substituents of the aryl group in the present invention are fluorine atoms and chlorine atoms.
  • S(O) 0-2 or “-S(O) 0-2 -” means S, S(O) and S(O) 2 .
  • S(O) 1- 2 or "-S(O) 1-2 -” means S(O) and S(O) 2 .
  • alkyl means a linear or branched monovalent saturated aliphatic hydrocarbon, which can be viewed as a group derived from an alkane losing one hydrogen atom.
  • C 1-6 alkyl is a straight-chain or branched alkyl group having 1 to 6 (eg, 1, 2, 3, 4, 5 or 6) carbons, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1- Dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl and 2-ethylbutyl.
  • C 1-4 alkyl refers to a straight-chain or branched alkyl group with 1 to 3 carbons, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl and tert-butyl.
  • C 1-3 alkyl is a straight or branched chain alkyl group having 1 to 3 carbons, including but not limited to methyl, ethyl, n-propyl and isopropyl.
  • alkylene refers to a linear or branched divalent group obtained by further losing 1 H from the “alkyl” described above.
  • the alkylene group has 1 to 12 carbon atoms, preferably 1, 2, 3, 4, 5, or 6 carbon atoms, such as methylene, ethylene, propylene, or butylene.
  • C 1-3 alkylene includes methylene, ethylene, propylene and isopropylene, with methylene being preferred.
  • haloalkyl refers to an alkyl group substituted by one or more halogens (including C 1 to 6 alkyl, C 1 to 4 alkyl, C 1 to 3 alkyl as described above) .
  • C 1-6 alkoxy means the group C 1-6 alkyl-O-, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy base, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, 1-methylpropoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy, 1,1-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy and 2-ethylbutoxy.
  • C 1-4 alkoxy means the group C 1-3 alkyl-O-, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy ,isobutoxy, sec-butoxy and tert-butoxy.
  • C 1-3 alkoxy means the group C 1-3 alkyl-O-, including but not limited to methoxy, ethoxy, n-propoxy and isopropoxy.
  • alkenyl means a linear or branched monovalent aliphatic hydrocarbon radical containing one or more double bonds.
  • an alkenyl group has 2 to 6 carbon atoms (“C 2-6 alkenyl”), such as 2 to 4 carbon atoms (“C 2-4 alkenyl”), or 2 to 3 carbon atoms atom (“C 2-3 alkenyl”).
  • the compound may exist in pure E (ent ought) form, pure Z (zusammen) form, or any mixture thereof.
  • alkynyl means a straight or branched monovalent aliphatic hydrocarbon group containing one or more triple bonds.
  • an alkynyl group has 2, 3, 4, 5, or 6 carbon atoms (“C 2-6 alkynyl”), such as 2 to 4 carbon atoms (“C 2-4 alkynyl”), or 2 to 3 carbon atoms ("C 2-3 alkynyl”), such as ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc.
  • the alkynyl group is optionally substituted with one or more (such as 1 to 3) substituents that may be the same or different.
  • cycloalkyl refers to having, for example, 3-10 (suitably 3-8, more suitably 3-7, 3-6 , 4-6, 5-6, 8-10 or 9-10) ring carbon atoms that are saturated (i.e., “cycloalkyl” and “cycloalkylene") or partially unsaturated (i.e., have One or more double bonds (ie, “cycloalkenyl” and “cycloalkenylene”) and/or triple bonds) monocyclic or polycyclic (eg, bicyclic) fused hydrocarbon rings.
  • cycloalkyl are monocyclic cycloalkanes having 3-7 or 3-6 ring carbon atoms (C 3-7 or C 3-6 ) base or cycloalkenyl ring.
  • cycloalkyl are bicyclic cycloalkyl groups having 8-10 or 9-10 ring carbon atoms (C 8-10 or C 9-10 ) Or cycloalkenyl ring.
  • Cycloalkyl is In some embodiments, cycloalkyl includes aryl-fused cycloalkyl as long as the entire ring system is non
  • cycloalkyl and cycloalkylene refer to saturated monocyclic or polycyclic (such as bicyclic) fused hydrocarbon rings (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cycloalkylene, etc. Pentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclo, e.g. ). Said cycloalkyl and cycloalkylene groups have from 3 to 10 carbon atoms, suitably from 3 to 8, for example from 3 to 7, 3 to 6, 4 to 6 or 5 to 6 carbon atoms.
  • cycloalkyl and “cycloalkylene” are monocyclic cycloalkyl rings having 3-7 or 3-6 ring carbon atoms (C 3-7 or C 3-6 ). In some embodiments, "cycloalkyl” and “cycloalkylene” are bicyclic cycloalkyl rings having 8-10 or 9-10 ring carbon atoms (C 8-10 or C 9-10 ).
  • cycloalkenyl and “cycloalkenylene” refer to a monocyclic or polycyclic (such as bicyclic) fused hydrocarbon ring (e.g., a monocyclic ring) having 1 or more double bonds within the ring. , such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or bicyclo) .
  • Said cycloalkenyl and "cycloalkenylene” groups have from 3 to 10 carbon atoms, suitably from 3 to 8, for example from 3 to 7, 3 to 6, 4 to 6 or 5 to 6.
  • "cycloalkenyl” and “cycloalkenylene” are monocyclic cycloalkenyl rings having 3-7 or 3-6 ring carbon atoms (C 3-7 or C 3-6 ).
  • "cycloalkenyl” and “cycloalkenylene” have 8-10 or 9-10 rings. Bicyclic cycloalkenyl ring of carbon atoms (C 8 to 10 or C 9 to 10 ).
  • heterocyclyl refers to saturated (i.e., “heterocycloalkyl” and “heterocycloalkylene") or partially unsaturated (e.g., “heterocycloalkyl” and “heterocycloalkylene”) , a monocyclic or bicyclic cyclic structure with one or more double bonds (i.e., “heterocycloalkenyl” and “heterocycloalkenylene”)) in the ring, which has 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and 1 or more (eg 1, 2, 3 or 4) heteroatom-containing groups selected from O, S and N.
  • saturated i.e., “heterocycloalkyl” and “heterocycloalkylene”
  • partially unsaturated e.g., “heterocycloalkyl” and “heterocycloalkylene”
  • a monocyclic or bicyclic cyclic structure with one or more double bonds i.e.,
  • One or more ring carbon atoms in the heterocyclyl group may be replaced by C(O).
  • the S atom in the heterocyclyl group can be replaced by S(O) or S(O) 2 .
  • the heterocyclyl group may be attached to the remainder of the molecule through any of the carbon atoms or a nitrogen atom, if present.
  • a 3-10 membered heterocyclyl group is a group having 3-10 (eg 3-8, 3-7, 3-6, 4-6 or 5-6) carbon atoms and heteroatoms in the ring .
  • heterocyclyl In some embodiments, "heterocyclyl”, “heterocyclyl” and “heterocyclylene” have 3-7, 3-6 or 5-6 ring members (3-7 membered, 3-6 membered or 5-6 membered) monocyclic heterocycloalkyl or heterocycloalkenyl ring. In some embodiments, “heterocyclyl”, “heterocycle” and “heterocyclylene” are bicyclic heterocycles having 8-10 or 9-10 ring members (8-10 membered or 9-10 membered) Alkyl or heterocycloalkenyl ring. Heterocyclyl groups may be monocyclic, fused or spirocyclic.
  • Heterocyclyl rings can be fused to aryl, heteroaryl or cycloalkyl rings, where the ring attached to the parent structure is heterocyclyl.
  • Heterocyclyl groups include nitrogen-containing heterocyclic groups, oxygen-containing bridged cyclic groups and sulfur-containing heterocyclic groups.
  • Examples that can be cited include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, dioxa Cyclopentenyl (dioxolinyl), pyrrolidinyl, pyrrolidonyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl , piperidonyl, hexahydropyrimidinyl, triazinealkyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, azacyclooctyl Alkyl, dihydropyrrolyl, dihydroimidazolyl, azacyclooc
  • nitrogen-containing heterocyclyl refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms in the ring and at least one (eg 1, 2, 3 or 4) nitrogen atom, which may also optionally contain one or more (eg 1, 2, 3 or 4) ring members selected from N, O and S.
  • One or more ring carbon atoms in the nitrogen-containing heterocyclyl group may be replaced by C(O).
  • the S atom in the nitrogen-containing heterocyclyl group can be replaced by S(O) or S(O) 2 .
  • the nitrogen-containing heterocyclyl group may be connected to the remainder of the molecule through any one of the carbon atoms or a nitrogen atom.
  • the nitrogen-containing heterocyclic group may be a saturated nitrogen-containing monocyclic ring.
  • a 3- to 10-membered nitrogen-containing heterocyclyl group is a nitrogen-containing heterocyclyl group as defined above having 3 to 10 ring members in the ring, which includes but is not limited to a 3-membered nitrogen-containing heterocyclic group (such as aziridine Aldyl), 4-membered nitrogen-containing heterocycle (such as azetidinyl), 5-membered nitrogen-containing heterocycle (such as pyrrolyl, pyrrolidinyl (pyrrolidine ring), pyrrolinyl, pyrrolidonyl, imidazolyl, Imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), 6-membered nitrogen-containing heterocycle (such as piperidinyl (piperidinyl ring), piperidylketo, morpholinyl, thiomorpholinyl, piperazinyl),
  • heterocyclyl encompasses fused structures whose point of attachment to other groups can be on any ring in the fused structure. Accordingly, heterocyclyl groups of the present invention also include, but are not limited to, heterocyclyl-heterocyclyl, heterocyclyl-cycloalkyl, mono-heterocyclyl-monoheterocyclyl, mono-heterocyclyl-monocycloalkyl, e.g.
  • heterocyclyl also includes heteroaryl-fused heterocyclyl or cycloalkyl, as well as aryl-fused heterocyclyl, so long as the entire ring system is nonaromatic.
  • the heterocyclyl group includes a 5-6 membered monocyclic heteroaryl fused C 5-6 monocyclic cycloalkyl group, a 5-6 membered monocyclic heteroaryl fused 5-6 membered monocyclic heterocyclic group.
  • Ring groups, and benzo-fused 5-6 membered monocyclic heterocyclyl groups such as pyrrolotetrahydropyridyl, pyrazolotetrahydropyridyl, imidazotetrahydropyridyl, indolinyl or indoline ketone group.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing pairs of adjacent carbon atoms) groups having a conjugated pi electron system, preferably 6 to 10 membered rings, such as phenyl and naphthyl, more preferably phenyl.
  • the aryl ring can be condensed on a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 3-8 membered cycloalkyl and benzo 3-8 membered heterocyclyl.
  • heteroaryl or “heteroaryl ring” refers to a heteroaromatic system having 5 to 14 ring atoms having 1 to 4 independently selected from N, O, and S Heterocyclic atoms.
  • One or more ring carbon atoms in a heteroaryl group may be replaced by C(O).
  • Heteroaryl groups may be benzo-fused.
  • the heteroaryl group is preferably 5 to 10 membered.
  • the heteroaryl group is a 5- or 6-membered heteroaryl group, such as, but not limited to, pyridyl, pyridonyl, pyrimidinyl, pyrimidinonyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl , oxazolyl, furyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl.
  • the heteroaryl group is an 8-10 membered or 9-10 bicyclic heteroaryl group, including 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered bicyclic ring systems.
  • Examples include, but are not limited to, benzothiazolyl, benzisothiazolyl, imidazopyridinyl, quinolyl, indolyl, pyrrolopyridazinyl, benzofuranyl, benzothienyl, indazolyl, benzene Oxazolyl, benzisoxazolyl, quinazolinyl, pyrrolopyridyl, pyrazopyrimidinyl, imidazopyridazinyl, pyrazopyridyl, triazolopyridyl, isoquinolinyl , tetrahydroisoquinolinyl, benzimidazolyl, cinnolinyl, indolyl, phthalazinyl, isoindolyl, pteridyl, purinyl, furazyl, benzofurazyl, quinoxalyl Phyllinyl, naphthyridinyl
  • 5-6 membered heteroaromatic ring and “5-6 membered heteroaryl” are used interchangeably.
  • the term “5-6 membered heteroaryl” means a monocyclic group with a conjugated ⁇ electron system composed of 5 to 6 ring atoms, of which 1, 2, 3 or 4 ring atoms are independently selected from O, S and N heteroatoms, the remainder being carbon atoms, wherein the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • a 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.
  • fused means that two or more cyclic structures share two adjacent atoms with each other.
  • fused ring refers to a 5 to 20 membered all-carbon polycyclic group in which each ring in the ring system shares an adjacent pair of carbon atoms with other rings in the system, one or Multiple rings can contain one or more double bonds, but no ring has a fully conjugated ⁇ electron system.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed ring alkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl groups.
  • the carbon atoms in the fused ring may optionally be replaced by heteroatoms of O, S, and N, which also include "fused heterocycles.”
  • fused heterocycle refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the ring system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may Contains one or more double bonds but not one
  • a ring has a fully conjugated pi electron system, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • esters means esters derived from compounds of each general formula herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the present invention). compound).
  • the compounds of the present invention may themselves be esters.
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.
  • the compounds of the invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise as structural elements of the crystal lattice of the compounds a polar solvent, in particular such as water, methanol or ethanol.
  • a polar solvent in particular such as water, methanol or ethanol.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • nitrogen-containing heterocycles are capable of forming N-oxides; those skilled in the art will recognize that nitrogen-containing heterocycles are capable of forming N-oxides. Nitrogen-containing heterocycle. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • N-oxides of heterocyclic and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl Hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyldioxirane are used to oxidize heterocyclic and tertiary amines.
  • MCPBA m-chloroperoxybenzoic acid
  • alkyl Hydroperoxides such as tert-butyl hydroperoxide
  • sodium perborate and dioxirane such as dimethyldioxirane
  • metabolites of the compounds of the invention ie substances formed in the body upon administration of the compounds of the invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic hydrolysis, etc. of the administered compound.
  • the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce metabolites thereof.
  • the invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity when administered into or onto the body. can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compound that are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by E.B. Roche, American Pharmaceutical Association).
  • prodrugs of the invention may be prepared, for example, by using certain moieties known to those skilled in the art as "pro-moiety” (e.g. described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985)) Prepared by substituting appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention containing protecting groups.
  • protecting groups In any process for preparing the compounds of the invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any relevant molecules, thereby forming chemically protected forms of the compounds of the invention. This can be achieved by conventional protecting groups, for example, in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. GMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference.
  • the protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
  • the term "about” means within ⁇ 10%, preferably ⁇ 5%, and more preferably ⁇ 2% of the stated value.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.
  • the compounds described in the present invention are named according to their chemical structural formulas. If the naming of a compound representing the same compound does not match the chemical structural formula, the chemical structural formula shall prevail.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal.
  • the light source is CuK ⁇ radiation.
  • the scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
  • the solvent used in the present invention is commercially available.
  • the compound of the present invention has strong inhibitory activity against STING and can be used to prevent and/or treat STING-mediated diseases or conditions.
  • the compounds of the invention have improved pharmacokinetic properties (e.g. improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (e.g. reduced cardiotoxicity) ) and/or fewer side effects) and other more excellent properties.
  • reaction solution is diluted with water (20 mL). Release, extract with ethyl acetate (20mL x 2), combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, and concentrate to obtain C009-9e (800mg, yield: 33.2%).
  • THP1 cell line (from ATCC, lot number TIB-202)
  • T75 culture bottle (Corning, 430641); 2. 96-well plate (Corning, 3599); 3. Pipette (5ml, 10ml, 25ml, 50ml) (Thermo Scientific, 159625159633); 4. Pipette tip (10 ⁇ l ,200 ⁇ l,1ml) (Axygen, T-300-R-S/T-200-Y-R-S/T-1000-B-R-S).
  • Biosafety operation cabinet (Thermo Scientific, 1300 Series A2); 2. Centrifuge (Eppendorf, 5702); 3. Carbon dioxide incubator (Thermo Scientific, 371); 4. Cell counter (Invitrogen, C10281); 5. Transfer Liquid container controller (BIOHIT, Easypet); 6. Inverted microscope (Olympus, CKX41); 7. Pipette (BIOHIT, Proline Plus); 8. Vortex mixer (IKA, MS3 basic); 9. EnVision microplate reader (Perkin Elmer, 2014).
  • the compound of the present invention has strong inhibitory activity against STING.
  • test compound and reference compound 500 ⁇ M spike solution: Add 5 ⁇ L of 10 mM stock solution to 95 ⁇ L ACN, 1.5 ⁇ M spike solution in microsomes (0.75 mg/mL): Add 1.5 ⁇ L of 500 ⁇ M spike solution and 18.75 ⁇ L of 20 Mg/mL liver microsomes was added to 479.75 ⁇ L of K/Mg buffer;
  • c.3 ⁇ NADPH stock solution (6mM, 5mg/mL) is made by dissolving NADPH in buffer;
  • the compounds of the present invention exhibit good liver microsomal stability.
  • mice Male C57BL/6N mice, weighing 18-22g, fasted overnight before the test.
  • Blood was collected from the orbital venous plexus at 15 minutes, 30 minutes and 1, 2, 4, 6, 8 and 24 hours after administration.
  • About 0.08 mL at each time point was placed in 1.5 mL of EDTA-2K anticoagulant.
  • centrifuge tubes blood samples were centrifuged (3200g, 10 minutes, 4°C) within 2 hours to obtain plasma samples.
  • Plasma samples were frozen and stored in an ultra-low temperature freezer at -70°C to -80°C before processing. Before sample processing, take the plasma samples out of the refrigerator. After thawing at room temperature, add 20 ⁇ L of plasma samples to a 96-well plate, then add 120 ⁇ L of acetonitrile-precipitated protein containing internal standard, vortex to mix, and centrifuge at 4°C and 4950g for 15 minutes. The supernatant was mixed with equal volumes of 0.1% formic acid water for LC-MS/MS analysis.
  • the compounds of the present invention exhibit good pharmacokinetic properties.

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Abstract

一类具有STING抑制作用的化合物或其药学上可接受的盐，及其在制备STING异常表达相关疾病的药物中的应用。具体公开了式I和式I'所示化合物或其药学上可接受的盐。

Description

具有STING抑制作用的酰胺类化合物及其药物组合物和用途 技术领域
本申请涉及具有干扰素基因刺激因子(STING)抑制作用的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，包含其的药物组合物，以及它们在用于预防和/或治疗与STING异常表达相关的疾病的用途。
背景技术
干扰素基因刺激因子(stimulator of interferon genes，STING)，也被称为跨膜蛋白173、干扰素调节因子3的调控激活因子以及内质网干扰素刺激蛋白等，主要表达于人的巨噬细胞、T淋巴细胞、树突状细胞、内皮细胞、上皮细胞及成纤维细胞等的粗面内质网、线粒体及微粒体的外膜上。其可特异性识别并结合细菌的第二信使(cyclic di-AMP,cyclic di-GMP和cyclic 3',3'-cGAMP)和由环状GMP-AMP合成酶(cGAS)合成的天然环二核苷酸(CDN)配体。cGAS参与检测自身或外来DNA，如病原体的DNA、肿瘤来源的DNA和泄露的线粒体或核DNA。一旦识别dsDNA,cGAS将GTP和ATP催化合成为2',3'-cGAMP，从而导致STING的激活。结合配体的STING转运至高尔基体，并启动下游信号的级联反应，包括招募丝氨酸/苏氨酸蛋白激酶(TBK1)，磷酸化干扰素调节转录因子(IRF3)和核因子κB(NF-κB),并产生I型干扰素和促炎性细胞因子，如白介素6(IL-6)，肿瘤坏死因子α(TNFα)等。
STING在病毒、细菌及寄生虫感染触发的天然免疫反应、机体的肿瘤免疫过程以及细胞自噬过程中发挥重要的枢纽作用；通过自身的磷酸化、泛素化和二聚化修饰调节蛋白质合成和IFN表达，在机体的多个免疫环节中发挥关键作用。许多病毒可以通过与cGAS-STING通路上的信号蛋白相互作用，进而刺激机体产生与正常的免疫应答反应数量不等的干扰素，引起病毒的增殖或自身免疫性疾病；肿瘤细胞增殖能使抗原提呈细胞中的STING活化，从而激活T细胞介导的适应性免疫过程，发挥抗肿瘤作用。
现有技术中，主要有两大类STING激动剂：环二核苷酸类(CDN)衍生物和非核苷酸类小分子，以及两大类STING抑制剂：共价抑制剂和非共价抑制剂，此外还包含了一些机理未阐明的STING间接调控剂。
发明内容
化合物
在一个方面，本发明提供了下式I所示化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，其选自：
其中，
表示单键或双键；
L0选自单键、-NH-、-CH2-、-S(O)1-2-、-C(O)-；
L1选自-C-、-S-、S(O)-；
L2选自单键、-CH2-、-O-、-S(O)0-2-和-NH-，其中所述-CH2-和-NH-任选地被Ra取代1～3次；
环A选自C3～10饱和或部分不饱和的单环或双环环烃基、3～10元饱和或部分不饱和的单环或双环杂环基、C6-10芳基和5～10元单环或双环杂芳基；
X选自CRaRb、NRa、O、S和S(O)2；
Y1、Y2、Y3独立地任选自-CH2-、-NH-、-O-、-S-；所述的-CH2-和-NH-中的H在化合价允许的条件下可任选地被R1取代1或2次；
Z选自-CH2-、-NH-；所述的-CH2-和-NH-中的氢在化合价允许的条件下可任选地被R1取代1或2次；
R1选自H、CN、OH、卤素、C1～6烷基、3～6元环烷基、3～6元杂环烷基、苯基、5～6元杂芳基、C1～6烷氧基、O-3～6元环烷基、O-3～6元杂环烷基、O-苯基、O-5～6元杂芳基、-C(O)-O-C1～6烷基；所述的C1～6烷基、3～6元环烷基、3～6元杂环烷基、苯基、5～6元杂芳基可任选地被Ra取代1～3次；
R2选自H、N(Rb)2、CN、C(O)、S(O)0-2、卤素、C1～3烷基、C1～3烷氧基；所述的C1～3烷基和C1～3烷氧基可任选地被Ra取代1～3次；
R3选自H、C1～6烷基、3～6元环烷基、3～6元杂环烷基、CH2-O-C1～6烷基、CH2-NH-C1～6烷基、CH2-3～6元环烷基，CH2-3～6元杂环烷基；所述的C1～6烷基、3～6元环烷基、3～6元杂环烷基可任选地被Ra取代1～3次；
其中R3任选地与环A的环原子连接以形成C3～7饱和或部分不饱和的单环环烃基、3～7元饱和或部分不饱和的单环杂环基、苯基、或者5或6元杂芳基，其中所述环烃基、杂环基、芳基和杂芳基任选地被Ra取代1～3次；
R4选自H、CN、C1～6烷基、3～7元环烷基、3～7元杂环烷基、苯基、5～6元杂芳基、C1～3亚烷基-3～7元环烷基、C1～3亚烷基-3～7元杂环烷基、C1～3亚烷基-苯基、C1～3亚烷基-5～6元杂芳基；所述的C1～6烷基、3～7元环烷基、3～7元杂环烷基、苯基、5～6元杂芳基可任选地被Rb取代1～3次；
p选自1、2和3；
q选自0、1、2和3；
Ra独立地选自H、F、Cl、和C1～3烷基；
Rb独立地选自H、F、Cl、Br、I、NH2、OH、C1-3烷基、C1-3烷氧基和CN，所述C1～3烷基和C1～3烷氧基任选被卤素取代1～3次。
在一个方面，本发明提供了下式I’所示化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，其选自：
其中，
环A、X、Y1、Y2、Y3、Z、R1、R2、p、q、Ra、Rb定义同前；
R5选自H、CN、C1～6烷基、C1～6烷氧基、3～7元环烷基、3～7元杂环烷基、苯基、5～6元杂芳基、CH2-O-C1～6烷基、CH2-NH-C1～6烷基、CH2-3～6元环烷基、CH2-3～6元杂环烷基、CH2-苯基、CH2-5～6元杂芳基；所述的C1～6烷基、3～6元环烷基、3～6元杂环烷基、苯基、5～6元杂芳基可任选地被Rb取代1～3次；
其中R5可进一步与环A的环原子一起形成5～7元环，所述的5～7元可任选地被Ra取代1～3次，所述的5～7元环可为碳环、杂环、芳环、杂芳环；
m选自0、1、2和3。
本发明的一些方案中，L0选自单键、-NH-、-CH2-、-C(O)-。
本发明的一些方案中，L1选自-C-、-S(O)-。
本发明的一些方案中，L2选自单键、-CH2-、-O-、-S(O)-、-NH-；所述的-CH2-和-NH-可任选地被Ra取代1～3次。
本发明的一些方案中，L0选自单键、-NH-、-C(O)-。
本发明的一些方案中，所述Y1、Y2和Y3各自独立地选自CH2、CH、NH、N、O和S，其中所述CH2、CH和NH在化合价允许的条件下任选地被R1取代1或2次。
本发明的一些方案中，所述Z选自CH2、CH、NH和N，其中所述CH2、CH和NH在化合价允许的条件下任选地被R1取代1或2次。
本发明的一些方案中，其中Y1、Y2、Y3和Z各自为CH；或者Y1、Y2、Y3和Z中的一个N，其余均为CH。
本发明的一些方案中，所述结构单元部分选自：
本发明的一些方案中，所述X选自NRa、O、S和S(O)2。
本发明的一些方案中，所述R1选自H、N(Rb)2、CN、OH、卤素、C1～3烷基、C1～3烷氧基、C3～6环烷基、3～6元杂环烷基、苯基、5或6元杂芳基、-O-C3～6环烷基、-O-3～6元杂环烷基、-O-苯基、-O-5或6元杂芳基、-C(O)-O-C1～3烷基和-C(O)-NRaRb，其中所 述C1～3烷基、C1～3烷氧基、C3～6环烷基、3～6元杂环烷基、苯基和5～6元杂芳基任选地被Ra取代1～3次；其中Ra和Rb独立地选自H和C1～6烷基，其中所述C1～6烷基任选被卤素取代1～3次。
本发明的一些方案中，所述R1选自H、NH2、-NH(C1～3烷基)、-N(C1～3烷基)2、CN、OH、F、Cl、Br、C1～3烷基、C1～3卤代烷基、C1～3烷氧基、3～6元杂环烷基、5或6元杂芳基、-O-C3～6环烷基、-O-苯基、-C(O)-O-C1～3烷基、-C(O)-NH2、-C(O)-NH(C1～3烷基)、-C(O)-N(C1～3烷基)2，其中所述C3～6环烷基、3～6元杂环烷基、苯基和5～6元杂芳基任选地被Ra取代1～3次。
本发明的一些方案中，所述R1选自NH2、CN、OH、F、Cl、Br、CH3、CH2CH3、CH(CH3)CH3、CF3、甲氧基、-C(O)OCH3、-C(O)-N(CH3)2、环丙基、环丙基氧基、苯氧基。
本发明的一些方案中，R1选自H、F、Cl、Br、CH3、CH2CH3、CH(CH3)CH3、OCH3、OH、C(O)OCH3、所述R1可任选地被Ra取代1～3次。
本发明的一些方案中，所述R1选自CN、OH、F、Cl、CF3、甲氧基。
本发明的一些方案中，所述结构单元部分选自：
本发明的一些方案中，所述环A选自C3～6饱和或部分不饱和的单环环烃基、C8～10饱和或部分不饱和的双环环烃基、3～6元饱和或部分不饱和的单环杂环基、8～10元饱和或部分不饱和的双环杂环基、C6-10芳基、5或6元杂芳基和8～10元双环杂芳基。
本发明的一些方案中，环A选自吡啶、咪唑、哒嗪、恶唑、异恶唑、苯环、噻唑、嘧啶、吡嗪、喹啉、异喹啉、苯并咪唑、咪唑并吡啶和萘啶；其中，所述环A可任选地被R2取代1～3次。
本发明的一些方案中，环A选自 其中，所述环A可任选地被R2取代1～3次。
本发明的一些方案中，环A选自 其中，所述环A可任选地被R2取代1～3次。
本发明的一些方案中，所述环A选自C3～6环烷基、3～6元杂环烷基、3～6元单环杂环烯基、8～10元双环杂环烯基、苯基、具有1、2、3或4个氮杂原子和0或1个氧或硫杂原子的5或6元杂芳基(例如吡啶、咪唑、哒嗪、噁唑、异噁唑、噻唑、嘧啶、吡嗪)和具有1、2、3、4、5或6个氮杂原子和0或1个氧或硫杂原子的8～10元双环杂芳基(例如喹啉、异喹啉、苯并咪唑、咪唑并吡啶和萘啶)。
本发明的一些方案中，所述环A选自： 其中：以所示的字母“a”和“b”标识的键之一与L0连接，另一个与L1连接；Xa和Xg各自独立地选自CH2、O、S和NH；Xb、Xc、Xd、Xe、Xf和Xh分别独立地选自CH和N；并且，Xa、Xb、Xc和Xd中至少一个是可以取代的。
本发明的一些方案中，所述环A选自 其中：以所示的字母“a”和“b”标识的键之一与L0连接，另一个与L1连接；Xa和Xg各自独立地选自CH2、O、S和NH；Xb、Xc、Xd、Xe、Xf和Xh分别独立地选自CH和N；并且，Xa、Xb、Xc和Xd中至少一个是可以取代的。
本发明的一些方案中，所述R2选自H、NH2、CN、F、Cl、甲基、乙基、-CH2F、-CHF2、-CH2CH2F、-CH2-OH、甲氧基。
本发明的一些方案中，所述R2选自H、F、Cl、氰基、氧代、CH3。
本发明的一些方案中，所述L1选自C和S(O)。
本发明的一些方案中，R3选自H、CH3、CH2CH3、CH(CH3)CH3、CH2CH2CH3、CH2CH2CH2CH3、CH2OCH3、CH2NHCH3、所述R3可任选地被Ra取代1～3次。
本发明的一些方案中，所述R3选自H、CH3、-CH2CH3、-CH(CH3)CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH2OCH3、-CH2NHCH3。
本发明的一些方案中，当R3进一步与环A的环原子一起形成5～6元环，所述的5～6元环选自其中，所述的5～6元环可任选地被Ra取代1～3次。
本发明的一些方案中，所述L2选自单键、-CH2-、-O-和S(O)，其中所述-CH2-任选地被Ra取代1～3次。
本发明的一些方案中，R4选自H、CH3、CH2CH3、CH2CH2CH3、CH2CH2CH2CH3、CH2CH(CH3)CH2CH3、CH2CH2CH(CH3)CH3、CH(CH3)CH3、C(CH3)3、CN、环丙基、环丁基、环己基、环庚基、苯基、甲基-环丁基、甲基-环己基、甲基-环庚基、甲基-苯基、哌啶、吡啶、嘧啶、吡嗪、吡唑；所述R4可任选地被Rb取代1～3次。
本发明的一些方案中，所述R4选自C1～4卤代烷基、C3～7环烷基、3～7元杂环烷基、-CH2-C3～7环烷基、-CH2-苯基、-CH2-5～6元杂芳基和-CH2-C(O)-3～7元杂环烷基，其中所述环烷基、杂环烷基、苯基和杂芳基任选地被Rb取代1～3次，其中Rb独立地选自F、Cl、CN和被F或Cl取代1～3次的甲基或乙基。
本发明的一些方案中，所述R4选自H、CN、-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH2CH(CH3)CH2CH3、-CH2CH2CH(CH3)CH3、-CH(CH3)CH3、-C(CH3)3、-CH2CHF2、-CH2CF3、-CH2CH2CF3、-CH(CH3)CF3、-CH2CH2CH2CF3、
本发明的一些方案中，所述R4选自-CH2CF3和
本发明的一些方案中，R5选自H、CN、CH3、CH2CH3、CH(CH3)CH3、CH2CH2CH3、C(CH3)3、CH2CH2CH2CH3、CN、苯基、CH2OCH3、CH2NHCH3、 哌啶、吡啶、嘧啶；所述R3可任选地被Ra取代1～3次。
本发明的一些方案中，当R5进一步与环A的环原子一起形成5～6元环，所述的5～6元环选自其中，所述的5～6元环可任选地被Ra取代1～3次。
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自：
其中环A、R1、R2、R3、R4、L2、q、m同前定义。
本发明还有一些方案是由上述各变量任意组合而来。
本发明提供根据本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异 构体、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物选自：
本发明提供根据本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物选自：
本发明提供根据本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物选自：
在一些实施方案中，本发明化合物的立体异构体是构型异构体。在一些实施方案中，所述构型异构体是顺反异构体(cis-/trans-异构体)，也称作几何异构体(E-/Z-异构体)。在一些实施方案中，所述构型异构体是对映异构体。在一些实施方案中，所述构型异构体是非对映对映异构体。在一些实施方案中，本发明的化合物是外消旋的。
本发明的药学上可接受的盐包括酸加成盐及碱盐。在一些实施方案中，本发明化合物的药学上可接受的盐是例如、但不限于甲酸盐。
本发明的药学上可接受的盐可呈非溶剂化及溶剂化形式存在。
药物组合物和治疗方法
在另一方面，本申请还提供药物组合物，其包含本发明的化合物(包括式I-A以及式I的化合物)、或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，以及药学上可接受的载体。
本发明的化合物及其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药在治疗中可以单独使用或与至少一种其他治疗剂组合使用。
本发明还提供药物组合物，其含有如上文所述的本发明化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，以及一种或两种以上其他治疗活性成分。
在另一个方面，本申请提供本发明的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物，其用作药物。
在另一个方面，本申请提供本发明的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物，其用作STING抑制剂。
在另一个方面，本申请提供本发明的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物在制备作为STING抑制剂的药物中的用途。
在一些实施方案中，所述STING抑制剂或药物是用于治疗和/或预防肿瘤和/或癌症。
本发明的化合物是STING抑制剂，具有优秀的STING受体抑制活性。这些STING抑制剂化合物能够治疗和/或预防STING介导的疾病或病症及相关疾病或病症。
在一个方面，本申请提供本发明的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物在制备用于预防和/或治疗STING介导的疾病或病症及相关疾病或病症的药物中的用途。
在另一个方面，本申请提供用于预防和/或治疗个体的STING介导的疾病或病症及相关疾病或病症的方法，其包括向所述个体施用治疗有效量的本发明的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物。
在一些实施方案中，所述STING介导的疾病或病症是肿瘤和/或癌症。在一些实施方案案中，所述的肿瘤和/或癌症包括但不限于黑色素瘤、甲状腺瘤、头颈癌、宫颈癌、乳腺癌、卵巢癌、前列腺癌、睾丸癌、尿路上皮癌、膀胱癌、非小细胞肺癌、小细胞肺癌、结直肠腺瘤、肉瘤、肠道间质瘤、胃癌、食道癌、结肠直肠癌、胰腺癌、小肠癌、肾癌、肝癌、肝细胞癌、胆管细胞癌、间皮瘤、淋巴瘤、白血病、骨髓异常增生综合症、多发性骨髓瘤、浆细胞瘤、成神经细胞瘤、成视网膜细胞瘤和生殖细胞瘤。
在一些实施方案中，所述STING介导的疾病或病症是中枢神经系统、周围神经系统和自主神经系统疾病或病症。在一些实施方案中，所述中枢神经系统、周围神经系统和自主神经系统疾病或病症包括但不限于癫痫样失语、脑脊髓炎、黄斑变性、阿尔珀斯病、胼胝体发育不全、艾卡迪综合征、交替性偏瘫、阿尔茨海默氏病、血管性痴呆、肌萎缩侧索硬化症、蛛网膜囊肿、蛛网膜炎、阿斯伯格综合征、共济失调远程扩张症、注意缺陷多动障碍、自闭症、自主神经功能障碍、肌萎缩、良性颅内高压、宾斯旺格病、脑萎缩、脑巨人症、脑动脉硬化、舞蹈病、慢性炎症性脱髓鞘性多发性神经病、先天性面瘫、皮质基底节变性、颅动脉炎、颅缝早闭、克雅氏病、累积性创伤障碍、库欣综合征、巨细胞包涵体病、糖尿病性神经病变、弥漫性硬化症、肌张力障碍、巨细胞动脉炎、巨细胞包涵体病、面肌痉挛、遗传性痉挛性截瘫、多发性神经炎性遗传病、带状疱疹、亨廷顿病、重症肌无力、髓细胞性弥漫性硬化症、帕金森病、闭锁综合征、腰椎间盘疾病、偏头痛、线粒体肌病、莫比乌斯综合征、单体肌萎缩、运动神经元病、多梗死性痴呆、多发性硬化症、肌阵挛、神经肌强直、面肌萎缩、多灶性白质脑病、硬化性脊髓灰质炎、带状疱疹、脊髓损伤。
在一些实施方案中，所述STING介导的疾病或病症是STING相关病症，包括但不限于I型干扰素病、Aicardi-Goutières综合征(AGS)、狼疮、类风湿性关节炎。
在一些实施方案中，所述STING介导的疾病或病症是自身免疫性疾病，包括但不限于类风湿性关节炎、系统性红斑狼疮、多发性硬化症、克罗恩病(CD)、炎症性肠病(IBD)、溃疡性结肠炎(UC)、自身免疫性结肠炎、医源性自身免疫性结肠炎、溃疡性结肠炎、由一种或多种化学治疗剂诱导的结肠炎、由过继细胞疗法治疗诱导的结肠炎、肠易激综合征、硬皮病、银屑病、皮肤T细胞淋巴瘤、葡萄膜炎、粘膜炎。
在一些实施方案中，所述STING介导的疾病或病症及相关疾病或病症包括但不限 于：黑色素瘤、甲状腺瘤、头颈癌、宫颈癌、乳腺癌、卵巢癌、前列腺癌、睾丸癌、尿路上皮癌、膀胱癌、非小细胞肺癌、小细胞肺癌、结直肠腺瘤、肉瘤、肠道间质瘤、胃癌、食道癌、结肠直肠癌、胰腺癌、小肠癌、肾癌、肝癌、肝细胞癌、胆管细胞癌、间皮瘤、淋巴瘤、白血病、骨髓异常增生综合症、多发性骨髓瘤、浆细胞瘤、成神经细胞瘤、成视网膜细胞瘤和生殖细胞瘤。
在一些实施方案中，所述STING介导的疾病或病症及相关疾病或病症包括但不限于：脑脊髓炎、黄斑变性、阿尔茨海默氏病、血管性痴呆、蛛网膜炎、自主神经功能障碍、肌萎缩、脑萎缩、舞蹈病、肌张力障碍、巨细胞动脉炎、面肌痉挛、带状疱疹、亨廷顿病、重症肌无力、帕金森病、闭锁综合征、腰椎间盘疾病、偏头痛、多发性硬化症。
在一些实施方案中，所述STING介导的疾病或病症及相关疾病或病症包括但不限于：类风湿性关节炎、系统性红斑狼疮、多发性硬化症、克罗恩病、炎症性肠病、溃疡性结肠炎、自身免疫性结肠炎、肠易激综合征、硬皮病、银屑病。
在一些实施方案中，所述STING介导的疾病或病症及相关疾病或病症包括但不限于：银屑病、银屑病性关节炎、接触性皮炎、特异性皮炎、白癜风、类风湿性关节炎、系统性红斑狼疮、I型糖尿病、多发性硬化、克罗恩病、炎症性肠病、溃疡性结肠炎、自身免疫性结肠炎、肠易激综合征、硬皮病、哮喘、肾小球肾炎、牙周疾病、睫状体扁平部炎、移植排异、神经退行性疾病、肥胖症、高血压、脑脊髓炎、黄斑变性、阿尔茨海默氏病、血管性痴呆、蛛网膜炎、自主神经功能障碍、肌萎缩、脑萎缩、舞蹈病、肌张力障碍、巨细胞动脉炎、面肌痉挛、带状疱疹、亨廷顿病、重症肌无力、帕金森病、闭锁综合征、腰椎间盘疾病、偏头痛、多发性硬化症。
如本文中所使用的，“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
除非另外说明，否则如本文中所使用，术语“治疗”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展。术语“预防”意指防止形成这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
定义和说明
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤(即，这些术语也涵盖术语“基本上由……组成”和“由……组成”)。
如本文中所使用，术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
除非另有说明，术语“异构体”意在包括立体异构体、几何异构体、顺反异构体、对映异构体、旋光异构体、非对映异构体和互变异构体。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型，用直形实线键和直形虚线键表示立体中心的相对构型，用波浪线表示楔形实线键或楔形虚线键或用波浪线表示直形实线键或直形虚线键
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含 量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D-和L-异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必须出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR)0-，表示该连接基团为单键。
当一个取代基数量为0时，表示该取代基是不存在的，比如-A-(R)0表示该结构实际上是-A。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基的键可以交叉连接到一个环上的两个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元表示其取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的。
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键直形虚线键或波浪线表示。
如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。
如本文中所使用，术语“卤代”、“卤素”和“卤素原子”意指氟原子、氯原子、溴原子、碘原子等。优选作为本发明的芳基的取代基的卤素原子是氟原子和氯原子。
如本文中所使用，术语“S(O)0-2或“-S(O)0-2-”意指S、S(O)和S(O)2。术语“S(O)1-2或“-S(O)1-2-”意指S(O)和S(O)2。
如本文中所使用，术语“烷基”意指直链或支链的单价饱和脂肪族烃，其可以看作由烷烃失去1个氢原子而得到的基团。术语“C1～6烷基”是具有1至6个(例如1、2、3、4、5或6个)碳的直链或支链烷基，包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、1-甲基丙基、正戊基、异戊基、2-甲基丁基、1,1-二甲基丙基、1-乙基丙基、正己基、4-甲基戊基和2-乙基丁基。术语“C1～4烷基”是具有1至3个碳的直链或支链烷基，包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。术语“C1～3烷基”是具有1至3个碳的直链或支链烷基，包括但不限于甲基、乙基、正丙基和异丙基。
如本文中所使用，术语“亚烷基”表示由上文所述的“烷基”进一步失去1个H而得到的直链或支链的二价基团。在一些实施方案中，亚烷基具有1至12个碳原子，优选具有1、2、3、4、5或6个碳原子，例如亚甲基、亚乙基、亚丙基或亚丁基。术语“C1～3亚烷基”包括亚甲基、亚乙基、亚丙基和亚异丙基，优选亚甲基。
如本文中所使用，术语“卤代烷基”是指被一个或多个卤素取代的烷基(包括上文所述的C1～6烷基、C1～4烷基C1～3烷基)。
如本文中所使用，术语“C1～6烷氧基”意指基团C1-6烷基-O-，包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、1-甲基丙氧基、正戊基氧基、异戊基氧基、2-甲基丁氧基、1,1-二甲基丙氧基、1-乙基丙氧基、正己基氧基、4-甲基戊基氧基和2-乙基丁氧基。术语“C1～4烷氧基”意指基团C1-3烷基-O-，包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基 和叔丁氧基。术语“C1～3烷氧基”意指基团C1-3烷基-O-，包括但不限于甲氧基、乙氧基、正丙氧基和异丙氧基。
如本文中所使用，术语“烯基”意指直链或支链的单价脂肪族烃基，其包含一个或多个双键。在一些实施方案中，烯基具有2-6个碳原子(“C2-6烯基”)，例如2至4个碳原子(“C2-4烯基”)、或2至3个碳原子(“C2-3烯基”)。所述烯基的实例包括例如-CH＝CH2、-CH2CH＝CH2、-C(CH3)＝CH2、-CH2-CH＝CH-CH3、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。当本发明的化合物含有烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。
如本文中所使用，术语“炔基”意指直链或支链的单价脂肪族烃基，其包含一个或多个三键。在一些实施方案中，炔基具有2、3、4、5或6个碳原子(“C2-6炔基”)，例如2至4个碳原子(“C2-4炔基”)、或2至3个碳原子(“C2-3炔基”)，例如乙炔基、2-丙炔基、2-丁炔基、1,3-丁二炔基等。所述炔基任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。
如本文中所使用，术语“环烃基”、“烃环”和“亚环烃基”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-7、3-6、4-6、5-6、8-10或9-10个)环碳原子的饱和(即，“环烷基”和“亚环烷基”)或部分不饱和的(即在环内具有一个或多个双键(即，“环烯基”和“亚环烯基”)和/或三键)单环或多环(例如双环)稠合烃环。在一些实施方案中，“环烃基”、“烃环”和“亚环烃基”是具有3-7或3-6个环碳原子(C3～7或C3～6)的单环环烷基或环烯基环。在一些实施方案中，“环烃基”、“烃环”和“亚环烃基”是具有8-10或9-10个环碳原子(C8～10或C9～10)的双环环烷基或环烯基环。实例包括但不限于(亚)环丙基(环)、(亚)环丁基(环)、(亚)环戊基(环)、(亚)环己基(环)、(亚)环庚基(环)、(亚)环辛基(环)、(亚)环壬基(环)、(亚)环丁烯基(环)、(亚)环戊烯基(环)、(亚)环己烯基(环)、(亚)环庚烯基(环)、(亚)环辛烯基(环)、(亚)环壬烯基(环)等。环烃基是在一些实施方案中，环烃基包括芳基稠合的环烃基，只要整个环系统是非芳香性的。
如本文中所使用，术语“环烷基”和“亚环烷基”指饱和的单环或多环(诸如双环)稠合烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，例如)。所述环烷基和亚环烷基具有3至10个碳原子，适合地具有3-8个，例如3-7、3-6、4-6或5-6个碳原子。在一些实施方案中，“环烷基”和“亚环烷基”是具有3-7或3-6个环碳原子(C3～7或C3～6)的单环环烷基环。在一些实施方案中，“环烷基”和“亚环烷基”是具有8-10或9-10个环碳原子(C8～10或C9～10)的双环环烷基环。
如本文中所使用，术语“环烯基”和“亚环烯基”是指在环内具有1个或多个双键的单环或多环(诸如双环)稠合烃环(例如单环，诸如环丙烯基、环丁烯基、环戊烯基、环戊二烯、环己烯基、环己二烯基、环庚烯基、环辛烯基、环壬烯基，或双环)。所述环烯基和“亚环烯基”具有3至10个碳原子，适合地具有3-8个，例如3-7、3-6、4-6或5-6个。在一些实施方案中，“环烯基”和“亚环烯基”是具有3-7或3-6个环碳原子(C3～7或C3～6)的单环环烯基环。在一些实施方案中，“环烯基”和“亚环烯基”是具有8-10或9-10个环 碳原子(C8～10或C9～10)的双环环烯基环。
如本文中所使用，术语“杂环基”、“杂环”和“亚杂环基”指饱和(即，“杂环烷基”和“亚杂环烷基”)或部分不饱和(例如，在环内具有一个或多个双键(即，“杂环烯基”和“亚杂环烯基”))的单环或双环环状结构，其在环中具有2、3、4、5、6、7、8或9个碳原子和1个或多个(例如1个、2个、3个或4个)选自O、S和N的含杂原子的基团。杂环基中的1或多个环碳原子可以被C(O)替代。杂环基中的S原子可以被S(O)或S(O)2替代。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地，3-10元杂环基为在环中具有3-10个(例如3-8、3-7、3-6、4-6或5-6个)碳原子及杂原子的基团。在一些实施方案中，“杂环基”、“杂环”和“亚杂环基”是具有3-7、3-6个或5-6个环成员(3-7元、3-6元或5-6元)的单环杂环烷基或杂环烯基环。在一些实施方案中，“杂环基”、“杂环”和“亚杂环基”是具有8-10或9-10个环成员(8-10元或9-10元)的双环杂环烷基或杂环烯基环。杂环基可以是单环的、稠合的或螺环。杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中连接至母体结构的环为杂环基。杂环基包括含氮杂环基、含氧桥环基和含硫杂环基。可以列举的实例包括但不限于环氧乙烷基、氮丙啶基、氮杂环丁烷基(azetidinyl)、氧杂环丁烷基(oxetanyl)、四氢呋喃基、四氢噻吩基、二氧杂环戊烯基(dioxolinyl)、吡咯烷基、吡咯烷酮基、噁唑烷、噻唑烷基、吡唑烷基、咪唑烷基、吡唑烷基、吡咯啉基、四氢吡喃基、哌啶基、哌啶酮基、六氢嘧啶基、三嗪烷基、吗啉基、二噻烷基(dithianyl)、硫代吗啉基、哌嗪基、三噻烷基(trithianyl)、氮杂环辛烷基、二氢吡咯基、二氢咪唑基、氮杂环辛烯基。
如本文中所使用，术语“含氮杂环基”指饱和或不饱和的单环或双环基团，其在环中具有2、3、4、5、6、7、8或9个碳原子和至少一个(例如1、2、3或4个)氮原子，其还可任选地包含一个或多个(例如1、2、3或4个)选自N、O和S的环成员。含氮杂环基中的一个或多个环碳原子可以被C(O)替代。含氮杂环基中的S原子可以被S(O)或S(O)2替代。所述含氮杂环基可以通过所述碳原子中的任一个或氮原子与分子的其余部分连接。所述含氮杂环基可以为饱和含氮单环。特别地，3至10元含氮杂环基为在环中具有3-10个环成员的如上文所定义的含氮杂环基，其包括但不限于3元含氮杂环(如氮丙啶基)、4元含氮杂环(如氮杂环丁烷基)、5元含氮杂环(如吡咯基、吡咯烷基(吡咯烷环)、吡咯啉基、吡咯烷酮基、咪唑基、咪唑烷基、咪唑啉基、吡唑基、吡唑啉基)、6元含氮杂环(如哌啶基(哌啶环)、哌啶基酮基、吗啉基、硫吗啉基、哌嗪基)、7元含氮杂环、8元双环含氮杂环基、9元双环含氮杂环基和10元双环含氮杂环基等。
如本文中所使用，术语“杂环基”涵盖稠合结构，其与其他基团的连接点可以在稠合结构中的任一环上。因此，本发明的杂环基还包括但不限于杂环基并杂环基、杂环基并环烷基、单杂环基并单杂环基、单杂环基并单环烷基，例如3-7元(单)杂环基并3-7元(单)杂环基、3-7元(单)杂环基并(单)环烷基、3-7元(单)杂环基并C4-6(单)环烷基，其实例包括但不限于吡咯烷基并环丙基、环戊基并氮杂环丙基、吡咯烷基并环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、吡咯烷基并哌嗪基、哌啶基并吗啉基、 在一些实施方案中，杂环基还包括杂芳基稠合的杂环基或环烃基，以及芳基稠合的杂环基，只要整个环系统是非芳香性的。在一些实施方案中，杂环基包括5-6元单环杂芳基稠合的C5-6单环环烃基，5-6元单环杂芳基稠合的5-6元单环杂环基，以及苯并稠合的5-6元单环杂环基，例如吡咯并四氢吡啶基、吡唑并四氢吡啶基、咪唑并四氢吡啶基、吲哚啉基或吲哚啉酮基。
如本文中所使用，术语“芳基”是指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元环，例如苯基和萘基，更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，包括苯并3-8元环烷基、苯并3-8元杂环基。
如本文中所使用，术语“杂芳基”或“杂芳基环”是指具有5至14个环原子的杂芳族体系，其具有1至4个独立地选自N、O和S的杂环原子。杂芳基中的1或多个环碳原子可以被C(O)替代。杂芳基可以是苯并稠合的。杂芳基优选为5至10元的。在一些实施方案中，杂芳基为5元或6元杂芳基，例如但不限于吡啶基、吡啶酮基、嘧啶基、嘧啶酮基、吡嗪基、哒嗪基、噻唑基、噻吩基、噁唑基、呋喃基、吡咯基、吡唑基、三唑基、四唑基、异噁唑基、异噻唑基、咪唑基、三嗪基、噁二唑基、噻二唑基。在一些实施方案中，杂芳基为8-10元或9-10双环杂芳基，包括5元/5元、5元/6元或6元/6元双环体系。实例包括但不限于苯并噻唑基、苯并异噻唑基、咪唑并吡啶基、喹啉基、吲哚基、吡咯并哒嗪基、苯并呋喃基、苯并噻吩基、吲唑基、苯并噁唑基、苯并异噁唑基、喹唑啉基、吡咯并吡啶基、吡唑并嘧啶基、咪唑并哒嗪基、吡唑并吡啶基、三唑并吡啶基、异喹啉基、四氢异喹啉基、苯并咪唑基、噌啉基、中氮茚基、酞嗪基、异吲哚基、蝶啶基、嘌呤基、呋咱基、苯并呋咱基、喹喔啉基、萘啶基或呋喃并吡啶基。
除非另有规定，如本文中所使用，术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用。术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其中1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。
如本文中所使用，术语“稠合”意指两个或两个以上环状结构彼此共用两个相邻的原子。
如本文中所使用，术语“稠环”指5至20元的全碳多环基团，该环体系中的每个环与该体系中的其他环共享毗邻的一对碳原子，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环中的碳原子可任选地被O、S、N的杂原子替代，即也包括“稠杂环”。
本发明的术语“稠杂环”指5至20元的多环杂环基团，该环体统中的每个环与该体系中的其他环共享毗邻的一对原子，一个或多个环可以含有一个或多个双键，但没有一 个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是0至2的整数)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。
如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成N-氧化物；本领域技术人员会识别能够形成N-氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的，包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist,Comprehensive Organic Synthesis,vol.7,pp 748-750；A.R.Katritzky和A.J.Boulton,Eds.,Academic Press；以及G.W.H.Cheeseman和E.S.G.Werstiuk，Advances in Heterocyclic Chemistry,vol.22,pp 390-392,A.R.Katritzky和A.J.Boulton,Eds.,Academic Press。
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、脱脂化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)及“Bioreversible Carriers in Drug Design,”Pergamon Press,1987(E.B.Roche编辑，American Pharmaceutical Association)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在Protective  Groups in Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973；和T.W.Greene&P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley&Sons,1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。
如本文中所使用，术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所述的化合物是依据化学结构式命名的。如果表示同一化合物的化合物命名与化学结构式不符，则以化学结构式为准。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
本发明所使用的溶剂可经市售获得。
化合物依据本领域常规命名原则或者使用软件命名，市售化合物采用供应商目录名称。
有益效果
作为新型的STING抑制剂，本发明化合物对STING有很强的抑制活性，可用于预防和/或治疗STING介导的疾病或病症。本发明的化合物具有改善的药物代谢动力学性质(例如改善的生物利用度、改善的代谢稳定性、合适的半衰期和作用持续时间)、改善的安全性(较低的毒性(例如降低的心脏毒性)和/或较少的副作用)等更优异的性质。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
中间体int1：
int1制备方法：
(1)将化合物1a(25.00g，128.86mmol)溶解在N,N-二甲基甲酰胺(250mL)中，在0℃下滴加三氟乙酸酐(28.69g，136.59mmol)。在室温搅拌3小时后，将混合物倒入1000mL水中，抽滤得到沉淀物并在1000mL 20％NaOH中加热回流过夜。反应液冷 却到室温后用二氯甲烷萃取两次，水层用盐酸酸化，过滤并真空干燥得到化合物1b。
(2)将化合物1b(17.00g，71.1486.91mmol)溶解在四氢呋喃(170mL)中，然后将在0℃下加入三乙胺(21.59g，213.42mmol)、叠氮磷酸二苯酯(39.16g，142.28mmol)。反应液在室温下搅拌过夜。反应结束后旋走大部分四氢呋喃，加入甲醇使体系析出固体，抽滤后晾干得到化合物1c。
(3)将化合物1c(17.00g，64.15mmol)溶解在叔丁醇(170mL)中，混合液在氮气保护下80℃搅拌过夜。反应结束后，将反应液冷却至室温，减压浓缩后用硅胶板层析纯化，用(石油醚:乙酸乙酯＝4:1)洗脱得化合物1d。
(4)将化合物1d(9.00g，28.94mmol)溶解在氯化氢/1,4-二氧六环溶液(4M,90mL)中，反应液在室温下搅拌16h。反应结束后减压浓缩得化合物int1，LCMS(ESI)m/z:212.0[M+H]+.
中间体int2：
Int2制备方法：
(1)将化合物1a(25.00g，164.92mmol)溶解在N,N-二甲基甲酰胺(250mL)中，在0℃下滴加三氟乙酸酐(36.72g，174.82mmol)。在室温搅拌3小时后，将混合物倒入1000mL水中，抽滤得到沉淀物并在1000mL 20％NaOH中加热回流过夜。反应液冷却到室温后用二氯甲烷萃取两次，水层用盐酸酸化，过滤并真空干燥得到化合物2a。
(2)将化合物2a(17.00g，86.91mmol)溶解在四氢呋喃(170mL)中，然后将在0℃下加入三乙胺(26.38g，260.73mmol)、叠氮磷酸二苯酯(47.84g，173.82mmol)。反应液在室温下搅拌过夜。反应结束后旋走大部分四氢呋喃，加入甲醇使体系析出固体，抽滤后晾干得到化合物2b。
(3)将化合物2b(17.00g，77.06mmol)溶解在叔丁醇(170mL)中，混合液在氮气保护下80℃搅拌过夜。反应结束后，将反应液冷却至室温，减压浓缩后用硅胶板层析纯化，用(石油醚:乙酸乙酯＝4:1)洗脱得化合物2c。
(4)将化合物2c(9.00g，33.74mmol)溶解在氯化氢/1,4-二氧六环溶液(4M,90mL)中，反应液在室温下搅拌16h。反应结束后减压浓缩得化合物int2，LCMS(ESI)m/z:167.0[M+H]+.
中间体int3：
Int3制备方法：
(1)将3a(17.6g，108.0mmol)溶解在二氯甲烷(200mL)中，然后在室温下依次加入N,N-二异丙基乙胺(53.4mL，323.3mmol)和3b(30g，129.3mmol)。反应液在40℃下搅拌16小时。反应结束后，反应液用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝1:1)洗脱得产物3c(15.3g)。
(2)将3c(15.0g，61.18mmol)溶解在二氯甲烷(200mL)和甲醇(20ml)混合液中，然后在室温下滴加水合肼(68％)(3.063g，122.37mmol)。反应液在室温下搅拌2小时。反应完成后过滤沉淀，用5N氨水(200ml)冲洗滤液。用二氯甲烷萃取水相两次，萃取结束有机相用无水硫酸钠干燥。干燥后常温减压浓缩后加入乙醇(50ml)和浓盐酸(6ml)，反应液呈酸性,将反应液减压旋干，得产物int3(5.3g)，1H NMR(400MHz,DMSO)δ4.77–4.70(m,2H).
中间体int4：
Int4制备方法：
(1)将3b(3.24g，10.19mmol)、4a(2g，9.26mmol)和三苯基膦(5.34g，10.19mmol)溶解在超干四氢呋喃(20mL)中，然后在0℃滴加偶氮二甲酸二叔丁酯(4.69g，10.19mmol)的四氢呋喃(10mL)溶液。反应液在0℃下搅拌4小时。反应结束后，反应液加入水(50mL)稀释,用二氯甲烷萃取和饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(0-20％乙酸乙酯/石油醚)洗脱得化合物4b(1g)。1H NMR(400MHz,DMSO_d6)δ7.88–7.85(m,2H),7.79–7.77-4.42(m,2H),4.79–4.78(m,1H),3.06–2.96(m,4H).
(2)将4b(1g，3.95mmol)溶解在二氯甲烷(20mL)和甲醇(2ml)混合液中，然后在室温下滴加水合肼(68％)(0.4mL，7.9mmol)。反应液在室温下搅拌2小时。反应完成后过滤沉淀，用5N氨水(20ml)冲洗滤液。用二氯甲烷萃取水相两次，萃取结束有机相用无水硫酸钠干燥。干燥后常温减压浓缩除去大部分二氯甲烷后加入乙醇(20mL)和浓盐酸(2ml)，反应液呈酸性，后减压旋干后得到化合物int4(400mg)。1H NMR(400MHz,DMSO_d6)δ11.13(s,2H),4.76–4.75(m,1H),3.07–2.97(m,2H),2.85–2.73(m,2H).
实施例1
合成路线：
将化合物C001-1a(1.0g，6.09mmol，1eq)和化合物int 3(1.1g，9.75mmol，1.6eq)和对甲苯磺酸水合物(1.4g，7.31mmol，1.2eq)溶解在乙腈(25.0mL)中，在90℃下搅拌4h。反应结束后旋干溶剂，残余物用柱层析纯化，用(石油醚:乙酸乙酯＝1:1)洗脱得化合物C001-1b(1.3g，81.7％)，白色的固体。LCMS(ESI)m/z:260.0[M-H]-.
(2)将化合物C001-1b(100mg，0.38mmol，1eq)、T3P(50％in DMF)(366mg，0.57mmol，0.37mL,1.5eq)和化合物int 2(86mg，0.42mmol，1.1eq)溶解在N,N-二甲基酰胺(4.0mL)中，向混合物中滴加三乙胺(155mg，1.53mmol，4.0eq)，在室温下搅拌过夜。反应结束后，用乙酸乙酯和水萃取反应液，合并有机相所得残余物通过Prep-HPLC纯化得C001(33.30mg，21.2％)。LCMS(ESI)m/z:410.1[M+H]+.1H NMR(400MHz,DMSO_d6)δ11.15(s,1H),10.27(s,1H),8.07(d,J＝8.0Hz,2H),8.01(s,1H),7.91(s,1H),7.82(d,J＝8.0Hz,2H),7.40(d,J＝12.0Hz,1H),7.12(d,J＝8.0Hz,1H),4.85(q,J＝8.0Hz,2H),2.32(s,3H).
实施例2：
合成路线：
将化合物C001-1b(100mg，0.38mmol，1eq)、T3P(50％in DMF)(366mg，0.57mmol，0.37mL,1.5eq)和化合物int 1(104mg，0.42mmol，1.1eq)溶解在N,N-二甲基酰胺(4.0mL)中，向混合物中滴加三乙胺(155mg，1.53mmol，4.0eq)，在室温下搅拌过夜。反应结束后，用乙酸乙酯和水萃取反应液，合并有机相所通过Prep-HPLC纯化得C002(66.00mg，18.9％)。LCMS(ESI)m/z:454.0[M+H]+.1H NMR(400MHz,DMSO_d6)δ11.15(s,1H),10.27(s,1H),8.15(d,J＝4.0Hz,1H),8.06(d,J＝8.0Hz,2H),7.90(d,J＝4.0Hz,1H),7.82(d,J＝8.0Hz,2H),7.35(d,J＝8.0Hz,1H),7.22(dd,J＝8.0,2.0Hz,1H),4.85(q,J＝8.0Hz,2H),2.32(s,3H).
实施例3：
合成路线：
(1)将C003-3a(300mg，1.83mmol)和int4(350mg，2.19mmol，)和对甲苯磺酸水合物(417mg，2.19mmol)溶解在乙腈(10.0mL)中，在90℃下搅拌4h。反应结束后旋干溶剂，残余物用柱层析纯化，用(石油醚:乙酸乙酯＝1:1)洗脱得化合物C003-3b(200mg)。
(2)将C003-3b(150mg，0.56mmol)、HATU(197mg，0.83mmol，)和int2(283mg，1.39mmol)溶解在N,N-二甲基酰胺(6.0mL)中，向混合物中滴加三乙胺(338mg，3.34mmol)，在室温下搅拌过夜。反应结束后，用乙酸乙酯和水萃取反应液，合并有机相所得残余物通过反相制备纯化得化合物C003(21.60mg)。1H NMR(400MHz,DMSO_d6)δ11.14(s,1H),10.24(s,1H),8.05(d,J＝8.0Hz,2H),8.00(s,1H),7.91(d,J＝2.0Hz,1H),7.82(d,J＝8.0Hz,2H),7.39(d,J＝8.4Hz,1H),7.11(d,J＝8.4Hz,1H),4.84(s,1H),3.13–2.99(m,2H),2.87–2.73(m,2H),2.29(s,3H).
实施例4：
合成路线：
(1)将C004-4a(158mg，0.98mmol)和int2(200mg，0.98mmol)溶解在四氢呋喃(2mL)中，添加三乙胺(0.3mL)。将混合物在室温下搅拌反应过夜。反应结束后加水(10mL)稀释，用乙酸乙酯(10mL)萃取三次，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化，洗脱得C004-4b(210mg)。
(2)将C004-4b(110mg，0.34mmol)、int4(108mg，0.68mmol)和对甲苯磺酸(13mg，0.068mmol)溶解在乙腈(2mL)中。反应液在90℃下反应16h。反应结束后用乙酸乙酯(10mL)萃取三次，合并有机相。有机相用饱和盐水洗涤，无水硫酸钠干燥，真空浓缩后，所得残余物送制备分析纯化得化合物C004(18.41mg)。1H NMR(400MHz,DMSO_d6)δ10.97(s,1H),8.74(s,1H),8.58(s,1H),7.60(d,J＝8.0Hz,2H),7.55–7.53(m,2H),7.36(d,J＝8.0Hz,1H),7.09(dd,J＝8.0,4.0Hz,1H),4.76-4.74(m,1H),3.07–2.96(m,2H),2.78–2.73(m,2H),2.20(s,3H).
实施例5：
合成路线：
(1)将C005-5a(158mg，0.98mmol)和int2(200mg，0.98mmol)溶解在四氢呋喃(2mL)中，加入三乙胺(0.3mL)。将混合物在室温下搅拌反应过夜。反应结束后加水稀释，用乙酸乙酯萃取，合并有机相，再用无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化，洗脱得C005-5b(210mg)。
(2)将C005-5b(400mg，1.22mmol)、int3(168mg，1.46mmol)和对甲苯磺酸(46mg，0.244mmol)溶解在乙腈(5mL)中。反应液在90℃下反应16h。反应结束后用乙酸乙酯萃取，合并有机相。有机相用盐水洗，无水硫酸钠干燥，真空浓缩后，所得残余物送制备分析纯化得化合物C005(50.28mg)。1H NMR(400MHz,DMSO_d6)δ10.98(s,1H),8.74(s,1H),8.57(s,1H),7.62–7.59(m,2H),7.56–7.52(m,4H),7.36(d,J＝8.4Hz,1H),7.09(d,d,J＝8.4,2.0Hz,1H),4.76(q,J＝11.2Hz,2H),2.23(s,3H).
实施例6：
合成路线：
(1)在闷罐中将C006-6a(4g，25.71mmol)溶解在氨水(50mL)中，在130℃下搅拌16h。反应结束后，待冷却后浓缩反应液。用柱层析纯化，用(二氯甲烷:甲醇＝50:1)洗脱得C006-6b(2.3g)。
(2)将C006-6b(1g，7.34mmol)溶解在超干四氢呋喃(10.0mL)中，加入吡 啶(1.2mL，14.68mmol)。氮气置换三次，在0℃下搅拌20min。将C006-6c(1.3g，7.34mmol)溶解在超干四氢呋喃(5mL)中，缓慢滴加至溶液中，在室温下搅拌16小时，得C006-6d，反应结束后，将int2(2.44g，14.68mmol)溶解在超干四氢呋喃(10mL)中，加入到反应液中，升温至40℃，搅拌16h。反应结束后，过滤反应液，用(二氯甲烷:甲醇＝10:1)洗脱固体得C006-6e(350mg)。
(3)将C006-6e(100mg，0.30mmol)，int3(54mg，0.36mmol)和对甲苯磺酸水合物(11mg，0.06mmol)溶解在乙腈(2.0mL)中，在60℃下搅拌4小时。反应结束后，将反应液浓缩，所得残留物用(二氯甲烷:甲醇＝10:1)洗脱固体得化合物C006(27.44mg)。1H NMR(400MHz,DMSO_d6)δ11.05(s,1H),10.02(s,1H),9.60(s,1H),8.59(d,J＝4.0Hz,1H),8.04(dd,J＝8.0,2.0Hz,1H),7.67–7.62(m,2H),7.54(s,1H),7.39(d,J＝12.0Hz,1H),7.12(dd,J＝8.0,2.0Hz,1H),4.80(q,J＝8.0Hz,2H),2.27(s,3H).
实施例7：
合成路线：
(1)将C006-6a(100mg，0.30mmol)，int4(56mg，0.45mmol)和对甲苯磺酸水合物(11mg，0.06mmol)溶解在乙腈(3.0mL)中，在60℃下搅拌4小时。反应结束后，将反应液过滤，滤液减压浓缩，所得残余物用硅胶板层析分离(二氯甲烷:甲醇＝10:1)得化合物C007(26.93mg)。1H NMR(400MHz,CD3OD)δ8.61(s,1H),8.13–8.07(m,1H),7.56(s,1H),7.53(d,J＝4.0Hz,1H),7.34(d,J＝12.0Hz,1H),7.24(s,1H),7.11(dd,J＝12.0,2.0Hz,1H),4.81–4.79(m,1H),3.04–2.92(m,2H),2.79–2.72(m,2H),2.29(s,3H).
实施例8：
合成路线：
(1)将C008-8a(800mg，4.1mmol，1eq)和C008-8b(672mg，4.52mmol，1.1eq)溶解在甲苯(16mL)中，置换氮气，在100℃下搅拌2h。反应结束后旋干溶剂，所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝1:1)洗脱得C008-8c(350mg)。
(2)将C008-8c(250mg，0.7331mmol，1eq)，int4(140mg，0.8805mmol，1.2eq)和对甲苯磺酸水合物(14mg，0.0733mmol，0.1eq)溶解在乙腈(5.0mL)中，在60℃下搅拌16h。反应结束后，反应完成后减压浓缩。送制备分析纯化得化合物C008(47.10mg)。1H NMR(400MHz,DMSO_d6)δ10.95(s,1H),8.16(s,1H),7.69(d,J＝8.0Hz,2H),7.57(s,1H),7.41(d,J＝8.0Hz,3H),7.32(d,J＝8.0Hz,1H),7.04(d,J＝4.0Hz,1H),4.83–4.74(m,1H),3.34(s,3H),3.08–2.95(m,2H),2.84–2.50(m,2H),2.24(s,3H).
实施例9：
合成路线
(1)将C009-9a(4.5g,37.77mmol)溶解在超干四氢呋喃(45mL)中，氮气置换三次，反应液降温至0℃。控制温度在0-5℃之间，将甲基溴化镁(4M，28mL，113.31mmol)缓慢滴加到溶液中。滴加完毕后，继续搅拌3h。反应结束后，反应液用饱和氯化铵(5mL)淬灭，加水(50mL)稀释后，用乙酸乙酯(50mL x 2)萃取，合并有机相,用饱和氯化钠洗涤，无水硫酸钠干燥，过滤，浓缩得C009-9b(3.5g，收率：68.1％)。
(2)将C009-9b(1g，7.34mmol)溶解在超干四氢呋喃(10.0mL)中，加入吡啶(1.2mL，14.68mmol)。氮气置换三次，降温到0℃，将C009-9c(1.46g，8.07mmol)溶解在超干四氢呋喃(5mL)中，缓慢滴加至上述溶液中。反应液自然升温到室温，搅拌16小时，得C009-9d，将int2(2.45g，14.68mmol)溶解在超干四氢呋喃(10mL)中，加入到反应液中，升温至40℃，继续搅拌16h。反应结束后，反应液加水(20mL)稀 释，用乙酸乙酯(20mL x 2)萃取，合并有机相,用饱和氯化钠洗涤，无水硫酸钠干燥，过滤，浓缩得C009-9e(800mg，收率：33.2％)。
(3)将C009-9e(100mg，0.30mmol)，int3(54.5mg，0.36mmol)和对甲苯磺酸水合物(11.4mg，0.06mmol)溶解在N,N-二甲基甲酰胺(2.0mL)中，在60℃下搅拌4小时。反应结束后，过滤反应液，送制备分析纯化得化合物C009(19.14mg，收率：15.0％)。1H NMR(400MHz,CD3OD)δ8.66(d,J＝2.0Hz,1H),8.00(dd,J＝8.4,2.4Hz,1H),7.85(d,J＝8.4Hz,1H),7.52(d,J＝2.0Hz,1H),7.49(s,1H),7.33(d,J＝8.8Hz,1H),7.10(dd,J＝8.8,2.0Hz,1H),4.66(q,J＝8.8Hz,2H),2.32(s,3H).
实施例10：
合成路线
(1)于250mL单口反应瓶中将原料C010-10a(4.00g，18.52mmol)溶解在甲苯(60mL)中，加入催化剂四(三苯基膦)钯(1.07g，0.93mmol)和C010-10b(7.5mL，22.22mmol)，氮气保护下油浴加热至110℃搅拌反应16小时。反应完全后(TLC显示无原料)，反应液作为粗品C010-10c溶液直接投入下一步骤。
(2)向盛有粗品C010-10c(70mL，18.52mmol)的250mL单口瓶中加入盐酸水溶液(1mol/L，100mL，100mmol)，油浴60℃搅拌2小时。反应完成后冷却至室温，分出有机相，剩余水相用乙酸乙酯(60mL)萃取两次。向合并后的有机相中加入氟化钾饱和水溶液(2mL)，室温搅拌0.5小时，抽滤，滤液用无水硫酸钠干燥，再过滤后，滤液减压浓缩，所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝1:3)洗脱得C010-10d(2.9g)。1H NMR(400MHz,DMSO_d6)δ9.22–9.18(m,1H),8.46(dd,J＝8.0,2.0Hz,1H),8.18(d,J＝8.0Hz,1H),3.92(s,3H),2.68(s,3H).
(3)向装有C010-10d(2.9g，16mmol)、一水合氢氧化锂(7g，160mmol)的单口瓶中倒入溶剂甲醇(70mL)和水(17.5mL)，室温搅拌过夜。反应完成后减压浓缩除去大部分甲醇，加1M HCl调节pH～4,二氯甲烷(50mL)萃取三次，合并有机相，无水硫酸钠干燥，过滤减压浓缩,即得C010-10e(276mg)。1H NMR(400MHz,DMSO_d6)δ13.54(br.s,1H),8.45(dd,J＝8.0,2.0Hz,1H),8.16(d,J＝8.0Hz,1H),2.68(s,3H).
(4)向装有C010-10e(276mg，1.21mmol)的100mL单口瓶中加入化合物int2(295mg，1.45mmol)、HATU(553mg，1.45mmol)、二氯甲烷(13mL)和N,N-二异丙基乙胺(1.2mL，7.27mmol)，氮气置换三次后，室温搅拌过夜。反应完成后加入水(20mL)，分出有机相并用无水硫酸钠干燥，过滤后减压浓缩干即得粗品C010-10f(400mg)，可直接用于下一步。LCMS(ESI)m/z:313.9[M+H]+.
(5)向装有C010-10f(400mg，1.21mmol)的50mL单口瓶中加入化合物int3(244mg，1.45mmol)、一水合对甲苯磺酸(46mg，0.24mmol)和超干溶剂乙腈(7mL)，油浴60℃搅拌2小时。反应完成后减压浓缩干，所得残余物送高效液相制备分析纯化得化合物C010(16.66mg)。1H NMR(400MHz,CD3OD)δ9.05(s,1H),8.29(d,J＝8.0Hz,1H),8.23(d,J＝8.0Hz,1H),7.85(d,J＝1.6Hz,1H),7.72(s,1H),7.36(d,J＝7.2Hz,1H),7.14(d,J＝8.4Hz,1H),4.77–4.70(m,2H),2.38(d,J＝1.6Hz,3H).
实施例11：
合成路线
(1)将化合物C011-11a(1.0g，4.631mmol)溶解在甲苯(10mL)中，加入C010-10b(2.0g，5.555mmol)和四(三苯基膦)钯(530mg，0.463mmol)，氮气保护下在110℃恒温搅拌16h。反应结束后，加1M稀盐酸后在60℃恒温搅拌2h，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，合并有机相所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝2:1)洗脱得C011-11b(600mg)。LCMS(ESI)m/z:180.0[M+H]+.
(2)将C011-11b(600mg，3.348mmol)和氢氧化锂(701mg，16.743mmol)溶解在四氢呋喃：水＝2:1(10ml)中，室温下搅拌2h。反应结束后滴加1M稀盐酸调节pH值至3～4，然后用二氯甲烷萃取，合并有机相用无水硫酸钠干燥，过滤，减压浓缩后得到粗品C011-11c(380mg)。LCMS(ESI)m/z:164.1[M+H]+.
(3)将C011-11c(250mg,1.515mmol)溶解在N,N-二甲基甲酰胺(5mL)中，加入HATU(94mg，0.727mmol)和化合物int2(120mg，0.727mmol)，反应体系在氮气 保护下室温搅拌5min，再加入三乙胺(0.5ml，3.636mmol)，然后在室温下恒温搅拌反应2h。反应结束后，减压浓缩除去大部分溶剂，TLC(PE/EA:1/1)板分离纯化得C011-11d(200mg)。LCMS(ESI)m/z:313.8[M+H]+.
(4)将粗品C011-11d(120mg，0.383mmol)溶解在乙腈(5mL)中，加入化合物int3(70mg，0.460mmol)和一水合对甲苯磺酸(15mg，0.077mmol)，然后氮气保护下在60℃恒温搅拌4h。反应结束后浓缩反应液，反相制备分析纯化得化合物C011(40.25mg)。LCMS(ESI)m/z:411.1[M+H]+.
实施例12：
合成路线
将C012-12a(200mg，1.116mmol)和氢氧化锂(234mg，5.581mmol)溶解在四氢呋喃：水＝2:1(10ml)中，室温下搅拌2h。反应结束后滴加1M稀盐酸pH值至3～4，然后用二氯甲烷萃取三次，有机相用无水硫酸钠干燥，过滤，减压浓缩溶后得到粗品C012-12b(110mg)。LCMS(ESI)m/z:166.1[M+H]+.
(1)将C012-12b(280mg,1.679mmol)溶解在二氯甲烷(10mL)中，加入HATU(262mg，2.036mmol)和化合物int2(338mg，2.036mmol)，然后在氮气保护下室温搅拌5min，再加入三乙胺(1.4ml，10.182mmol)，然后在室温下继续搅拌反应2h。反应结束后，反应液减压浓缩除去大部分溶剂，TLC板分离(PE/EA:1/1)得C012-12c(200mg)。LCMS(ESI)m/z:313.9[M+H]+。1H NMR(400MHz,DMSO_d6)δ11.22(s,1H),10.68(s,1H),9.01–8.94(m,1H),8.50–8.45(m,1H),8.07(dd,J＝5.2,1.6Hz,1H),7.91(dd,J＝9.6,2.4Hz,2H),7.41(d,J＝8.4Hz,1H),7.12(dd,J＝8.4,2.0Hz,1H),2.72(s,3H).
(2)将粗品C012-12c(240mg，0.767mmol)溶解在N,N-二甲基甲酰胺(5mL)中，加入int3(138mg,0.920mmol)和一水合对甲苯磺酸(29mg，0.153mmol)，然后氮气保护下在60℃恒温搅拌4h。反应结束后浓缩反应液，反相制备分析纯化得化合物C012(89.16mg)。LCMS(ESI)m/z:411.1[M+H]+.
实施例13：
合成路线：
(1)将化合物D003-3a(5.00g，26.57mmol)溶解在吡啶(50mL)中，添加二氧化锡(7.37g，66.34mmol)。将混合物在110℃下搅拌反应16h。反应结束后过滤，滤液减压浓缩后用1M盐酸水溶液(100mL)稀释，再用乙酸乙酯萃取(60mL x 3)，合并有机相，再用无水硫酸钠干燥，减压浓缩，所得残余物用反相柱分离纯化，洗脱、冻干得化合物D003-3b(2.0g，34％)。LCMS(ESI)m/z:217.3[M-H]-.
(2)将化合物D003-3b(100mg，0.64mmol)和化合物int 2(93mg，0.64mmol)溶解在N,N-二甲基甲酰胺(2mL)中，然后在0℃下加入T3P/DMF溶液(440mg，0.69mmol)。反应液在0℃下搅拌5mins后加入三乙胺(0.2mL)。反应液在室温下搅拌3h。反应结束后，向反应液加入水(20mL),用乙酸乙酯(10mL x 3)萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩后，所得残余物用反相制备分析纯化得化合物D003(15.45mg，9.16％)，白色固体。LCMS(ESI)m/z:365.1[M-H]-.1H NMR(400MHz,DMSO_d6)δ11.30(s,1H),11.12(s,1H),8.27(d,J＝8.0Hz,2H),8.00(d,J＝8.0Hz,2H),7.96(t,J＝4.0Hz,2H),7.42(d,J＝8.0Hz,1H),7.14(dd,J＝8.0,2.0Hz,1H).
实施例14：
合成路线：
将化合物D003-3b(100mg，0.64mmol)和化合物int 1(158mg，0.64mmol)溶解在N,N-二甲基甲酰胺(2mL)中，然后在0℃下加入T3P/DMF溶液(440mg，0.69mmol)。反应液在0℃下搅拌5mins后加入三乙胺(0.2mL)。反应液在室温下搅拌3h。反应结束后，向反应液加入水(20mL),用乙酸乙酯(10mL x 3)萃取，合并有机相。有机相用饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩后，所得残余物用反相制备分析纯化得化合物D004(6.86mg，2.61％)，黄色固体。LCMS(ESI)m/z:413.1[M+H]+.1H NMR(400MHz,DMSO_d6)δ11.32(s,1H),11.13(s,1H),8.27(d,J＝8.0Hz,2H),8.12(d,J＝8.0Hz,1H),7.99(t,J＝4.0Hz,2H),7.94(t,J＝4.0Hz,1H),7.39(d,J＝8.0Hz,1H),7.24(dd,J＝8.0,2.0Hz,1H).
各实施例的1H NMR和MS数据如下表所示：
表1:1H NMR和MS数据

生物测试数据
实验例1：体外细胞活实验
A.主要材料
细胞系：
THP1细胞系(来自ATCC，批号TIB-202)
试剂：
1.DPBS(Invitrogen，14190-144)；2.FBS(GIBCO，10099-141)；3.DMSO(Sigma，D8418-1L)；4.PMA(MCE，HY-18739)；5.RPMI培养基1640(Invitrogen，A10491-01)；6.Pen/Strep青链霉素混合液(GIBCO，15140-122)；7.IFNb ELISA试剂盒(R&D，DY814-05)。
耗材：
1.T75培养瓶(Corning，430641)；2.96孔板(Corning，3599)；3.移液管(5ml,10ml,25ml,50ml)(Thermo Scientific，159625159633)；4.移液枪枪头(10μl,200μl,1ml)(Axygen，T-300-R-S/T-200-Y-R-S/T-1000-B-R-S)。
仪器：
1.生物安全操作柜(Thermo Scientific，1300 Series A2)；2.离心机(Eppendorf，5702)；3.二氧化碳培养箱(Thermo Scientific，371)；4.细胞计数器(Invitrogen，C10281)；5.移液器控制器(BIOHIT，Easypet)；6.倒置显微镜(Olympus，CKX41)；7.移液器(BIOHIT，Proline Plus)；8.涡流混合器(IKA，MS3 basic)；9.EnVision酶标仪(Perkin Elmer，2014)。
B.方法(THP1细胞中的人IFN-β检测)
a)THP1细胞系
RPMI培养基1640,10％FBS,1％PS中悬浮培养10^6细胞/mL，37℃&5％CO2培养箱。
移种100μL/孔至96孔板中，其包含50ng/mL PMA，置于37℃&5％CO2培养箱。
b)IFN-β检测
1.用DPBS洗涤培养的THP1细胞，加入100μL无FBS的RPMI培养液1640；
2.加入25μL化合物(终DMSO为0.1％)并置于37℃，5％CO2培养箱中培养；
3.用Lip3000转染1μg/mL dsDNA并置于37℃，5％CO2培养箱中培养；
4.离心，将上清液转移至96孔板中；
5.使用IFN-βELISA试剂盒监测IFN-β水平。
c)IFN-βELISA试剂盒
1.在不含载体蛋白的PBS中将Capture抗体稀释至工作浓度。在96孔板中每孔加入100μL稀释的Capture抗体。将96孔板密封后在室温下过夜培养。
2.抽吸出每个孔中的培养液并用缓冲洗涤液洗涤，重复两次或共洗涤三次。使用喷瓶向每个孔填充洗涤缓冲液(400μL)进行洗涤。
3.加入300μL稀释剂试剂来封闭培养板，置于室温培养1～2小时。
4.重复步骤2中的抽吸/洗涤两次。
5.向稀释剂试剂中加入100μL样品(Supes)或标准品，用胶条覆盖并在室温下培养2小时。
6.重复步骤2中的抽吸/洗涤两次。
7.向每孔中加入100μL检测抗体，稀释于稀释剂试剂中。
8.用新的胶条覆盖并在室温下培养2小时。
9.重复步骤2中的抽吸/洗涤两次。
10.向每孔中加入100μL Streptavidin-HRP工作稀释液。用新的胶条覆盖并在室温下培养2小时(避光)。
11.向每孔中加入50μL终止液。
12.在EnVision酶标仪上读取化学发光信号OD450。
C.实验结果：
表2体外活性测试结果
结论：本发明化合物对STING有强的抑制活性。
实验例2：(人/小鼠)肝微粒体代谢稳定性
1.实验设计：测定浓度：1μM；对照化合物：睾酮；培养条件：于37℃下培养0、5、15、30、45分钟；测定方法：LC-MS/MS；计算方法：T1/2＝0.693/K(K是ln[浓度]相对于温育时间图的速率常数)，Clint＝(0.693/T1/2)×(1/(微粒体蛋白浓度(0.5mg/mL)))×比例因子。
其中，下表为人微粒体中内在清除预测的比例因子，
2.实验方法：
a.预热0.1M K-buffer，5nM MgCl2，pH＝7.4；
b.测试化合物和参比化合物的实验溶液，500μM添加溶液：将5μL10mM储备溶液加入95μL ACN中，1.5μM微粒体中的掺加溶液(0.75mg/mL)：将1.5μL的500μM的添加溶液和18.75μL的20Mg/mL肝微粒体加入到479.75μL的K/Mg缓冲液中；
c.3×NADPH的原液(6mM，5mg/mL)是将NADPH溶解于缓冲液中；
d.将30μL含有0.75mg/mL微粒体溶液的1.5μM的添加溶液分配到指定用于不同时间点(0，5，15，30，45分钟)的测定板上；
e.在0分钟时，将150μL含IS的ACN加入平板的孔中，然后加入15μL NADPH储备溶液(6mM，步骤3)；
f.将所有其它板在37℃下预孵育5分钟；
g.向板中加入15μL NADPH储备溶液以开始反应和计时；
h.在5分钟、15分钟、30分钟和45分钟时，分别向相应板的孔中加入150μL含有IS的ACN以终止反应；
i.淬灭后，在振动器上将板摇动10分钟(600rpm/分钟)，然后在6000rpm下离心15分钟；10.将80μL上清液从每个孔转移到含有140μL水的96孔样品板中，用于LC/MS分析。
3.分析方法：检测方法：LC-MS/MS-11(8050)，内标：甲苯磺丁脲，MS条件为睾酮和待测化合物正离子ESI；甲苯磺丁脲负离子ESI；流动相：流动相A为0.1％FA与水中，流动相B为0.1％FA于ACN中；柱及规格：ACQUITY UPLC HSS T3 1.8um 2.1*50mm。
LC条件：
4.实验结果：

结论：本发明化合物表现出良好的肝微粒体稳定性。
实验例3：小鼠药代动力学实验
1、实验方法：雄性C57BL/6N小鼠，体重18-22g，试验前禁食过夜。待测化合物溶媒中，其中IV组按2mg/kg静脉注射(n＝3)给药，PO组按10mg/kg经口管饲法(n＝3)给药。在给药后15分钟、30分钟和1,、2、4、6、8及24小时通过眼眶静脉丛取血，每个时间点约0.08mL，置于含EDTA-2K抗凝剂的1.5mL离心管中，血样在2小时内经离心处理(3200g，10分钟，4℃)获得血浆样品。血浆样品在处理前冻存于-70℃至-80℃超低温冰箱中。样品处理前将血浆样品从冰箱取出，室温解冻后，分别20μL血浆样品加入到96孔板中，然后加入120μL含内标的乙腈沉淀蛋白，涡旋混合后，于4℃，4950g离心15分钟，取上清与0.1％甲酸水等体积混匀进行LC-MS/MS分析。
2、实验结果：
结论：本发明化合物表现出良好的药代动力学性质。
本文中使用实施例对本发明的原理及实施方式进行了阐述，以上实施例只是用于帮助理解本发明而不是对其进行限制。应当指出，对于本领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的范围。

Claims (13)

  1. 式(I)所示化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，
    其中，
    表示单键或双键；
    L0选自单键、-NH-、-CH2-、-S(O)1-2-、-C(O)-；
    L1选自-C-、-S-、S(O)-；
    L2选自单键、-CH2-、-O-、-S(O)0-2-和-NH-，其中所述-CH2-和-NH-任选地被Ra取代1～3次；
    环A选自C3～10饱和或部分不饱和的单环或双环环烃基、3～10元饱和或部分不饱和的单环或双环杂环基、C6-10芳基和5～10元单环或双环杂芳基；
    X选自CRaRb、NRa、O、S和S(O)2；
    Y1、Y2、Y3独立地任选自-CH2-、-NH-、-O-、-S-；所述的-CH2-和-NH-中的H在化合价允许的条件下可任选地被R1取代1或2次；
    Z选自-CH2-、-NH-；所述的-CH2-和-NH-中的氢在化合价允许的条件下可任选地被R1取代1或2次；
    R1选自H、CN、OH、卤素、C1～6烷基、3～6元环烷基、3～6元杂环烷基、苯基、5～6元杂芳基、C1～6烷氧基、O-3～6元环烷基、O-3～6元杂环烷基、O-苯基、O-5～6元杂芳基、-C(O)-O-C1～6烷基；所述的C1～6烷基、3～6元环烷基、3～6元杂环烷基、苯基、5～6元杂芳基可任选地被Ra取代1～3次；
    R2选自H、N(Rb)2、CN、C(O)、S(O)0-2、卤素、C1～3烷基、C1～3烷氧基；所述的C1～3烷基和C1～3烷氧基可任选地被Ra取代1～3次；
    R3选自H、C1～6烷基、3～6元环烷基、3～6元杂环烷基、CH2-O-C1～6烷基、CH2-NH-C1～6烷基、CH2-3～6元环烷基，CH2-3～6元杂环烷基；所述的C1～6烷基、3～6元环烷基、3～6元杂环烷基可任选地被Ra取代1～3次；
    其中R3任选地与环A的环原子连接以形成C3～7饱和或部分不饱和的单环环烃基、3～7元饱和或部分不饱和的单环杂环基、苯基、或者5或6元杂芳基，其中所述环烃基、杂环基、芳基和杂芳基任选地被Ra取代1～3次；
    R4选自H、CN、C1～6烷基、3～7元环烷基、3～7元杂环烷基、苯基、5～6元杂芳基、C1～3亚烷基-3～7元环烷基、C1～3亚烷基-3～7元杂环烷基、C1～3亚烷基-苯基、C1～3亚烷基-5～6元杂芳基；所述的C1～6烷基、3～7元环烷基、3～7元杂环烷基、苯基、5～6元杂芳基可任选地被Rb取代1～3次；
    p选自1、2和3；
    q选自0、1、2和3；
    Ra独立地选自H、F、Cl、和C1～3烷基；
    Rb独立地选自H、F、Cl、Br、I、NH2、OH、C1-3烷基、C1-3烷氧基和CN，所述C1～3烷基和C1～3烷氧基任选被卤素取代1～3次。
  2. 式(I’)所示化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，
    其中，
    环A、X、Y1、Y2、Y3、Z、R1、R2、p、q、Ra、Rb定义同前；
    R5选自H、CN、C1～6烷基、C1～6烷氧基、3～7元环烷基、3～7元杂环烷基、苯基、5～6元杂芳基、CH2-O-C1～6烷基、CH2-NH-C1～6烷基、CH2-3～6元环烷基、CH2-3～6元杂环烷基、CH2-苯基、CH2-5～6元杂芳基；所述的C1～6烷基、3～6元环烷基、3～6元杂环烷基、苯基、5～6元杂芳基可任选地被Rb取代1～3次；
    其中R5可进一步与环A的环原子一起形成5～7元环，所述的5～7元可任选地被Ra取代1～3次，所述的5～7元环可为碳环、杂环、芳环、杂芳环；
    m选自0、1、2和3。
  3. 根据权利要求1或2所示化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，所述环A选自C3～6饱和或部分不饱和的单环环烃基、C8～10饱和或部分不饱和的双环环烃基、3～6元饱和或部分不饱和的单环杂环基、8～10元饱和或部分不饱和的双环杂环基、C6-10芳基、5或6元杂芳基和8～10元双环杂芳基；
    和/或，所述的环A选自吡啶、咪唑、哒嗪、恶唑、异恶唑、苯环、噻唑、嘧啶、吡嗪、喹啉、异喹啉、苯并咪唑、咪唑并吡啶和萘啶；其中，所述环A可任选地被R2取代1～3次；
    和/或，所述的环A选自 其中环A可任选地被R2取代1～3次；
    和/或，所述的环A选自 其中环A可任选地被R2取代1～3次；
    和/或，所述环A选自C3～6环烷基、3～6元杂环烷基、3～6元单环杂环烯基、8～10元双环杂环烯基、苯基、具有1、2、3或4个氮杂原子和0或1个氧或硫杂原子的5或6元杂芳基(例如吡啶、咪唑、哒嗪、噁唑、异噁唑、噻唑、嘧啶、吡嗪)和具有1、2、3、4、5或6个氮杂原子和0或1个氧或硫杂原子的8～10元双环杂芳基(例如喹啉、异喹啉、苯并咪唑、咪唑并吡啶和萘啶)；
    和/或，所述环A选自： 其中：以所示的字母“a”和“b”标识的键之一与L0连接，另一个与L1连接；Xa和Xg各自独立地选自CH2、O、S和NH；Xb、Xc、Xd、Xe、Xf和Xh分别独立地选自CH和N；并且，Xa、Xb、Xc和Xd中至少一个是可以取代的；
    和/或，所述环A选自 其中：以所示的字母“a”和“b”标识的键之一与L0连接，另一个与L1连接；Xa和Xg各自独立地选自CH2、O、S和NH；Xb、Xc、Xd、Xe、Xf和Xh分别独立地选自CH和N；并且，Xa、Xb、Xc和Xd中至少一个是可以取代的。
  4. 根据权利要求1或2所示化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，所述L0选自单键、-NH-、-CH2-、-C(O)-；
    和/或，所述L1选自-C-、-S(O)-；
    和/或，所述L2选自单键、-CH2-、-O-、-S(O)-、-NH-；所述的-CH2-和-NH-可任选地被Ra取代1～3次；
    和/或，所述L0选自单键、-NH-、-C(O)-；
    和/或，所述Y1、Y2和Y3各自独立地选自CH2、CH、NH、N、O和S，其中所述CH2、CH和NH在化合价允许的条件下任选地被R1取代1或2次；
    和/或，所述Z选自CH2、CH、NH和N，其中所述CH2、CH和NH在化合价允许的条件下任选地被R1取代1或2次；
    和/或，所述X选自NRa、O、S和S(O)2；
    和/或，其中Y1、Y2、Y3和Z各自为CH；或者Y1、Y2、Y3和Z中的一个N，其余均为CH。
  5. 根据权利要求1或2所示化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，所述结构单元部分选自：
    和/或，所述结构单元部分选自：
    和/或，所述R1选自H、N(Rb)2、CN、OH、卤素、C1～3烷基、C1～3烷氧基、C3～6环烷基、3～6元杂环烷基、苯基、5或6元杂芳基、-O-C3～6环烷基、-O-3～6元杂环烷基、-O-苯基、-O-5或6元杂芳基、-C(O)-O-C1～3烷基和-C(O)-NRaRb，其中所述C1～3烷基、C1～3烷氧基、C3～6环烷基、3～6元杂环烷基、苯基和5～6元杂芳基任选地被Ra取代1～3次；其中Ra和Rb独立地选自H和C1～6烷基，其中所述C1～6烷基任选被卤素取代1～3 次；
    和/或，所述R1选自H、NH2、-NH(C1～3烷基)、-N(C1～3烷基)2、CN、OH、F、Cl、Br、C1～3烷基、C1～3卤代烷基、C1～3烷氧基、3～6元杂环烷基、5或6元杂芳基、-O-C3～6环烷基、-O-苯基、-C(O)-O-C1～3烷基、-C(O)-NH2、-C(O)-NH(C1～3烷基)、-C(O)-N(C1～3烷基)2，其中所述C3～6环烷基、3～6元杂环烷基、苯基和5～6元杂芳基任选地被Ra取代1～3次；
    和/或，所述R1选自NH2、CN、OH、F、Cl、Br、CH3、CH2CH3、CH(CH3)CH3、CF3、甲氧基、-C(O)OCH3、-C(O)-N(CH3)2、环丙基、环丙基氧基、苯氧基；
    和/或，所述R1选自H、F、Cl、Br、CH3、CH2CH3、CH(CH3)CH3、OCH3、OH、C(O)OCH3、所述R1可任选地被Ra取代1～3次；
    和/或，所述R1选自CN、OH、F、Cl、CF3、甲氧基。
  6. 根据权利要求1或2所示化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，所述R2选自H、NH2、CN、F、Cl、甲基、乙基、-CH2F、-CHF2、-CH2CH2F、-CH2-OH、甲氧基；
    和/或，所述R2选自H、F、Cl、氰基、氧代、CH3；
    和/或，所述R3选自H、CH3、CH2CH3、CH(CH3)CH3、CH2CH2CH3、CH2CH2CH2CH3、CH2OCH3、CH2NHCH3、所述R3可任选地被Ra取代1～3次
    和/或，所述R3选自H、CH3、-CH2CH3、-CH(CH3)CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH2OCH3、-CH2NHCH3；
    和/或，其中当R3进一步与环A的环原子一起形成5～6元环，所述的5～6元环选自其中，所述的5～6元环可任选地被Ra取代1～3次。
  7. 根据权利要求1或2所示化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，所述R4选自H、CH3、CH2CH3、CH2CH2CH3、CH2CH2CH2CH3、CH2CH(CH3)CH2CH3、CH2CH2CH(CH3)CH3、CH(CH3)CH3、C(CH3)3、CN、环丙基、环丁基、环己基、环庚基、苯基、甲基-环丁基、甲基-环己基、甲基-环庚基、甲基-苯基、哌啶、吡啶、嘧啶、吡嗪、吡唑；所述R4可任选地被Rb取代1～3次；
    和/或，所述R4选自C1～4卤代烷基、C3～7环烷基、3～7元杂环烷基、-CH2-C3～7环烷基、-CH2-苯基、-CH2-5～6元杂芳基和-CH2-C(O)-3～7元杂环烷基，其中所述环烷基、杂 环烷基、苯基和杂芳基任选地被Rb取代1～3次，其中Rb独立地选自F、Cl、CN和被F或Cl取代1～3次的甲基或乙基
    和/或，所述R4选自H、CN、-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH2CH(CH3)CH2CH3、-CH2CH2CH(CH3)CH3、-CH(CH3)CH3、-C(CH3)3、-CH2CHF2、-CH2CF3、-CH2CH2CF3、-CH(CH3)CF3、-CH2CH2CH2CF3、
    和/或，所述R4选自-CH2CF3和
    和/或，所述R5选自H、CN、CH3、CH2CH3、CH(CH3)CH3、CH2CH2CH3、C(CH3)3、CH2CH2CH2CH3、CN、苯基、CH2OCH3、CH2NHCH3、 哌啶、吡啶、嘧啶；所述R3可任选地被Ra取代1～3次；
    和/或，其中当R5进一步与环A的环原子一起形成5～6元环，所述的5～6元环选自其中，所述的5～6元环可任选地被Ra取代1～3次。
  8. 根据权利要求1～7任意一项所示化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，其选自
    其中，
    环A、R1、R2、R3、R4、L2、q、m如权利要求1～7任意一项所定义。
  9. 根据权利要求1～8任意一项所示化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物选自：
    和/或，
  10. 药物组合物，其包含根据权利要求1至9中任一项所述的化合物、或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，以及药学上可接受的载体。
  11. 权利要求1至9中任一项所述的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药、或者根据权利要求10所述的药物组合物在制备作为STING抑制剂的药物中的用途。
  12. 权利要求1至9中任一项所述的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药、或者根据权利要求10所述的药物组合物在制备用于预防和/或治疗STING介导的疾病或病症及相关疾病或病症的药物中的用途。
  13. 根据权利要求12所述的用途，其中所述STING介导的疾病或病症选自：银屑病、银屑病性关节炎、接触性皮炎、特异性皮炎、白癜风、类风湿性关节炎、系统性红斑狼疮、I型糖尿病、多发性硬化、克罗恩病、炎症性肠病、溃疡性结肠炎、自身免疫性结肠炎、肠易激综合征、硬皮病、哮喘、肾小球肾炎、牙周疾病、睫状体扁平部炎、移植排异、神经退行性疾病、肥胖症、高血压、脑脊髓炎、黄斑变性、阿尔茨海默氏病、血管性痴呆、蛛网膜炎、自主神经功能障碍、肌萎缩、脑萎缩、舞蹈病、肌张力障碍、巨细胞动脉炎、面肌痉挛、带状疱疹、亨廷顿病、重症肌无力、帕金森病、闭锁综合征、腰椎间盘疾病、偏头痛、多发性硬化症。
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