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WO2024131772A1 - Composé contenant de l'oxime ayant un effet inhibiteur de sting, composition pharmaceutique de celui-ci et son utilisation - Google Patents

Composé contenant de l'oxime ayant un effet inhibiteur de sting, composition pharmaceutique de celui-ci et son utilisation Download PDF

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Publication number
WO2024131772A1
WO2024131772A1 PCT/CN2023/139786 CN2023139786W WO2024131772A1 WO 2024131772 A1 WO2024131772 A1 WO 2024131772A1 CN 2023139786 W CN2023139786 W CN 2023139786W WO 2024131772 A1 WO2024131772 A1 WO 2024131772A1
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Prior art keywords
alkyl
cycloalkyl
membered
alkylene
mmol
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PCT/CN2023/139786
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English (en)
Chinese (zh)
Inventor
贺川
翟文强
赵梦婷
刘东舟
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Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
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Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
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Priority to CN202380086853.9A priority Critical patent/CN120476113A/zh
Publication of WO2024131772A1 publication Critical patent/WO2024131772A1/fr
Anticipated expiration legal-status Critical
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present application relates to compounds having an inhibitory effect on stimulator of interferon genes (STING) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, metabolites, isotope-labeled compounds or prodrugs thereof, pharmaceutical compositions containing the same, and their use in preventing and/or treating diseases associated with abnormal STING expression.
  • STING interferon genes
  • Stimulator of interferon genes also known as transmembrane protein 173, regulatory activator of interferon regulatory factor 3, and endoplasmic reticulum interferon stimulator protein, is mainly expressed on the outer membrane of rough endoplasmic reticulum, mitochondria and microsomes of human macrophages, T lymphocytes, dendritic cells, endothelial cells, epithelial cells and fibroblasts. It can specifically recognize and bind to bacterial second messengers (cyclic di-AMP, cyclic di-GMP and cyclic 3',3'-cGAMP) and natural cyclic dinucleotide (CDN) ligands synthesized by cyclic GMP-AMP synthase (cGAS).
  • bacterial second messengers cyclic di-AMP, cyclic di-GMP and cyclic 3',3'-cGAMP
  • CDN natural cyclic dinucleotide
  • cGAS is involved in the detection of self or foreign DNA, such as pathogen DNA, tumor-derived DNA, and leaked mitochondrial or nuclear DNA. Once dsDNA is recognized, cGAS catalyzes the synthesis of GTP and ATP into 2',3'-cGAMP, leading to the activation of STING.
  • STING bound to the ligand is transported to the Golgi apparatus and initiates a cascade of downstream signals, including the recruitment of serine/threonine protein kinase (TBK1), phosphorylation of interferon-regulated transcription factor (IRF3) and nuclear factor ⁇ B (NF- ⁇ B), and the production of type I interferons and proinflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor ⁇ (TNF ⁇ ).
  • TNK1 serine/threonine protein kinase
  • IRF3 interferon-regulated transcription factor
  • NF- ⁇ B nuclear factor ⁇ B
  • type I interferons and proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor ⁇ (TNF ⁇ ).
  • STING plays an important pivotal role in the natural immune response triggered by viral, bacterial and parasitic infections, the body's tumor immunity process and cellular autophagy; it regulates protein synthesis and IFN expression through its own phosphorylation, ubiquitination and dimerization modification, and plays a key role in multiple immune links of the body.
  • Many viruses can interact with signaling proteins in the cGAS-STING pathway, thereby stimulating the body to produce interferons in quantities that vary from normal immune responses, causing viral proliferation or autoimmune diseases; tumor cell proliferation can activate STING in antigen-presenting cells, thereby activating T cell-mediated adaptive immune processes and exerting anti-tumor effects.
  • STING agonists cyclic dinucleotide (CDN) derivatives and non-nucleotide small molecules
  • STING inhibitors covalent inhibitors and non-covalent inhibitors
  • STING indirect regulators whose mechanisms are not clear.
  • the present application provides a compound of the present invention (such as a compound of Formula I-A as defined below) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof.
  • the compounds of the present invention have STING inhibitory activity and can be used to prevent and/or treat STING-mediated diseases or conditions, including conditions, diseases or disorders (e.g., autoimmune diseases or cancer) involving STING activation (e.g., overactivated STING signaling).
  • the compounds of the present 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 cardiac toxicity) and/or fewer side effects), less prone to drug resistance and other more excellent properties.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the present application provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, for use as a drug.
  • the present application provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, which is used as a STING inhibitor.
  • the present application provides use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament as a STING inhibitor.
  • the present application provides use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for preventing and/or treating STING-mediated diseases or disorders and related diseases or disorders.
  • the present application provides a method for preventing and/or treating a STING-mediated disease or condition and related diseases or conditions in an individual, comprising administering to the individual a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention.
  • the STING-mediated disease or condition is selected from:
  • Tumors and/or cancers including 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 intestine cancer, kidney cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, mesothelioma, lymphoma, leukemia, myelodysplastic syndrome, multiple myeloma, plasmacytoma, neuroblastoma, retinoblastoma, and germ cell tumor;
  • Central nervous system, peripheral nervous system and autonomic nervous system diseases or disorders including but not limited to epileptic aphasia, encephalomyelitis, macular degeneration, Alpers disease, corpus callosum agenesis, Aicardi syndrome, alternating hemiplegia, Alzheimer's disease, vascular dementia, amyotrophic lateral sclerosis, arachnoid cysts, meningitis, Asperger syndrome, ataxia teleectasia, attention deficit hyperactivity disorder, autism, autonomic dysfunction, muscular atrophy, benign intracranial hypertension, Binswanger disease, brain atrophy, brain gigantism, cerebral arteriosclerosis, chorea, chronic inflammatory demyelinating polyneuropathy, congenital facial palsy, cortical basal degeneration, cranial arteritis, Craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing syndrome, giant cell inclusion disease, diabetic neuropathy, diffuse sclerosis, dystonia, giant
  • STING-associated conditions including type I interferonopathies, Aicardi-Goutines syndrome (AGS), lupus, and rheumatoid arthritis;
  • Autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Crohn's disease (CD), inflammatory bowel disease (IBD), ulcerative colitis (UC), autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by adoptive cell therapy treatment, irritable bowel syndrome, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis; and
  • Psoriatic arthritis contact dermatitis, atopic dermatitis, vitiligo, type 1 diabetes, asthma, glomerulonephritis, periodontal disease, pars planitis, transplant rejection, neurodegenerative diseases, obesity, hypertension.
  • the present application provides a compound of the following formula IA:
  • L 0 is selected from -NH-, -NH-C(O)-NH-, -NH-S(O)- and -NH-S(O) 2 -;
  • L is selected from C, S and S(O);
  • L 2 is selected from a single bond, -CH 2 -, -O-, -S(O) 0-2 - and -NH-, wherein said -CH 2 - and -NH- are optionally substituted 1 to 3 times by Ra ;
  • Ring A is selected from C 3-10 saturated or partially unsaturated monocyclic or bicyclic cycloalkyl, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic group, C 6-10 aryl group and 5-10 membered monocyclic or bicyclic heteroaryl group;
  • Ring B is selected from C 3-6 saturated or partially unsaturated monocyclic hydrocarbon group, 3-6 membered saturated or partially unsaturated monocyclic heterocyclic group, phenyl group and 5 or 6 membered heteroaryl group;
  • X is selected from CR a R b , NR a , O, S and S(O) 2 ;
  • Q is selected from CR a and N;
  • R1 is selected from the group consisting of H, N( Rb ) 2 , CN, OH, halogen, C1 ⁇ 6 alkyl, C1 ⁇ 6 alkoxy, C3 ⁇ 6 cycloalkyl, 3 ⁇ 6 membered heterocycloalkyl, C6-10 aryl, 5 ⁇ 10 membered heteroaryl, -OC3 ⁇ 6 cycloalkyl, -O-3 ⁇ 6 membered heterocycloalkyl, -OC6-10 aryl, -O-5 ⁇ 10 membered heteroaryl, -C(O)-OC1 ⁇ 6 alkyl, -C(O)-NRaRb, -NRb - C (O) -C1 ⁇ 6 alkyl, -S(O)-C1 ⁇ 6 alkyl, -S(O)2-C1 ⁇ 6 alkyl, -S(O)-OC1 ⁇ 6 alkyl, -S(O)-NRaRb, -S(O)
  • R2 is selected from H, N( Rb ) 2 , CN, OH, halogen, C1-6 alkyl, C1-6 alkoxy , oxo, -C(O) -NRaRb , -NRb -C (O) -C1-6 alkyl , -C1-3 alkyl-NH( C1-3 alkyl), -C1-3 alkyl-N( C1-3 alkyl) 2 , -S(O) -C1-6 alkyl, -S(O) 2 - C1-6 alkyl, -S(O) -OC1-6 alkyl, -S(O)-NRaRb, -S(O) 2 - OC1-6 alkyl, -S(O) 2- NRaRb, C3-10 saturated or partially unsaturated cycloalkyl, 5-10 membered saturated or partially unsaturated heterocyclic group, C 6-10 membered aryl and 5-10 membered heteroaromatic groups, wherein the alky
  • R3 is selected from H, C1 ⁇ 6 alkyl, C3 ⁇ 6 cycloalkyl, 3 ⁇ 6 membered heterocycloalkyl, -C1 ⁇ 6 alkylene-OC1 ⁇ 6 alkyl, -C1 ⁇ 6 alkylene-NH-C1 ⁇ 6 alkyl, -C1 ⁇ 6 alkylene -N(C1 ⁇ 6 alkyl) 2 , -C1 ⁇ 6 alkylene-C3 ⁇ 6 cycloalkyl, -C1 ⁇ 6 alkylene-3 ⁇ 6 membered heterocycloalkyl, -C1 ⁇ 6 alkylene- C6-10 aryl and -C1 ⁇ 6 alkylene-5 or 6 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted 1 to 3 times by Ra , and
  • R 3 is optionally linked to a ring atom of ring A to form a C 3-7 saturated or partially unsaturated monocyclic cycloalkyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl, a phenyl, or a 5- or 6-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted 1 to 3 times by Ra ;
  • R4 is selected from H, CN, OH, NH2 , halogen, C1 ⁇ 6 alkyl, -C1 ⁇ 6 alkylene- OC1 ⁇ 6 alkyl, -C1 ⁇ 6 alkylene-NH-C1 ⁇ 6 alkyl, C3 ⁇ 10 cycloalkyl, C7 ⁇ 12 spirocycloalkyl, C7-10 bridged cycloalkyl, 3 ⁇ 10 membered heterocycloalkyl, 5-12 membered spiroheterocycloalkyl, 6 to 9 membered bridged heterocycloalkyl, C6 ⁇ 10 aryl, 5 ⁇ 10 membered heteroaryl, -C1 ⁇ 6 alkylene- C3 ⁇ 7 cycloalkyl, -C1 ⁇ 6 alkylene-3 ⁇ 7 membered heterocycloalkyl, -C1 ⁇ 6 alkylene -C6 ⁇ 10 aryl, -C1 ⁇ 6 alkylene-5 ⁇
  • p is selected from 1, 2 and 3;
  • q is selected from 0, 1, 2 and 3;
  • Ra is independently selected from H, halogen, NH2 , OH, CN, C1-6 alkyl, -C(O) -Rc , -S(O) -Rc , -S(O) 2- Rc , -C(O)-ORc, -S (O) -ORc , -S(O) 2 - ORc , -C(O) -NHRc , -S(O) -NHRc and -S(O) 2 - NHRc , wherein the C1-6 alkyl is optionally substituted 1 to 3 times by halogen;
  • R b is independently selected from H, halogen, NH 2 , OH, CN, C 1-6 alkyl and C 1-6 alkoxy, wherein the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted 1 to 3 times by halogen; and
  • R c is independently selected from C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl optionally substituted with NH 2 , OH, CN and 1 to 3 halogens.
  • R 1 is selected from H, N(R b ) 2 , CN, OH, halogen, C 1 ⁇ 6 alkyl, C 1 ⁇ 6 alkoxy, C 3 ⁇ 6 cycloalkyl, 3 ⁇ 6 membered heterocycloalkyl, C 6-10 aryl, 5 ⁇ 10 membered heteroaryl, -OC 3 ⁇ 6 cycloalkyl, -O-3 ⁇ 6 membered heterocycloalkyl, -OC 6-10 aryl, -O-5 ⁇ 10 membered heteroaryl, -C(O)-OC 1 ⁇ 6 alkyl, -C(O)-NR a R b , -NR b -C(O)-C 1 ⁇ 6 alkyl, and -S(O) 2 -C 1 ⁇ 6 alkyl, wherein the C 1 ⁇ 6 alkyl, C 1 ⁇ 6 alkoxy, C 3 ⁇ 6 cycloalkyl, 3 ⁇ 6 membered heterocycloalkyl, C 6-10 aryl, 5
  • R 2 is selected from H, N(R b ) 2 , CN, OH, halogen, C 1 ⁇ 6 alkyl, C 1 ⁇ 6 alkoxy, oxo, -C(O)-NR a R b , -NR b -C(O)-C 1 ⁇ 6 alkyl, C 1 ⁇ 3 alkyl-NH(C 1 ⁇ 3 alkyl), -C 1 ⁇ 3 alkyl-N(C 1 ⁇ 3 alkyl) 2 , -S(O) 2 -C 1 ⁇ 6 alkyl, C 3 ⁇ 10 saturated or partially unsaturated cycloalkyl, 5 ⁇ 10 membered saturated or partially unsaturated heterocyclyl, C 6-10 aryl and 5 ⁇ 10 membered heteroaromatic, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaromatic are optionally substituted 1 to 3 times by Ra .
  • R4 is selected from H, CN, OH, NH2 , halogen, C1 ⁇ 6 alkyl, -C1 ⁇ 6 alkylene-OC1 ⁇ 6 alkyl, -C1 ⁇ 6 alkylene-NH-C1 ⁇ 6 alkyl , C3 ⁇ 10 cycloalkyl, 3 ⁇ 7 membered heterocycloalkyl, 7-11 membered spiroheterocycloalkyl, C6 ⁇ 10 aryl, 5 ⁇ 10 membered heteroaryl, -C1 ⁇ 6 alkylene- C3 ⁇ 7 cycloalkyl, -C1 ⁇ 6 alkylene-3 ⁇ 7 membered heterocycloalkyl, -C1 ⁇ 6 alkylene-C6 ⁇ 10 aryl, -C1 ⁇ 6 alkylene-5 ⁇ 10 membered heteroaryl, -C1 ⁇ 6 alkylene-C(O)-C3 ⁇ 7 cycloalkyl, -C
  • R 1 is selected from H, N(R b ) 2 , CN, OH, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OC 3-6 cycloalkyl, -O-3-6 membered heterocycloalkyl, -OC 6-10 aryl, -O-5-10 membered heteroaryl, -C(O)-OC 1-6 alkyl, -C(O)-NR a R b and -NR b -C(O)-C 1-6 alkyl, wherein said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted 1 to 3 times by Ra ; and/or
  • R 2 is selected from H, N(R b ) 2 , CN, OH, halogen, C 1-6 alkyl, C 1-6 alkoxy, oxo, -C(O)-NR a R b , -NR b -C(O)-C 1-6 alkyl, C 3-10 saturated or partially unsaturated cycloalkyl, 5-10 membered saturated or partially unsaturated heterocyclyl, C 6-10 aryl and 5-10 membered heteroaromatic, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaromatic are optionally substituted 1 to 3 times by Ra ; and/or
  • R4 is selected from H, CN, OH, NH2 , halogen, C1 ⁇ 6 alkyl, -C1 ⁇ 6 alkylene-OC1 ⁇ 6 alkyl , -C1 ⁇ 6 alkylene-NH-C1 ⁇ 6 alkyl, C3 ⁇ 7 cycloalkyl, 3 ⁇ 7 membered heterocycloalkyl, C6 ⁇ 10 aryl, 5 ⁇ 10 membered heteroaryl, -C1 ⁇ 6 alkylene- C3 ⁇ 7 cycloalkyl, -C1 ⁇ 6 alkylene-3 ⁇ 7 membered heterocycloalkyl, -C1 ⁇ 6 alkylene- C6 ⁇ 10 aryl, -C1 ⁇ 6 alkylene-5 ⁇ 10 membered heteroaryl, -C1 ⁇ 6 alkylene-C(O) -C3 ⁇ 7 cycloalkyl, -C1 ⁇ 6 alkylene-C(O)-3 ⁇ 7 membered heterocycloalky
  • L 0 is -NH-.
  • the compound of Formula IA has a structure shown in Formula IB or Formula IC:
  • Ring B is selected from a C 6 saturated or partially unsaturated monocyclic cycloalkyl, a 6-membered saturated or partially unsaturated monocyclic heterocyclyl, a phenyl group, and a 6-membered heteroaryl group.
  • the Part of The compound of formula IA has the structure shown in formula ID or IE:
  • Y 1 , Y 2 and Y 3 are each independently selected from CH 2 , CH, NH, N, O and S, wherein said CH 2 , CH and NH are optionally substituted 1 or 2 times by R 1 as valency permits; and
  • Z is selected from CH 2 , CH, NH and N, wherein said CH 2 , CH and NH are optionally substituted 1 or 2 times by R 1 as valency permits.
  • the compound of Formula IA has a structure shown in Formula IF or IG:
  • Y 1 , Y 2 , Y 3 and Z are each CH; or one N among Y 1 , Y 2 , Y 3 and Z is CH.
  • X is selected from NR a , O, S, and S(O) 2 , wherein:
  • Ra is selected from H, C1-6 alkyl, -C(O) -Rc , -S(O) -Rc and -S(O) 2 - Rc , wherein the C1-6 alkyl is optionally substituted 1 to 3 times by halogen, and
  • R c is selected from C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl optionally substituted by NH 2 , OH, CN and 1 to 3 halogens.
  • X is selected from NR a , O, S and S(O) 2 , wherein:
  • Ra is selected from H, C1-3 alkyl, -C(O) -Rc , -S(O) -Rc and -S(O) 2 - Rc , wherein the C1-3 alkyl is optionally substituted 1 to 3 times by F, Cl, Br or I, and
  • R c is selected from C 1-3 alkyl, C 2-3 alkenyl and C 2-3 alkynyl optionally substituted by NH 2 , OH, CN and 1 to 3 halogens.
  • X is selected from NR a , O, S and S(O) 2 , wherein:
  • R a is selected from H, C 1-3 alkyl and -C(O)-R c , and
  • R c is selected from C 1-3 alkyl, C 2-3 alkenyl and C 2-3 alkynyl.
  • Q is selected from CR a and N, wherein R a is selected from H, halogen, NH 2 , OH, CN, and C 1-6 alkyl, and wherein the C 1-6 alkyl is optionally substituted 1 to 3 times with halogen.
  • Q is selected from CR a and N, wherein R a is selected from H and C 1-3 alkyl, and wherein the C 1-3 alkyl is optionally substituted 1 to 3 times with halogen.
  • Q is selected from CH and N.
  • R 1 is selected from H, N(R b ) 2 , CN, OH, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OC 3-6 cycloalkyl, -O-3-6 membered heterocycloalkyl, -OC 6-10 aryl, -O-5-10 membered heteroaryl, -C(O)-OC 1-6 alkyl, -C(O)-NR a R b and -S(O) 2 -C 1-6 alkyl, wherein said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl , 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted 1 to 3 times by Ra ,
  • R 1 is selected from H, N(R b ) 2 , CN, OH, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OC 3-6 cycloalkyl, -O-3-6 membered heterocycloalkyl, -OC 6-10 aryl, -O-5-10 membered heteroaryl, -C(O)-OC 1-6 alkyl, -C(O)-NR a R b and -S(O) 2 -C 1-6 alkyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted 1 to 3 times by Ra ,
  • R 1 is selected from H, N(R b ) 2 , CN, OH, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -OC 3-6 cycloalkyl, -O-3-6 membered heterocycloalkyl, -O-phenyl, -O-5- or 6-membered heteroaryl, -C(O)-OC 1-3 alkyl and -C(O)-NR a R b , wherein the C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally substituted 1 to 3 times by Ra ,
  • Ra and Rb are independently selected from H and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted 1 to 3 times by halogen.
  • R 1 is selected from H, N(R b ) 2 , CN, OH, F, Cl, Br, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -OC 3-6 cycloalkyl, -O-3-6 membered heterocycloalkyl, -O-phenyl, -O-5- or 6-membered heteroaryl, -C(O)-OC 1-3 alkyl and -C(O)-NR a R b , wherein the C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally substituted 1 to 3 times by Ra ,
  • Ra and Rb are independently selected from H and C1-3 alkyl, preferably H, methyl and ethyl.
  • 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 ⁇ 3 alkyl, C 1 ⁇ 3 haloalkyl, C 1 ⁇ 3 alkoxy, 3 ⁇ 6 membered heterocycloalkyl, 5 or 6 membered heteroaryl, -OC 3 ⁇ 6 cycloalkyl, -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 times by Ra .
  • 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 , -S(O) 2 -CH 3 , cyclopropyl, Cyclopropyloxy, phenoxy and
  • 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 and
  • R 1 is selected from CN, OH, F, Cl, CF 3 , methoxy, -C(O)OCH 3 , -C(O)-N(CH 3 ) 2 , Cyclopropyloxy, phenoxy and
  • Ra is as defined above in any of the embodiments.
  • Ra is as defined above in any of the embodiments.
  • the compound of Formula IA has the structure shown in Formula IH to IO:
  • Ra is as defined above in any of the embodiments.
  • the ring A is selected from a C 3-6 saturated or partially unsaturated monocyclic cycloalkyl, a C 8-10 saturated or partially unsaturated bicyclic cycloalkyl, a 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl, an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl, a C 6-10 aryl, a 5- or 6-membered heteroaryl, and an 8-10 membered bicyclic heteroaryl.
  • the ring A is selected from C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered monocyclic heterocycloalkenyl, 8-10 membered bicyclic heterocycloalkenyl, phenyl, 5- or 6-membered heteroaryl having 1, 2, 3 or 4 nitrogen heteroatoms and 0 or 1 oxygen or sulfur heteroatoms, and 8-10 membered bicyclic heteroaryl having 1, 2, 3, 4, 5 or 6 nitrogen heteroatoms and 0 or 1 oxygen or sulfur heteroatoms.
  • the ring A is selected from:
  • Xa and Xg are each independently selected from CH2 , O, S and NH;
  • Xb , Xc, Xd , Xe , Xf and Xh are each independently selected from CH and N;
  • At least one of Xa , Xb , Xc and Xd may be substituted.
  • the ring A is selected from:
  • the ring A is selected from:
  • the ring A is selected from:
  • the ring A is preferably selected from:
  • the bond shown identified with the letter “a” is attached to L 0
  • the bond shown identified with the letter “b” is attached to L 1 .
  • R 2 is selected from H, N(R b ) 2 , CN, OH, halogen, C 1-6 alkyl, C 1-6 alkoxy, oxo, -C(O)-NR a R b , -NR b -C(O)-C 1-6 alkyl, C 1-3 alkyl-NH(C 1-3 alkyl), -C 1-3 alkyl-N(C 1-3 alkyl) 2 , -S(O) 2 -C 1-6 alkyl, C 3-6 saturated or partially unsaturated cycloalkyl, 5-6 membered saturated or partially unsaturated heterocyclyl, phenyl and 5-6 membered aromatic heteroyl,
  • it is selected from H, N(R b ) 2 , CN, OH, halogen, C 1-6 alkyl, C 1-6 alkoxy, oxo, -C(O)-NR a R b , -NR b -C(O)-C 1-6 alkyl, C 3-6 saturated or partially unsaturated cycloalkyl, 5-6 membered saturated or partially unsaturated heterocyclic group, phenyl and 5-6 membered aromatic heteroyl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic group, phenyl and aromatic heteroyl are optionally substituted 1 to 3 times by Ra ,
  • Ra is selected from H, halogen, NH2 , OH, CN and C1-6 alkyl
  • R b is selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted 1 to 3 times by halogen.
  • R 2 is selected from H, NH 2 , NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , CN, OH, halogen, C 1-3 alkyl, C 1-3 alkoxy, oxo, -C(O)-NR a R b , -NR b -C(O)-C 1-3 alkyl, and a 5-6 membered aromatic hetero group having 1, 2 or 3 nitrogen hetero atoms and 0 or 1 oxygen or sulfur hetero atoms, wherein the alkyl and aromatic hetero groups are optionally substituted 1 to 3 times by Ra ,
  • Ra is selected from H, F, Cl, NH2 , OH, CN and C1-3 alkyl
  • R b is selected from H and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted 1-3 times by F or Cl.
  • R 2 is preferably selected from C 3-6 cycloalkyl.
  • R 2 is selected from H, NH 2 , NH (C 1-3 alkyl), N (C 1-3 alkyl) 2 , CN, OH, F, Cl, Br, C 1-3 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl and OH, C 1-3 alkoxy, oxo, -C (O) -NH (C 1-3 alkyl), -C (O) -N (C 1-3 alkyl) 2 and pyrrole, pyrazolyl or triazolyl optionally substituted by 1 substituent selected from C 1-3 alkyl.
  • R 2 is preferably selected from -C (O) -NH 2 , cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R2 is selected from H, NH2 , -NHCH3 , CN, OH, F, Cl, methyl, ethyl, -CH2F , -CHF2 , -CH2CH2F, -CH2 - OH , methoxy, oxo, -C(O) -NHCH3 , -C(O)-N( CH3 ) 2 , and Additionally or alternatively, R 2 is preferably selected from cyclopropyl, -CH 2 -NH(CH 3 ), -CH 2 -N(CH 3 ) 2 , -S(O) 2 -CH 3 and -C(O)-NH 2 .
  • R 2 is selected from -S(O)-C 1-6 alkyl, -S(O) 2 -C 1-6 alkyl
  • p is 1 or 2
  • q is 0, 1 or 2.
  • L 1 is selected from C and S(O).
  • R3 is selected from H, C1 ⁇ 6 alkyl, C3 ⁇ 6 cycloalkyl, 3 ⁇ 6 membered heterocycloalkyl, -C1 ⁇ 3 alkylene- OC1 ⁇ 6 alkyl, -C1 ⁇ 3 alkylene-NH-C1 ⁇ 6 alkyl, -C1 ⁇ 3 alkylene-N(C1 ⁇ 6 alkyl) 2 , -C1 ⁇ 3 alkylene-C3 ⁇ 6 cycloalkyl, -C1 ⁇ 3 alkylene-3 ⁇ 6 membered heterocycloalkyl, -C1 ⁇ 3 alkylene-phenyl and -C1 ⁇ 3 alkylene-5 or 6 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted 1 to 3 times by Ra ,
  • R3 is selected from H, C1 ⁇ 6 alkyl, C3 ⁇ 6 cycloalkyl, 3 ⁇ 6 membered heterocycloalkyl, -C1 ⁇ 3 alkylene-OC1 ⁇ 6 alkyl, -C1 ⁇ 3 alkylene-NH-C1 ⁇ 6 alkyl, -C1 ⁇ 3 alkylene-N(C1 ⁇ 3 alkyl) 2 , -C1 ⁇ 3 alkylene- C3 ⁇ 6 cycloalkyl and -C1 ⁇ 3 alkylene-3 ⁇ 6 membered heterocycloalkyl, wherein the alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted 1 to 3 times by Ra ,
  • Ra is selected from halogen, NH2 , OH, CN and C1-6 alkyl.
  • R 3 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -CH 2 -OC 1-6 alkyl, -CH 2 -NH-C 1-6 alkyl, -CH 2 -C 3-6 cycloalkyl and -CH 2 -3-6 membered heterocycloalkyl, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally substituted 1 to 3 times by Ra ,
  • Ra is selected from the group consisting of F, Cl, NH2 , OH and CN, preferably F.
  • 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 ,
  • R is linked to a ring atom of ring A at the ortho position to L to form a C3-7 saturated or partially unsaturated monocyclic cycloalkyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl, a phenyl, or a 5- or 6-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted 1 to 3 times by Ra .
  • R3 is connected to the ring atom of ring A in the ortho position to L1 to form a C5-6 saturated or partially unsaturated monocyclic cycloalkyl, or a 5- or 6-membered saturated or partially unsaturated monocyclic heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted 1 to 3 times by Ra .
  • R 3 is linked to a ring atom of ring A at an ortho position to L 1 to form a ring structure selected from the following, which is optionally substituted 1 to 3 times by Ra :
  • the ring atoms identified with the letters "c” and “d” as shown are ring atoms of the ring A, and the double bond identified with the letter “e” as shown is connected to the N atom to which L1 and L2 are connected.
  • the ring A, L 1 and R 3 together form a structure selected from the group consisting of:
  • the double bond identified by the letter “e” as shown is connected to the N atom connected to L 1 and L 2 , and the double bond identified by the letter “f” as shown is connected to L 0 .
  • L 2 is selected from a single bond, -CH 2 -, -O-, and S(O), wherein said -CH 2 - is optionally substituted 1 to 3 times by Ra .
  • R4 is selected from:
  • R4 is selected from H, CN, OH, NH2 , halogen, C1 ⁇ 6 alkyl, -C1 ⁇ 3 alkylene- OC1 ⁇ 6 alkyl, -C1 ⁇ 3 alkylene-NH-C1 ⁇ 6 alkyl, C3 ⁇ 10 (preferably C3 ⁇ 7 ) cycloalkyl, 3 ⁇ 7 membered heterocycloalkyl, 7-11 membered spiroheterocycloalkyl, phenyl, 5 ⁇ 6 membered heteroaryl, -C1 ⁇ 3 alkylene-C3 ⁇ 7 cycloalkyl, -C1 ⁇ 3 alkylene-3 ⁇ 7 membered heterocycloalkyl, -C1 ⁇ 3 alkylene-phenyl, -C1 ⁇ 3 alkylene-5 ⁇ 6 membered heteroaryl, -C1 ⁇ 3 alkylene-C(O)-C3 ⁇ 7 cycloalkyl, -C1 ⁇ 3
  • H CN, OH, NH2 , halogen, C1-6 alkyl, -C1-3 alkylene- OC1-6 alkyl, -C1-3 alkylene-NH- C1-6 alkyl, C3-7 cycloalkyl, 3-7 -membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl , -C1-3 alkylene-C3-7 cycloalkyl, -C1-3 alkylene -3-7 -membered heterocycloalkyl , -C1-3 alkylene-phenyl, -C1-3 alkylene -5-6-membered heteroaryl, -C1-3 alkylene-C(O) -C3-7 cycloalkyl, -C1-3 alkylene-C(O)-3-7-membered heterocycloalkyl, -C1-3 alkylene-C(O)-phenyl and -C1-3 1-3 alkylene-C(O)-5-6 membered heteroary
  • R b is independently selected from F, Cl, Br, NH 2 , OH, CN, C 1-6 alkyl and C 1-6 alkoxy, wherein the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted 1 to 3 times by F, Cl or Br.
  • R4 is selected from:
  • R b is substituted 1 to 3 times ,
  • H CN, C 1-6 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C 1-3 alkylene-C 3-7 cycloalkyl, -C 1-3 alkylene-3-7 membered heterocycloalkyl, -C 1-3 alkylene-phenyl, -C 1-3 alkylene-5-6 membered heteroaryl, -C 1-3 alkylene-C(O)-C 3-7 cycloalkyl, -C 1-3 alkylene-C(O)-3-7 membered heterocycloalkyl, -C 1-3 alkylene-C(O)-phenyl and -C 1-3 alkylene - C(O)-5-6 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted 1 to 3 times by R
  • R b is independently selected from F, Cl, NH 2 , OH, CN and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted 1 to 3 times by F or Cl.
  • R4 is selected from 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 , (include ), Additionally or alternatively, R4 is selected from (include ).
  • the present application provides a compound of formula I-F or I-G as described above, wherein:
  • R1 is selected from H, CN, halogen, C1-6 haloalkyl, C1-6 alkoxy, 3-6 membered heterocycloalkyl, 5- or 6-membered heteroaryl, -C(O)-NH( C1-3 alkyl) and -C(O)-N(C 1-3 alkyl) 2 , wherein the 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted by Ra with a C 1-6 alkyl substituent;
  • p 1 or 2;
  • the ring A is selected from
  • R2 is selected from H, NH2 , CN, OH, halogen, C1-6 alkyl, C1-6 alkoxy, oxo , -C(O) -NRaRb , phenyl and 5-6 membered aromatic hetero groups, wherein the alkyl, alkoxy, phenyl and aromatic hetero groups are optionally substituted 1 to 3 times by Ra ,
  • Ra is selected from H, halogen, OH and C1-6 alkyl
  • R b is selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted 1 to 3 times by halogen;
  • q 0, 1, or 2;
  • L 1 is C
  • R 3 is selected from H, C 1-6 alkyl and C 3-6 cycloalkyl
  • R3 is linked to a ring atom of ring A in an ortho position to L1 , so that ring A, L1 and R3 together form wherein the double bond identified by the letter “e” as shown is connected to the N atom connected to L 1 and L 2 , and the double bond identified by the letter “f” as shown is connected to the NH as L 0 ;
  • L2 is -O-
  • R is selected from C1-6 haloalkyl, C3-10 cycloalkyl, 3-7 membered heterocycloalkyl, 7-11 membered spiroheterocycloalkyl , -C1-6 alkylene-C3-7 cycloalkyl, -C1-6 alkylene -3-7 membered heterocycloalkyl, -C1-3 alkylene-phenyl, -C1-3 alkylene-5-6 membered heteroaryl, -C1-6 alkylene-C(O) -C3-7 cycloalkyl, -C1-6 alkylene-C(O) -3-7 membered heterocycloalkyl, -C1-6 alkylene-C(O)-phenyl and -C1-6 alkylene-C(O) -5-6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, spiroheterocycloalkyl, phenyl and heteroaryl are optionally substituted 1 to 3
  • R b is independently selected from F, Cl, CN and C 1-3 alkyl substituted 1 to 3 times by F or Cl.
  • the Partially selected is the Partially selected
  • R 1 is selected from H, CN, F, Cl, C 1-3 haloalkyl, C 1-3 alkoxy, 3-6 membered heterocycloalkyl, 5- or 6-membered heteroaryl, and -C(O)-N(C 1-3 alkyl) 2 , wherein the 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted 1-3 times by C 1-3 alkyl;
  • R 1 is selected from H, CN, F, Cl, CF 3 , methoxy, -C(O)-N(CH 3 ) 2 ,
  • the ring A is selected from
  • the ring A is selected from
  • the ring A is selected from
  • R 2 is selected from H, NH 2 , CN, OH, F, Cl, C 1-3 alkoxy, oxo, -C(O)-NH(C 1-3 alkyl), -C(O)-N(C 1-3 alkyl) 2 , C 1-3 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl and OH, and pyrrole, pyrazolyl or triazolyl optionally substituted with 1 substituent selected from C 1-3 alkyl.
  • R 2 is selected from H, F, CN, OH, NH 2 , oxo, methoxy, methyl, ethyl, -CHF 2 , -CH 2 CH 2 F, -CH 2 -OH, -C(O)-NHCH 3 , -C(O)-N(CH 3 ) 2 and
  • R 3 is selected from H, CH 3 , -CH 2 CH 3 , -CH(CH 3 )CH 3 , -CH 2 CH 2 CH 3 and
  • R 3 is attached to a ring atom of Ring A at an ortho position to L 1 , such that Ring A, L 1 and R 3 together form
  • R 3 is attached to a ring atom of Ring A at an ortho position to L 1 , such that Ring A, L 1 and R 3 together form
  • R4 is selected from C1 ⁇ 6 haloalkyl, C3 ⁇ 7 cycloalkyl, 3 ⁇ 7 membered heterocycloalkyl, -C1 ⁇ 6 alkylene-C3 ⁇ 7 cycloalkyl, -C1 ⁇ 6 alkylene-3 ⁇ 7 membered heterocycloalkyl, -C1 ⁇ 3 alkylene-phenyl, -C1 ⁇ 3 alkylene-5 ⁇ 6 membered heteroaryl, -C1 ⁇ 6 alkylene-C(O)-C3 ⁇ 7 cycloalkyl, -C1 ⁇ 6 alkylene-C(O)-3 ⁇ 7 membered heterocycloalkyl, -C1 ⁇ 6 alkylene-C(O)-phenyl and -C1 ⁇ 6 alkylene-C(O)-5 ⁇ 6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl
  • R 4 is selected from C 1-4 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, 7-11 membered spiroheterocycloalkyl, -CH 2 -C 3-7 cycloalkyl, -CH 2 -phenyl, -CH 2 -5-6 membered heteroaryl and -CH 2 -C(O)-3-7 membered heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, spiroheterocycloalkylphenyl and heteroaryl are optionally substituted 1 to 3 times by R b ,
  • R b is independently selected from F, Cl, CN, and a methyl or ethyl group substituted 1 to 3 times by F or Cl.
  • R4 is selected from C1-4 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocycloalkyl, -CH2 -C3-7 cycloalkyl, -CH2 -phenyl, -CH2-5-6 membered heteroaryl and -CH2 -C(O) -3-7 membered heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted 1 to 3 times by Rb ,
  • R b is independently selected from F, Cl, CN, and a methyl or ethyl group substituted 1 to 3 times by F or Cl.
  • R 4 is selected from -CH 2 CF 3 , -CH 2 CH 2 CH 2 CF 3 , (include ),
  • R 4 is selected from -CH 2 CF 3 , -CH 2 CH 2 CH 2 CF 3 , (include ),
  • R4 is selected from (include ).
  • L 0 is selected from -NH-, -NH-C(O)-NH- and NH-S(O) 1-2 -;
  • L 1 is selected from -C- and -S(O) 0-2 -;
  • L 2 is selected from a single bond, -CH 2 -, -O-, -S(O) 0-2 - and -NH-, wherein said -CH 2 -, -NH- and -S(O) 0-2 - may be optionally substituted 1 to 3 times by Ra ;
  • Ring A is a monocyclic or bicyclic ring structure, wherein the monocyclic ring is selected from a 4-6 membered carbocyclic ring, a 4-6 membered heterocyclic ring, a 5-6 membered aromatic heterocyclic ring and a 5-6 membered aromatic ring, and the bicyclic ring is selected from a 7-10 membered fused ring or fused heterocyclic ring formed by condensing any two independent ones of a 4-6 membered carbocyclic ring, a 4-6 membered heterocyclic ring, a 5-6 membered aromatic heterocyclic ring and a 5-6 membered aromatic ring;
  • Ring B is selected from a 5- to 7-membered carbocyclic ring, a 5- to 7-membered heterocyclic ring, a 5- to 7-membered aromatic heterocyclic ring, and a 5- to 6-membered aromatic ring;
  • X is selected from -CH 2 -, -NH-, -O- and -S-, wherein said -CH 2 - and -NH- may be optionally substituted 1 to 2 times by Ra ;
  • 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 and -C(O)-OC 1-6 alkyl, wherein the C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl may be optionally substituted 1 to 3 times by Ra;
  • R 2 is selected from H, N(R b ) 2 , CN, C(O), S(O) 0-2 , halogen, C 1-3 alkyl and C 1-3 alkoxy, wherein the C 1-3 alkyl and C 1-3 alkoxy may be optionally substituted 1 to 3 times by Ra ;
  • R 3 is selected from H, C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, CH 2 -OC 1-6 alkyl, CH 2 -NH-C 1-6 alkyl, CH 2 -3-6 membered cycloalkyl and CH 2 -3-6 membered heterocycloalkyl, wherein the C 1-6 alkyl, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl may be optionally substituted 1 to 3 times by R a ;
  • R 3 may further form a 5- to 7-membered ring together with the ring atoms of ring A, wherein the 5- to 7-membered ring may be optionally substituted 1 to 3 times by Ra , and the 5- to 7-membered ring may be a carbocyclic ring, a heterocyclic ring, an aromatic ring, or a heteroaromatic ring;
  • R4 is selected from H, CN, C1-6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C1-3 alkylene-3-7 membered cycloalkyl, -C1-3 alkylene-3-7 membered heterocycloalkyl, -C1-3 alkylene-phenyl and -C1-3 alkylene- 5-6 membered heteroaryl, wherein the C1-6 alkyl , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl may be optionally substituted 1 to 3 times by Rb ;
  • p is selected from 1, 2 and 3;
  • q is selected from 0, 1, 2 and 3;
  • Ra is independently selected from H, F, Cl and C1-3 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, wherein the C 1-3 alkyl and C 1-3 alkoxy are optionally substituted 1 to 3 times by halogen.
  • X is selected from -CH 2 -, -NH-, -O- and -S-, wherein said -CH 2 - and -NH- may be optionally substituted 1 to 2 times by Ra ;
  • Y 1 , Y 2 , and Y 3 are independently selected from -CH 2 -, -NH-, -O-, and -S-, wherein the H in -CH 2 - and -NH- may be optionally substituted by R 1 once or twice under conditions permitting by chemical valence;
  • Z is selected from -CH 2 - and -NH-, wherein the H in said -CH 2 - and -NH- can be optionally substituted 1 or 2 times by R 1 under the conditions permitted by chemical valence;
  • L is selected from -C- and -S(O)-;
  • L 2 is selected from a single bond, -CH 2 -, -O-, -S(O)- and -NH-, wherein said -CH 2 - and -NH- may be optionally substituted 1 to 3 times by Ra ;
  • Ring A is a monocyclic or bicyclic ring structure, wherein the monocyclic ring is selected from a 4-6 membered carbocyclic ring, a 4-6 membered heterocyclic ring, a 5-6 membered aromatic heterocyclic ring and a 5-6 membered aromatic ring, and the bicyclic ring is selected from a 7-10 membered fused ring or fused heterocyclic ring formed by condensing any two independent ones of a 4-6 membered carbocyclic ring, a 4-6 membered heterocyclic ring, a 5-6 membered aromatic heterocyclic ring and a 5-6 membered aromatic ring;
  • 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 and -C(O)-OC 1-6 alkyl, wherein the C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl may be optionally substituted 1 to 3 times by Ra;
  • R 2 is selected from H, F, Cl, NH 2 , cyano, oxo, C 1-3 alkyl and C 1-3 alkoxy, wherein the C 1-3 alkyl and C 1-3 alkoxy may be optionally substituted 1 to 3 times by Ra ;
  • R 3 is selected from H, C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -CH 2 -OC 1-6 alkyl, -CH 2 -NH-C 1-6 alkyl, -CH 2 -3-6 membered cycloalkyl and -CH 2 -3-6 membered heterocycloalkyl, wherein the C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl may be optionally substituted 1 to 3 times by Ra ;
  • R 3 may further form a 5- to 7-membered ring together with the ring atoms of ring A, and the 5- to 7-membered ring may be optionally substituted 1 to 3 times by Ra ;
  • R4 is selected from H, CN, C1-6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C1-3 alkylene-3-7 membered cycloalkyl, -C1-3 alkylene-3-7 membered heterocycloalkyl, -C1-3 alkylene-phenyl and -C1-3 alkylene- 5-6 membered heteroaryl, wherein the C1-6 alkyl , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl may be optionally substituted 1 to 3 times by Rb ;
  • p is selected from 1, 2 and 3;
  • q is selected from 0, 1, 2 and 3;
  • Ra is independently selected from H, F, Cl, C1-3 alkyl and C1-3 haloalkyl
  • R b is independently selected from H, F, Cl, Br, I, NH 2 , OH, C 1-3 alkyl, C 1-3 alkoxy and CN, wherein the C 1-3 alkyl and C 1-3 alkoxy are optionally substituted 1 to 3 times by halogen.
  • Ring A is selected from pyridine, imidazole, pyridazine, oxazole, isoxazole, benzene ring, thiazole, pyrimidine, pyrazine, quinoline, isoquinoline, benzimidazole, imidazopyridine and naphthyridine, wherein Ring A is optionally substituted 1 to 3 times by R2 .
  • Ring A is selected from The ring A may be optionally substituted by R 2 1 to 3 times.
  • Ring A is selected from
  • the ring A may be optionally substituted by R 2 1 to 3 times.
  • R 1 is selected from H, F, Cl, Br, CH 3 , CH 2 CH 3 , CH(CH 3 )CH 3 , OCH 3 , OH, COOCH 3 , wherein said R 1 may be optionally substituted by Ra 1 to 3 times.
  • R 2 is selected from H, F, Cl, cyano, oxo, CH 3 .
  • 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 , CH2OCH3 , CH2NHCH3 ,
  • the R 3 may be optionally substituted 1 to 3 times by Ra .
  • R4 is selected from H, CH3 , CH2CH3, CH2CH2CH3 , CH2CH2CH2CH3 , CH2CH ( CH3 ) CH2CH3 , CH2CH2CH ( CH3 )CH3, CH ( CH3 ) CH3 , C( CH3 ) 3 , CN, cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, cycloheptyl, phenyl, methyl-cyclopropyl, methyl- cyclobutyl , methyl-cyclopentyl, methyl-cyclohexyl, methyl-cycloheptyl, methyl-phenyl, piperidine, pyridine, pyrimidine, pyrazine, pyrazole, butylene oxide, pentane oxide, hexane oxide, azetidine, pyrrolidine, pyrrolidone, piperidone, wherein said R4 can
  • R 3 is further taken together with the ring atoms of ring A to form a 5-6 membered ring selected from The 5- to 6-membered ring may be optionally substituted 1 to 3 times by Ra .
  • Y 1 , Y 2 , and Y 3 are independently selected from -CH 2 - and -NH-, wherein the H in -CH 2 - and -NH- can be optionally substituted by R 1 once or twice under the conditions permitted by valence;
  • Z is selected from -CH 2 - and -NH-, wherein the H in said -CH 2 - and -NH- can be optionally substituted 1 or 2 times by R 1 under the conditions permitted by chemical valence;
  • Ring A is a monocyclic or bicyclic ring structure, wherein the monocyclic ring is selected from a 4-6 membered carbocyclic ring, a 4-6 membered heterocyclic ring, a 5-6 membered aromatic heterocyclic ring and a 5-6 membered aromatic ring, and the bicyclic ring is selected from a 7-10 membered fused ring or fused heterocyclic ring formed by condensing any two independent ones of a 4-6 membered carbocyclic ring, a 4-6 membered heterocyclic ring, a 5-6 membered aromatic heterocyclic ring and a 5-6 membered aromatic ring;
  • 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 and -C(O)-OC 1-6 alkyl, wherein the C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl may be optionally substituted 1 to 3 times by Ra;
  • R 2 is selected from H, F, Cl, NH 2 , cyano, oxo, C 1-3 alkyl and C 1-3 alkoxy, wherein the C 1-3 alkyl and C 1-3 alkoxy may be optionally substituted 1 to 3 times by Ra ;
  • R 3 is selected from H, C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -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, wherein the C 1-6 alkyl, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl may be optionally substituted 1 to 3 times by R a ;
  • R 3 may further form a 5- to 7-membered ring together with the ring atoms of ring A, and the 5- to 7-membered ring may be optionally substituted 1 to 3 times by Ra ;
  • R4 is selected from H, CN, C1-6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C1-3 alkylene-3-7 membered cycloalkyl, -C1-3 alkylene-3-7 membered heterocycloalkyl, -C1-3 alkylene-phenyl and -C1-3 alkylene- 5-6 membered heteroaryl, wherein the C1-6 alkyl , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl may be optionally substituted 1 to 3 times by Rb ;
  • the present application provides the compound described above, which has a structure shown in Formula II-1 or Formula II-2:
  • Ring A, R 1 , R 2 , R 3 , R 4 , and L 2 are as defined above.
  • the present application provides the compound described above, which has a structure shown in Formula II-3:
  • Ring A, R 1 , R 2 , R 3 , R 4 and L 2 are the same as defined above.
  • the present application provides the above-mentioned compound, which has a structure shown in Formula III-1, III-2, III-3 or III-4:
  • Xa , Xb , Xc , Xd , Xe , Xf are independently selected from CH or N; R1 , R2 , R3 , R4 , L1 , L2 are as defined above.
  • the present application provides the compound described above, which has a structure shown in Formula III-5 or III-1a:
  • Xa , Xb , Xc , Xd are independently selected from CH or N; R1 , R2 , R3 , R4 , L1 , L2 are as defined above.
  • the present application provides the compound described above, which has a structure shown in Formula IV-1 or IV-2:
  • X a , X b , X c , X d are independently selected from CH or N; R 1 , R 2 , R 3 , R 4 are as defined above.
  • the present application provides the compound described above, which has a structure shown in Formula V-1 or V-2:
  • X a , X b , X c , X d are independently selected from CH or N; R 1 , R 2 , R 3 , R 4 are as defined above.
  • the present invention encompasses compounds resulting from any combination of the various embodiments.
  • the present application provides a compound according to the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound is selected from:
  • the present application provides a compound according to the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound is selected from:
  • the present application provides a compound according to the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound is selected from:
  • the present application provides a compound according to the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound is selected from:
  • the present application provides a compound according to the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound is selected from:
  • the stereoisomers of the compounds of the invention are configurational isomers.
  • the configurational isomers are cis-/trans-isomers, also known as geometric isomers (E-/Z-isomers).
  • the configurational isomers are enantiomers.
  • the configurational isomers are diastereoisomers.
  • the compounds of the invention are racemic.
  • the pharmaceutically acceptable salts of the present invention include acid addition salts and base salts.
  • the pharmaceutically acceptable salt of the compound of the present invention is, for example, but not limited to, formate.
  • the pharmaceutically acceptable salts of the present invention may exist in unsolvated as well as solvated forms.
  • compositions and methods of treatment are provided.
  • the present application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention (including a compound of Formula I-A and Formula I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the compounds of the present invention and pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, metabolites, isotopically labeled compounds or prodrugs thereof may be used alone or in combination with at least one other therapeutic agent in therapy.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention as described above or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug, and one or more thereof He therapeutic active ingredients.
  • the present application provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, for use as a drug.
  • the present application provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, which is used as a STING inhibitor.
  • the present application provides use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament as a STING inhibitor.
  • the STING inhibitor or drug is used to treat and/or prevent tumors and/or cancer.
  • the compounds of the present invention are STING inhibitors and have excellent STING receptor inhibitory activity. These STING inhibitor compounds can treat and/or prevent STING-mediated diseases or conditions and related diseases or conditions.
  • the present application provides the use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for preventing and/or treating STING-mediated diseases or disorders and related diseases or disorders.
  • the present application provides a method for preventing and/or treating a STING-mediated disease or condition and related diseases or conditions in an individual, comprising administering to the individual a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention.
  • the STING-mediated disease or condition is a tumor and/or cancer.
  • the tumor and/or cancer include, but are not limited to, 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 intestine cancer, kidney cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, mesothelioma, lymphoma, leukemia, myelodysplastic syndrome, multiple myeloma, plasmacytoma, neuroblastoma, retinoblastoma, and germ cell tumor.
  • the STING-mediated disease or disorder is a disease or disorder of the central nervous system, peripheral nervous system, and autonomic nervous system.
  • the diseases or disorders of the central nervous system, peripheral nervous system, and autonomic nervous system include, but are not limited to, epileptic aphasia, encephalomyelitis, macular degeneration, Alpers disease, corpus callosum agenesis, Aicardi syndrome, alternating hemiplegia, Alzheimer's disease, vascular dementia, amyotrophic lateral sclerosis, arachnoid cysts, arachnoiditis, Asperger syndrome, ataxia teledilation, attention deficit hyperactivity disorder, autism, autonomic dysfunction, muscular atrophy, benign intracranial hypertension, Binswanger disease, brain atrophy, brain gigantism, cerebral arteriosclerosis, chorea, chronic inflammatory demyelinating polyneuropathy, congenital facial palsy, cortical basal degeneration, cranial artery Inflammation
  • the STING-mediated disease or disorder is a STING-associated disorder, including but not limited to type I interferonopathy, Aicardi-Goutines syndrome (AGS), lupus, rheumatoid arthritis.
  • STING-associated 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), inflammatory bowel disease (IBD), ulcerative colitis (UC), autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by adoptive cell therapy treatment, irritable bowel syndrome, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, mucositis.
  • autoimmune disease including but not limited to rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Crohn's disease (CD), inflammatory bowel disease (IBD), ulcerative colitis (UC), autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more
  • the STING-mediated disease or condition and related diseases or conditions include, but are not limited to, melanoma, thyroid tumor, head and neck cancer, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, 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, kidney cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, mesothelioma, lymphoma, leukemia, myelodysplastic syndrome, multiple myeloma, plasmacytoma, neuroblastoma, retinoblastoma and germ cell tumor.
  • the STING-mediated diseases or conditions and related diseases or conditions include, but are not limited to, encephalomyelitis, macular degeneration, Alzheimer's disease, vascular dementia, arachnoiditis, autonomic dysfunction, muscular atrophy, brain 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 conditions and related diseases or conditions 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 conditions and related diseases or conditions include, but are not limited to, psoriasis, psoriatic arthritis, contact dermatitis, atopic dermatitis, vitiligo, rheumatoid arthritis, systemic lupus erythematosus, type I diabetes, multiple sclerosis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, autoimmune colitis, irritable bowel syndrome, scleroderma, asthma, glomerulonephritis, periodontal disease, pars planitis, transplant rejection, neurodegenerative diseases, obesity, hypertension, encephalomyelitis, macular degeneration, Alzheimer's disease, vascular dementia, arachnoiditis, autonomic dysfunction, muscular atrophy, brain atrophy, chorea, dystonia, giant cell arteritis, hemifacial spasm, herpes zoster, Huntington's disease, myasthenia gravis, Parkinson'
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle with which a therapeutic agent is administered and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • “individual” includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or 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 a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and 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 basic and acidic functional groups, and thus can be converted into any base or
  • salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.
  • the term “isomer” is intended to include stereoisomers, geometric isomers, cis-trans isomers, enantiomers, optical isomers, diastereomers and tautomers.
  • 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, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are considered
  • the alkyl group and the like may contain additional asymmetric carbon atoms. All of these isomers and their mixtures are included in the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of one another.
  • cis-trans isomers or “geometric isomers” arises from the inability of a double bond or single bond forming a ring carbon atom to rotate freely.
  • diastereomer refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.
  • the key is a solid wedge. and dotted wedge key
  • a straight solid bond To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key
  • a wavy line Denotes a solid wedge bond or dotted wedge key
  • use a wavy line Represents a straight solid bond or straight dashed key
  • the terms “enriched in one isomer”, “isomerically enriched”, “enriched in one enantiomer” or “enantiomerically enriched” mean that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer 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 or 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%.
  • the term “isomer 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 and 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 present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (for example, a carbamate is generated from an amine).
  • the compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound.
  • the compound may be labeled with a radioactive isotope, such as tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ).
  • deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are replaced.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituent can be arbitrary on the basis of chemical achievable.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice.
  • 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 When a substituent has bonds that cross-link to two or more atoms in a ring, the substituent may be bonded to any atom in the ring, e.g. Indicates that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • the substituent When the substituent is listed without specifying the atom through which it is connected to the When a substituted group is attached, the substituent can be bonded through any atom thereof.
  • a pyridyl group as a substituent can be bonded to the substituted group through any carbon atom on the pyridine ring.
  • linking direction is arbitrary.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds to become a group with a corresponding valence.
  • the chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy line express.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.
  • the number of atoms in a ring is generally defined as the ring member number, for example, "5-7 membered ring” refers to a “ring” having 5-7 atoms arranged around it.
  • halo means fluorine atom, chlorine atom, bromine atom, iodine atom, etc.
  • Preferred halogen atoms as substituents of the aryl group of the present invention are fluorine atom and chlorine atom.
  • 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 regarded as a group obtained by losing 1 hydrogen atom from an alkane.
  • C 1-6 alkyl is a linear or branched alkyl having 1 to 6 (e.g., 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 is a linear or branched alkyl having 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 refers to a straight or branched chain alkyl group having 1 to 3 carbons, including but not limited to methyl, ethyl, n-propyl and isopropyl.
  • alkylene means a linear or branched divalent group obtained by further losing 1 H from the above-mentioned "alkyl”.
  • the alkylene 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, preferably methylene.
  • haloalkyl refers to an alkyl group (including the C1-6 alkyl, C1-4 alkyl and C1-3 alkyl groups described above) substituted by one or more halogens.
  • C 1-6 alkoxy means a group C 1-6 alkyl-O-, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, 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 a 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 a 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 group containing one or more double bonds.
  • the alkenyl group has 2-6 carbon atoms ("C 2-6 alkenyl”), for example, 2 to 4 carbon atoms (“C 2-4 alkenyl”), or 2 to 3 carbon atoms ("C 2-3 alkenyl”).
  • the compounds of the invention may be present in the pure E (ent ought) form, the pure Z (zusammen) form or any mixture thereof.
  • alkynyl means a linear or branched monovalent aliphatic hydrocarbon group containing one or more triple bonds.
  • the alkynyl group has 2, 3, 4, 5 or 6 carbon atoms ("C 2-6 alkynyl”), for example 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) identical or different substituents.
  • fused means that two or more ring structures share two adjacent atoms with each other.
  • bridge means that two or more ring structures share two non-adjacent atoms with each other.
  • spiro or “spiro-connected” means that two or more ring structures share 1 atom with each other.
  • cycloalkyl refers to saturated (i.e., “cycloalkyl” and “cycloalkylene") or partially unsaturated (i.e., having one or more double bonds (i.e., “cycloalkenyl” and “cycloalkenylene”) and/or triple bonds in the ring) monocyclic or polycyclic rings 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.
  • cycloalkyl are monocyclic cycloalkyl or cycloalkenyl rings having 3-7 or 3-6 ring carbon atoms ( C3-7 or C3-6 ).
  • cycloalkyl are bicyclic cycloalkyl or cycloalkenyl rings having 8-10 or 9-10 ring carbon atoms ( C8-10 or C9-10 ).
  • Cycloalkyl is, in some embodiments, cycloalkyl includes aryl-fused cycloalkyl, as long as the entire ring system is non-aromatic.
  • cycloalkyl and cycloalkylene refer to a saturated monocyclic or polycyclic (such as bicyclic) fused hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring such as ).
  • the cycloalkyl and cycloalkylene groups have 3 to 10 carbon atoms, suitably 3-8, for example 3-7, 3-6, 4-6 or 5-6 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 ).
  • spirocycloalkyl refers to a cyclic group formed by two or more "cycloalkyl” as defined above as components, with any two of the components sharing one carbon atom.
  • C 7-12 spirocycloalkyl and “C 7-12 spirocycloalkylene” refer to a cyclic structure containing 7 to 12 (e.g., 5-12 or 7-11) carbon atoms formed by at least two cycloalkyl rings, wherein any two of the cycloalkyl rings share only one atom.
  • bridged cycloalkyl refers to a cyclic group formed by two or more "cycloalkyl” as defined above as components, with any two of the components sharing two carbon atoms that are not adjacent to each other.
  • C7-10 bridged cycloalkyl and C7-10 bridged cycloalkylene refer to a cyclic structure containing 7 to 12 (e.g., 6-10, 6-9, or 6-8) carbon atoms formed by two cycloalkyl rings sharing two carbon atoms that are not adjacent to each other.
  • cycloalkenyl and “cycloalkenylene” refer to monocyclic or polycyclic (such as bicyclic) fused hydrocarbon rings (e.g., monocyclic, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or bicyclic) having one or more double bonds in the ring.
  • monocyclic such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or bicyclic
  • the cycloalkenyl and "cycloalkenylene” have 3 to 10 carbon atoms, suitably 3-8, such as 3-7, 3-6, 4-6 or 5-6.
  • "cycloalkenyl” and “cycloalkenylene” are monocyclic cycloalkenyl rings having 3-7 or 3-6 ring carbon atoms (C3 ⁇ 7 or C3 ⁇ 6 ).
  • "cycloalkenyl” and “cycloalkenylene” are bicyclic cycloalkenyl rings having 8-10 or 9-10 ring carbon atoms ( C8-10 or C9-10 ).
  • heterocyclyl refers to a saturated (i.e., “heterocycloalkyl” and “heterocycloalkylene") or partially unsaturated (e.g., having one or more double bonds within the ring (i.e., “heterocycloalkenyl” and “heterocycloalkenylene”)) monocyclic or bicyclic fused ring structure having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and 1 or more (e.g., 1, 2, 3 or 4) heteroatom-containing groups selected from O, S and N in the ring.
  • One or more of the ring carbon atoms in the heterocyclyl may be replaced by C(O).
  • the S atom in the heterocyclyl may be replaced by S(O) or S(O) 2 .
  • the heterocyclyl may be attached to the rest of the molecule via any of the carbon atoms or the nitrogen atom, if present.
  • 3-10 yuan heterocyclic radical is a group having 3-10 (e.g., 3-8, 3-7, 3-6, 4-6 or 5-6) carbon atoms and heteroatoms in the ring.
  • heterocyclic radical In some embodiments, "heterocyclic radical”, “heterocycle” and “heterocyclylene” are monocyclic heterocycloalkyl or heterocycloalkenyl rings with 3-7, 3-6 or 5-6 ring members (3-7 yuan, 3-6 yuan or 5-6 yuan). In some embodiments, “heterocyclic radical”, “heterocycle” and “heterocyclylene” are bicyclic heterocycloalkyl or heterocycloalkenyl rings with 8-10 or 9-10 ring members (8-10 yuan or 9-10 yuan).
  • heterocyclic ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic radical.
  • Heterocyclic radicals include nitrogen-containing heterocyclic radicals, oxygen-containing bridged rings and sulfur-containing heterocyclic radicals.
  • Examples that may be mentioned include, but are not limited to, oxirane, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, piperidonyl, hexahydropyrimidinyl, triazinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, azocanyl, dihydropyrrolyl, dihydroimidazolyl, azooctenyl.
  • nitrogen-containing heterocyclic group refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and at least one (e.g., 1, 2, 3 or 4) nitrogen atom in the ring, which may also optionally contain one or more (e.g., 1, 2, 3 or 4) ring members selected from N, O and S.
  • One or more ring carbon atoms in the nitrogen-containing heterocyclic group may be replaced by C(O).
  • the S atom in the nitrogen-containing heterocyclic group may be replaced by S(O) or S(O) 2 .
  • the nitrogen-containing heterocyclic group may be connected to the rest 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 heterocyclic group is a nitrogen-containing heterocyclic group as defined above having 3-10 ring members in the ring, including but not limited to a 3-membered nitrogen-containing heterocyclic group.
  • ring such as aziridine
  • 4-membered nitrogen-containing heterocycle such as azetidinyl
  • 5-membered nitrogen-containing heterocycle such as pyrrolyl, pyrrolidinyl (pyrrolidine ring), pyrrolinyl, pyrrolidinone, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl
  • 6-membered nitrogen-containing heterocycle such as piperidinyl (piperidine ring), piperidinylone, morpholinyl, thiomorpholinyl, piperazinyl
  • 7-membered nitrogen-containing heterocycle such as piperidinyl (piperidine ring), piperidinylone, morpholinyl, thiomorpholinyl, piperazinyl
  • 7-membered nitrogen-containing heterocycle 8-membered bicyclic nitrogen-containing heterocyclic group, 9-membered bicyclic nitrogen-containing heterocyclic group
  • heterocyclyl encompasses fused structures, and the point of connection with other groups can be on any ring in the fused structure. Therefore, the heterocyclyl of the present invention also includes, but is not limited to, heterocyclyl and heterocyclyl, heterocyclyl and cycloalkyl, monoheterocyclyl and monoheterocyclyl, monoheterocyclyl and monocycloalkyl, such as 3-7 membered (mono) heterocyclyl and 3-7 membered (mono) heterocyclyl, 3-7 membered (mono) heterocyclyl and (mono) cycloalkyl, 3-7 membered (mono) heterocyclyl and C 4-6 (mono) cycloalkyl, examples of which include, but are not limited to, pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidin
  • heterocyclyl includes 5-6 membered monocyclic heteroaryl-fused C 5-6 monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl-fused 5-6 membered monocyclic heterocyclyl, and benzo-fused 5-6 membered monocyclic heterocyclyl, such as pyrrolotetrahydropyridinyl, pyrazolotetrahydropyridinyl, imidazotetrahydropyridinyl, indolyl or indolinone.
  • spiroheterocycloalkyl refers to a cyclic group formed by two or more "heterocycloalkyl” as defined above as components, by any two of the components sharing one carbon atom, having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 1 or more (e.g. 1, 2, 3 or 4) heteroatoms selected from O, S and N in the ring.
  • One or more ring carbon atoms in the spiroheterocycloalkyl may be replaced by C(O).
  • the S atom in the spiroheterocyclyl may be replaced by S(O) or S(O) 2 .
  • the spiroheterocycloalkyl is 5-12-membered, and more preferably 5-11 (e.g. 5-10 or 7-9)-membered.
  • spiroheterocycloalkyl is divided into monospiroheterocycloalkyl, dispiroheterocycloalkyl, or polyspiroheterocycloalkyl, and preferably refers to monospiroheterocycloalkyl or dispiroheterocycloalkyl, and more preferably 4-membered/4-membered, 3-membered/5-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiroheterocycloalkyl.
  • bridged heterocycloalkyl refers to a cyclic group formed by two or more "heterocycloalkyl” as defined above as components, by any two of the components sharing two atoms that are not adjacent to each other, and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 1 or more (e.g., 1, 2, 3 or 4) heteroatoms selected from O, S and N in the ring.
  • One or more ring carbon atoms in the bridged heterocycloalkyl can be replaced by C (O).
  • the S atom in the bridged heterocyclic group can be replaced by S (O) or S (O) 2.
  • the bridged heterocycloalkyl is 6 to 9 yuan, and more preferably 6-8 yuan.
  • the bridged heterocycloalkyl is divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocycloalkyl, and preferably refers to a bicyclic, tricyclic or tetracyclic bridged heterocycloalkyl, and more preferably a bicyclic or tricyclic bridged heterocycloalkyl.
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated ⁇ electron system, preferably a 6- to 10-membered ring, such as phenyl and naphthyl, more preferably phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, including a benzo 3- to 8-membered cycloalkyl, a benzo 3- to 8-membered heterocyclyl.
  • heteroaryl or “heteroaryl ring” refers to a heteroaromatic system with 5 to 14 ring atoms, which has 1 to 4 heterocyclic atoms independently selected from N, O and S.
  • One or more ring carbon atoms in the heteroaryl can be replaced by C (O).
  • the heteroaryl can be benzo-fused.
  • the heteroaryl is preferably 5 to 10 yuan.
  • the heteroaryl is a 5- or 6-yuan heteroaryl, such as but not limited to pyridyl, pyridone, pyrimidinyl, pyrimidone, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl.
  • pyridyl such as but not limited to pyridyl, pyridone, pyrimidinyl, pyrimidone, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrrolyl, pyrazolyl, triazolyl, tetra
  • the heteroaryl is 8-10 yuan or 9-10 bicyclic heteroaryl, including 5 yuan/5 yuan, 5 yuan/6 yuan or 6 yuan/6 yuan bicyclic system.
  • Examples include, but are not limited to, benzothiazolyl, benzisothiazolyl, imidazopyridinyl, quinolinyl, indolyl, pyrrolopyridazinyl, benzofuranyl, benzothiophenyl, indazolyl, benzoxazolyl, benzisoxazolyl, quinazolinyl, pyrrolopyridinyl, pyrazolopyrimidinyl, imidazopyridazinyl, pyrazolopyridinyl, triazolopyridinyl, isoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, cinnolinyl, indolizinyl, phthalazinyl, isoindolyl, pteridinyl, purinyl, furazanyl, benzofurazanyl, quinoxalinyl, naphthyridiny
  • 5-6 membered heteroaromatic ring and “5-6 membered heteroaryl” can be used interchangeably.
  • the term “5-6 membered heteroaryl” means a monocyclic group consisting of 5 to 6 ring atoms with a conjugated ⁇ electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • the 5-6 membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl.
  • fused ring refers to a 5- to 20-membered all-carbon polycyclic group, each ring in the ring system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a complete Fully conjugated ⁇ electron system.
  • 6 to 14 members more preferably 7 to 10 members.
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • the carbon atoms in the condensed ring can be optionally replaced by heteroatoms of O, S, or N, i.e., also including "condensed heterocycles".
  • fused heterocycle refers to a polycyclic heterocyclic group of 5 to 20 yuan, each ring in the ring system shares a pair of atoms adjacent to other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon.
  • m is an integer from 0 to 2
  • 6 to 14 yuan more preferably 7 to 10 yuan.
  • the number of the constituent rings it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic radical, preferably a bicyclic or tricyclic, more preferably a 5 yuan/5 yuan or 5 yuan/6 yuan bicyclic fused heterocyclic radical.
  • esters means an ester derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form).
  • physiologically hydrolyzable esters which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form.
  • the compounds of the present invention themselves may also be esters.
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • the compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol.
  • polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol.
  • the amount of polar solvents, in particular water may exist in a stoichiometric or non-stoichiometric ratio.
  • nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane.
  • peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA)
  • hydrogen peroxide alkyl hydroperoxides such as tert-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxirane such as dimethyldioxirane
  • metabolites of the compounds of the present invention i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc. of the administered compound.
  • the present invention includes metabolites of the compounds of the present invention, including compounds prepared by contacting the compounds of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity and can be converted into compounds of the present invention having the desired activity when administered into or onto the body, for example, by hydrolytic cleavage.
  • prodrugs will be functional group derivatives of the compounds that are easily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E. B. Roche, ed., American Pharmaceutical Association).
  • Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties” (e.g. as described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).
  • the present invention also encompasses compounds of the present invention containing protecting groups.
  • protecting groups In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference.
  • the protecting groups may be removed at an appropriate subsequent stage using methods known in the art.
  • the term "about” means within ⁇ 10% of the stated numerical value, preferably within ⁇ 5%, and more preferably within ⁇ 2%.
  • 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 synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.
  • the compounds described in the present invention are named according to the chemical structural formula. If the compound name and the chemical structural formula representing the same compound do not match, the chemical structural formula shall prevail.
  • the structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data of the cultured single crystal using a Bruker D8venture diffractometer, with CuK ⁇ radiation as the light source, and scanning Scanning method: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.
  • SXRD single crystal X-ray diffraction
  • the solvent used in the present invention is commercially available.
  • the compounds of the present invention have strong inhibitory activity on STING and can be used to prevent and/or treat STING-mediated diseases or conditions.
  • the compounds of the present 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 cardiac toxicity) and/or fewer side effects), less prone to drug resistance, and other more excellent properties.
  • Benzyl bromide (8.37 g, 48.96 mmol) was dripped into the reaction solution, and tetrabutylammonium iodide (1.81 g, 4.90 mmol) was quickly added under nitrogen protection after the dripping was completed, and then The mixture was continued in an ice-water bath for 10 minutes, and then stirred at room temperature for 12 hours. After the reaction was complete, the reaction was quenched with an aqueous ammonium chloride solution (17 mL), and most of the tetrahydrofuran was concentrated under reduced pressure.
  • the organic phase was concentrated under reduced pressure (temperature controlled at 20°C) to remove most of the dichloromethane.
  • Dilute hydrochloric acid (1 mol/L, 15 mL) was added to the concentrate and stirred for 0.5 hours.
  • the aqueous phase was separated and extracted twice with dichloromethane.
  • the aqueous phase was lyophilized to obtain compound int9 (214 mg).
  • the raw material 44a (28.2 g, 256 mmol) was dissolved in acetonitrile (130 mL) and water (130 mL), and chromium trichloride (13.6 g, 51.2 mmol) was added, and then stirred at 80°C for 24 hours. After the reaction was complete, most of the acetonitrile was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (200 mL), washed with brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure.
  • reaction solution was acidic and extracted again with purified water (100 ml) and dichloromethane (100 ml) twice.
  • the aqueous phase was freeze-dried to obtain int33 (600 mg).
  • the crude product obtained by distillation of the organic phase under reduced pressure was dissolved in THF, and 4 M HCl (5 ml) was added, and then the solution was heated to 60°C and stirred for 2 h. After the reaction, water (10 ml) was added to the reaction solution, and then ethyl acetate (10 ml x 3) was added for extraction. Saturated KF (10 ml) was added to the organic phase, and stirred for 30 minutes. The solid was filtered off, and the filtrate was separated. The organic phase was washed with saturated brine, and then anhydrous sodium sulfate was added for drying. The organic phase was filtered and concentrated under reduced pressure.
  • Aqueous hydrochloric acid solution (4 mol/L, 90 mL, 360 mmol) was added to the reaction flask containing the mixed solution of 46d (150 mL, 34.18 mmol), and the reaction solution was rapidly stirred in an oil bath at 60°C for 2 hours. After the reaction was completed, it was cooled to room temperature, the organic phase was separated, and the aqueous phase was extracted three times with dichloromethane (200 mL). The organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure.
  • the aqueous phase was extracted with dichloromethane (5 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure (to remove ammonia). The residue was dissolved in dichloromethane (20 mL), and dilute hydrochloric acid (1 mol/L, 10 mL) was added to the above solution and stirred for 1 hour. The aqueous phase was separated and freeze-dried to obtain int47 (268 mg).
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • Embodiment 5 is a diagrammatic representation of Embodiment 5:
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • Embodiment 8 is a diagrammatic representation of Embodiment 8
  • Embodiment 9 is a diagrammatic representation of Embodiment 9:
  • Embodiment 10 is a diagrammatic representation of Embodiment 10:
  • Embodiment 11 is a diagrammatic representation of Embodiment 11:
  • Embodiment 14 is a diagrammatic representation of Embodiment 14:
  • Embodiment 15 is a diagrammatic representation of Embodiment 15:
  • SFC separation method System: Waters SFC 150; Column: Column size: 250*25mm 10m; Mobile phase A: supercritical CO2, Mobile phase B: MEOH (+0.1% 7.0mol/l ammonia in MEOH); A:B:80:20; Wavelength: 214nm; Flow rate: 100ml/min; Column temperature: room temperature; Back pressure: 100bar; Injection: 3mL; Cycle time: 4.1 minutes; Solvent: Methanol: redistilled grade, Supercritical CO2: Food grade; Preparation of sample solution: Dissolve the sample in about 20mL MeOH.
  • Embodiment 18 is a diagrammatic representation of Embodiment 18:
  • Embodiment 19 is a diagrammatic representation of Embodiment 19:
  • Embodiment 20 is a diagrammatic representation of Embodiment 20.
  • Embodiment 21 is a diagrammatic representation of Embodiment 21.
  • Embodiment 22 is a diagrammatic representation of Embodiment 22.
  • Embodiment 23 is a diagrammatic representation of Embodiment 23.
  • Embodiment 24 is a diagrammatic representation of Embodiment 24.
  • Embodiment 25 is a diagrammatic representation of Embodiment 25.
  • Embodiment 26 is a diagrammatic representation of Embodiment 26.
  • Embodiment 27 is a diagrammatic representation of Embodiment 27.
  • Embodiment 28 is a diagrammatic representation of Embodiment 28:
  • Embodiment 29 is a diagrammatic representation of Embodiment 29.
  • Embodiment 31 is a diagrammatic representation of Embodiment 31.
  • Embodiment 32 is a diagrammatic representation of Embodiment 32.
  • Embodiment 33 is a diagrammatic representation of Embodiment 33.
  • Embodiment 34 is a diagrammatic representation of Embodiment 34.
  • Embodiment 35 is a diagrammatic representation of Embodiment 35.
  • Embodiment 36 is a diagrammatic representation of Embodiment 36.
  • Embodiment 37 is a diagrammatic representation of Embodiment 37.
  • Embodiment 38 is a diagrammatic representation of Embodiment 38.
  • Embodiment 39 is a diagrammatic representation of Embodiment 39.
  • Embodiment 40 is a diagrammatic representation of Embodiment 40.
  • Embodiment 41 is a diagrammatic representation of Embodiment 41.
  • Embodiment 42 is a diagrammatic representation of Embodiment 42.
  • Embodiment 43 is a diagrammatic representation of Embodiment 43.
  • Embodiment 44 is a diagrammatic representation of Embodiment 44.
  • Embodiment 45 is a diagrammatic representation of Embodiment 45.
  • Embodiment 46 is a diagrammatic representation of Embodiment 46.
  • step 1
  • Embodiment 47 is a diagrammatic representation of Embodiment 47.
  • Embodiment 48 is a diagrammatic representation of Embodiment 48.
  • Embodiment 49 is a diagrammatic representation of Embodiment 49.
  • Embodiment 50 is a diagrammatic representation of Embodiment 50.
  • Embodiment 51 is a diagrammatic representation of Embodiment 51.
  • Embodiment 52 is a diagrammatic representation of Embodiment 52.
  • Embodiment 53 is a diagrammatic representation of Embodiment 53.
  • Embodiment 54 is a diagrammatic representation of Embodiment 54:
  • Embodiment 55 is a diagrammatic representation of Embodiment 55:
  • Embodiment 56 is a diagrammatic representation of Embodiment 56.
  • Embodiment 57
  • Embodiment 58

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Abstract

La présente invention concerne un composé ayant un effet inhibiteur de STING et une composition pharmaceutique de celui-ci, et son utilisation dans la préparation d'un médicament pour prévenir et/ou traiter des maladies associées à une expression anormale de STING. Plus précisément, le composé possède une structure représentée par la formule (I-A).
PCT/CN2023/139786 2022-12-20 2023-12-19 Composé contenant de l'oxime ayant un effet inhibiteur de sting, composition pharmaceutique de celui-ci et son utilisation Ceased WO2024131772A1 (fr)

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CN106866571A (zh) * 2017-01-20 2017-06-20 中国药科大学 杂环脲类化合物及其药物组合物和应用
CN108601351A (zh) * 2015-12-21 2018-09-28 拜耳作物科学股份公司 2-氨基-5-酮肟-嘧啶衍生物及其用于防治不希望的植物生长的用途
WO2020150417A2 (fr) * 2019-01-17 2020-07-23 Ifm Due, Inc. Composés et compositions pour traiter des états pathologiques associés à une activité de sting
CN111683926A (zh) * 2018-01-26 2020-09-18 企业治疗学有限公司 化合物
CN112823036A (zh) * 2018-07-03 2021-05-18 艾福姆德尤股份有限公司 用于治疗与sting活性有关的疾病的化合物和组合物
CN114364672A (zh) * 2019-06-18 2022-04-15 辉瑞大药厂 苯并异噁唑磺酰胺衍生物
WO2023036289A1 (fr) * 2021-09-10 2023-03-16 上海海和药物研究开发股份有限公司 Composé d'acide hydroxamique ayant une activité inhibitrice de l'enpp1 et son utilisation
WO2023122777A1 (fr) * 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Dérivés d'oxime utiles en tant qu'activateurs de lymphocytes t
WO2024032597A1 (fr) * 2022-08-11 2024-02-15 杭州中美华东制药有限公司 Composé amide ayant un effet inhibiteur de sting, composition pharmaceutique et utilisation associée

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007081630A2 (fr) * 2005-12-21 2007-07-19 Janssen Pharmaceutica, N.V. Inhibiteurs substitues de la pyrimidinyl kinase
WO2016115282A1 (fr) * 2015-01-13 2016-07-21 Vanderbilt University Composés à substituants benzisoxazole en tant que potentialisateurs allostériques de mglur4, compositions, et méthodes de traitement de dysfonctionnements neurologiques
US20180021312A1 (en) * 2015-01-13 2018-01-25 Vanderbilt University Benzoisoxazole-substituted compounds as mglur4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
CN108601351A (zh) * 2015-12-21 2018-09-28 拜耳作物科学股份公司 2-氨基-5-酮肟-嘧啶衍生物及其用于防治不希望的植物生长的用途
CN106866571A (zh) * 2017-01-20 2017-06-20 中国药科大学 杂环脲类化合物及其药物组合物和应用
CN111683926A (zh) * 2018-01-26 2020-09-18 企业治疗学有限公司 化合物
CN112823036A (zh) * 2018-07-03 2021-05-18 艾福姆德尤股份有限公司 用于治疗与sting活性有关的疾病的化合物和组合物
WO2020150417A2 (fr) * 2019-01-17 2020-07-23 Ifm Due, Inc. Composés et compositions pour traiter des états pathologiques associés à une activité de sting
CN114364672A (zh) * 2019-06-18 2022-04-15 辉瑞大药厂 苯并异噁唑磺酰胺衍生物
WO2023036289A1 (fr) * 2021-09-10 2023-03-16 上海海和药物研究开发股份有限公司 Composé d'acide hydroxamique ayant une activité inhibitrice de l'enpp1 et son utilisation
WO2023122777A1 (fr) * 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Dérivés d'oxime utiles en tant qu'activateurs de lymphocytes t
WO2024032597A1 (fr) * 2022-08-11 2024-02-15 杭州中美华东制药有限公司 Composé amide ayant un effet inhibiteur de sting, composition pharmaceutique et utilisation associée

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