WO2024131772A1 - Oxime-containing compound having sting inhibitory effect, pharmaceutical composition thereof, and use thereof - Google Patents

Oxime-containing compound having sting inhibitory effect, pharmaceutical composition thereof, and use thereof Download PDF

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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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alkyl
cycloalkyl
membered
alkylene
mmol
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PCT/CN2023/139786
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French (fr)
Chinese (zh)
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贺川
翟文强
赵梦婷
刘东舟
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杭州中美华东制药有限公司
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Publication of WO2024131772A1 publication Critical patent/WO2024131772A1/en

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  • 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

The present application relates to a compound having a STING inhibitory effect and a pharmaceutical composition thereof, and use thereof in the preparation of a medicament for preventing and/or treating diseases related to abnormal STING expression. Specifically, the compound has a structure represented by formula (I-A).

Description

具有STING抑制作用的含肟化合物及其药物组合物和用途Oxime compounds with STING inhibitory effect and pharmaceutical compositions and uses thereof 技术领域Technical Field
本申请涉及具有干扰素基因刺激因子(STING)抑制作用的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，包含其的药物组合物，以及它们在用于预防和/或治疗与STING异常表达相关的疾病的用途。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.
背景技术Background technique
干扰素基因刺激因子(stimulator of interferon genes，STING)，也被称为跨膜蛋白173、干扰素调节因子3的调控激活因子以及内质网干扰素刺激蛋白等，主要表达于人的巨噬细胞、T淋巴细胞、树突状细胞、内皮细胞、上皮细胞及成纤维细胞等的粗面内质网、线粒体及微粒体的外膜上。其可特异性识别并结合细菌的第二信使(cyclic di-AMP,cyclic di-GMP和cyclic 3',3'-cGAMP)和由环状GMP-AMP合成酶(cGAS)合成的天然环二核苷酸(CDN)配体。cGAS参与检测自身或外来DNA，如病原体的DNA、肿瘤来源的DNA和泄露的线粒体或核DNA。一旦识别dsDNA,cGAS将GTP和ATP催化合成为2',3'-cGAMP，从而导致STING的激活。结合配体的STING转运至高尔基体，并启动下游信号的级联反应，包括招募丝氨酸/苏氨酸蛋白激酶(TBK1)，磷酸化干扰素调节转录因子(IRF3)和核因子κB(NF-κB),并产生I型干扰素和促炎性细胞因子，如白介素6(IL-6)，肿瘤坏死因子α(TNFα)等。Stimulator of interferon genes (STING), 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). 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 κB (NF-κB), and the production of type I interferons and proinflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor α (TNFα).
STING在病毒、细菌及寄生虫感染触发的天然免疫反应、机体的肿瘤免疫过程以及细胞自噬过程中发挥重要的枢纽作用；通过自身的磷酸化、泛素化和二聚化修饰调节蛋白质合成和IFN表达，在机体的多个免疫环节中发挥关键作用。许多病毒可以通过与cGAS-STING通路上的信号蛋白相互作用，进而刺激机体产生与正常的免疫应答反应数量不等的干扰素，引起病毒的增殖或自身免疫性疾病；肿瘤细胞增殖能使抗原提呈细胞中的STING活化，从而激活T细胞介导的适应性免疫过程，发挥抗肿瘤作用。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.
现有技术中，主要有两大类STING激动剂：环二核苷酸类(CDN)衍生物和非核苷酸类小分子，以及两大类STING抑制剂：共价抑制剂和非共价抑制剂，此外还包含了一些机理未阐明的STING间接调控剂。In the existing technology, there are two main categories of STING agonists: cyclic dinucleotide (CDN) derivatives and non-nucleotide small molecules, and two main categories of STING inhibitors: covalent inhibitors and non-covalent inhibitors. In addition, there are also some STING indirect regulators whose mechanisms are not clear.
发明内容Summary of the invention
在一个方面，本申请提供本发明的化合物(诸如如下文所定义的式I-A的化合物)或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药。本发明的化合物具有STING抑制活性，可用于预防和/或治疗STING介导的疾病或病症，其中涉及STING活化(例如，过度激活的STING信号传导)的病症、疾病或障碍(例如，自身免疫性疾病或癌症)。本发明的化合物具有改善的药物代谢动力学性质(例如改善的生物利用度、改善的代谢稳定性、合适的半衰期和作用持续时间)、改善的安全性(较低的毒性(例如降低的心脏毒性)和/或较少的副作用)、较不易产生耐药性等更优异的性质。In one aspect, 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.
在另一个方面，本申请提供药物组合物，其包含本发明的化合物、或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，以及药学上可接受的载体。In another aspect, the present application provides 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.
在另一个方面，本申请提供本发明的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物，其用作药物。In another aspect, 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.
在另一个方面，本申请提供本发明的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物，其用作STING抑制剂。In another aspect, 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.
在另一个方面，本申请提供本发明的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物在制备作为STING抑制剂的药物中的用途。In another aspect, 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.
在另一个方面，本申请提供本发明的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物在制备用于预防和/或治疗STING介导的疾病或病症及相关疾病或病症的药物中的用途。 In another aspect, 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.
在另一个方面，本申请提供用于预防和/或治疗个体的STING介导的疾病或病症及相关疾病或病症的方法，其包括向所述个体施用治疗有效量的本发明的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物。In another aspect, 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.
在一些实施方案中，所述STING介导的疾病或病症选自：In some embodiments, the STING-mediated disease or condition is selected from:
肿瘤和/或癌症，包括黑色素瘤、甲状腺瘤、头颈癌、宫颈癌、乳腺癌、卵巢癌、前列腺癌、睾丸癌、尿路上皮癌、膀胱癌、非小细胞肺癌、小细胞肺癌、结直肠腺瘤、肉瘤、肠道间质瘤、胃癌、食道癌、结肠直肠癌、胰腺癌、小肠癌、肾癌、肝癌、肝细胞癌、胆管细胞癌、间皮瘤、淋巴瘤、白血病、骨髓异常增生综合症、多发性骨髓瘤、浆细胞瘤、成神经细胞瘤、成视网膜细胞瘤和生殖细胞瘤；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;
中枢神经系统、周围神经系统和自主神经系统疾病或病症，包括但不限于癫痫样失语、脑脊髓炎、黄斑变性、阿尔珀斯病、胼胝体发育不全、艾卡迪综合征、交替性偏瘫、阿尔茨海默氏病、血管性痴呆、肌萎缩侧索硬化症、蛛网膜囊肿、蛛网膜炎、阿斯伯格综合征、共济失调远程扩张症、注意缺陷多动障碍、自闭症、自主神经功能障碍、肌萎缩、良性颅内高压、宾斯旺格病、脑萎缩、脑巨人症、脑动脉硬化、舞蹈病、慢性炎症性脱髓鞘性多发性神经病、先天性面瘫、皮质基底节变性、颅动脉炎、颅缝早闭、克雅氏病、累积性创伤障碍、库欣综合征、巨细胞包涵体病、糖尿病性神经病变、弥漫性硬化症、肌张力障碍、巨细胞动脉炎、巨细胞包涵体病、面肌痉挛、遗传性痉挛性截瘫、多发性神经炎性遗传病、带状疱疹、亨廷顿病、重症肌无力、髓细胞性弥漫性硬化症、帕金森病、闭锁综合征、腰椎间盘疾病、偏头痛、线粒体肌病、莫比乌斯综合征、单体肌萎缩、运动神经元病、多梗死性痴呆、多发性硬化症、肌阵挛、神经肌强直、面肌萎缩、多灶性白质脑病、硬化性脊髓灰质炎和脊髓损伤；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 cell arteritis, giant cell inclusion disease, hemifacial spasm, hereditary spastic paraplegia, multiple neuritis genetic disease, herpes zoster, Huntington disease, myasthenia gravis, diffuse myeloid sclerosis, Parkinson disease, locked-in syndrome, lumbar disc disease, migraine, mitochondrial myopathy, Möbius syndrome, monosomic muscular dystrophy, motor neuron disease, multi-infarct dementia, multiple sclerosis, myoclonus, neuromyotonia, hemifacial muscular atrophy, multifocal leukoencephalopathy, sclerosing poliomyelitis, and spinal cord injury;
STING相关病症，包括I型干扰素病、Aicardi-Goutières综合征(AGS)、狼疮和类风湿性关节炎；STING-associated conditions, including type I interferonopathies, Aicardi-Goutières syndrome (AGS), lupus, and rheumatoid arthritis;
自身免疫性疾病，包括类风湿性关节炎、系统性红斑狼疮、多发性硬化症、克罗恩病(CD)、炎症性肠病(IBD)、溃疡性结肠炎(UC)、自身免疫性结肠炎、医源性自身免疫性结肠炎、溃疡性结肠炎、由一种或多种化学治疗剂诱导的结肠炎、由过继细胞疗法治疗诱导的结肠炎、肠易激综合征、硬皮病、银屑病、皮肤T细胞淋巴瘤、葡萄膜炎和粘膜炎；以及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
银屑病性关节炎、接触性皮炎、特异性皮炎、白癜风、I型糖尿病、哮喘、肾小球肾炎、牙周疾病、睫状体扁平部炎、移植排异、神经退行性疾病、肥胖症、高血压。Psoriatic arthritis, contact dermatitis, atopic dermatitis, vitiligo, type 1 diabetes, asthma, glomerulonephritis, periodontal disease, pars planitis, transplant rejection, neurodegenerative diseases, obesity, hypertension.
化合物Compound
在一个方面，本申请提供下式I-A的化合物：
In one aspect, the present application provides a compound of the following formula IA:
或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof,
其中：in:
L0选自-NH-、-NH-C(O)-NH-、-NH-S(O)-和-NH-S(O)2-；L 0 is selected from -NH-, -NH-C(O)-NH-, -NH-S(O)- and -NH-S(O) 2 -;
LC为 L C is
L1选自C、S和S(O)；L is selected from C, S and S(O);
L2选自单键、-CH2-、-O-、-S(O)0-2-和-NH-，其中所述-CH2-和-NH-任选地被Ra取代1～3次；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 ;
环A选自C3～10饱和或部分不饱和的单环或双环环烃基、3～10元饱和或部分不饱和的单环或双环杂环基、C6-10芳基和5～10元单环或双环杂芳基； 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;
环B选自C3～6饱和或部分不饱和的单环环烃基、3～6元饱和或部分不饱和的单环杂环基、苯基和5或6元杂芳基；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选自CRaRb、NRa、O、S和S(O)2；X is selected from CR a R b , NR a , O, S and S(O) 2 ;
Q选自CRa和N；Q is selected from CR a and N;
R1选自H、N(Rb)2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、C3～6环烷基、3～6元杂环烷基、C6-10芳基、5～10元杂芳基、-O-C3～6环烷基、-O-3～6元杂环烷基、-O-C6-10芳基、-O-5～10元杂芳基、-C(O)-O-C1～6烷基、-C(O)-NRaRb、-NRb-C(O)-C1～6烷基、-S(O)-C1～6烷基、-S(O)2-C1～6烷基、-S(O)-O-C1～6烷基、-S(O)-NRaRb、-S(O)2-O-C1～6烷基和-S(O)2-NRaRb，其中所述C1～6烷基、C1～6烷氧基、C3～6环烷基、3～6元杂环烷基、C6-10芳基和5～10元杂芳基任选地被Ra取代1～3次； 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) 2 - OC1~ 6 alkyl and -S(O)2- NRaRb , wherein the 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, 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted 1-3 times by Ra ;
R2选自H、N(Rb)2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、氧代基、-C(O)-NRaRb、-NRb-C(O)-C1～6烷基、-C1～3烷基-NH(C1～3烷基)、-C1～3烷基-N(C1～3烷基)2、-S(O)-C1～6烷基、-S(O)2-C1～6烷基、-S(O)-O-C1～6烷基、-S(O)-NRaRb、-S(O)2-O-C1～6烷基、-S(O)2-NRaRb、C3～10饱和或部分不饱和的环烃基、5～10元饱和或部分不饱和的杂环基、C6-10芳基和5～10元芳杂基，其中所述烷基、烷氧基、环烃基、杂环基、芳基和芳杂基任选地被Ra取代1～3次； 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 alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaromatic groups are optionally substituted 1 to 3 times by Ra ;
R3选自H、C1～6烷基、C3～6环烷基、3～6元杂环烷基、-C1～6亚烷基-O-C1～6烷基、-C1～6亚烷基-NH-C1～6烷基、-C1～6亚烷基-N(C1～6烷基)2、-C1～6亚烷基-C3～6环烷基、-C1～6亚烷基-3～6元杂环烷基、-C1～6亚烷基-C6-10芳基和-C1～6亚烷基-5或6元杂芳基，其中所述烷基、亚烷基、环烷基、杂环烷基、芳基和杂芳基任选地被Ra取代1～3次，并且 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
其中R3任选地与环A的环原子连接以形成C3～7饱和或部分不饱和的单环环烃基、3～7元饱和或部分不饱和的单环杂环基、苯基、或者5或6元杂芳基，其中所述环烃基、杂环基、芳基和杂芳基任选地被Ra取代1～3次；wherein 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选自H、CN、OH、NH2、卤素、C1～6烷基、-C1～6亚烷基-O-C1～6烷基、-C1～6亚烷基-NH-C1～6烷基、C3～10环烷基、C7～12螺环烷基、C7-10桥环烷基、3～10元杂环烷基、5-12元螺杂环烷基、6至9元桥杂环烷基、C6～10芳基、5～10元杂芳基、-C1～6亚烷基-C3～7环烷基、-C1～6亚烷基-3～7元杂环烷基、-C1～6亚烷基-C6～10芳基、-C1～6亚烷基-5～10元杂芳基、-C1～6亚烷基-C(O)-C3～7环烷基、-C1～6亚烷基-C(O)-3～7元杂环烷基、-C1～6亚烷基-C(O)-C6～10芳基和-C1～6亚烷基-C(O)-5～10元杂芳基，其中所述烷基、亚烷基、环烷基、螺环烷基、桥环烷基、杂环烷基、螺杂环烷基、桥杂环烷基、芳基和杂芳基在每次出现时任选地被Rb取代1～3次； 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-5~10 membered heteroaryl, -C1~ 6 alkylene-C(O)-C3 ~7 cycloalkyl, -C 1-6 alkylene-C(O)-3-7 membered heterocycloalkyl, -C 1-6 alkylene-C(O)-C 6-10 aryl and -C 1-6 alkylene-C(O)-5-10 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, spirocycloalkyl, bridged cycloalkyl, heterocycloalkyl, spiroheterocycloalkyl, bridged heterocycloalkyl, aryl and heteroaryl are optionally substituted 1-3 times by R b at each occurrence;
p选自1、2和3；p is selected from 1, 2 and 3;
q选自0、1、2和3；q is selected from 0, 1, 2 and 3;
Ra独立地选自H、卤素、NH2、OH、CN、C1～6烷基、-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和-S(O)2-NHRc，其中所述C1～6烷基任选被卤素取代1～3次；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;
Rb独立地选自H、卤素、NH2、OH、CN、C1-6烷基和C1-6烷氧基，其中所述C1～6烷基和C1～6烷氧基任选被卤素取代1～3次；以及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
Rc独立地选自任选地被NH2、OH、CN和1～3个卤素取代的C1-6烷基、C2-6烯基和C2-6炔基。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.
在一些实施方案中，R1选自H、N(Rb)2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、C3～6环烷基、3～6元杂环烷基、C6-10芳基、5～10元杂芳基、-O-C3～6环烷基、-O-3～6元杂环烷基、-O-C6-10芳基、-O-5～10元杂芳基、-C(O)-O-C1～6烷基、-C(O)-NRaRb、-NRb-C(O)-C1～6烷基和-S(O)2-C1～6烷基，其中所述C1～6烷基、C1～6烷氧基、C3～6环烷基、3～6元杂环烷基、C6-10芳基和5～10元杂芳基任选地被Ra取代1～3次。In some embodiments, 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, and 5~10 membered heteroaryl are optionally substituted 1 to 3 times with Ra .
在一些实施方案中，R2选自H、N(Rb)2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、氧代基、-C(O)-NRaRb、-NRb-C(O)-C1～6烷基、C1～3烷基-NH(C1～3烷基)、-C1～3烷基-N(C1～3烷基)2、-S(O)2-C1～6烷基、C3～10饱和或部分不饱和的环烃基、5～10元饱和或部分不饱和的杂环基、C6-10芳基和5～10元芳杂基，其中所述烷基、烷氧基、环烃基、杂环基、芳基和芳杂基任选地被Ra取代1～3次。In some embodiments, 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 .
在一些实施方案中，R4选自H、CN、OH、NH2、卤素、C1～6烷基、-C1～6亚烷基-O-C1～6烷基、-C1～6亚烷基-NH-C1～6烷基、C3～10环烷基、3～7元杂环烷基、7-11元螺杂环烷基、C6～10芳基、5～10元杂芳基、-C1～6亚烷基-C3～7环烷基、-C1～6亚烷基-3～7元杂环烷基、-C1～6亚烷基-C6～10芳基、-C1～6亚烷基-5～10元杂芳基、-C1～6亚烷基-C(O)-C3～7环烷基、-C1～6亚烷基-C(O)-3～7元杂环烷基、-C1～6亚烷基-C(O)-C6～10芳基和-C1～6亚烷基-C(O)-5～10元杂芳基，其中所述烷基、亚烷基、环烷基、杂环烷基、螺杂环烷基、芳基和杂芳基在每次出现时任选地被Rb取代1～3次。 In some embodiments, 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, -C1 ~6 alkylene-C(O)-3~7 membered heterocycloalkyl, -C1~6 alkylene-C(O)-C -C 1-6 alkylene-C(O) -5-10 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, spiroheterocycloalkyl, aryl and heteroaryl are optionally substituted 1 to 3 times by R b at each occurrence.
在一些进一步的实施方案中，R1选自H、N(Rb)2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、C3～6环烷基、3～6元杂环烷基、C6-10芳基、5～10元杂芳基、-O-C3～6环烷基、-O-3～6元杂环烷基、-O-C6-10芳基、-O-5～10元杂芳基、-C(O)-O-C1～6烷基、-C(O)-NRaRb和-NRb-C(O)-C1～6烷基，其中所述C1～6烷基、C1～6烷氧基、C3～6环烷基、3～6元杂环烷基、C6-10芳基和5～10元杂芳基任选地被Ra取代1～3次；和/或In some further embodiments, 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
R2选自H、N(Rb)2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、氧代基、-C(O)-NRaRb、-NRb-C(O)-C1～6烷基、C3～10饱和或部分不饱和的环烃基、5～10元饱和或部分不饱和的杂环基、C6-10芳基和5～10元芳杂基，其中所述烷基、烷氧基、环烃基、杂环基、芳基和芳杂基任选地被Ra取代1～3次；和/或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选自H、CN、OH、NH2、卤素、C1～6烷基、-C1～6亚烷基-O-C1～6烷基、-C1～6亚烷基-NH-C1～6烷基、C3～7环烷基、3～7元杂环烷基、C6～10芳基、5～10元杂芳基、-C1～6亚烷基-C3～7环烷基、-C1～6亚烷基-3～7元杂环烷基、-C1～6亚烷基-C6～10芳基、-C1～6亚烷基-5～10元杂芳基、-C1～6亚烷基-C(O)-C3～7环烷基、-C1～6亚烷基-C(O)-3～7元杂环烷基、-C1～6亚烷基-C(O)-C6～10芳基和-C1～6亚烷基-C(O)-5～10元杂芳基，其中所述烷基、亚烷基、环烷基、杂环烷基、芳基和杂芳基在每次出现时任选地被Rb取代1～3次。 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 heterocycloalkyl, -C1 ~6 alkylene-C(O)-C6 ~10 aryl and -C1~6 1-6 alkylene-C(O)-5-10 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted 1-3 times by R b at each occurrence.
在一些实施方案中，L0为-NH-。In some embodiments, L 0 is -NH-.
在一些实施方案中，所述式I-A的化合物具有式I-B或式I-C所示的结构：
In some embodiments, the compound of Formula IA has a structure shown in Formula IB or Formula IC:
在一些上文所述的实施方案中，环B选自C6饱和或部分不饱和的单环环烃基、6元饱和或部分不饱和的单环杂环基、苯基和6元杂芳基。In some of the embodiments described above, 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.
在一些实施方案中，所述部分为所述式I-A的化合物具有式I-D或I-E所示的结构：
In some embodiments, the Part of The compound of formula IA has the structure shown in formula ID or IE:
其中：in:
表示单键或双键，条件是相邻的两个不同时为双键； represents a single bond or a double bond, provided that two adjacent Not a double bond at the same time;
Y1、Y2和Y3各自独立地选自CH2、CH、NH、N、O和S，其中所述CH2、CH和NH在化合价允许的条件下任选地被R1取代1或2次；以及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选自CH2、CH、NH和N，其中所述CH2、CH和NH在化合价允许的条件下任选地被R1取代1或2次。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.
在一些实施方案中，所述式I-A的化合物具有式I-F或I-G所示的结构：
In some embodiments, the compound of Formula IA has a structure shown in Formula IF or IG:
其中Y1、Y2、Y3和Z各自为CH；或者Y1、Y2、Y3和Z中的一个N，其余均为CH。wherein 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.
在一些此类实施方案中，所述部分选自：
In some such embodiments, the Some selected from:
在一些上文所述的实施方案中，X选自NRa、O、S和S(O)2，其中：In some of the embodiments described above, X is selected from NR a , O, S, and S(O) 2 , wherein:
Ra选自H、C1～6烷基、-C(O)-Rc、-S(O)-Rc和-S(O)2-Rc，其中所述C1～6烷基任选被卤素取代1～3次，并且 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
Rc选自任选地被NH2、OH、CN和1～3个卤素取代的C1-6烷基、C2-6烯基和C2-6炔基。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.
在一些优选的实施方案中，X选自NRa、O、S和S(O)2，其中：In some preferred embodiments, X is selected from NR a , O, S and S(O) 2 , wherein:
Ra选自H、C1～3烷基、-C(O)-Rc、-S(O)-Rc和-S(O)2-Rc，其中所述C1～3烷基任选被F、Cl、Br或I取代1～3次，并且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
Rc选自任选地被NH2、OH、CN和1～3个卤素取代的C1-3烷基、C2-3烯基和C2-3炔基。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.
在一些更优选的实施方案中，X选自NRa、O、S和S(O)2，其中：In some more preferred embodiments, X is selected from NR a , O, S and S(O) 2 , wherein:
Ra选自H、C1～3烷基和-C(O)-Rc，并且R a is selected from H, C 1-3 alkyl and -C(O)-R c , and
Rc选自C1-3烷基、C2-3烯基和C2-3炔基。R c is selected from C 1-3 alkyl, C 2-3 alkenyl and C 2-3 alkynyl.
在一些更优选的实施方案中，X选自NH、N(C(O)-CH＝CH2)、S和S(O)2。In some more preferred embodiments, X is selected from NH, N(C(O)-CH= CH2 ), S, and S(O) 2 .
在一些上文所述的实施方案中，Q选自CRa和N，其中Ra选自H、卤素、NH2、OH、CN和C1～6烷基，并且其中所述C1～6烷基任选被卤素取代1～3次。In some of the above-described embodiments, 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.
在一些优选的实施方案中，Q选自CRa和N，其中Ra选自H和C1～3烷基，并且其中所述C1～3烷基任选被卤素取代1～3次。In some preferred embodiments, 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.
在一些更优选的实施方案中，Q选自CH和N。In some more preferred embodiments, Q is selected from CH and N.
在一些上文所述的实施方案中，R1选自H、N(Rb)2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、C3～6环烷基、3～6元杂环烷基、C6-10芳基、5～10元杂芳基、-O-C3～6环烷基、-O-3～6元杂环烷基、-O-C6-10芳基、-O-5～10元杂芳基、-C(O)-O-C1～6烷基、-C(O)-NRaRb和-S(O)2-C1～6烷基，其中所述C1～6烷基、C1～6烷氧基、C3～6环烷基、3～6元杂环烷基、C6-10芳基和5～10元杂芳基任选地被Ra取代1～3次，In some of the embodiments described above, 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 ,
优选地，R1选自H、N(Rb)2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、C3～6环烷基、3～6元杂环烷基、C6-10芳基、5～10元杂芳基、-O-C3～6环烷基、-O-3～6元杂环烷基、-O-C6-10芳基、-O-5～10元杂芳基、-C(O)-O-C1～6烷基、-C(O)-NRaRb和-S(O)2-C1～6烷基，其中所述C1～6烷基、C1～6烷氧基、C3～6环烷基、3～6元杂环烷基、C6-10芳基和5～10元杂芳基任选地被Ra取代1～3次，Preferably, 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 ,
更优选地，R1选自H、N(Rb)2、CN、OH、卤素、C1～3烷基、C1～3烷氧基、C3～6环烷基、3～6元杂环烷基、苯基、5或6元杂芳基、-O-C3～6环烷基、-O-3～6元杂环烷基、-O-苯基、-O-5或6元杂芳基、-C(O)-O-C1～3烷基和-C(O)-NRaRb，其中所述C1～3烷基、C1～3烷氧基、C3～6环烷基、3～6元杂环烷基、苯基和5～6元杂芳基任选地被Ra取代1～3次， More preferably, 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 ,
其中Ra和Rb独立地选自H和C1～6烷基，其中所述C1～6烷基任选被卤素取代1～3次。wherein 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.
在一些优选的实施方案中，R1选自H、N(Rb)2、CN、OH、F、Cl、Br、C1～3烷基、C1～3卤代烷基、C1～3烷氧基、C3～6环烷基、3～6元杂环烷基、苯基、5或6元杂芳基、-O-C3～6环烷基、-O-3～6元杂环烷基、-O-苯基、-O-5或6元杂芳基、-C(O)-O-C1～3烷基和-C(O)-NRaRb，其中所述C3～6环烷基、3～6元杂环烷基、苯基和5～6元杂芳基任选地被Ra取代1～3次，In some preferred embodiments, 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 ,
其中Ra和Rb独立地选自H和C1～3烷基，优选H、甲基和乙基。wherein Ra and Rb are independently selected from H and C1-3 alkyl, preferably H, methyl and ethyl.
在一些更优选的实施方案中，R1选自H、NH2、-NH(C1～3烷基)、-N(C1～3烷基)2、CN、OH、F、Cl、Br、C1～3烷基、C1～3卤代烷基、C1～3烷氧基、3～6元杂环烷基、5或6元杂芳基、-O-C3～6环烷基、-O-苯基、-C(O)-O-C1～3烷基、-C(O)-NH2、-C(O)-NH(C1～3烷基)、-C(O)-N(C1～3烷基)2，其中所述C3～6环烷基、3～6元杂环烷基、苯基和5～6元杂芳基任选地被Ra取代1～3次。In some more preferred embodiments, 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 .
在一些更优选的实施方案中，R1选自NH2、CN、OH、F、Cl、Br、CH3、CH2CH3、CH(CH3)CH3、CF3、甲氧基、-C(O)OCH3、-C(O)-N(CH3)2、-S(O)2-CH3、环丙基、环丙基氧基、苯氧基和 In some more preferred embodiments, 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
在一些更优选的实施方案中，R1选自NH2、CN、OH、F、Cl、Br、CH3、CH2CH3、CH(CH3)CH3、CF3、甲氧基、-C(O)OCH3、-C(O)-N(CH3)2、环丙基、环丙基氧基、苯氧基和 In some more preferred embodiments, 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
在一些更优选的实施方案中，R1选自CN、OH、F、Cl、CF3、甲氧基、-C(O)OCH3、-C(O)-N(CH3)2、环丙基氧基、苯氧基和 In some more preferred embodiments, 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
在一些上文所述的实施方案中，所述部分选自：In some of the above-described embodiments, the Some selected from:
在一些此类实施方案中，Ra如上文任意实施方案所定义。 In some such embodiments, Ra is as defined above in any of the embodiments.
在一些更优选的实施方案中，所述部分选自： In some more preferred embodiments, the Some selected from:
在一些此类实施方案中，Ra如上文任意实施方案所定义。 In some such embodiments, Ra is as defined above in any of the embodiments.
在一些上文所述的实施方案中，所述化合物式I-A的化合物具有式I-H至I-O所示的结构：
In some of the embodiments described above, the compound of Formula IA has the structure shown in Formula IH to IO:
在一些此类实施方案中，Ra如上文任意实施方案所定义。 In some such embodiments, Ra is as defined above in any of the embodiments.
在一些上文所述的实施方案中，所述部分选自：In some of the above-described embodiments, the Some selected from:
额外地或替代地，所述部分选自 Additionally or alternatively, the Partially selected
在一些上文所述的实施方案中，所述环A选自C3～6饱和或部分不饱和的单环环烃基、C8～10饱和或部分不饱和的双环环烃基、3～6元饱和或部分不饱和的单环杂环基、8～10元饱和或部分不饱和的双环杂环基、C6-10芳基、5或6元杂芳基和8～10元双环杂芳基。In some of the embodiments described above, 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.
在一些优选的实施方案中，所述环A选自C3～6环烷基、3～6元杂环烷基、3～6元单环杂环烯基、8～10元双环杂环烯基、苯基、具有1、2、3或4个氮杂原子和0或1个氧或硫杂原子的5或6元杂芳基和具有1、2、3、4、5或6个氮杂原子和0或1个氧或硫杂原子的8～10元双环杂芳基。In some preferred embodiments, 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.
在一些优选的实施方案中，所述环A选自：In some preferred embodiments, the ring A is selected from:
以及 as well as
以下结构(1)-(18)：
The following structures (1)-(18):
优选 Best
其中：in:
以所示的字母“a”和“b”标识的键之一与L0连接，另一个与L1连接；One of the bonds identified with the letters "a" and "b" shown is connected to L 0 , and the other is connected to L 1 ;
Xa和Xg各自独立地选自CH2、O、S和NH； Xa and Xg are each independently selected from CH2 , O, S and NH;
Xb、Xc、Xd、Xe、Xf和Xh分别独立地选自CH和N；并且 Xb , Xc, Xd , Xe , Xf and Xh are each independently selected from CH and N; and
在所述结构(1)和(2)中，Xa、Xb、Xc和Xd中至少一个是可以取代的。In the structures (1) and (2), at least one of Xa , Xb , Xc and Xd may be substituted.
额外地或替代地，所述环A选自：
Additionally or alternatively, the ring A is selected from:
其中以所示的字母“a”和“b”标识的键之一与L0连接，另一个与L1连接。One of the bonds identified by the letters "a" and "b" shown is connected to L0 , and the other is connected to L1 .
在一些优选的实施方案中，所述环A选自：

In some preferred embodiments, the ring A is selected from:

在一些更优选的实施方案中，所述环A选自：
In some more preferred embodiments, the ring A is selected from:
额外地或替代地，所述环A优选地选自： Additionally or alternatively, the ring A is preferably selected from:
其中以所示的字母“a”和“b”标识的键之一与L0连接，另一个与L1连接。One of the bonds identified by the letters "a" and "b" shown is connected to L0 , and the other is connected to L1 .
在一些此类实施方案中，所示的以字母“a”标识的键与L0连接，并且所示的以字母“b”标识的键与L1连接。In some such embodiments, the bond shown identified with the letter "a" is attached to L 0 , and the bond shown identified with the letter "b" is attached to L 1 .
在一些上文所述的实施方案中，R2选自H、N(Rb)2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、氧代基、-C(O)-NRaRb、-NRb-C(O)-C1～6烷基、C1～3烷基-NH(C1～3烷基)、-C1～3烷基-N(C1～3烷基)2、-S(O)2-C1～6烷基、C3～6饱和或部分不饱和的环烃基、5～6元饱和或部分不饱和的杂环基、苯基和5～6元芳杂基，In some of the embodiments described above, 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,
优选地选自H、N(Rb)2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、氧代基、-C(O)-NRaRb、-NRb-C(O)-C1～6烷基、C3～6饱和或部分不饱和的环烃基、5～6元饱和或部分不饱和的杂环基、苯基和5～6元芳杂基，其中所述烷基、烷氧基、环烃基、杂环基、苯基和芳杂基任选地被Ra取代1～3次，Preferably, 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 ,
其中Ra选自H、卤素、NH2、OH、CN和C1～6烷基；并且wherein Ra is selected from H, halogen, NH2 , OH, CN and C1-6 alkyl; and
其中Rb选自H和C1～6烷基，其中所述C1～6烷基任选被卤素取代1～3次。 wherein 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.
在一些优选的实施方案中，R2选自H、NH2、NH(C1～3烷基)、N(C1～3烷基)2、CN、OH、卤素、C1～3烷基、C1～3烷氧基、氧代基、-C(O)-NRaRb、-NRb-C(O)-C1～3烷基和具有1、2或3个氮杂原子和0或1个氧或硫杂原子的5～6元芳杂基，其中所述烷基和芳杂基任选地被Ra取代1～3次，In some preferred embodiments, 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 ,
其中Ra选自H、F、Cl、NH2、OH、CN和C1～3烷基；并且wherein Ra is selected from H, F, Cl, NH2 , OH, CN and C1-3 alkyl; and
其中Rb选自H和C1～3烷基，其中所述C1～3烷基任选被F或Cl取代1～3次。wherein 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.
额外地或替代地，R2优选选自C3～6环烷基。Additionally or alternatively, R 2 is preferably selected from C 3-6 cycloalkyl.
在一些更优选的实施方案中，R2选自H、NH2、NH(C1～3烷基)、N(C1～3烷基)2、CN、OH、F、Cl、Br、任选地被1、2或3个独立地选自F、Cl和OH的取代基取代的C1～3烷基、C1～3烷氧基、氧代基、-C(O)-NH(C1～3烷基)、-C(O)-N(C1～3烷基)2和任选地被1个选自C1～3烷基的取代基取代的吡咯、吡唑基或三唑基。额外地或替代地，R2优选选自-C(O)-NH2、环丙基、环丁基、环戊基和环己基。In some more preferred embodiments, 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. Additionally or alternatively, R 2 is preferably selected from -C (O) -NH 2 , cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
在一些更优选的实施方案中，R2选自H、NH2、-NHCH3、CN、OH、F、Cl、甲基、乙基、-CH2F、-CHF2、-CH2CH2F、-CH2-OH、甲氧基、氧代基、-C(O)-NHCH3、-C(O)-N(CH3)2和额外地或替代地，R2优选选自环丙基、-CH2-NH(CH3)、-CH2-N(CH3)2、-S(O)2-CH3和-C(O)-NH2。In some more preferred embodiments, 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 .
在一些实施方案中，R2选自-S(O)-C1～6烷基、-S(O)2-C1～6烷基In some embodiments, R 2 is selected from -S(O)-C 1-6 alkyl, -S(O) 2 -C 1-6 alkyl
在一些上文所述的实施方案中，p为1或2In some of the embodiments described above, p is 1 or 2
在一些上文所述的实施方案中，q为0、1或2。In some of the embodiments described above, q is 0, 1 or 2.
在一些上文所述的实施方案中，L1选自C和S(O)。In some of the embodiments described above, L 1 is selected from C and S(O).
在一些上文所述的实施方案中，R3选自H、C1～6烷基、C3～6环烷基、3～6元杂环烷基、-C1～3亚烷基-O-C1～6烷基、-C1～3亚烷基-NH-C1～6烷基、-C1～3亚烷基-N(C1～6烷基)2、-C1～3亚烷基-C3～6环烷基、-C1～3亚烷基-3～6元杂环烷基、-C1～3亚烷基-苯基和-C1～3亚烷基-5或6元杂芳基，其中所述烷基、亚烷基、环烷基、杂环烷基、芳基和杂芳基任选地被Ra取代1～3次，In some of the embodiments described above, 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 ,
优选地，R3选自H、C1～6烷基、C3～6环烷基、3～6元杂环烷基、-C1～3亚烷基-O-C1～6烷基、-C1～3亚烷基-NH-C1～6烷基、-C1～3亚烷基-N(C1～3烷基)2、-C1～3亚烷基-C3～6环烷基和-C1～3亚烷基-3～6元杂环烷基，其中所述烷基、亚烷基、环烷基和杂环烷基任选地被Ra取代1～3次，Preferably, 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 ,
其中Ra选自卤素、NH2、OH和CN和C1～6烷基。wherein Ra is selected from halogen, NH2 , OH, CN and C1-6 alkyl.
在一些优选的实施方案中，R3选自H、C1～6烷基、C3～6环烷基、3～6元杂环烷基、-CH2-O-C1～6烷基、-CH2-NH-C1～6烷基、-CH2-C3～6环烷基和-CH2-3～6元杂环烷基，其中所述烷基、环烷基和杂环烷基任选地被Ra取代1～3次，In some preferred embodiments, 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 ,
其中Ra选自F、Cl、NH2、OH和CN，优选F。wherein Ra is selected from the group consisting of F, Cl, NH2 , OH and CN, preferably F.
在一些更优选的实施方案中，R3选自H、CH3、-CH2CH3、-CH(CH3)CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH2OCH3、-CH2NHCH3、 In some more preferred embodiments, 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 ,
在另一些上文所述的实施方案中，R3与在L1邻位的环A的环原子连接以形成C3～7饱和或部分不饱和的单环环烃基、3～7元饱和或部分不饱和的单环杂环基、苯基、或者5或6元杂芳基，其中所述环烃基、杂环基、芳基和杂芳基任选地被Ra取代1～3次。In other embodiments described above, 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 .
在一些优选的实施方案中，R3与在L1邻位的环A的环原子连接以形成C5～6饱和或部分不饱和的单环环烃基、或者5或6元饱和或部分不饱和的单环杂环基，其中所述环烃基和杂环基任选地被Ra取代1～3次。In some preferred embodiments, 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 .
在一些更优选的实施方案中，R3与在L1邻位的环A的环原子连接以形成选自以下的环结构，其任选地被Ra取代1～3次：

In some more preferred embodiments, 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 :

优选 Best
其中：in:
表示单键或双键， represents a single bond or a double bond,
以所示的字母“c”和“d”标识的环原子为所述环A的环原子，以所示的字母“e”标识的双键连接至与L1和L2连接的N原子。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.
在一些此类实施方案中，所述环A、L1和R3一起形成选自以下的结构：
In some such embodiments, the ring A, L 1 and R 3 together form a structure selected from the group consisting of:
其中以所示的字母“e”标识的双键连接至与L1和L2连接的N原子，以所示的字母“f”标识的双键连接至与L0。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 .
在一些上文所述的实施方案中，L2选自单键、-CH2-、-O-和S(O)，其中所述-CH2-任选地被Ra取代1～3次。In some of the embodiments described above, 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 .
在一些上文所述的实施方案中，R4选自：In some of the embodiments described above, R4 is selected from:
R4选自H、CN、OH、NH2、卤素、C1～6烷基、-C1～3亚烷基-O-C1～6烷基、-C1～3亚烷基-NH-C1～6烷基、C3～10(优选C3～7)环烷基、3～7元杂环烷基、7-11元螺杂环烷基、苯基、5～6元杂芳基、-C1～3亚烷基-C3～7环烷基、-C1～3亚烷基-3～7元杂环烷基、-C1～3亚烷基-苯基、-C1～3亚烷基-5～6元杂芳基、-C1～3亚烷基-C(O)-C3～7环烷基、-C1～3亚烷基-C(O)-3～7元杂环烷基、-C1～3亚烷基-C(O)-苯基和-C1～3亚烷基-C(O)-5～6元杂芳基，其中所述烷基、亚烷基、环烷基、杂环烷基、螺杂环烷基、苯基和杂芳基在每次出现时任选地被Rb取代1～3次， 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 alkylene-C(O)-3~7 membered heterocycloalkyl, -C1 ~3 alkylene-C(O)-phenyl and -C1~3 1-3 alkylene-C(O)-5-6 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, spiroheterocycloalkyl, phenyl and heteroaryl are optionally substituted 1-3 times by R b at each occurrence,
优选H、CN、OH、NH2、卤素、C1～6烷基、-C1～3亚烷基-O-C1～6烷基、-C1～3亚烷基-NH-C1～6烷基、C3～7环烷基、3～7元杂环烷基、苯基、5～6元杂芳基、-C1～3亚烷基-C3～7环烷基、-C1～3亚烷基-3～7元杂环烷基、-C1～3亚烷基-苯基、-C1～3亚烷基-5～6元杂芳基、-C1～3亚烷基-C(O)-C3～7环烷基、-C1～3亚烷基-C(O)-3～7元杂环烷基、-C1～3亚烷基-C(O)-苯基和-C1～3亚烷基-C(O)-5～6元杂芳基，其中所述烷基、亚烷基、环烷基、杂环烷基、苯基和杂芳基在每次出现时任选地被Rb取代1～3次，Preferred are 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 heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted 1-3 times by R b at each occurrence,
其中Rb独立地选自F、Cl、Br、NH2、OH、CN、C1-6烷基和C1-6烷氧基，其中所述C1～6烷基和C1～6烷氧基任选被F、Cl或Br取代1～3次。wherein 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.
在一些优选的实施方案中，R4选自：In some preferred embodiments, R4 is selected from:
H、CN、C1～6烷基、C3～7环烷基、3～7元杂环烷基、7-11元螺杂环烷基、苯基、5～6元杂芳基、-C1～3亚烷基-C3～7环烷基、-C1～3亚烷基-3～7元杂环烷基、-C1～3亚烷基-苯基、-C1～3亚烷基-5～6元杂芳基、-C1～3亚烷基-C(O)-C3～7环烷基、-C1～3亚烷基-C(O)-3～7元杂环烷基、-C1～3亚烷基-C(O)-苯基和-C1～3亚烷基-C(O)-5～6元杂芳基，其中所述烷基、亚烷基、环烷基、杂环烷基、螺杂环烷基、苯基和杂芳基任选地被Rb取代1～3次， R b is substituted 1 to 3 times , ​ ​ ​ ​
优选H、CN、C1～6烷基、C3～7环烷基、3～7元杂环烷基、苯基、5～6元杂芳基、-C1～3亚烷基-C3～7环烷基、-C1～3亚烷基-3～7元杂环烷基、-C1～3亚烷基-苯基、-C1～3亚烷基-5～6元杂芳基、-C1～3亚烷基-C(O)-C3～7环烷基、-C1～3亚烷基-C(O)-3～7元杂环烷基、-C1～3亚烷基-C(O)-苯基和-C1～3亚烷基-C(O)-5～6元杂芳基，其中所述烷基、亚烷基、环烷基、杂环烷基、苯基和杂芳基任选地被Rb取代1～3次，Preferred are 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 b ,
其中Rb独立地选自F、Cl、NH2、OH、CN和C1-3烷基，其中所述C1～3烷基任选被F或Cl取代1～3次。wherein 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.
在一些更优选的实施方案中，R4选自H、CN、-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH2CH(CH3)CH2CH3、-CH2CH2CH(CH3)CH3、-CH(CH3)CH3、-C(CH3)3、-CH2CHF2、-CH2CF3、-CH2CH2CF3、-CH(CH3)CF3、-CH2CH2CH2CF3、 (包括)、 额外地或替代地，R4选自(包括)。In some more preferred embodiments, 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 ).
在一些实施方案中，本申请提供如上文所述的式I-F或I-G的化合物，其中：In some embodiments, the present application provides a compound of formula I-F or I-G as described above, wherein:
所述部分选自 Said Partially selected
R1选自H、CN、卤素、C1～6卤代烷基、C1～6烷氧基、3～6元杂环烷基、5或6元杂芳基、-C(O)-NH(C1～3 烷基)和-C(O)-N(C1～3烷基)2，其中所述3～6元杂环烷基和5～6元杂芳基任选地被Ra取代C1～6烷基次； 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为1或2；p is 1 or 2;
所述环A选自 The ring A is selected from
R2选自H、NH2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、氧代基、-C(O)-NRaRb、苯基和5～6元芳杂基，其中所述烷基、烷氧基、苯基和芳杂基任选地被Ra取代1～3次， 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 ,
其中Ra选自H、卤素、OH和C1～6烷基；并且wherein Ra is selected from H, halogen, OH and C1-6 alkyl; and
其中Rb选自H和C1～6烷基，其中所述C1～6烷基任选被卤素取代1～3次；wherein 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为0、1或2；q is 0, 1, or 2;
L1为C；L 1 is C;
R3选自H、C1～6烷基和C3～6环烷基；R 3 is selected from H, C 1-6 alkyl and C 3-6 cycloalkyl;
或者，R3与在L1邻位的环A的环原子连接，从而所述环A、L1和R3一起形成 其中以所示的字母“e”标识的双键连接至与L1和L2连接的N原子，以所示的字母“f”标识的双键连接至与作为L0的NH；Alternatively, 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为-O-； L2 is -O-;
R4选自C1～6卤代烷基、C3～10环烷基、3～7元杂环烷基、7-11元螺杂环烷基、-C1～6亚烷基-C3～7环烷基、-C1～6亚烷基-3～7元杂环烷基、-C1～3亚烷基-苯基、-C1～3亚烷基-5～6元杂芳基、-C1～6亚烷基-C(O)-C3～7环烷基、-C1～6亚烷基-C(O)-3～7元杂环烷基、-C1～6亚烷基-C(O)-苯基和-C1～6亚烷基-C(O)-5～6元杂芳基，其中所述环烷基、杂环烷基、螺杂环烷基、苯基和杂芳基任选地被Rb取代1～3次， 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 times by R,
其中Rb独立地选自F、Cl、CN和被F或Cl取代1～3次的C1-3烷基。wherein R b is independently selected from F, Cl, CN and C 1-3 alkyl substituted 1 to 3 times by F or Cl.
在一些优选的实施方案中，所述部分选自 In some preferred embodiments, the Partially selected
在一些优选的实施方案中，R1选自H、CN、F、Cl、C1～3卤代烷基、C1～3烷氧基、3～6元杂环烷基、5或6元杂芳基和-C(O)-N(C1～3烷基)2，其中所述3～6元杂环烷基和5～6元杂芳基任选地被C1～3烷基取代1～3次； In some preferred embodiments, 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;
在一些更优选的实施方案中，R1选自H、CN、F、Cl、CF3、甲氧基、-C(O)-N(CH3)2、 In some more preferred embodiments, R 1 is selected from H, CN, F, Cl, CF 3 , methoxy, -C(O)-N(CH 3 ) 2 ,
在一些优选的实施方案中，所述环A选自 In some preferred embodiments, the ring A is selected from
在另一些优选的实施方案中，所述环A选自 In other preferred embodiments, the ring A is selected from
在一些优选的实施方案中，所述环A选自 In some preferred embodiments, the ring A is selected from
在一些优选的实施方案中，R2选自H、NH2、CN、OH、F、Cl、C1～3烷氧基、氧代基、-C(O)-NH(C1～3烷基)、-C(O)-N(C1～3烷基)2、任选地被1、2或3个独立地选自F、Cl和OH的取代基取代的C1～3烷基、和任选地被1个选自C1～3烷基的取代基取代的吡咯、吡唑基或三唑基。In some preferred embodiments, 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.
在一些更优选的实施方案中，R2选自H、F、CN、OH、NH2、氧代基、甲氧基、甲基、乙基、-CHF2、-CH2CH2F、-CH2-OH、-C(O)-NHCH3、-C(O)-N(CH3)2和 In some more preferred embodiments, 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
在一些优选的实施方案中，R3选自H、CH3、-CH2CH3、-CH(CH3)CH3、-CH2CH2CH3和 In some preferred embodiments, R 3 is selected from H, CH 3 , -CH 2 CH 3 , -CH(CH 3 )CH 3 , -CH 2 CH 2 CH 3 and
在一些优选的实施方案中，R3与在L1邻位的环A的环原子连接，从而所述环A、L1和R3一起形成 In some preferred embodiments, 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
在一些优选的实施方案中，R3与在L1邻位的环A的环原子连接，从而所述环A、L1和R3一起形成 In some preferred embodiments, 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
在一些优选的实施方案中，R4选自C1～6卤代烷基、C3～7环烷基、3～7元杂环烷基、-C1～6亚烷基-C3～7环烷基、-C1～6亚烷基-3～7元杂环烷基、-C1～3亚烷基-苯基、-C1～3亚烷基-5～6元杂芳基、-C1～6亚烷基-C(O)-C3～7环烷基、-C1～6亚烷基-C(O)-3～7元杂环烷基、-C1～6亚烷基-C(O)-苯基和-C1～6亚烷基-C(O)-5～6元杂芳基，其中所述环烷基、杂环烷基、苯基和杂芳基任选地被Rb取代1～3次。In some preferred embodiments, 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 are optionally substituted 1 to 3 times by Rb .
在另一些优选的实施方案中，R4选自C1～4卤代烷基、C3～7环烷基、3～7元杂环烷基、7-11元螺杂环烷基、-CH2-C3～7环烷基、-CH2-苯基、-CH2-5～6元杂芳基和-CH2-C(O)-3～7元杂环烷基，其中所述环烷基、杂环烷基、螺杂环烷基苯基和杂芳基任选地被Rb取代1～3次，In other preferred embodiments, 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 ,
其中Rb独立地选自F、Cl、CN和被F或Cl取代1～3次的甲基或乙基。wherein R b is independently selected from F, Cl, CN, and a methyl or ethyl group substituted 1 to 3 times by F or Cl.
在一些优选的实施方案中，R4选自C1～4卤代烷基、C3～7环烷基、3～7元杂环烷基、-CH2-C3～7环烷基、-CH2-苯基、-CH2-5～6元杂芳基和-CH2-C(O)-3～7元杂环烷基，其中所述环烷基、杂环烷基、苯基和杂芳基任选地被Rb取代1～3次，In some preferred embodiments, 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 ,
其中Rb独立地选自F、Cl、CN和被F或Cl取代1～3次的甲基或乙基。wherein R b is independently selected from F, Cl, CN, and a methyl or ethyl group substituted 1 to 3 times by F or Cl.
在一些更优选的实施方案中，R4选自-CH2CF3、-CH2CH2CH2CF3、 (包括)、 In some more preferred embodiments, R 4 is selected from -CH 2 CF 3 , -CH 2 CH 2 CH 2 CF 3 , (include ),
在一些更优选的实施方案中，R4选自-CH2CF3、-CH2CH2CH2CF3、 (包括)、 In some more preferred embodiments, R 4 is selected from -CH 2 CF 3 , -CH 2 CH 2 CH 2 CF 3 , (include ),
额外地或替代地，R4选自(包括)。Additionally or alternatively, R4 is selected from (include ).
在另一方面，本申请还提供下式I所示的化合物：
On the other hand, the present application also provides a compound shown in the following formula I:
或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化 合物或前药，or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled Compounds or prodrugs,
其中：in:
表示单键或双键； represents a single bond or a double bond;
L0选自-NH-、-NH-C(O)-NH-和NH-S(O)1-2-；L 0 is selected from -NH-, -NH-C(O)-NH- and NH-S(O) 1-2 -;
L1选自-C-和-S(O)0-2-；L 1 is selected from -C- and -S(O) 0-2 -;
L2选自单键、-CH2-、-O-、-S(O)0-2-和-NH-，其中所述-CH2-、-NH-和-S(O)0-2-可任选地被Ra取代1～3次；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 ;
环A为单环或双环的环系结构，其中所述单环选自4～6元碳环、4～6元杂环、5～6元芳杂环和5～6元芳环，所述的双环选自由4～6元碳环、4～6元杂环、5～6元芳杂环和5～6元芳环中独立的任两种稠合成的7～10元稠环或稠杂环；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;
环B选自5～7元碳环、5～7元杂环、5～7元芳杂环和5～6元芳环；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选自-CH2-、-NH-、-O-和-S-，其中所述-CH2-和-NH-可任选地被Ra取代1～2次；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 ;
R1选自H、CN、OH、卤素、C1～6烷基、3～6元环烷基、3～6元杂环烷基、苯基、5～6元杂芳基、C1～6烷氧基、-O-3～6元环烷基、-O-3～6元杂环烷基、-O-苯基、-O-5～6元杂芳基和-C(O)-O-C1～6烷基，其中所述C1～6烷基、3～6元环烷基、3～6元杂环烷基、苯基和5～6元杂芳基可任选地被Ra取代1～3次；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;
R2选自H、N(Rb)2、CN、C(O)、S(O)0-2、卤素、C1～3烷基和C1～3烷氧基，其中所述C1～3烷基和C1～3烷氧基可任选地被Ra取代1～3次；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 ;
R3选自H、C1～6烷基、3～6元环烷基、3～6元杂环烷基、CH2-O-C1～6烷基、CH2-NH-C1～6烷基、CH2-3～6元环烷基和CH2-3～6元杂环烷基，其中所述C1～6烷基、3～6元环烷基和3～6元杂环烷基可任选地被Ra取代1～3次；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 ;
其中R3可进一步与环A的环原子一起形成5～7元环，其中所述5～7元环可任选地被Ra取代1～3次，并且所述5～7元环可为碳环、杂环、芳环、杂芳环；wherein 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选自H、CN、C1～6烷基、3～7元环烷基、3～7元杂环烷基、苯基、5～6元杂芳基、-C1～3亚烷基-3～7元环烷基、-C1～3亚烷基-3～7元杂环烷基、-C1～3亚烷基-苯基和-C1～3亚烷基-5～6元杂芳基，其中所述C1～6烷基、3～7元环烷基、3～7元杂环烷基、苯基和5～6元杂芳基可任选地被Rb取代1～3次； 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选自1、2和3；p is selected from 1, 2 and 3;
q选自0、1、2和3；q is selected from 0, 1, 2 and 3;
Ra独立地选自H、F、Cl和C1～3烷基；Ra is independently selected from H, F, Cl and C1-3 alkyl;
Rb独立地选自H、F、Cl、Br、I、NH2、OH、C1-3烷基、C1-3烷氧基和CN，其中所述C1～3烷基和C1～3烷氧基任选被卤素取代1～3次。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.
在另一方面，本申请还提供下式I’所示的化合物：
On the other hand, the present application also provides a compound represented by the following formula I':
或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof,
其中：in:
表示单键或双键； represents a single bond or a double bond;
X选自-CH2-、-NH-、-O-和-S-，其中所述-CH2-和-NH-可任选地被Ra取代1～2次；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 ;
Y1、Y2、Y3独立地选自-CH2-、-NH-、-O-和-S-，其中所述-CH2-和-NH-中的H在化合价允许的条件下可任选地被R1取代1或2次；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选自-CH2-和-NH-，其中所述-CH2-和-NH-中的H在化合价允许的条件下可任选地被R1取代1或2次；Z 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;
L1选自-C-和-S(O)-； L is selected from -C- and -S(O)-;
L2选自单键、-CH2-、-O-、-S(O)-和-NH-，其中所述-CH2-和-NH-可任选地被Ra取代1～3次； 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 ;
环A为单环或双环的环系结构，其中所述的单环选自4～6元碳环、4～6元杂环、5～6元芳杂环和5～6元芳环，所述双环选自4～6元碳环、4～6元杂环、5～6元芳杂环和5～6元芳环中独立的任两种稠合成的7～10元稠环或稠杂环；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;
R1选自H、CN、OH、卤素、C1～6烷基、3～6元环烷基、3～6元杂环烷基、苯基、5～6元杂芳基、C1～6烷氧基、-O-3～6元环烷基、-O-3～6元杂环烷基、-O-苯基、-O-5～6元杂芳基和-C(O)-O-C1～6烷基，其中所述C1～6烷基、3～6元环烷基、3～6元杂环烷基、苯基和5～6元杂芳基可任选地被Ra取代1～3次；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;
R2选自H、F、Cl、NH2、氰基、氧代、C1～3烷基和C1～3烷氧基，其中所述C1～3烷基和C1～3烷氧基可任选地被Ra取代1～3次；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 ;
R3选自H、C1～6烷基、3～6元环烷基、3～6元杂环烷基、-CH2-O-C1～6烷基、-CH2-NH-C1～6烷基、-CH2-3～6元环烷基和-CH2-3～6元杂环烷基，其中所述C1～6烷基、3～6元环烷基、3～6元杂环烷基可任选地被Ra取代1～3次；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 ;
其中R3可进一步与环A的环原子一起形成5～7元环，所述的5～7元环可任选地被Ra取代1～3次；wherein 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选自H、CN、C1～6烷基、3～7元环烷基、3～7元杂环烷基、苯基、5～6元杂芳基、-C1～3亚烷基-3～7元环烷基、-C1～3亚烷基-3～7元杂环烷基、-C1～3亚烷基-苯基和-C1～3亚烷基-5～6元杂芳基，其中所述C1～6烷基、3～7元环烷基、3～7元杂环烷基、苯基和5～6元杂芳基可任选地被Rb取代1～3次； 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选自1、2和3；p is selected from 1, 2 and 3;
q选自0、1、2和3；q is selected from 0, 1, 2 and 3;
Ra独立地选自H、F、Cl、C1～3烷基和C1～3卤代烷基；Ra is independently selected from H, F, Cl, C1-3 alkyl and C1-3 haloalkyl;
Rb独立地选自H、F、Cl、Br、I、NH2、OH、C1-3烷基、C1-3烷氧基和CN，其中所述C1～3烷基和C1～3烷氧基任选被卤素取代1～3次。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.
在一些实施方案中，环A选自吡啶、咪唑、哒嗪、噁唑、异噁唑、苯环、噻唑、嘧啶、吡嗪、喹啉、异喹啉、苯并咪唑、咪唑并吡啶和萘啶，其中所述环A可任选地被R2取代1～3次。In some embodiments, 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 .
在一些实施方案中，环A选自 其中所述环A可任选地被R2取代1～3次。In some embodiments, Ring A is selected from The ring A may be optionally substituted by R 2 1 to 3 times.
在一些实施方案中，环A选自 In some embodiments, Ring A is selected from
其中所述环A可任选地被R2取代1～3次。The ring A may be optionally substituted by R 2 1 to 3 times.
在一些实施方案中，R1选自H、F、Cl、Br、CH3、CH2CH3、CH(CH3)CH3、OCH3、OH、COOCH3、其中所述R1可任选地被Ra取代1～3次。In some embodiments, 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.
在一些实施方案中，R2选自H、F、Cl、氰基、氧代、CH3。In some embodiments, R 2 is selected from H, F, Cl, cyano, oxo, CH 3 .
在一些实施方案中，R3选自H、CH3、CH2CH3、CH(CH3)CH3、CH2CH2CH3、CH2CH2CH2CH3、CH2OCH3、CH2NHCH3、所述R3可任选地被Ra取代1～3次。In some embodiments, 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 .
在一些实施方案中，R4选自H、CH3、CH2CH3、CH2CH2CH3、CH2CH2CH2CH3、CH2CH(CH3)CH2CH3、CH2CH2CH(CH3)CH3、CH(CH3)CH3、C(CH3)3、CN、环丙基、环丁基、环戊基、环己基、环庚基、苯基、甲基-环丙基、甲基-环丁基、甲基-环戊基、甲基-环己基、甲基-环庚基、甲基-苯基、哌啶、吡啶、嘧啶、吡嗪、吡唑、环氧丁烷、环氧戊烷、环氧己烷、氮杂环丁烷、吡咯烷、吡咯烷酮、哌啶酮，其中所述R4可任选地被Rb取代1～3次。In some embodiments, 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 be optionally substituted 1 to 3 times by Rb .
在一些实施方案中，R3进一步与环A的环原子一起形成5～6元环，所述5～6元环选自 其中所述5～6元环可任选地被Ra取代1～3次。In some embodiments, 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 .
在另一方面，本申请还提供下式I”所示的化合物：
On the other hand, the present application also provides a compound shown in the following formula I":
或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof,
其中：in:
表示单键或双键； represents a single bond or a double bond;
Y1、Y2、Y3独立地任选自-CH2-和-NH-，其中所述的-CH2-和-NH-中的H在化合价允许的条件下可任选地被R1取代1或2次；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选自-CH2-和-NH-，其中所述-CH2-和-NH-中的H在化合价允许的条件下可任选地被R1取代1或2次；Z 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;
环A为单环或双环的环系结构，其中所述的单环选自4～6元碳环、4～6元杂环、5～6元芳杂环和5～6元芳环，所述的双环选自由4～6元碳环、4～6元杂环、5～6元芳杂环和5～6元芳环中独立的任两种稠合成的7～10元稠环或稠杂环；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;
R1选自H、CN、OH、卤素、C1～6烷基、3～6元环烷基、3～6元杂环烷基、苯基、5～6元杂芳基、C1～6烷氧基、-O-3～6元环烷基、-O-3～6元杂环烷基、-O-苯基、-O-5～6元杂芳基和-C(O)-O-C1～6烷基，其中所述C1～6烷基、3～6元环烷基、3～6元杂环烷基、苯基和5～6元杂芳基可任选地被Ra取代1～3次；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;
R2选自H、F、Cl、NH2、氰基、氧代、C1～3烷基和C1～3烷氧基，其中所述C1～3烷基和C1～3烷氧基可任选地被Ra取代1～3次；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 ;
R3选自H、C1～6烷基、3～6元环烷基、3～6元杂环烷基、-CH2-O-C1～6烷基、-CH2-NH-C1～6烷基、-CH2-3～6元环烷基、-CH2-3～6元杂环烷基，其中所述C1～6烷基、3～6元环烷基和3～6元杂环烷基可任选地被Ra取代1～3次；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 ;
其中R3可进一步与环A的环原子一起形成5～7元环，所述5～7元环可任选地被Ra取代1～3次； wherein 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选自H、CN、C1～6烷基、3～7元环烷基、3～7元杂环烷基、苯基、5～6元杂芳基、-C1～3亚烷基-3～7元环烷基、-C1～3亚烷基-3～7元杂环烷基、-C1～3亚烷基-苯基和-C1～3亚烷基-5～6元杂芳基，其中所述C1～6烷基、3～7元环烷基、3～7元杂环烷基、苯基和5～6元杂芳基可任选地被Rb取代1～3次； 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 ;
其中，p、q、Ra、Rb同前文所定义。Wherein, p, q, Ra and Rb are the same as defined above.
在一些方案所述中，本申请提供上文所述化合物，所述化合物具有式II-1或式II-2所示的结构：
In some embodiments, the present application provides the compound described above, which has a structure shown in Formula II-1 or Formula II-2:
或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，其中环A、R1、R2、R3、R4、L2同文所定义。or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein Ring A, R 1 , R 2 , R 3 , R 4 , and L 2 are as defined above.
在一些实施方案中，本申请提供上文所述化合物，所述化合物具有式II-3所示的结构：
In some embodiments, the present application provides the compound described above, which has a structure shown in Formula II-3:
或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，其中环A、R1、R2、R3、R4、L2同前文所定义。or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein Ring A, R 1 , R 2 , R 3 , R 4 and L 2 are the same as defined above.
在一些实施方案中，本申请提供上文所述化合物，所述化合物具有式III-1、III-2、III-3或III-4所示的结构：
In some embodiments, the present application provides the above-mentioned compound, which has a structure shown in Formula III-1, III-2, III-3 or III-4:
或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，其中Xa、Xb、Xc、Xd、Xe、Xf分别独立地选自CH或N；R1、R2、R3、R4、L1、L2同前文所定义。or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein Xa , Xb , Xc , Xd , Xe , Xf are independently selected from CH or N; R1 , R2 , R3 , R4 , L1 , L2 are as defined above.
在一些实施方案中，本申请提供上文所述化合物，所述化合物具有式III-5或III-1a所示的结构：
In some embodiments, the present application provides the compound described above, which has a structure shown in Formula III-5 or III-1a:
或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，其中Xa、Xb、Xc、Xd分别独立地选自CH或N；R1、R2、R3、R4、L1、L2同前文所定义。or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein Xa , Xb , Xc , Xd are independently selected from CH or N; R1 , R2 , R3 , R4 , L1 , L2 are as defined above.
在一些实施方案中，本申请提供上文所述化合物，所述化合物具有式IV-1或IV-2所示的结构：
In some embodiments, the present application provides the compound described above, which has a structure shown in Formula IV-1 or IV-2:
或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，其中Xa、Xb、Xc、Xd分别独立地选自CH或N；R1、R2、R3、R4同前文所定义。or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein 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.
在一些实施方案中，本申请提供上文所述化合物，所述化合物具有式V-1或V-2所示的结构：
In some embodiments, the present application provides the compound described above, which has a structure shown in Formula V-1 or V-2:
或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，其中Xa、Xb、Xc、Xd分别独立地选自CH或N；R1、R2、R3、R4同前文所定义。or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein 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.
本发明涵盖对各个实施方案进行任意组合所得的化合物。The present invention encompasses compounds resulting from any combination of the various embodiments.
在一些实施方案中，本申请提供根据本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物选自：In some 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:
(包括 ) (include )
在另一些实施方案中，本申请提供根据本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物选自：


In other 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:


在另一些实施方案中，本申请提供根据本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物选自：

In other 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:

在另一些实施方案中，本申请提供根据本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物选自：


In other 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:


在另一些实施方案中，本申请提供根据本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物选自：In other 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:
(包括)、 (include ),
在一些实施方案中，本发明化合物的立体异构体是构型异构体。在一些实施方案中，所述构型异构体是顺反异构体(cis-/trans-异构体)，也称作几何异构体(E-/Z-异构体)。在一些实施方案中，所述构型异构体是对映异构体。在一些实施方案中，所述构型异构体是非对映对映异构体。在一些实施方案中，本发明的化合物是外消旋的。In some embodiments, the stereoisomers of the compounds of the invention are configurational isomers. In some embodiments, the configurational isomers are cis-/trans-isomers, also known as geometric isomers (E-/Z-isomers). In some embodiments, the configurational isomers are enantiomers. In some embodiments, the configurational isomers are diastereoisomers. In some embodiments, the compounds of the invention are racemic.
本发明的药学上可接受的盐包括酸加成盐及碱盐。在一些实施方案中，本发明化合物的药学上可接受的盐是例如、但不限于甲酸盐。The pharmaceutically acceptable salts of the present invention include acid addition salts and base salts. In some embodiments, the pharmaceutically acceptable salt of the compound of the present invention is, for example, but not limited to, formate.
本发明的药学上可接受的盐可呈非溶剂化及溶剂化形式存在。The pharmaceutically acceptable salts of the present invention may exist in unsolvated as well as solvated forms.
药物组合物和治疗方法Pharmaceutical compositions and methods of treatment
在另一方面，本申请还提供药物组合物，其包含本发明的化合物(包括式I-A以及式I的化合物)、或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，以及药学上可接受的载体。On the other hand, the present application also provides 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.
本发明的化合物及其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药在治疗中可以单独使用或与至少一种其他治疗剂组合使用。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.
本发明还提供药物组合物，其含有如上文所述的本发明化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，以及一种或两种以上其 他治疗活性成分。The present invention also provides 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.
在另一个方面，本申请提供本发明的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物，其用作药物。In another aspect, 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.
在另一个方面，本申请提供本发明的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物，其用作STING抑制剂。In another aspect, 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.
在另一个方面，本申请提供本发明的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物在制备作为STING抑制剂的药物中的用途。In another aspect, 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.
在一些实施方案中，所述STING抑制剂或药物是用于治疗和/或预防肿瘤和/或癌症。In some embodiments, the STING inhibitor or drug is used to treat and/or prevent tumors and/or cancer.
本发明的化合物是STING抑制剂，具有优秀的STING受体抑制活性。这些STING抑制剂化合物能够治疗和/或预防STING介导的疾病或病症及相关疾病或病症。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.
在一个方面，本申请提供本发明的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物在制备用于预防和/或治疗STING介导的疾病或病症及相关疾病或病症的药物中的用途。In one aspect, 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.
在另一个方面，本申请提供用于预防和/或治疗个体的STING介导的疾病或病症及相关疾病或病症的方法，其包括向所述个体施用治疗有效量的本发明的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物。In another aspect, 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.
在一些实施方案中，所述STING介导的疾病或病症是肿瘤和/或癌症。在一些实施方案案中，所述的肿瘤和/或癌症包括但不限于黑色素瘤、甲状腺瘤、头颈癌、宫颈癌、乳腺癌、卵巢癌、前列腺癌、睾丸癌、尿路上皮癌、膀胱癌、非小细胞肺癌、小细胞肺癌、结直肠腺瘤、肉瘤、肠道间质瘤、胃癌、食道癌、结肠直肠癌、胰腺癌、小肠癌、肾癌、肝癌、肝细胞癌、胆管细胞癌、间皮瘤、淋巴瘤、白血病、骨髓异常增生综合症、多发性骨髓瘤、浆细胞瘤、成神经细胞瘤、成视网膜细胞瘤和生殖细胞瘤。In some embodiments, the STING-mediated disease or condition is a tumor and/or cancer. In some embodiments, 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.
在一些实施方案中，所述STING介导的疾病或病症是中枢神经系统、周围神经系统和自主神经系统疾病或病症。在一些实施方案中，所述中枢神经系统、周围神经系统和自主神经系统疾病或病症包括但不限于癫痫样失语、脑脊髓炎、黄斑变性、阿尔珀斯病、胼胝体发育不全、艾卡迪综合征、交替性偏瘫、阿尔茨海默氏病、血管性痴呆、肌萎缩侧索硬化症、蛛网膜囊肿、蛛网膜炎、阿斯伯格综合征、共济失调远程扩张症、注意缺陷多动障碍、自闭症、自主神经功能障碍、肌萎缩、良性颅内高压、宾斯旺格病、脑萎缩、脑巨人症、脑动脉硬化、舞蹈病、慢性炎症性脱髓鞘性多发性神经病、先天性面瘫、皮质基底节变性、颅动脉炎、颅缝早闭、克雅氏病、累积性创伤障碍、库欣综合征、巨细胞包涵体病、糖尿病性神经病变、弥漫性硬化症、肌张力障碍、巨细胞动脉炎、巨细胞包涵体病、面肌痉挛、遗传性痉挛性截瘫、多发性神经炎性遗传病、带状疱疹、亨廷顿病、重症肌无力、髓细胞性弥漫性硬化症、帕金森病、闭锁综合征、腰椎间盘疾病、偏头痛、线粒体肌病、莫比乌斯综合征、单体肌萎缩、运动神经元病、多梗死性痴呆、多发性硬化症、肌阵挛、神经肌强直、面肌萎缩、多灶性白质脑病、硬化性脊髓灰质炎、带状疱疹、脊髓损伤。In some embodiments, the STING-mediated disease or disorder is a disease or disorder of the central nervous system, peripheral nervous system, and autonomic nervous system. In some embodiments, 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, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, giant cell inclusion disease, diabetic neuropathy, diffuse sclerosis, dystonia, giant cell arteritis, giant cell inclusion disease, hemifacial spasm, hereditary spastic paraplegia, multiple neuritis genetic disease, herpes zoster, Huntington's disease, myasthenia gravis, diffuse myeloid sclerosis, Parkinson's disease, locked-in syndrome, lumbar disc disease, migraine, mitochondrial myopathy, Moebius syndrome, monosomic muscular dystrophy, motor neuron disease, multi-infarct dementia, multiple sclerosis, myoclonus, neuromyotonia, hemifacial muscular atrophy, multifocal leukoencephalopathy, sclerosing poliomyelitis, herpes zoster, spinal cord injury.
在一些实施方案中，所述STING介导的疾病或病症是STING相关病症，包括但不限于I型干扰素病、Aicardi-Goutières综合征(AGS)、狼疮、类风湿性关节炎。In some embodiments, the STING-mediated disease or disorder is a STING-associated disorder, including but not limited to type I interferonopathy, Aicardi-Goutières syndrome (AGS), lupus, rheumatoid arthritis.
在一些实施方案中，所述STING介导的疾病或病症是自身免疫性疾病，包括但不限于类风湿性关节炎、系统性红斑狼疮、多发性硬化症、克罗恩病(CD)、炎症性肠病(IBD)、溃疡性结肠炎(UC)、自身免疫性结肠炎、医源性自身免疫性结肠炎、溃疡性结肠炎、由一种或多种化学治疗剂诱导的结肠炎、由过继细胞疗法治疗诱导的结肠炎、肠易激综合征、硬皮病、银屑病、皮肤T细胞淋巴瘤、葡萄膜炎、粘膜炎。In some embodiments, 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.
在一些实施方案中，所述STING介导的疾病或病症及相关疾病或病症包括但不限于：黑色素瘤、甲状腺瘤、头颈癌、宫颈癌、乳腺癌、卵巢癌、前列腺癌、睾丸癌、尿路上皮癌、膀胱癌、非小细胞肺癌、小细胞肺癌、结直肠腺瘤、肉瘤、肠道间质瘤、胃癌、食道癌、结肠直肠癌、胰腺癌、小肠癌、肾癌、肝癌、肝细胞癌、胆管细胞癌、间皮瘤、淋巴瘤、白血病、骨髓异常增生综合症、多发性骨髓瘤、浆细胞瘤、成神经细胞瘤、成视网膜细胞瘤和生殖细胞瘤。In some embodiments, 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.
在一些实施方案中，所述STING介导的疾病或病症及相关疾病或病症包括但不限于：脑脊髓炎、黄斑变性、阿尔茨海默氏病、血管性痴呆、蛛网膜炎、自主神经功能障碍、肌萎缩、脑萎缩、舞蹈病、肌张力障碍、巨细胞动脉炎、面肌痉挛、带状疱疹、亨廷顿病、重症肌无力、帕金森病、闭锁 综合征、腰椎间盘疾病、偏头痛、多发性硬化症。In some embodiments, 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.
在一些实施方案中，所述STING介导的疾病或病症及相关疾病或病症包括但不限于：类风湿性关节炎、系统性红斑狼疮、多发性硬化症、克罗恩病、炎症性肠病、溃疡性结肠炎、自身免疫性结肠炎、肠易激综合征、硬皮病、银屑病。In some embodiments, 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.
在一些实施方案中，所述STING介导的疾病或病症及相关疾病或病症包括但不限于：银屑病、银屑病性关节炎、接触性皮炎、特异性皮炎、白癜风、类风湿性关节炎、系统性红斑狼疮、I型糖尿病、多发性硬化、克罗恩病、炎症性肠病、溃疡性结肠炎、自身免疫性结肠炎、肠易激综合征、硬皮病、哮喘、肾小球肾炎、牙周疾病、睫状体扁平部炎、移植排异、神经退行性疾病、肥胖症、高血压、脑脊髓炎、黄斑变性、阿尔茨海默氏病、血管性痴呆、蛛网膜炎、自主神经功能障碍、肌萎缩、脑萎缩、舞蹈病、肌张力障碍、巨细胞动脉炎、面肌痉挛、带状疱疹、亨廷顿病、重症肌无力、帕金森病、闭锁综合征、腰椎间盘疾病、偏头痛、多发性硬化症。In some embodiments, 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's disease, locked-in syndrome, lumbar disc disease, migraine, multiple sclerosis.
如本文中所使用的，“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。As used herein, "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.
除非另外说明，否则如本文中所使用，术语“治疗”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展。术语“预防”意指防止形成这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状。Unless otherwise indicated, as used herein, the terms "treat," ...
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。As used herein, "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.).
定义和说明Definition and Description
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。Unless otherwise defined below, the meanings of all technical terms and scientific terms used herein are intended to be the same as those generally understood by those skilled in the art. Reference to the technology used herein is intended to refer to the technology generally understood in the art, including those changes in technology or replacement of equivalent technology that are obvious to those skilled in the art. Although it is believed that the following terms are well understood by those skilled in the art, the following definitions are still set forth to better explain the present invention.
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤(即，这些术语也涵盖术语“基本上由……组成”和“由……组成”)。The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps (i.e., these terms also encompass the terms "consisting essentially of" and "consisting of").
如本文中所使用，术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。As used herein, 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.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "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. When the compounds of the invention contain relatively acidic functional groups, 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. When the compounds of the invention contain relatively basic functional groups, 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 acid addition salt.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。Pharmaceutically acceptable 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.
除非另有说明，术语“异构体”意在包括立体异构体、几何异构体、顺反异构体、对映异构体、旋光异构体、非对映异构体和互变异构体。Unless otherwise indicated, the term "isomer" is intended to include stereoisomers, geometric isomers, cis-trans isomers, enantiomers, optical isomers, diastereomers and tautomers.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属 于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。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.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise indicated, the term "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.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.
除非另有说明，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型，用直形实线键和直形虚线键表示立体中心的相对构型，用波浪线表示楔形实线键或楔形虚线键或用波浪线表示直形实线键或直形虚线键 Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Denotes a solid wedge bond or dotted wedge key Or use a wavy line Represents a straight solid bond or straight dashed key
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。Unless otherwise indicated, 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%.
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。Unless otherwise indicated, 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%.
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D-和L-异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。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. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), 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. In addition, 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).
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound may be labeled with a radioactive isotope, such as tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ). For another example, 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.
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必须出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "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. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "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.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
当一个连接基团的数量为0时，比如-(CRR)0-，表示该连接基团为单键。When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
当一个取代基数量为0时，表示该取代基是不存在的，比如-A-(R)0表示该结构实际上是-A。When the number of a substituent is 0, it means that the substituent does not exist, for example, -A-(R) 0 means that the structure is actually -A.
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A.
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
当一个取代基的键可以交叉连接到一个环上的两个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元表示其取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被 取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。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. 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. For example, a pyridyl group as a substituent can be bonded to the substituted group through any carbon atom on the pyridine ring.
当所列举的连接基团没有指明其连接方向，其连接方向是任意的。When the listed linking group does not indicate its linking direction, the linking direction is arbitrary.
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键直形虚线键或波浪线表示。Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When 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.
如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。Unless otherwise specified, 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.
如本文中所使用，术语“卤代”、“卤素”和“卤素原子”意指氟原子、氯原子、溴原子、碘原子等。优选作为本发明的芳基的取代基的卤素原子是氟原子和氯原子。As used herein, the terms "halo", "halogen" and "halogen atom" mean 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.
如本文中所使用，术语“S(O)0-2或“-S(O)0-2-”意指S、S(O)和S(O)2。术语“S(O)1-2或“-S(O)1-2-”意指S(O)和S(O)2。As used herein, the term "S(O) 0-2 or "-S(O) 0-2 -" means S, S(O) and S(O) 2 . The term "S(O) 1-2 or "-S(O) 1-2 -" means S(O) and S(O) 2 .
如本文中所使用，术语“烷基”意指直链或支链的单价饱和脂肪族烃，其可以看作由烷烃失去1个氢原子而得到的基团。术语“C1～6烷基”是具有1至6个(例如1、2、3、4、5或6个)碳的直链或支链烷基，包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、1-甲基丙基、正戊基、异戊基、2-甲基丁基、1,1-二甲基丙基、1-乙基丙基、正己基、4-甲基戊基和2-乙基丁基。术语“C1～4烷基”是具有1至3个碳的直链或支链烷基，包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。术语“C1～3烷基”是具有1至3个碳的直链或支链烷基，包括但不限于甲基、乙基、正丙基和异丙基。As used herein, the term "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. The term "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. The term "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. The term "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.
如本文中所使用，术语“亚烷基”表示由上文所述的“烷基”进一步失去1个H而得到的直链或支链的二价基团。在一些实施方案中，亚烷基具有1至12个碳原子，优选具有1、2、3、4、5或6个碳原子，例如亚甲基、亚乙基、亚丙基或亚丁基。术语“C1～3亚烷基”包括亚甲基、亚乙基、亚丙基和亚异丙基，优选亚甲基。As used herein, the term "alkylene" means a linear or branched divalent group obtained by further losing 1 H from the above-mentioned "alkyl". In some embodiments, 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. The term "C 1-3 alkylene" includes methylene, ethylene, propylene and isopropylene, preferably methylene.
如本文中所使用，术语“卤代烷基”是指被一个或多个卤素取代的烷基(包括上文所述的C1～6烷基、C1～4烷基C1～3烷基)。As used herein, the term "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.
如本文中所使用，术语“C1～6烷氧基”意指基团C1-6烷基-O-，包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、1-甲基丙氧基、正戊基氧基、异戊基氧基、2-甲基丁氧基、1,1-二甲基丙氧基、1-乙基丙氧基、正己基氧基、4-甲基戊基氧基和2-乙基丁氧基。术语“C1～4烷氧基”意指基团C1-3烷基-O-，包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基。术语“C1～3烷氧基”意指基团C1-3烷基-O-，包括但不限于甲氧基、乙氧基、正丙氧基和异丙氧基。As used herein, the term "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. The term "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. The term "C 1-3 alkoxy" means a group C 1-3 alkyl-O-, including but not limited to methoxy, ethoxy, n-propoxy and isopropoxy.
如本文中所使用，术语“烯基”意指直链或支链的单价脂肪族烃基，其包含一个或多个双键。在一些实施方案中，烯基具有2-6个碳原子(“C2-6烯基”)，例如2至4个碳原子(“C2-4烯基”)、或2至3个碳原子(“C2-3烯基”)。所述烯基的实例包括例如-CH＝CH2、-CH2CH＝CH2、-C(CH3)＝CH2、-CH2-CH＝CH-CH3、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。当本发明的化合物含有烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。As used herein, the term "alkenyl" means a linear or branched monovalent aliphatic hydrocarbon group containing one or more double bonds. In some embodiments, 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"). Examples of the alkenyl group include, for example, -CH=CH 2 , -CH 2 CH=CH 2 , -C(CH 3 )=CH 2 , -CH 2 -CH=CH-CH 3 , 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the invention contain an alkenyl group, the compounds may be present in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof.
如本文中所使用，术语“炔基”意指直链或支链的单价脂肪族烃基，其包含一个或多个三键。在一些实施方案中，炔基具有2、3、4、5或6个碳原子(“C2-6炔基”)，例如2至4个碳原子(“C2-4炔基”)、或2至3个碳原子(“C2-3炔基”)，例如乙炔基、2-丙炔基、2-丁炔基、1,3-丁二炔基等。所述炔基任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。As used herein, the term "alkynyl" means a linear or branched monovalent aliphatic hydrocarbon group containing one or more triple bonds. In some embodiments, 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.
如本文中所使用，术语“稠合”意指两个或两个以上环状结构彼此共用两个相邻的原子。As used herein, the term "fused" means that two or more ring structures share two adjacent atoms with each other.
如本文中所使用，术语“桥”或“桥接”意指两个或两个以上环状结构彼此共用两个不相邻的原子。As used herein, the term "bridge" or "bridged" means that two or more ring structures share two non-adjacent atoms with each other.
如本文中所使用，术语“螺”或“螺接”意指两个或两个以上环状结构彼此共用1个原子。As used herein, the term "spiro" or "spiro-connected" means that two or more ring structures share 1 atom with each other.
如本文中所使用，术语“环烃基”、“烃环”和“亚环烃基”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-7、3-6、4-6、5-6、8-10或9-10个)环碳原子的饱和(即，“环烷基”和“亚环烷基”)或部分不饱和的(即在环内具有一个或多个双键(即，“环烯基”和“亚环烯基”)和/或三键)单环或多 环(例如双环)稠合烃环。在一些实施方案中，“环烃基”、“烃环”和“亚环烃基”是具有3-7或3-6个环碳原子(C3～7或C3～6)的单环环烷基或环烯基环。在一些实施方案中，“环烃基”、“烃环”和“亚环烃基”是具有8-10或9-10个环碳原子(C8～10或C9～10)的双环环烷基或环烯基环。实例包括但不限于(亚)环丙基(环)、(亚)环丁基(环)、(亚)环戊基(环)、(亚)环己基(环)、(亚)环庚基(环)、(亚)环辛基(环)、(亚)环壬基(环)、(亚)环丁烯基(环)、(亚)环戊烯基(环)、(亚)环己烯基(环)、(亚)环庚烯基(环)、(亚)环辛烯基(环)、(亚)环壬烯基(环)等。环烃基是在一些实施方案中，环烃基包括芳基稠合的环烃基，只要整个环系统是非芳香性的。As used herein, the terms "cycloalkyl", "hydrocarbon ring" and "cycloalkylene" refer 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. In some embodiments, "cycloalkyl", "hydrocarbon ring" and "cycloalkylene" are monocyclic cycloalkyl or cycloalkenyl rings having 3-7 or 3-6 ring carbon atoms ( C3-7 or C3-6 ). In some embodiments, "cycloalkyl", "hydrocarbon ring" and "cycloalkylene" are bicyclic cycloalkyl or cycloalkenyl rings having 8-10 or 9-10 ring carbon atoms ( C8-10 or C9-10 ). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc. Cycloalkyl is, in some embodiments, cycloalkyl includes aryl-fused cycloalkyl, as long as the entire ring system is non-aromatic.
如本文中所使用，术语“环烷基”和“亚环烷基”指饱和的单环或多环(诸如双环)稠合烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，例如 )。所述环烷基和亚环烷基具有3至10个碳原子，适合地具有3-8个，例如3-7、3-6、4-6或5-6个碳原子。在一些实施方案中，“环烷基”和“亚环烷基”是具有3-7或3-6个环碳原子(C3～7或C3～6)的单环环烷基环。在一些实施方案中，“环烷基”和“亚环烷基”是具有8-10或9-10个环碳原子(C8～10或C9～10)的双环环烷基环。As used herein, the terms "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. In some embodiments, "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 ).
术语“螺环烷基”是指由两个或更多个如上文所定义的“环烷基”作为组件，通过任意两个所述组件共用一个碳原子而形成的环状基团。例如，“C7-12螺环烷基”和“C7-12螺亚环烷基”是指由至少两个环烷基环形成的含有7至12个(例如5-12或7-11个)碳原子的环状结构，其中任意两个所述环烷基环仅共用一个原子。The term "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. For example, "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.
如本文中所使用，术语“桥环烷基”是指由两个或更多个如上文所定义的“环烷基”作为组件，通过任意两个所述组件共用彼此不相邻的两个碳原子而形成的环状基团。例如，“C7-10桥环烷基”和“C7-10桥亚环烷基”是指由共用彼此不相邻的两个碳原子的两个环烷基环形成的含有7至12个(例如6-10、6-9、或6-8个)碳原子的环状结构。As used herein, the term "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. For example, " 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.
如本文中所使用，术语“环烯基”和“亚环烯基”是指在环内具有1个或多个双键的单环或多环(诸如双环)稠合烃环(例如单环，诸如环丙烯基、环丁烯基、环戊烯基、环戊二烯、环己烯基、环己二烯基、环庚烯基、环辛烯基、环壬烯基，或双环)。所述环烯基和“亚环烯基”具有3至10个碳原子，适合地具有3-8个，例如3-7、3-6、4-6或5-6个。在一些实施方案中，“环烯基”和“亚环烯基”是具有3-7或3-6个环碳原子(C3～7或C3～6)的单环环烯基环。在一些实施方案中，“环烯基”和“亚环烯基”是具有8-10或9-10个环碳原子(C8～10或C9～10)的双环环烯基环。As used herein, the terms "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. The cycloalkenyl and "cycloalkenylene" have 3 to 10 carbon atoms, suitably 3-8, such as 3-7, 3-6, 4-6 or 5-6. In some embodiments, "cycloalkenyl" and "cycloalkenylene" are monocyclic cycloalkenyl rings having 3-7 or 3-6 ring carbon atoms (C3 ~7 or C3 ~6 ). In some embodiments, "cycloalkenyl" and "cycloalkenylene" are bicyclic cycloalkenyl rings having 8-10 or 9-10 ring carbon atoms ( C8-10 or C9-10 ).
如本文中所使用，术语“杂环基”、“杂环”和“亚杂环基”指饱和(即，“杂环烷基”和“亚杂环烷基”)或部分不饱和(例如，在环内具有一个或多个双键(即，“杂环烯基”和“亚杂环烯基”))的单环或双环稠合环状结构，其在环中具有2、3、4、5、6、7、8或9个碳原子和1个或多个(例如1个、2个、3个或4个)选自O、S和N的含杂原子的基团。杂环基中的1或多个环碳原子可以被C(O)替代。杂环基中的S原子可以被S(O)或S(O)2替代。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地，3-10元杂环基为在环中具有3-10个(例如3-8、3-7、3-6、4-6或5-6个)碳原子及杂原子的基团。在一些实施方案中，“杂环基”、“杂环”和“亚杂环基”是具有3-7、3-6个或5-6个环成员(3-7元、3-6元或5-6元)的单环杂环烷基或杂环烯基环。在一些实施方案中，“杂环基”、“杂环”和“亚杂环基”是具有8-10或9-10个环成员(8-10元或9-10元)的双环杂环烷基或杂环烯基环。杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中连接至母体结构的环为杂环基。杂环基包括含氮杂环基、含氧桥环基和含硫杂环基。可以列举的实例包括但不限于环氧乙烷基、氮丙啶基、氮杂环丁烷基(azetidinyl)、氧杂环丁烷基(oxetanyl)、四氢呋喃基、四氢噻吩基、二氧杂环戊烯基(dioxolinyl)、吡咯烷基、吡咯烷酮基、噁唑烷、噻唑烷基、吡唑烷基、咪唑烷基、吡唑烷基、吡咯啉基、四氢吡喃基、哌啶基、哌啶酮基、六氢嘧啶基、三嗪烷基、吗啉基、二噻烷基(dithianyl)、硫代吗啉基、哌嗪基、三噻烷基(trithianyl)、氮杂环辛烷基、二氢吡咯基、二氢咪唑基、氮杂环辛烯基。As used herein, the terms "heterocyclyl", "heterocycle" and "heterocyclylene" refer 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. In particular, 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. 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). The 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.
如本文中所使用，术语“含氮杂环基”指饱和或不饱和的单环或双环基团，其在环中具有2、3、4、5、6、7、8或9个碳原子和至少一个(例如1、2、3或4个)氮原子，其还可任选地包含一个或多个(例如1、2、3或4个)选自N、O和S的环成员。含氮杂环基中的一个或多个环碳原子可以被C(O)替代。含氮杂环基中的S原子可以被S(O)或S(O)2替代。所述含氮杂环基可以通过所述碳原子中的任一个或氮原子与分子的其余部分连接。所述含氮杂环基可以为饱和含氮单环。特别地，3至10元含氮杂环基为在环中具有3-10个环成员的如上文所定义的含氮杂环基，其包括但不限于3元含氮杂 环(如氮丙啶基)、4元含氮杂环(如氮杂环丁烷基)、5元含氮杂环(如吡咯基、吡咯烷基(吡咯烷环)、吡咯啉基、吡咯烷酮基、咪唑基、咪唑烷基、咪唑啉基、吡唑基、吡唑啉基)、6元含氮杂环(如哌啶基(哌啶环)、哌啶基酮基、吗啉基、硫吗啉基、哌嗪基)、7元含氮杂环、8元双环含氮杂环基、9元双环含氮杂环基和10元双环含氮杂环基等。As used herein, the term "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. In particular, 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, 8-membered bicyclic nitrogen-containing heterocyclic group, 9-membered bicyclic nitrogen-containing heterocyclic group and 10-membered bicyclic nitrogen-containing heterocyclic group, etc.
如本文中所使用，术语“杂环基”涵盖稠合结构，其与其他基团的连接点可以在稠合结构中的任一环上。因此，本发明的杂环基还包括但不限于杂环基并杂环基、杂环基并环烷基、单杂环基并单杂环基、单杂环基并单环烷基，例如3-7元(单)杂环基并3-7元(单)杂环基、3-7元(单)杂环基并(单)环烷基、3-7元(单)杂环基并C4-6(单)环烷基，其实例包括但不限于吡咯烷基并环丙基、环戊基并氮杂环丙基、吡咯烷基并环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、吡咯烷基并哌嗪基、哌啶基并吗啉基、在一些实施方案中，杂环基还包括杂芳基稠合的杂环基或环烃基，以及芳基稠合的杂环基，只要整个环系统是非芳香性的。在一些实施方案中，杂环基包括5-6元单环杂芳基稠合的C5-6单环环烃基，5-6元单环杂芳基稠合的5-6元单环杂环基，以及苯并稠合的5-6元单环杂环基，例如吡咯并四氢吡啶基、吡唑并四氢吡啶基、咪唑并四氢吡啶基、吲哚啉基或吲哚啉酮基。As used herein, the term "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, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and morpholinyl, In some embodiments, heterocyclyl also includes heteroaryl-fused heterocyclyl or cycloalkyl, and aryl-fused heterocyclyl, as long as the entire ring system is non-aromatic. In some embodiments, 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.
术语“螺杂环烷基”是指由两个或更多个如上文所定义的“杂环烷基”作为组件，通过任意两个所述组件共用一个碳原子而形成的环状基团，其在环中具有2、3、4、5、6、7、8、9或10个碳原子和1个或多个(例如1个、2个、3个或4个)选自O、S和N的杂原子。螺杂环烷基中的1或多个环碳原子可以被C(O)替代。螺杂环基中的S原子可以被S(O)或S(O)2替代。优选地，螺杂环烷基是5-12元的，并且更优选5-11(例如5-10或7-9)元的。根据共用螺原子的数量，螺杂环烷基分为单螺杂环烷基、二螺杂环烷基、或多螺杂环烷基，并且优选地是指单螺杂环烷基或二螺杂环烷基，并且更优选4元/4元、3元/5元、4元/5元、4元/6元、5元/5元、或5元/6元单螺杂环烷基。The term "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 . Preferably, the spiroheterocycloalkyl is 5-12-membered, and more preferably 5-11 (e.g. 5-10 or 7-9)-membered. According to the number of common spiro atoms, 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.
如本文中所使用，术语“桥杂环烷基”是指由两个或更多个如上文所定义的“杂环烷基”作为组件，通过任意两个所述组件共用彼此不相邻的两个原子而形成的环状基团，其在环中具有2、3、4、5、6、7、8、9或10个碳原子和1个或多个(例如1个、2个、3个或4个)选自O、S和N的杂原子。桥杂环烷基中的1或多个环碳原子可以被C(O)替代。桥杂环基中的S原子可以被S(O)或S(O)2替代。优选地，桥杂环烷基是6至9元的，并且更优选6-8元的。根据成员环的数量，桥杂环烷基分为双环、三环、四环或多环桥杂环烷基，并且优选地是指双环、三环或四环桥杂环烷基，并且更优选双环或三环桥杂环烷基。As used herein, the term "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. Preferably, the bridged heterocycloalkyl is 6 to 9 yuan, and more preferably 6-8 yuan. According to the number of member rings, 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.
如本文中所使用，术语“芳基”是指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元环，例如苯基和萘基，更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，包括苯并3-8元环烷基、苯并3-8元杂环基。As used herein, the term "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 π 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.
如本文中所使用，术语“杂芳基”或“杂芳基环”是指具有5至14个环原子的杂芳族体系，其具有1至4个独立地选自N、O和S的杂环原子。杂芳基中的1或多个环碳原子可以被C(O)替代。杂芳基可以是苯并稠合的。杂芳基优选为5至10元的。在一些实施方案中，杂芳基为5元或6元杂芳基，例如但不限于吡啶基、吡啶酮基、嘧啶基、嘧啶酮基、吡嗪基、哒嗪基、噻唑基、噻吩基、噁唑基、呋喃基、吡咯基、吡唑基、三唑基、四唑基、异噁唑基、异噻唑基、咪唑基、三嗪基、噁二唑基、噻二唑基。在一些实施方案中，杂芳基为8-10元或9-10双环杂芳基，包括5元/5元、5元/6元或6元/6元双环体系。实例包括但不限于苯并噻唑基、苯并异噻唑基、咪唑并吡啶基、喹啉基、吲哚基、吡咯并哒嗪基、苯并呋喃基、苯并噻吩基、吲唑基、苯并噁唑基、苯并异噁唑基、喹唑啉基、吡咯并吡啶基、吡唑并嘧啶基、咪唑并哒嗪基、吡唑并吡啶基、三唑并吡啶基、异喹啉基、四氢异喹啉基、苯并咪唑基、噌啉基、中氮茚基、酞嗪基、异吲哚基、蝶啶基、嘌呤基、呋咱基、苯并呋咱基、喹喔啉基、萘啶基或呋喃并吡啶基。As used herein, the term "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. In some embodiments, 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. In some embodiments, 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, naphthyridinyl, or furopyridinyl.
除非另有规定，如本文中所使用，术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用。术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其中1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。Unless otherwise specified, as used herein, the terms "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 π 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.
如本文中所使用，术语“稠环”指5至20元的全碳多环基团，该环体系中的每个环与该体系中的其他环共享毗邻的一对碳原子，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完 全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环中的碳原子可任选地被O、S、N的杂原子替代，即也包括“稠杂环”。As used herein, the term "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 π electron system. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, 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".
本发明的术语“稠杂环”指5至20元的多环杂环基团，该环体统中的每个环与该体系中的其他环共享毗邻的一对原子，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是0至2的整数)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。The term "fused heterocycle" of the present invention 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 π 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. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to 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.
如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。As used herein, the term "ester" 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). The compounds of the present invention themselves may also be esters.
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。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.
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。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. The amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio.
本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成N-氧化物；本领域技术人员会识别能够形成N-氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的，包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist,Comprehensive Organic Synthesis,vol.7,pp 748-750；A.R.Katritzky和A.J.Boulton,Eds.,Academic Press；以及G.W.H.Cheeseman和E.S.G.Werstiuk，Advances in Heterocyclic Chemistry,vol.22,pp 390-392,A.R.Katritzky和A.J.Boulton,Eds.,Academic Press。Those skilled in the art will appreciate that not all 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. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see, for example: T.L.Gilchrist, Comprehensive Organic Synthesis, vol.7, pp 748-750; A.R.Katritzky and A.J.Boulton, Eds., Academic Press; and G.W.H.Cheeseman and E.S.G.Werstiuk, Advances in Heterocyclic Chemistry, vol.22, pp 390-392, A.R.Katritzky and A.J.Boulton, Eds., Academic Press.
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、脱脂化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。Also included within the scope of the present invention are 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. Thus, 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.
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)及“Bioreversible Carriers in Drug Design,”Pergamon Press,1987(E.B.Roche编辑，American Pharmaceutical Association)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。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. Typically such 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)).
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973；和T.W.Greene&P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley&Sons,1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。The present invention also encompasses compounds of the present invention containing 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.
如本文中所使用，术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。As used herein, the term "about" means within ±10% of the stated numerical value, preferably within ±5%, and more preferably within ±2%.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。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.
本发明所述的化合物是依据化学结构式命名的。如果表示同一化合物的化合物命名与化学结构式不符，则以化学结构式为准。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.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫 描方式：扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。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. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data of the cultured single crystal using a Bruker D8venture diffractometer, with CuKα 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.
本发明所使用的溶剂可经市售获得。The solvent used in the present invention is commercially available.
化合物依据本领域常规命名原则或者使用软件命名，市售化合物采用供应商目录名称。Compounds are named according to the conventional nomenclature in the art or using The software names were used, and commercially available compounds were named using the supplier's catalog names.
有益效果Beneficial Effects
作为新型的STING抑制剂，本发明化合物对STING有很强的抑制活性，可用于预防和/或治疗STING介导的疾病或病症。本发明的化合物具有改善的药物代谢动力学性质(例如改善的生物利用度、改善的代谢稳定性、合适的半衰期和作用持续时间)、改善的安全性(较低的毒性(例如降低的心脏毒性)和/或较少的副作用)、较不易产生耐药性等更优异的性质。As a novel STING inhibitor, 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.
具体实施方式Detailed ways
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention is described in detail below by way of examples, but it is not intended to impose any adverse limitations on the present invention. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed therein. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.
中间体int1：3-溴-5-氯-1-(三异丙基甲硅烷基)-1H-吲哚
Intermediate int1: 3-bromo-5-chloro-1-(triisopropylsilyl)-1H-indole
int1制备方法：将5-氯-1H-吲哚1a(5.00g，0.033mmol)溶解在四氢呋喃(50mL)中，在0℃下添加氢化钠(1.45g，0.036mmol)。将混合物在0℃下搅拌1h。然后在0℃下加入三异丙基氯甲硅烷(7.66g，0.039mmol)。反应液在室温下搅拌1h。反应结束后用乙酸乙酯萃取，合并有机相。有机相用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝5:1)洗脱得到5-氯-1-(三异丙基甲硅烷基)-1H-吲哚1b(9.8g)。将化合物5-氯-1-(三异丙基甲硅烷基)-1H-吲哚1b(2.00g，6.50mmol)溶解在四氢呋喃(20mL)中，然后将在-30℃下加入N-溴代丁二酰亚胺(1.39g，7.82mmol)。反应液在-30℃下搅拌40min。反应结束后用乙酸乙酯萃取，合并有机相。有机相用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝10:1)洗脱得化合物int 1(1.2g)。LCMS(ESI)m/z:388.1[M+H]+.Preparation method of int1: 5-chloro-1H-indole 1a (5.00 g, 0.033 mmol) was dissolved in tetrahydrofuran (50 mL), and sodium hydride (1.45 g, 0.036 mmol) was added at 0°C. The mixture was stirred at 0°C for 1 h. Then triisopropylsilyl chloride (7.66 g, 0.039 mmol) was added at 0°C. The reaction solution was stirred at room temperature for 1 h. After the reaction was completed, it was extracted with ethyl acetate and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=5:1) to obtain 5-chloro-1-(triisopropylsilyl)-1H-indole 1b (9.8 g). The compound 5-chloro-1-(triisopropylsilyl)-1H-indole 1b (2.00 g, 6.50 mmol) was dissolved in tetrahydrofuran (20 mL), and then N-bromosuccinimide (1.39 g, 7.82 mmol) was added at -30 ° C. The reaction solution was stirred at -30 ° C for 40 min. After the reaction was completed, it was extracted with ethyl acetate and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE: EA = 10: 1) to obtain compound int 1 (1.2 g). LCMS (ESI) m/z: 388.1 [M + H] + .
中间体int2：
Intermediate int2:
Int2制备方法：Int2 preparation method:
(1)将化合物1a(25.00g，164.92mmol)溶解在N,N-二甲基甲酰胺(250mL)中，在0℃下滴加三氟乙酸酐(36.72g，174.82mmol)。在室温搅拌3小时后，将混合物倒入1000mL水中，抽滤得到沉淀物并在1000mL 20％NaOH中加热回流过夜。反应液冷却到室温后用二氯甲烷萃取两次，水层用盐酸酸化，过滤并真空干燥得到化合物2a。(1) Compound 1a (25.00 g, 164.92 mmol) was dissolved in N,N-dimethylformamide (250 mL), and trifluoroacetic anhydride (36.72 g, 174.82 mmol) was added dropwise at 0°C. After stirring at room temperature for 3 hours, the mixture was poured into 1000 mL of water, the precipitate was filtered and heated under reflux in 1000 mL 20% NaOH overnight. After the reaction solution was cooled to room temperature, it was extracted twice with dichloromethane, the aqueous layer was acidified with hydrochloric acid, filtered and dried in vacuo to obtain compound 2a.
(2)将化合物2a(17.00g，86.91mmol)溶解在四氢呋喃(170mL)中，然后将在0℃下加入三乙胺(26.38g，260.73mmol)、叠氮磷酸二苯酯(47.84g，173.82mmol)。反应液在室温下搅拌过夜。反应结束后旋走大部分四氢呋喃，加入甲醇使体系析出固体，抽滤后晾干得到化合物2b。(2) Compound 2a (17.00 g, 86.91 mmol) was dissolved in tetrahydrofuran (170 mL), and triethylamine (26.38 g, 260.73 mmol) and diphenylphosphoryl azide (47.84 g, 173.82 mmol) were then added at 0°C. The reaction solution was stirred overnight at room temperature. After the reaction was completed, most of the tetrahydrofuran was removed, and methanol was added to precipitate solids in the system. The solids were filtered and air-dried to obtain compound 2b.
(3)将化合物2b(17.00g，77.06mmol)溶解在叔丁醇(170mL)中，混合液在氮气保护下80℃搅拌过夜。反应结束后，将反应液冷却至室温，减压浓缩后用硅胶板层析纯化，用(石油醚:乙酸乙酯＝4:1)洗脱得化合物2c。(3) Compound 2b (17.00 g, 77.06 mmol) was dissolved in tert-butyl alcohol (170 mL), and the mixture was stirred at 80° C. overnight under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel chromatography, and eluted with (petroleum ether: ethyl acetate = 4:1) to obtain compound 2c.
(4)将化合物2c(9.00g，33.74mmol)溶解在氯化氢/1,4-二氧六环溶液(4M,90mL)中，反应液在室温下搅拌16h。反应结束后减压浓缩得化合物int2，LCMS(ESI)m/z:167.0[M+H]+.(4) Compound 2c (9.00 g, 33.74 mmol) was dissolved in a hydrogen chloride/1,4-dioxane solution (4 M, 90 mL), and the reaction solution was stirred at room temperature for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain compound int2, LCMS (ESI) m/z: 167.0 [M+H] + .
中间体int3：
Intermediate int3:
Int3制备方法：Int3 preparation method:
(1)将3a(17.6g，108.0mmol)溶解在二氯甲烷(200mL)中，然后在室温下依次加入N,N-二异丙基乙胺(53.4mL，323.3mmol)和3b(30g，129.3mmol)。反应液在40℃下搅拌16小时。反应结束后，反应液用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝1:1)洗脱得产物3c(15.3g)。(1) 3a (17.6 g, 108.0 mmol) was dissolved in dichloromethane (200 mL), and then N,N-diisopropylethylamine (53.4 mL, 323.3 mmol) and 3b (30 g, 129.3 mmol) were added in sequence at room temperature. The reaction solution was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=1:1) to obtain the product 3c (15.3 g).
(2)将3c(15.0g，61.18mmol)溶解在二氯甲烷(200mL)和甲醇(20ml)混合液中，然后在室温下滴加水合肼(68％)(3.063g，122.37mmol)。反应液在室温下搅拌2小时。反应完成后过滤沉淀，用5N氨水(200ml)冲洗滤液。用二氯甲烷萃取水相两次，萃取结束有机相用无水硫酸钠干燥。干燥后常温减压浓缩后加入乙醇(50ml)和浓盐酸(6ml)，反应液呈酸性,将反应液减压旋干，得产物int3(5.3g)，1H NMR(400MHz,DMSO)δ4.77–4.70(m,2H).(2) 3c (15.0 g, 61.18 mmol) was dissolved in a mixture of dichloromethane (200 mL) and methanol (20 ml), and then hydrazine hydrate (68%) (3.063 g, 122.37 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the precipitate was filtered and the filtrate was washed with 5N ammonia water (200 ml). The aqueous phase was extracted twice with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate after extraction. After drying, ethanol (50 ml) and concentrated hydrochloric acid (6 ml) were added after concentration under reduced pressure at room temperature. The reaction solution was acidic. The reaction solution was decompressed and dried to obtain the product int3 (5.3 g), 1 H NMR (400 MHz, DMSO) δ4.77–4.70 (m, 2H).
中间体int4：1-(6-氨基吡啶-3-基)乙烷-1-酮
Intermediate int4: 1-(6-aminopyridin-3-yl)ethane-1-one
Int4制备方法：在一个250mL的封口瓶中加入1-(6-氯吡啶-3-基)乙烷-1-酮4a(10.0g，64.5mmol)和浓氨水(50mL)。将混合物在130℃下搅拌16h。反应结束后,将反应液减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝5:1)洗脱得化合物int4(7g)。Preparation of Int4: 1-(6-chloropyridin-3-yl)ethane-1-one 4a (10.0 g, 64.5 mmol) and concentrated aqueous ammonia (50 mL) were added to a 250 mL sealed bottle. The mixture was stirred at 130 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with (PE:EA=5:1) to obtain compound int4 (7 g).
中间体int5：
Intermediate int5:
Int5制备方法：在一个100mL的封口瓶中将化合物4a(1.3g,8.36mmol)化合物int2(1.4g，8.36mmol)和对甲苯磺酸(1.45g，8.36mmol)溶于N,N二甲基甲酰胺(15ml)中，于120℃下反应过夜。反应冷却后，反应液用饱和食盐水(20mL)和水(20mL)稀释，乙酸乙酯(30mL x 3)萃取，合并有机相，并用饱和食盐水洗涤(20mL x 3),无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(0-40％乙酸乙酯/石油醚)洗脱得化合物int5(400mg)。LCMS(ESI):m/z＝391.1(M+H)+。Preparation of Int5: Compound 4a (1.3 g, 8.36 mmol), compound int2 (1.4 g, 8.36 mmol) and p-toluenesulfonic acid (1.45 g, 8.36 mmol) were dissolved in N, N-dimethylformamide (15 ml) in a 100 mL sealed bottle and reacted overnight at 120°C. After the reaction was cooled, the reaction solution was diluted with saturated brine (20 mL) and water (20 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (0-40% ethyl acetate/petroleum ether) to obtain compound int5 (400 mg). LCMS (ESI): m/z=391.1 (M+H) + .
中间体int6：
Intermediate int6:
Int6制备方法：Int6 preparation method:
(1)将化合物3b(3.24g，10.19mmol)、化合物6a(2g，9.26mmol)和三苯基膦(5.34g，10.19mmol)溶解在超干四氢呋喃(20mL)中，然后在0℃滴加偶氮二甲酸二叔丁酯(4.69g，10.19mmol)的四氢呋喃(10mL)溶液。反应液在0℃下搅拌4小时。反应结束后，反应液加入水(50mL)稀释,用二氯甲烷萃取和饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(0-20％乙酸乙酯/石油醚)洗脱得化合物6b(1g)。1H NMR(400MHz,DMSO_d6)δ7.88–7.85(m,2H),7.79–7.77-4.42(m,2H),4.79–4.78(m,1H),3.06–2.96(m,4H).(1) Compound 3b (3.24 g, 10.19 mmol), compound 6a (2 g, 9.26 mmol) and triphenylphosphine (5.34 g, 10.19 mmol) were dissolved in ultra-dry tetrahydrofuran (20 mL), and then a solution of di-tert-butyl azodicarboxylate (4.69 g, 10.19 mmol) in tetrahydrofuran (10 mL) was added dropwise at 0°C. The reaction solution was stirred at 0°C for 4 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL), extracted with dichloromethane and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (0-20% ethyl acetate/petroleum ether) to obtain compound 6b (1 g). 1 H NMR (400 MHz, DMSO_d6) δ7.88–7.85 (m, 2H), 7.79–7.77-4.42 (m, 2H), 4.79–4.78 (m, 1H), 3.06–2.96 (m, 4H).
(2)将化合物6b(1g，3.95mmol)溶解在二氯甲烷(20mL)和甲醇(2ml)混合液中，然后在室温下滴加水合肼(68％)(0.4mL，7.9mmol)。反应液在室温下搅拌2小时。反应完成后过滤沉淀，用5N氨水(20ml)冲洗滤液。用二氯甲烷萃取水相两次，萃取结束有机相用无水硫酸钠干燥。干燥后常温减压浓缩除去大部分二氯甲烷后加入乙醇(20mL)和浓盐酸(2ml)，反应液呈酸性，后减压旋干后得到化合物int6(400mg)。1H NMR(400MHz,DMSO_d6)δ11.13(s,2H),4.76–4.75(m,1H),3.07–2.97(m,2H),2.85–2.73(m,2H). (2) Compound 6b (1 g, 3.95 mmol) was dissolved in a mixture of dichloromethane (20 mL) and methanol (2 ml), and then hydrazine hydrate (68%) (0.4 mL, 7.9 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the precipitate was filtered and the filtrate was washed with 5N ammonia water (20 ml). The aqueous phase was extracted twice with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate after extraction. After drying, ethanol (20 mL) and concentrated hydrochloric acid (2 ml) were added after concentration at room temperature under reduced pressure to remove most of the dichloromethane. The reaction solution was acidic and then dried under reduced pressure to obtain compound int6 (400 mg). 1 H NMR (400 MHz, DMSO_d6) δ11.13 (s, 2H), 4.76–4.75 (m, 1H), 3.07–2.97 (m, 2H), 2.85–2.73 (m, 2H).
中间体int7：
Intermediate int7:
Int7制备方法：Int7 preparation method:
(1)将化合物7a(4.7g,34.6mmol)和化合物3b(6.2g,38.0mmol)置于250mL的三口烧瓶中，加入四氢呋喃(60mL)。氮气置换3次，0℃下加入三苯基膦(9.96g,38mmol)。然后滴加DBAD(8.76g,38mmol)的四氢呋喃溶液(20mL)，滴加时间10分钟。反应液自然升温至室温，并继续搅拌4小时。反应完成后，向反应液中加入100mL的水淬灭，用乙酸乙酯萃取(100mL x 3)，合并有机相，有机相用硫酸钠干燥,过滤，减压浓缩。浓缩物用硅胶柱层析纯化(0-20％乙酸乙酯/石油醚)得到化合物7b(3.7g)。1H NMR(400MHz,DMSO_d6)δ7.87(s,4H),4.43–4.42(m,1H),2.25–2.13(m,2H),1.99–1.87(m,6H).(1) Compound 7a (4.7 g, 34.6 mmol) and compound 3b (6.2 g, 38.0 mmol) were placed in a 250 mL three-necked flask and tetrahydrofuran (60 mL) was added. The atmosphere was replaced with nitrogen three times and triphenylphosphine (9.96 g, 38 mmol) was added at 0°C. Then a tetrahydrofuran solution (20 mL) of DBAD (8.76 g, 38 mmol) was added dropwise for 10 minutes. The reaction solution was naturally warmed to room temperature and stirred for 4 hours. After the reaction was completed, 100 mL of water was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (0-20% ethyl acetate/petroleum ether) to obtain compound 7b (3.7 g). 1 H NMR (400 MHz, DMSO_d6) δ7.87 (s, 4H), 4.43–4.42 (m, 1H), 2.25–2.13 (m, 2H), 1.99–1.87 (m, 6H).
(2)将化合物7b(3.7g,2.53mmol)置于100mL的单口瓶中，加入二氯甲烷(20mL)和甲醇(2mL),然后滴加水合肼(0.1mL,水中68％)反应液在室温下搅拌2小时。反应结束后，将体系用砂芯漏斗上过滤，用5％氨水(20mL)洗涤固体3次，用二氯甲烷萃取水相三次，合并有机相，真空浓缩除去大部分二氯甲烷。然后加入乙醇(20mL),滴加浓盐酸。所得混合物浓缩得到化合物int7(2.0g)。1H NMR(400MHz,DMSO_d6)δ10.94(s,3H),4.29(s,1H),1.99–1.83(m,8H).(2) Compound 7b (3.7 g, 2.53 mmol) was placed in a 100 mL single-mouth bottle, dichloromethane (20 mL) and methanol (2 mL) were added, and then hydrazine hydrate (0.1 mL, 68% in water) was added dropwise. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the system was filtered on a sand core funnel, the solid was washed 3 times with 5% ammonia water (20 mL), the aqueous phase was extracted 3 times with dichloromethane, the organic phases were combined, and most of the dichloromethane was removed by vacuum concentration. Then ethanol (20 mL) was added, and concentrated hydrochloric acid was added dropwise. The resulting mixture was concentrated to obtain compound int7 (2.0 g). 1H NMR (400 MHz, DMSO_d6) δ10.94 (s, 3H), 4.29 (s, 1H), 1.99–1.83 (m, 8H).
中间体int8：
Intermediate int8:
Int8制备方法：Int8 preparation method:
(1)在一个250mL的三口瓶中将化合物8a(5g,24.92mmol)溶于四氢呋喃(50ml)中，于0℃中缓慢滴加乙基溴化镁(8.8ml,29.91mmol，3M/L),反应液保持0℃下反应4h。反应结束后，反应液用饱和氯化铵溶液淬灭，用乙酸乙酯(20ml)萃取水相两次，有机相用无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝4:1)洗脱得化合物8b(3g)。(1) Compound 8a (5 g, 24.92 mmol) was dissolved in tetrahydrofuran (50 ml) in a 250 mL three-necked flask, and ethylmagnesium bromide (8.8 ml, 29.91 mmol, 3 M/L) was slowly added dropwise at 0°C. The reaction solution was kept at 0°C for 4 h. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution, the aqueous phase was extracted twice with ethyl acetate (20 ml), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain compound 8b (3 g).
(2)在一个50mL的封口瓶中加入化合物8b(150mg,0.887mmol)和int2(215mg，1.065mmol)溶于醋酸(3ml)中，于120下反应2h。TLC检测反应结束后，反应液减压浓缩得int8(300mg)。LCMS(ESI):m/z＝300.1(M+H)+。(2) Compound 8b (150 mg, 0.887 mmol) and int2 (215 mg, 1.065 mmol) were added to a 50 mL sealed bottle and dissolved in acetic acid (3 ml), and reacted at 120 °C for 2 h. After the reaction was completed by TLC detection, the reaction solution was concentrated under reduced pressure to obtain int8 (300 mg). LCMS (ESI): m/z = 300.1 (M+H) + .
中间体int9：
Intermediate int9:
Int9制备方法：Int9 preparation method:
(1)于1L三口反应瓶中将氢化钠(1.96g，48.86mmol)溶解在超干四氢呋喃(350mL)中，氮气保护下用冰水浴降温至0℃。将原料9a(5.00g，48.86mmol)溶解在超干四氢呋喃(50mL)中，用注射器将原料1溶液缓慢滴入反应瓶中(20分钟)，滴完后0℃下搅拌1小时。将溴化苄(8.37g，48.96mmol)滴入反应液，滴完后氮气保护下迅速加入四丁基碘化铵(1.81g，4.90mmol)，继 续冰水浴10分钟，然后室温搅拌12小时。反应完全后，用氯化铵水溶液(17mL)淬灭反应，减压浓缩出大部分四氢呋喃，用二氯甲烷(200mL)溶解残余物，食盐水(100mL)洗一遍，无水硫酸钠干燥并过滤，将滤液减压浓缩，所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝3:1)洗脱得化合物9b(3.2g)。(1) Sodium hydride (1.96 g, 48.86 mmol) was dissolved in ultra-dry tetrahydrofuran (350 mL) in a 1L three-necked reaction flask, and the temperature was cooled to 0°C in an ice-water bath under nitrogen protection. Raw material 9a (5.00 g, 48.86 mmol) was dissolved in ultra-dry tetrahydrofuran (50 mL), and the raw material 1 solution was slowly dripped into the reaction flask with a syringe (20 minutes), and stirred at 0°C for 1 hour after the dripping was completed. 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 residue was dissolved with dichloromethane (200 mL), washed once with brine (100 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 3:1) to obtain compound 9b (3.2 g).
(2)将9b(3.2g，17.11mmol)溶解在二氯甲烷(120mL)中，冰水浴下加入戴斯-马丁试剂(8.71g，20.54mmol)，加完后0℃下搅拌2小时。反应完成后过滤，二氯甲烷(50mL)润洗滤饼两次，减压浓缩滤液，所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝10:1)洗脱得9c(2.5g)。(2) 9b (3.2 g, 17.11 mmol) was dissolved in dichloromethane (120 mL), and Dess-Martin reagent (8.71 g, 20.54 mmol) was added under ice-water bath, and stirred at 0°C for 2 hours after the addition. After the reaction was completed, the mixture was filtered, and the filter cake was rinsed twice with dichloromethane (50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, and 9c (2.5 g) was obtained by eluting with (petroleum ether:ethyl acetate=10:1).
(3)将9c(2.5g，13.14mmol)溶解在超干1，2-二氯乙烷(12mL)中，加入双(2-甲氧基乙基)氨基三氟化硫(BAST，5mL，27.12mmol)，氮气保护下90℃搅拌过夜(16小时)。反应结束后，于冰水浴搅拌下向碳酸氢钠水溶液中滴加冷却后的反应液。滴完后室温搅拌0.5小时至无气泡冒出，分出有机相，二氯甲烷(30mL)萃取水相两次，合并有机相，无水硫酸钠干燥过滤，减压浓缩滤液。所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝20:1)洗脱得9d(1.1g)。(3) 9c (2.5 g, 13.14 mmol) was dissolved in ultra-dry 1,2-dichloroethane (12 mL), and bis(2-methoxyethyl)aminosulfur trifluoride (BAST, 5 mL, 27.12 mmol) was added. The mixture was stirred at 90°C overnight (16 hours) under nitrogen protection. After the reaction was completed, the cooled reaction solution was added dropwise to a sodium bicarbonate aqueous solution under stirring in an ice-water bath. After the addition was completed, the mixture was stirred at room temperature for 0.5 hours until no bubbles appeared. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 20:1) to obtain 9d (1.1 g).
(4)将9d(1.1g，5.18mmol)溶解在甲醇(36mL)中，加入醋酸(7.2mL)和钯碳(1.1g)，混合物置于高压反应釜内，氢气置换四次，调整高压反应釜内氢气压强为50psi，室温搅拌过夜(16小时)。反应完成后，压滤并用甲醇(10mL)润洗滤饼，常压90℃蒸馏，蒸出甲醇(顶温下降至40℃)。用无水乙醚(50mL)稀释冷却后的剩余溶液，搅拌下加入碳酸钠粉末(11g)，氮气保护(不置换)下搅拌2小时。压滤并用无水乙醚(10mL)润洗滤饼3次，常压40℃蒸馏无水乙醚，得粗品9e。(4) 9d (1.1 g, 5.18 mmol) was dissolved in methanol (36 mL), acetic acid (7.2 mL) and palladium carbon (1.1 g) were added, and the mixture was placed in an autoclave, replaced with hydrogen four times, and the hydrogen pressure in the autoclave was adjusted to 50 psi, and stirred at room temperature overnight (16 hours). After the reaction was completed, the filter cake was filtered and rinsed with methanol (10 mL), and distilled at 90°C under normal pressure to evaporate methanol (the top temperature dropped to 40°C). The remaining solution after cooling was diluted with anhydrous ether (50 mL), and sodium carbonate powder (11 g) was added under stirring, and stirred for 2 hours under nitrogen protection (without replacement). The filter cake was filtered and rinsed with anhydrous ether (10 mL) three times, and anhydrous ether was distilled at 40°C under normal pressure to obtain crude product 9e.
(5)于三口反应瓶中将3b(1.244g，7.63mmol)溶解在超干甲苯(42mL)，氮气置换并保护下，将反应瓶移至冰水浴中搅拌。将粗品9e(465mg，3.81mmol)溶解在超干四氢呋喃(6mL)中，注射器滴入反应液中。将三苯基膦(2.00g，7.63mmol)溶解在超干四氢呋喃(8mL)中，注射器滴入反应液中。将偶氮二甲酸二叔丁酯(DBAD，1.755g，7.63mmol)溶解在超干四氢呋喃(14mL)中，注射器缓慢滴加进反应液中，滴完后自然升至室温搅拌过夜(12小时)。反应结束后加水(40mL)淬灭，搅拌20分钟分出有机相，用二氯甲烷(40mL)萃取水相3次，合并有机相干燥过滤减压浓缩。所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝10:1)洗脱得9f(515mg)。(5) 3b (1.244 g, 7.63 mmol) was dissolved in ultra-dry toluene (42 mL) in a three-necked reaction flask. The reaction flask was moved to an ice-water bath and stirred under nitrogen replacement and protection. The crude product 9e (465 mg, 3.81 mmol) was dissolved in ultra-dry tetrahydrofuran (6 mL) and the mixture was dropped into the reaction solution by syringe. Triphenylphosphine (2.00 g, 7.63 mmol) was dissolved in ultra-dry tetrahydrofuran (8 mL) and the mixture was dropped into the reaction solution by syringe. Di-tert-butyl azodicarboxylate (DBAD, 1.755 g, 7.63 mmol) was dissolved in ultra-dry tetrahydrofuran (14 mL) and the mixture was slowly dropped into the reaction solution by syringe. After the mixture was dropped, the mixture was naturally heated to room temperature and stirred overnight (12 hours). After the reaction was completed, water (40 mL) was added to quench the mixture, and the mixture was stirred for 20 minutes to separate the organic phase. The aqueous phase was extracted 3 times with dichloromethane (40 mL). The organic phases were combined, dried, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using (petroleum ether:ethyl acetate=10:1) as the eluent to give 9f (515 mg).
(6)将9f(515mg，1.93mmol)溶解在二氯甲烷(4mL)和无水甲醇(0.4mL)的混合溶剂中，氮气保护下冰水浴降温至0℃，滴加水合肼(98％，197mg，3.86mmol)，滴完后自然升至室温反应2小时。过滤反应液，二氯甲烷(5mL)洗滤饼两次。水相用加入氨水调节pH＝9-10，用二氯甲烷(5mL)萃取两次。有机相减压浓缩(温度控制在20℃)除去大部分二氯甲烷。将稀盐酸(1mol/L，15mL)加入浓缩液中搅拌0.5小时，分出水相，再用二氯甲烷萃取两次，水相冻干得化合物int9(214mg)。(6) 9f (515 mg, 1.93 mmol) was dissolved in a mixed solvent of dichloromethane (4 mL) and anhydrous methanol (0.4 mL), cooled to 0°C in an ice-water bath under nitrogen protection, and hydrazine hydrate (98%, 197 mg, 3.86 mmol) was added dropwise. After the addition was complete, the temperature was naturally raised to room temperature and reacted for 2 hours. The reaction solution was filtered and the filter cake was washed twice with dichloromethane (5 mL). The aqueous phase was adjusted to pH = 9-10 by adding ammonia water and extracted twice with dichloromethane (5 mL). 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).
1H NMR(400MHz,DMSO_d6)δ11.09(br.s,3H),4.80(s,1H),2.48–2.01(m,6H). 1 H NMR (400 MHz, DMSO_d6) δ 11.09 (br.s, 3H), 4.80 (s, 1H), 2.48–2.01 (m, 6H).
中间体int10：
Intermediate int10:
Int10制备方法：Int10 preparation method:
(1)将10a(5g，33mmol)和硝酸银(0.588g，35mmol)溶解在乙腈(50mL)中。氮气置换三次，降温到0℃。向混合物中缓慢滴加苯酰氯(0.487g，35mmol)在室温下搅拌0.5h。反应结束后用水溶液(10mL)淬灭反应，加入乙酸乙酯(30mL)和水(30mL)，搅拌后静置分液，水相用乙酸乙酯(15mL)萃取三次，合并有机相。有机相用饱和食盐水洗三次，无水硫酸钠干燥，减压浓缩，所得粗品10b(5.3g)可直接用于下一步。(1) 10a (5 g, 33 mmol) and silver nitrate (0.588 g, 35 mmol) were dissolved in acetonitrile (50 mL). The mixture was replaced with nitrogen three times and cooled to 0°C. Benzoyl chloride (0.487 g, 35 mmol) was slowly added dropwise to the mixture and stirred at room temperature for 0.5 h. After the reaction was completed, the reaction was quenched with aqueous solution (10 mL), ethyl acetate (30 mL) and water (30 mL) were added, stirred and allowed to stand for separation, the aqueous phase was extracted three times with ethyl acetate (15 mL), and the organic phases were combined. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product 10b (5.3 g) was directly used in the next step.
(2)将粗品10b(5.3g，29.96mmol)和二氯化锡(25.56g，134.8mmol)溶解在溴化氢水溶液(100mL)中，室温下搅拌12h。反应结束后过滤，滤液减压浓缩得粗品10c(5g)。(2) The crude product 10b (5.3 g, 29.96 mmol) and tin dichloride (25.56 g, 134.8 mmol) were dissolved in aqueous hydrogen bromide solution (100 mL) and stirred at room temperature for 12 h. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product 10c (5 g).
(3)将10c(5g，31.9mmol)和4a(7.8g，38.3mmol)溶解在冰醋酸(100mL)中。氮气保护下混合物于130℃油浴中搅拌2h。反应结束后，将反应液冷却至室温，减压浓缩。所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝10:1)洗脱得int10(5g)。LCMS(ESI):m/z＝286.1(M+H)+。(3) 10c (5 g, 31.9 mmol) and 4a (7.8 g, 38.3 mmol) were dissolved in glacial acetic acid (100 mL). The mixture was stirred in an oil bath at 130°C for 2 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 10:1) to obtain int10 (5 g). LCMS (ESI): m/z = 286.1 (M+H) + .
中间体int11：
Intermediate int11:
Int11制备方法：Int11 preparation method:
(1)将11a(3g，19.6mmol)溶解在DMF(30mL)中，在0℃下，缓慢滴加TFAA(3mL，23.4mmol)，保持温度反应0.5h后，恢复到室温反应16h。将混合物真空浓缩旋干，加入水(10mL)常温搅拌0.5h。过滤，将所得固体加入20％氢氧化钠溶液(30mL)中,加热回流8h。冷却到室温后，用3N盐酸调节PH＝3，过滤，用水洗涤，得产物4.3g为11b。(1) 11a (3 g, 19.6 mmol) was dissolved in DMF (30 mL), and TFAA (3 mL, 23.4 mmol) was slowly added dropwise at 0°C. The temperature was maintained for 0.5 h, and then the mixture was returned to room temperature for 16 h. The mixture was concentrated in vacuo to dryness, and water (10 mL) was added and stirred at room temperature for 0.5 h. After filtering, the obtained solid was added to 20% sodium hydroxide solution (30 mL) and heated under reflux for 8 h. After cooling to room temperature, the pH was adjusted to 3 with 3N hydrochloric acid, filtered, and washed with water to obtain 4.3 g of the product 11b.
(2)将11b(2.0g 10.1mmol)和DPPA(5.6g 20.2mmol)溶解在THF(20mL)中，加入三乙胺(3.0g 30.3mmol)，在常温下搅拌16h。反应完毕后混合物用二氯甲烷萃取，合并有机相所得残余物即为11c(2.0g)直接进行下一步反应。(2) 11b (2.0 g 10.1 mmol) and DPPA (5.6 g 20.2 mmol) were dissolved in THF (20 mL), triethylamine (3.0 g 30.3 mmol) was added, and the mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was extracted with dichloromethane, and the organic phases were combined to obtain the residue 11c (2.0 g), which was directly used for the next step.
(3)将11c(2.0g)溶解在叔丁醇(20mL)中，在80℃下搅拌16h。反应完毕后，混合物用二氯甲烷萃取，合并有机相所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝2:1)洗脱得11d(600mg)。(3) 11c (2.0 g) was dissolved in tert-butanol (20 mL) and stirred at 80° C. for 16 h. After the reaction was completed, the mixture was extracted with dichloromethane, and the residue obtained by combining the organic phases was purified by column chromatography and eluted with (petroleum ether: ethyl acetate = 2:1) to obtain 11d (600 mg).
(4)将11d(600mg)溶解在盐酸二氧六环溶液(10mL)中，在常温下搅拌2h。反应完毕后，旋干得粗品11e(615mg)。(4) Dissolve 11d (600 mg) in a hydrochloric acid dioxane solution (10 mL) and stir at room temperature for 2 h. After the reaction is complete, spin dry to obtain a crude product 11e (615 mg).
(5)将11e(200mg，1.18mmol)和2-氯-5-乙酰基吡啶(168mg，1.08mmol，)溶解在冰乙酸(2mL)中，在130℃下搅拌4h。反应结束后旋干溶剂得粗品int11。LCMS(ESI)m/z:288.1[M+H]+.(5) 11e (200 mg, 1.18 mmol) and 2-chloro-5-acetylpyridine (168 mg, 1.08 mmol) were dissolved in glacial acetic acid (2 mL) and stirred at 130°C for 4 h. After the reaction, the solvent was dried to obtain crude int11. LCMS (ESI) m/z: 288.1 [M+H] + .
中间体int12：
Intermediate int12:
Int12制备方法：Int12 preparation method:
(1)将12a(10.0g，58.9mmol)溶解在N,N-二甲基甲酰胺(150mL)中，在℃下滴加三氟乙酸酐(14.86g，70.8mmol)。在室温搅拌16小时后，将混合物倒入300ml水中，抽滤得到沉淀物并在300ml 20％NaOH中加热回流过夜。反应液冷却到室温后调节pH＝3，用二氯甲烷萃取两次，水层用盐酸酸化，过滤并真空干燥得到12b(12.0g)。(1) 12a (10.0 g, 58.9 mmol) was dissolved in N,N-dimethylformamide (150 mL), and trifluoroacetic anhydride (14.86 g, 70.8 mmol) was added dropwise at ℃. After stirring at room temperature for 16 hours, the mixture was poured into 300 ml of water, the precipitate was filtered and heated to reflux in 300 ml of 20% NaOH overnight. After the reaction solution was cooled to room temperature, the pH was adjusted to 3, extracted twice with dichloromethane, the aqueous layer was acidified with hydrochloric acid, filtered and dried in vacuo to obtain 12b (12.0 g).
(2)将12b(3.0g，14.08mmol)溶解在四氢呋喃(50mL)中，然后将在0℃下加入三乙胺(4.28g，42.25mmol)、叠氮磷酸二苯酯(7.75g，28.17mmol)。反应液在室温下搅拌过夜。反应结束后减压浓缩除去大部分四氢呋喃，加入叔丁醇，减压浓缩，除去剩余的四氢呋喃得到12c(3g)。(2) 12b (3.0 g, 14.08 mmol) was dissolved in tetrahydrofuran (50 mL), and then triethylamine (4.28 g, 42.25 mmol) and diphenylphosphoryl azide (7.75 g, 28.17 mmol) were added at 0°C. The reaction solution was stirred at room temperature overnight. After the reaction was completed, the solution was concentrated under reduced pressure to remove most of the tetrahydrofuran, tert-butyl alcohol was added, and the solution was concentrated under reduced pressure to remove the remaining tetrahydrofuran to obtain 12c (3 g).
(3)将12c(3g，12.61mmol)溶解在叔丁醇(100mL)中，混合液在氮气保护下80℃搅拌过夜。反应结束后，将反应液冷却至室温，减压浓缩后用硅胶柱层析纯化(石油醚:乙酸乙酯＝4:1)洗脱得12d(600mg)。(3) 12c (3 g, 12.61 mmol) was dissolved in tert-butyl alcohol (100 mL), and the mixture was stirred at 80° C. overnight under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain 12d (600 mg).
(4)将12d(500mg，1.76mmol)溶解在TFA/DCM溶液(2/8mL)中，反应液在室温下搅拌2h。反应结束后减压浓缩得12e(600mg)。(4) 12d (500 mg, 1.76 mmol) was dissolved in TFA/DCM solution (2/8 mL), and the reaction solution was stirred at room temperature for 2 h. After the reaction was completed, the solution was concentrated under reduced pressure to obtain 12e (600 mg).
(5)将12e(600mg，3.26mmol)、4a(509mg，3.26mmol)、对甲苯磺酸(124mg，0.65mmol)溶解在DMF(8mL)中。混合液在氮气保护下120℃搅拌2h，反应结束后加乙酸乙酯稀释，再加 水，用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗涤2次，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶柱层析纯化，用(乙酸乙酯:石油醚＝1:1)洗脱得int12(200mg)。LCMS(ESI)m/z:304.1[M+H]+.(5) 12e (600 mg, 3.26 mmol), 4a (509 mg, 3.26 mmol), and p-toluenesulfonic acid (124 mg, 0.65 mmol) were dissolved in DMF (8 mL). The mixture was stirred at 120 °C for 2 h under nitrogen protection. After the reaction was completed, ethyl acetate was added to dilute the mixture. Water, extracted with ethyl acetate three times, combined the organic phases, washed twice with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with (ethyl acetate: petroleum ether = 1:1) to obtain int12 (200 mg). LCMS (ESI) m/z: 304.1 [M+H] + .
中间体int13：
Intermediate int13:
Int13制备方法：Int13 preparation method:
(1)将13a(1.0g，6.57mmol)分批加入提前降温到先0℃的发烟HNO3中。反应液在0℃下搅拌30min。反应结束后将混合液加入冰水中淬灭反应，产物析出，将产物用水洗一下，晾干，所得粗品13b(1.2g)直接用于下一步。(1) 13a (1.0 g, 6.57 mmol) was added in batches to fuming HNO 3 which had been cooled to 0°C in advance. The reaction solution was stirred at 0°C for 30 min. After the reaction was completed, the mixture was added to ice water to quench the reaction. The product precipitated, washed with water, and dried. The obtained crude product 13b (1.2 g) was directly used in the next step.
(2)将粗品13b(1.2g，6.09mmol)溶于醋酸(12mL)中，然后将SnCl2.2H2O(6.6g,30.45mmol)加入反应液中，加热至85℃，反应2小时。反应结束先过滤，再将滤液后减压浓缩，所得粗品(600mg)13c可直接用于下一步。(2) The crude product 13b (1.2 g, 6.09 mmol) was dissolved in acetic acid (12 mL), and then SnCl 2 .2H 2 O (6.6 g, 30.45 mmol) was added to the reaction solution, heated to 85°C, and reacted for 2 hours. After the reaction was completed, the filtrate was filtered and then concentrated under reduced pressure. The obtained crude product (600 mg) 13c was directly used in the next step.
(3)将13c(600mg，3.042mmol)、4a(510mg，3.648mmol)以及DIEA(1.2mL，6.06mmol)溶解在DMF(10mL)中。氮气保护下混合物于60℃油浴中搅拌3h。反应结束后，将反应液冷却至室温，减压浓缩。所得残余物反相制备纯化得int13(200mg)。(3) 13c (600 mg, 3.042 mmol), 4a (510 mg, 3.648 mmol) and DIEA (1.2 mL, 6.06 mmol) were dissolved in DMF (10 mL). The mixture was stirred in an oil bath at 60 °C for 3 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase preparation to obtain int13 (200 mg).
中间体int14：
Intermediate int14:
Int14制备方法：Int14 preparation method:
(1)将化合物14a(1.0g，8.19mmol，1.0eq)溶解在无水乙醚(30mL)中，反应体系降温至0℃。将LiAlH4(466mg，12.3mmol，1.5eq)缓慢加入到反应液中，加料完毕后反应温度升至室温搅拌18h。反应完毕后将混合物降温至0℃，加入2M NaOH溶液(1.0mL)，水(1.0mL)。过滤混合物，并用乙醚洗涤(2*10mL)，旋干有机相所得残余物用二氯甲烷萃取，在5-10℃环境下旋干得化合物14b(0.9g)。(1) Compound 14a (1.0 g, 8.19 mmol, 1.0 eq) was dissolved in anhydrous ether (30 mL), and the reaction system was cooled to 0°C. LiAlH4 (466 mg, 12.3 mmol, 1.5 eq) was slowly added to the reaction solution. After the addition was completed, the reaction temperature was raised to room temperature and stirred for 18 h. After the reaction was completed, the mixture was cooled to 0°C, and 2M NaOH solution (1.0 mL) and water (1.0 mL) were added. The mixture was filtered and washed with ether (2*10 mL). The organic phase was dried and the residue was extracted with dichloromethane and dried at 5-10°C to obtain compound 14b (0.9 g).
(2)将14b(0.8g，7.36mmol，1.2eq)，化合物3b(1.0g，6.13mmol，1.0eq)和三苯基磷(1.8g，6.75mmol，1.1eq)溶解在四氢呋喃(50mL)中，反应体系降温至0℃。将DBAD(1.5g，6.75mmol，1.1eq)溶于四氢呋喃(10mL)，缓慢滴到反应液中，滴加完毕后温度升至室温搅拌6h。反应完毕后旋干得到的混合物用乙酸乙酯和水进行萃取，合并有机相，所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝3:1)洗脱得化合物14c(1.2g)。(2) 14b (0.8 g, 7.36 mmol, 1.2 eq), compound 3b (1.0 g, 6.13 mmol, 1.0 eq) and triphenylphosphine (1.8 g, 6.75 mmol, 1.1 eq) were dissolved in tetrahydrofuran (50 mL), and the reaction system was cooled to 0°C. DBAD (1.5 g, 6.75 mmol, 1.1 eq) was dissolved in tetrahydrofuran (10 mL) and slowly dripped into the reaction solution. After the addition was complete, the temperature was raised to room temperature and stirred for 6 h. After the reaction was completed, the mixture was dried and extracted with ethyl acetate and water. The organic phases were combined and the residue was purified by column chromatography and eluted with (petroleum ether: ethyl acetate = 3:1) to obtain compound 14c (1.2 g).
(3)将14c(1.1g，4.34mmol，1eq)溶解在(二氯甲烷/甲醇＝10/1)(10mL)中，逐步滴加70％水合肼(0.6mL，8.69mmol，2eq)，在室温下搅拌2h。反应结束后过滤，用氨水冲洗滤液，用二氯甲烷和水萃取，合并有机相，旋蒸后加入乙醇，滴加浓盐酸至PH<1有固体析出，过滤得到化合物int14(750mg)。(3) 14c (1.1 g, 4.34 mmol, 1 eq) was dissolved in (dichloromethane/methanol = 10/1) (10 mL), and 70% hydrazine hydrate (0.6 mL, 8.69 mmol, 2 eq) was gradually added dropwise, and stirred at room temperature for 2 h. After the reaction was completed, the mixture was filtered, and the filtrate was washed with ammonia water, extracted with dichloromethane and water, and the organic phases were combined, ethanol was added after rotary evaporation, and concentrated hydrochloric acid was added dropwise until pH <1 and solid precipitated, and the compound int14 (750 mg) was obtained by filtration.
1H NMR(400MHz,DMSO_d6)δ8.11(s,3H),4.31–4.14(m,1H),4.13–3.98(m,1H),2.24–2.12(m,1H),1.81–1.66(m,1H),1.56–1.47(m,1H). 1 H NMR (400 MHz, DMSO_d6) δ8.11 (s, 3H), 4.31–4.14 (m, 1H), 4.13–3.98 (m, 1H), 2.24–2.12 (m, 1H), 1.81–1.66 (m, 1H), 1.56–1.47 (m, 1H).
中间体int15：
Intermediate int15:
Int15制备方法：Int15 preparation method:
(1)将化合物15a(5g,35.32mmol)溶解在超干四氢呋喃(50mL)中，氮气置换三次，在-78℃下搅拌20min。将异丙基溴化镁(2M,21mL，42.38mmol)缓慢滴加到溶液中。滴加完毕后，维持温度在-78℃，搅拌2h。反应结束后，加入饱和氯化铵溶液淬灭，混合物用乙酸乙酯萃取，合并有 机相所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝2:1)洗脱得化合物15b(2g)。LCMS(ESI)m/z:186.0[M+H]+.(1) Compound 15a (5 g, 35.32 mmol) was dissolved in ultra-dry tetrahydrofuran (50 mL), replaced with nitrogen three times, and stirred at -78 °C for 20 min. Isopropylmagnesium bromide (2 M, 21 mL, 42.38 mmol) was slowly added dropwise to the solution. After the addition was completed, the temperature was maintained at -78 °C and stirred for 2 h. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate and combined. The residue obtained from the organic phase was purified by column chromatography and eluted with (petroleum ether:ethyl acetate=2:1) to obtain compound 15b (2 g). LCMS (ESI) m/z: 186.0 [M+H] + .
(2)将15b(2g，10.77mmol)溶解在二氯甲烷(20.0mL)中，氮气置换三次，在0℃下搅拌20min。将戴斯-马丁试剂(5.5g，12.92mmol)缓慢滴加到溶液中。反应结束后，过滤反应液，混合物用水萃取，合并有机相所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝3:1)洗脱得化合物15c(1.18g)。LCMS(ESI)m/z:184.0[M+H]+.(2) 15b (2 g, 10.77 mmol) was dissolved in dichloromethane (20.0 mL), replaced with nitrogen three times, and stirred at 0°C for 20 min. Dess-Martin reagent (5.5 g, 12.92 mmol) was slowly added dropwise to the solution. After the reaction was completed, the reaction solution was filtered, the mixture was extracted with water, and the residue obtained by combining the organic phases was purified by column chromatography and eluted with (petroleum ether: ethyl acetate = 3:1) to obtain compound 15c (1.18 g). LCMS (ESI) m/z: 184.0 [M+H] + .
(3)将15c(1.18g，6.43mmol)，int2(1.3g，7.72mmol)溶解在醋酸(15.0mL)中，在130℃下搅拌4小时。反应结束后，浓缩反应液，用柱层析纯化，用(石油醚:乙酸乙酯＝4:1)洗脱得化合物int15(1.12g)。LCMS(ESI)m/z:314.1[M+H]+.(3) 15c (1.18 g, 6.43 mmol) and int2 (1.3 g, 7.72 mmol) were dissolved in acetic acid (15.0 mL) and stirred at 130°C for 4 hours. After the reaction, the reaction solution was concentrated and purified by column chromatography, and eluted with (petroleum ether: ethyl acetate = 4:1) to obtain compound int15 (1.12 g). LCMS (ESI) m/z: 314.1 [M+H] + .
中间体int16：
Intermediate int16:
Int16制备方法：Int16 preparation method:
(1)将化合物16a(6g，58.7mmol)，化合物3b(10.5g，64.6mmol)和三苯基膦(17g，64.6mmol)溶解在超干四氢呋喃(500mL)中，然后在0℃下加入偶氮二甲酸二叔丁酯(14.8g，64.6mmol)。反应液在0℃下搅拌至常温4小时。反应结束后，反应液用二氯甲烷和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝2:1)洗脱得化合物16b(10.3g，70％)。(1) Compound 16a (6 g, 58.7 mmol), compound 3b (10.5 g, 64.6 mmol) and triphenylphosphine (17 g, 64.6 mmol) were dissolved in ultra-dry tetrahydrofuran (500 mL), and di-tert-butyl azodicarboxylate (14.8 g, 64.6 mmol) was then added at 0°C. The reaction solution was stirred at 0°C until it reached room temperature for 4 hours. After the reaction was completed, the reaction solution was washed with dichloromethane and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=2:1) to obtain compound 16b (10.3 g, 70%).
(2)将16b(2g，8.1mmol)溶解在二氯甲烷(20mL)和甲醇(2ml)混合液中，然后在室温下滴加水合肼(68％)(810mg，16.2mmol)。反应液在室温下搅拌2小时。反应完成后过滤沉淀，用5N氨水(100ml)冲洗滤液。用二氯甲烷萃取水相两次，萃取结束有机相用无水硫酸钠干燥。干燥后常温减压浓缩后加入乙醇(20ml)和浓盐酸(1ml)，反应液呈酸性，后减压旋干后得到化合物int16(880mg)。(2) 16b (2 g, 8.1 mmol) was dissolved in a mixture of dichloromethane (20 mL) and methanol (2 ml), and then hydrazine hydrate (68%) (810 mg, 16.2 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the precipitate was filtered and the filtrate was rinsed with 5N ammonia water (100 ml). The aqueous phase was extracted twice with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate after extraction. After drying, ethanol (20 ml) and concentrated hydrochloric acid (1 ml) were added after concentration under reduced pressure at room temperature. The reaction solution was acidic and then vacuum dried to obtain compound int16 (880 mg).
1H NMR(400MHz,CD3OD)δ4.27–4.24(m,1H),3.97–3.92(m,2H),3.52–3.46(m,2H),2.05–2.01(m,2H),1.70–1.61(m,2H). 1 H NMR (400 MHz, CD 3 OD) δ 4.27–4.24 (m, 1H), 3.97–3.92 (m, 2H), 3.52–3.46 (m, 2H), 2.05–2.01 (m, 2H), 1.70–1.61 (m, 2H).
中间体int17：
Intermediate int17:
Int17制备方法：Int17 preparation method:
(1)将化合物17a(1.0g,10.745mmol)溶于二氯甲烷/甲醇(75ml/75ml)降温至-78℃,然后通入臭氧，直到溶液变蓝，再将化合物硼氢化钠(2.0g，50.05mmol)加入到反应液中，再升至室温，搅拌24h。反应结束后将混合液旋干，将产物溶于水(100ml)，再用乙酸乙酯萃取，将有机相旋干，所得粗品17b(600mg)可直接用于下一步。(1) Compound 17a (1.0 g, 10.745 mmol) was dissolved in dichloromethane/methanol (75 ml/75 ml) and cooled to -78°C. Ozone was then introduced until the solution turned blue. Sodium borohydride (2.0 g, 50.05 mmol) was then added to the reaction solution. The solution was warmed to room temperature and stirred for 24 h. After the reaction was completed, the mixture was dried by rotary evaporation, the product was dissolved in water (100 ml), and then extracted with ethyl acetate. The organic phase was dried by rotary evaporation, and the obtained crude product 17b (600 mg) was directly used in the next step.
(2)将粗品17b(600mg，6.185mmol)溶于THF(10ml)中，然后将PPh3(1.8g,6.80mmol)加入反应液中,降温至0℃，将DBAD(1.6g,6.8mmol)溶于THF中，加入3b，滴入到反应液中，反应在室温下搅拌6小时。反应完毕后，用乙酸乙酯和水进行萃取，合并有机相，所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝3:1)洗脱得化合物17c(600mg)。(2) The crude product 17b (600 mg, 6.185 mmol) was dissolved in THF (10 ml), and PPh 3 (1.8 g, 6.80 mmol) was then added to the reaction solution. The temperature was lowered to 0°C, DBAD (1.6 g, 6.8 mmol) was dissolved in THF, 3b was added, and the mixture was added dropwise to the reaction solution. The reaction was stirred at room temperature for 6 hours. After the reaction was completed, ethyl acetate and water were used for extraction, and the organic phases were combined. The residue was purified by column chromatography and eluted with (petroleum ether: ethyl acetate = 3:1) to obtain compound 17c (600 mg).
(3)将17c(600mg，2.479mmol，1eq)溶解在(二氯甲烷/甲醇＝10/1)(10mL)中，逐步滴加70％水合肼(0.3mL，4.958mmol，2eq)，在室温下搅拌2h。反应结束后过滤，用氨水冲洗滤液，用二氯甲烷和水萃取，合并有机相，旋蒸后加入乙醇，滴加浓盐酸至PH<1有固体析出，过滤得到化合物int17(200mg)。(3) 17c (600 mg, 2.479 mmol, 1 eq) was dissolved in (dichloromethane/methanol = 10/1) (10 mL), and 70% hydrazine hydrate (0.3 mL, 4.958 mmol, 2 eq) was gradually added dropwise, and stirred at room temperature for 2 h. After the reaction was completed, the mixture was filtered, and the filtrate was washed with ammonia water, extracted with dichloromethane and water, and the organic phases were combined, ethanol was added after rotary evaporation, and concentrated hydrochloric acid was added dropwise until pH <1, and solids were precipitated, which was filtered to obtain compound int17 (200 mg).
1H NMR(400MHz,DMSO-d6)δ11.18(s,3H),4.79–4.76(m,1H),2.96–2.91(m,1H),2.41–2.32(m,2H),2.30–2.20(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.18 (s, 3H), 4.79–4.76 (m, 1H), 2.96–2.91 (m, 1H), 2.41–2.32 (m, 2H), 2.30–2.20 (m, 2H).
中间体int18：
Intermediate int18:
Int18制备方法：Int18 preparation method:
(1)将化合物18a(5g，69.34mmol)和三苯基磷(13g，79.69mmol)溶解在超干四氢呋喃(50mL)中，氮气置换三次，加入3b，在0℃下搅拌20min。将偶氮二甲酸二叔丁酯(18.4g，79.89mmol)溶解在超干四氢呋喃(10mL)中，缓慢滴加到溶液中。滴加完毕后，反应液室温下搅拌16h。反应结束后，混合物用二氯甲烷萃取，合并有机相所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝2:1)洗脱得化合物18b(9g)。(1) Compound 18a (5 g, 69.34 mmol) and triphenylphosphine (13 g, 79.69 mmol) were dissolved in ultra-dry tetrahydrofuran (50 mL), replaced with nitrogen three times, and 3b was added. The mixture was stirred at 0°C for 20 min. Di-tert-butyl azodicarboxylate (18.4 g, 79.89 mmol) was dissolved in ultra-dry tetrahydrofuran (10 mL) and slowly added dropwise to the solution. After the addition was complete, the reaction solution was stirred at room temperature for 16 h. After the reaction was completed, the mixture was extracted with dichloromethane, and the residue obtained by combining the organic phases was purified by column chromatography and eluted with (petroleum ether: ethyl acetate = 2:1) to obtain compound 18b (9 g).
(2)将18b(9g，41.43mmol)溶解在二氯甲烷(90.0mL)和甲醇(10.0mL)的混合溶液中，氮气置换三次，在室温中将水合肼缓慢滴加至溶液中。在室温下搅拌2小时。反应结束后，混合物用二氯甲烷萃取，合并有机相后浓缩。浓缩物加入盐酸(6M)，水相用二氯甲烷洗涤，然后水相冻干得化合物int18(2g)。(2) 18b (9 g, 41.43 mmol) was dissolved in a mixed solution of dichloromethane (90.0 mL) and methanol (10.0 mL), and the mixture was replaced with nitrogen three times. Hydrazine hydrate was slowly added dropwise to the solution at room temperature. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was extracted with dichloromethane, and the organic phases were combined and concentrated. Hydrochloric acid (6 M) was added to the concentrate, the aqueous phase was washed with dichloromethane, and then the aqueous phase was lyophilized to obtain compound int18 (2 g).
1H NMR(400MHz,DMSO_d6)δ8.58(s,2H),5.75(d,J＝4.0Hz,1H),2.08–2.01(m,1H),1.88–1.83(m,1H),1.68–1.53(m,1H),1.52–1.42(m,1H),1.23–0.99(m,2H). 1 H NMR (400 MHz, DMSO_d6) δ8.58 (s, 2H), 5.75 (d, J＝4.0 Hz, 1H), 2.08–2.01 (m, 1H), 1.88–1.83 (m, 1H), 1.68–1.53 (m, 1H), 1.52–1.42 (m, 1H), 1.23–0.99 (m, 2H).
中间体int19：
Intermediate int19:
Int19制备方法：Int19 preparation method:
(1)将化合物3b(1.64g，10.08mmol)、化合物19a(1.00g，10.08mmol)和三苯基膦(2.64g，10.08mmol)溶解在超干四氢呋喃(20mL)中，然后在0℃下滴加偶氮二甲酸二异丙酯(2.04g，10.02mmol)。反应液在0℃下搅拌至常温16小时。反应结束后，反应液用二氯甲烷和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝4:1)洗脱得化合物19b(2.2g)。(1) Compound 3b (1.64 g, 10.08 mmol), compound 19a (1.00 g, 10.08 mmol) and triphenylphosphine (2.64 g, 10.08 mmol) were dissolved in ultra-dry tetrahydrofuran (20 mL), and diisopropyl azodicarboxylate (2.04 g, 10.02 mmol) was then added dropwise at 0°C. The reaction solution was stirred at 0°C until it reached room temperature for 16 hours. After the reaction was completed, the reaction solution was washed with dichloromethane and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain compound 19b (2.2 g).
(2)将19b(2.2g，8.65mmol)溶解在二氯甲烷(20mL)和甲醇(2ml)混合液中，然后在室温下滴加水合肼(68％)(866mg，17.30mmol)。反应液在室温下搅拌2小时。反应完成后过滤沉淀，用5N氨水(20ml)冲洗滤液。用二氯甲烷萃取水相两次，有机相用无水硫酸钠干燥，过滤。常温减压浓缩后加入乙醇(20m和浓盐酸(2ml)，反应液呈酸性，后减压旋干后得到化合物int19(150mg)。(2) 19b (2.2 g, 8.65 mmol) was dissolved in a mixture of dichloromethane (20 mL) and methanol (2 ml), and then hydrazine hydrate (68%) (866 mg, 17.30 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the precipitate was filtered and the filtrate was rinsed with 5N ammonia water (20 ml). The aqueous phase was extracted twice with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and filtered. After concentrating under reduced pressure at room temperature, ethanol (20 ml) and concentrated hydrochloric acid (2 ml) were added. The reaction solution was acidic and then dried under reduced pressure to obtain compound int19 (150 mg).
1H NMR(400MHz,DMSO_d6)δ8.93(d,J＝4.0Hz,2H),8.01(d,J＝4.0Hz,2H),5.42(s,2H). 1 H NMR (400 MHz, DMSO_d6) δ8.93 (d, J=4.0 Hz, 2H), 8.01 (d, J=4.0 Hz, 2H), 5.42 (s, 2H).
中间体int20：
Intermediate int20:
Int20制备方法：Int20 preparation method:
(1)将化合物3b(7.35g，45.05mmol)、化合物20a(5.00g，40.95mmol)和三苯基膦(11.82g，45.05mmol)溶解在超干四氢呋喃(80mL)中，然后在0℃滴加偶氮二甲酸二叔丁酯(10.4g，45.05mmol)的四氢呋喃溶液。反应液自然升温至常温，并搅拌16小时。反应结束后，反应液用二氯甲烷和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝4:1)洗脱得化合物20b(22g)。(1) Compound 3b (7.35 g, 45.05 mmol), compound 20a (5.00 g, 40.95 mmol) and triphenylphosphine (11.82 g, 45.05 mmol) were dissolved in ultra-dry tetrahydrofuran (80 mL), and then a tetrahydrofuran solution of di-tert-butyl azodicarboxylate (10.4 g, 45.05 mmol) was added dropwise at 0°C. The reaction solution was naturally heated to room temperature and stirred for 16 hours. After the reaction was completed, the reaction solution was washed with dichloromethane and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain compound 20b (22 g).
(2)将20b(11.00g，41.20mmol)溶解在二氯甲烷(50mL)和甲醇(5mL)混合液中，然 后在室温下滴加水合肼(68％)(4.10g，82.40mmol)。反应液在室温下搅拌2小时。反应完成后过滤沉淀，用5N氨水(20mL)冲洗滤液。用二氯甲烷萃取水相两次，萃取结束有机相用无水硫酸钠干燥。干燥后常温减压浓缩后加入乙醇(10mL和浓盐酸(2mL)，反应液呈酸性，后减压旋干后得到化合物int20(4.00g)。(2) 20b (11.00 g, 41.20 mmol) was dissolved in a mixture of dichloromethane (50 mL) and methanol (5 mL). Then, hydrazine hydrate (68%) (4.10 g, 82.40 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the precipitate was filtered and the filtrate was rinsed with 5N ammonia water (20 mL). The aqueous phase was extracted twice with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate after extraction. After drying, ethanol (10 mL) and concentrated hydrochloric acid (2 mL) were added after concentration at room temperature under reduced pressure. The reaction solution was acidic, and then the compound int20 (4.00 g) was obtained after decompression and spin drying.
1H NMR(400MHz,DMSO_d6)δ11.18(s,3H),4.10(d,J＝8.0Hz,1H),2.71–2.67(m,2H),2.52–2.40(m,3H). 1 H NMR (400 MHz, DMSO_d6) δ 11.18 (s, 3H), 4.10 (d, J = 8.0 Hz, 1H), 2.71–2.67 (m, 2H), 2.52–2.40 (m, 3H).
中间体int21：
Intermediate int21:
Int21制备方法：Int21 preparation method:
(1)将化合物21a(2.0g，11.656mmol)和二甲羟胺盐酸盐(2.274g，23.31mmol)和HATU(5.32g，13.99mmol)溶解在二氯甲烷(50.0mL)中，氮气保护下在室温下滴加DIEA(6.0mL，46.625mmol)，滴加完毕后，在室温下搅拌18h。反应结束后，加水淬灭，混合物用二氯甲烷萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝4:1)洗脱得化合物21b(1.576g)。LCMS(ESI)m/z:215.0[M+H]+.(1) Compound 21a (2.0 g, 11.656 mmol), dimethylhydroxylamine hydrochloride (2.274 g, 23.31 mmol) and HATU (5.32 g, 13.99 mmol) were dissolved in dichloromethane (50.0 mL), and DIEA (6.0 mL, 46.625 mmol) was added dropwise at room temperature under nitrogen protection. After the addition was complete, the mixture was stirred at room temperature for 18 h. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 4:1) to obtain compound 21b (1.576 g). LCMS (ESI) m/z: 215.0 [M+H] + .
(2)将21b(1.5g，8.157mmol)溶解在四氢呋喃(15mL)中，反应体系降温至0℃,氮气保护下缓慢滴加甲基溴化镁(3.0M in THF)(5.44mL,16.31mmol),加料完毕后反应温度升至室温，继续搅拌3h。反应完毕后，滴加饱和氯化铵溶液淬灭，混合物用二氯甲烷(15mL x 3)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得粗品21c(671mg)，直接用于下一步反应。LCMS(ESI)m/z:170.0[M+H]+.(2) 21b (1.5 g, 8.157 mmol) was dissolved in tetrahydrofuran (15 mL), the reaction system was cooled to 0°C, and methylmagnesium bromide (3.0 M in THF) (5.44 mL, 16.31 mmol) was slowly added dropwise under nitrogen protection. After the addition was completed, the reaction temperature rose to room temperature and stirring was continued for 3 h. After the reaction was completed, saturated ammonium chloride solution was added dropwise to quench, the mixture was extracted with dichloromethane (15 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 21c (671 mg), which was directly used in the next step. LCMS (ESI) m/z: 170.0 [M+H] + .
(3)将21c(200mg，1.07mmol)和int2(258mg，1.28mmol)溶解在醋酸(2mL)中，氮气保护下在120℃油浴中反应2h。反应结束后，将反应液减压浓缩，除去大部分乙酸。加水稀释，用乙酸乙酯萃取(20mL x 3)，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝2:1)洗脱得化合物int21(196mg)。1H NMR(400MHz,DMSO_d6)δ11.02(s,1H),9.28(s,1H),8.00(d,J＝8.0Hz,2H),7.77(s,1H),7.39(d,J＝12.0Hz,1H),7.11(d,J＝8.0Hz,1H),6.66(s,1H),2.64(s,3H),2.45(s,3H).(3) 21c (200 mg, 1.07 mmol) and int2 (258 mg, 1.28 mmol) were dissolved in acetic acid (2 mL) and reacted in an oil bath at 120 °C for 2 h under nitrogen protection. After the reaction, the reaction solution was concentrated under reduced pressure to remove most of the acetic acid. It was diluted with water and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 2:1) to obtain compound int21 (196 mg). 1H NMR (400MHz, DMSO_d6) δ11.02(s,1H),9.28(s,1H),8.00(d,J＝8.0Hz,2H),7.77(s,1H),7.39(d,J＝12.0Hz,1H),7.11(d,J＝8.0Hz,1H),6.66(s,1H),2.64(s,3H),2.45(s,3H).
中间体int22：
Intermediate int22:
Int22制备方法：Int22 preparation method:
(1)将22a(1g，5.25mmol)溶解在甲醇(15ml)中，然后在0℃下分批加入硼氢化钠(298mg，7.88mmol)。反应液在常温下搅拌至常温2小时。反应结束后，向反应液中加入用乙酸乙酯和饱和食盐水，用乙酸乙酯萃取三次。有机相用无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝4:1)洗脱得22b(1g)。(1) 22a (1 g, 5.25 mmol) was dissolved in methanol (15 ml), and then sodium borohydride (298 mg, 7.88 mmol) was added in batches at 0°C. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, ethyl acetate and saturated brine were added to the reaction solution, and the mixture was extracted with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain 22b (1 g).
(2)将22b(800mg，4.166mmol)、3b(747mg，4.583mmol)和三苯基膦(1.2g，4.583mmol)溶解在超干四氢呋喃(20mL)中，然后在0℃下加入偶氮二甲酸二叔丁酯(1g，4.583mmol)的四氢呋喃溶液(20mL)。反应液在0℃下搅拌至常温16小时。反应结束后，反应液用二氯甲烷和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝4:1)洗脱得 22c(1g)。(2) 22b (800 mg, 4.166 mmol), 3b (747 mg, 4.583 mmol) and triphenylphosphine (1.2 g, 4.583 mmol) were dissolved in ultra-dry tetrahydrofuran (20 mL), and then a tetrahydrofuran solution (20 mL) of di-tert-butyl azodicarboxylate (1 g, 4.583 mmol) was added at 0°C. The reaction solution was stirred at 0°C until the temperature reached room temperature for 16 hours. After the reaction was completed, the reaction solution was washed with dichloromethane and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain 22c(1g).
(3)将22c(500mg，1.483mmol)和10％钯炭(500mg)溶解在甲醇(5ml)中，然后在常温下加入醋酸(0.5ml)。反应液在氢气保护常温下搅拌3小时。反应结束后，将反应液过滤，滤饼用甲醇(10mL)洗涤，滤液加压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝4:1)洗脱得化合物22d(165mg)。(3) 22c (500 mg, 1.483 mmol) and 10% palladium on carbon (500 mg) were dissolved in methanol (5 ml), and then acetic acid (0.5 ml) was added at room temperature. The reaction solution was stirred for 3 hours at room temperature under hydrogen protection. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with methanol (10 mL), the filtrate was concentrated under pressure, and the residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain compound 22d (165 mg).
(4)将22d(800mg,3.235mmol)溶于二氯甲烷(10ml)中，在0℃下加入二乙胺基三氟化硫(625mg，3.882mmol)，于0℃下反应3h。向反应液中缓慢滴加水淬灭，二氯甲烷(10ml x 3)萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝4:1)洗脱得22e(250mg)。(4) 22d (800 mg, 3.235 mmol) was dissolved in dichloromethane (10 ml), and diethylaminosulfur trifluoride (625 mg, 3.882 mmol) was added at 0°C, and the mixture was reacted at 0°C for 3 h. Water was slowly added dropwise to the reaction solution to quench the mixture, and the mixture was extracted with dichloromethane (10 ml x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to give 22e (250 mg).
(5)将22e(250mg，1.00mmol)溶解在二氯甲烷(10mL)和甲醇(1ml)混合液中，然后在室温下滴加水合肼(68％)(100mg，2.01mmol)。反应液在室温下搅拌2小时。反应完成后过滤沉淀，滤液加入5N氨水(10ml)。用二氯甲烷萃取水相(10mL x 2)，有机相用无水硫酸钠干燥,过滤，常温减压浓缩后加入乙醇(5ml)和浓盐酸(0.5ml)，反应液呈酸性，后减压旋干后得到化合物int22(140mg)。1H NMR(400MHz,DMSO_d6)δ11.16(s,2H),4.75–4.70(m,1H),4.43(dd,J＝8.0,4.0Hz,2H),2.66–2.53(m,1H),2.30–2.21(m,2H),2.19–2.12(m,2H).(5) 22e (250 mg, 1.00 mmol) was dissolved in a mixture of dichloromethane (10 mL) and methanol (1 ml), and then hydrazine hydrate (68%) (100 mg, 2.01 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the precipitate was filtered and 5N ammonia water (10 ml) was added to the filtrate. The aqueous phase was extracted with dichloromethane (10 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure at room temperature, and then ethanol (5 ml) and concentrated hydrochloric acid (0.5 ml) were added. The reaction solution was acidic and then vacuum dried to obtain compound int22 (140 mg). 1H NMR (400MHz, DMSO_d6) δ11.16 (s, 2H), 4.75–4.70 (m, 1H), 4.43 (dd, J＝8.0, 4.0Hz, 2H), 2.66–2.53 (m, 1H), 2.30–2.21 (m, 2H), 2.19–2.12 (m, 2H).
中间体int23：
Intermediate int23:
Int23制备方法：Int23 preparation method:
(1)将23a(10.0g，71.357mmol)和23b(21.758g，142.714mmol)和碳酸氢钠(11.989g，142.714mmol)溶解在DMF(100.0mL)中，氮气保护下在100℃搅拌16h。反应结束后，反应液加水稀释，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，有机相减压浓缩，所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝2:1)洗脱得23c(4.52g)。(1) 23a (10.0 g, 71.357 mmol) and 23b (21.758 g, 142.714 mmol) and sodium bicarbonate (11.989 g, 142.714 mmol) were dissolved in DMF (100.0 mL) and stirred at 100° C. for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 2:1) to obtain 23c (4.52 g).
(2)将23c(1.0g，5.53mmol)溶解在四氢呋喃(10mL)中，反应体系降温至0℃。氮气保护下缓慢滴加LiAlH4(1.0M于THF,7.7mL,7.7mmol)。加料完毕后反应仍在0℃下搅拌1h。反应结束后，加饱和酒石酸钾钠溶液淬灭，搅拌30min。搅拌结束后混合物用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，合并有机相,减压浓缩，所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝1:0)到(石油醚:乙酸乙酯＝0:1)洗脱得23d(653mg)。(2) 23c (1.0 g, 5.53 mmol) was dissolved in tetrahydrofuran (10 mL), and the reaction system was cooled to 0°C. LiAlH4 (1.0 M in THF, 7.7 mL, 7.7 mmol) was slowly added dropwise under nitrogen protection. After the addition was completed, the reaction was still stirred at 0°C for 1 h. After the reaction was completed, saturated potassium sodium tartrate solution was added to quench and stirred for 30 min. After stirring, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography and eluted with (petroleum ether: ethyl acetate = 1:0) to (petroleum ether: ethyl acetate = 0:1) to obtain 23d (653 mg).
(3)将23d(1.2g，8.102mmol)和3b(1.586g，9.723mmol)和三苯基磷(3.187g，12.153mmol)溶解在四氢呋喃(2mL)中，反应体系降温至0℃，氮气保护下缓慢滴加DIAD(2.1mL,12.153mmol)。在室温下反应1h。反应结束后加水淬灭，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，合并有机相,减压浓缩，所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝2:1)洗脱得23e(1.4g)。(3) 23d (1.2 g, 8.102 mmol) and 3b (1.586 g, 9.723 mmol) and triphenylphosphine (3.187 g, 12.153 mmol) were dissolved in tetrahydrofuran (2 mL), the reaction system was cooled to 0°C, and DIAD (2.1 mL, 12.153 mmol) was slowly added dropwise under nitrogen protection. The reaction was allowed to react at room temperature for 1 h. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography and eluted with (petroleum ether: ethyl acetate = 2:1) to obtain 23e (1.4 g).
(4)将23e(220mg，0.750mmol)溶解在混合溶剂(DCM:MeOH＝10：1)(2ml)中，置换氮气三次后在室温下滴加水合肼(75mg,1.5mmol)，在室温下反应2h。反应结束后，将反应液过滤，然后加入水(5mL)和浓氨水(1mL)稀释，混合液用二氯甲烷萃取三次，有机相加无水硫酸钠干燥，过滤，室温浓缩除去大部分溶剂。重新加入水和二氯甲烷，再加浓盐酸调节pH＝2，二氯甲烷萃取两次，取水相冻干，即得化合物int23(41mg)。1H NMR(400MHz,DMSO_d6)δ11.14(s,3H),8.43(s,1H),7.90(s,1H)7.86(t,J＝60.0Hz,1H),5.04(s,2H).(4) 23e (220 mg, 0.750 mmol) was dissolved in a mixed solvent (DCM: MeOH = 10: 1) (2 ml), and hydrazine hydrate (75 mg, 1.5 mmol) was added dropwise at room temperature after replacing nitrogen three times. The mixture was reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was filtered, and then diluted with water (5 mL) and concentrated ammonia (1 mL). The mixed solution was extracted three times with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated at room temperature to remove most of the solvent. Water and dichloromethane were added again, and concentrated hydrochloric acid was added to adjust the pH to 2. The mixture was extracted with dichloromethane twice, and the aqueous phase was freeze-dried to obtain compound int23 (41 mg). 1 H NMR (400 MHz, DMSO_d6) δ11.14 (s, 3H), 8.43 (s, 1H), 7.90 (s, 1H) 7.86 (t, J = 60.0 Hz, 1H), 5.04 (s, 2H).
中间体int24：
Intermediate int24:
Int24制备方法：Int24 preparation method:
(1)将原料24a(10g，51.55mmol)溶解在甲苯(160mL)中，加入催化剂四(三苯基膦)钯(5.96g，5.16mmol)和化合物24b(22.34g，61.86mmol)，氮气保护下油浴加热至100℃搅拌反应4小时。反应完全后(TLC：PE/EA＝4/1)，所得反应液即为粗品化合物24c溶液直接用于下一步骤。 (1) The raw material 24a (10 g, 51.55 mmol) was dissolved in toluene (160 mL), and the catalyst tetrakis(triphenylphosphine)palladium (5.96 g, 5.16 mmol) and compound 24b (22.34 g, 61.86 mmol) were added. The mixture was heated to 100° C. in an oil bath under nitrogen protection and stirred for 4 hours. After the reaction was complete (TLC: PE/EA=4/1), the resulting reaction solution was the crude compound 24c solution, which was directly used in the next step.
(2)向化合物24c(180mL，51.55mmol)的混合溶液的反应瓶中加入盐酸水溶液(4mol/L，180mL，720mmol)，升温至60℃，并搅拌2小时。反应完成后，将反应液冷却至室温，分出有机相，水相用乙酸乙酯(100mL)萃取一次。合并有机相，并用饱和氟化钾水溶液(20mL)洗涤。过滤除去锡试剂后分出有机相，无水硫酸钠干燥有机相过滤后减压浓缩滤液，所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝9:1)洗脱得化合物24d(2.8g)。(2) Add hydrochloric acid aqueous solution (4 mol/L, 180 mL, 720 mmol) to the reaction flask of the mixed solution of compound 24c (180 mL, 51.55 mmol), heat to 60 ° C, and stir for 2 hours. After the reaction is completed, the reaction solution is cooled to room temperature, the organic phase is separated, and the aqueous phase is extracted once with ethyl acetate (100 mL). The organic phases are combined and washed with saturated potassium fluoride aqueous solution (20 mL). After filtering to remove the tin reagent, the organic phase is separated, the organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 9:1) to obtain compound 24d (2.8 g).
(3)将化合物24d(2.0g，12.73mmol)和int2(2.6g，12.73mmol)溶解在N，N-二甲基甲酰胺(40mL)中，加入N，N-二异丙基乙胺(4.9g，38.19mmol)。氮气置换3次，油浴加热至60℃搅拌1小时。反应结束后(6-LCMS)，冷却至室温后，搅拌下加水(160mL)稀释，固体析出，过滤，用水(40mL)洗滤饼。将滤饼减压旋蒸至干即得int24(3.1g)。LCMS(ESI)m/z:304.0[M+H]+.(3) Compound 24d (2.0 g, 12.73 mmol) and int2 (2.6 g, 12.73 mmol) were dissolved in N, N-dimethylformamide (40 mL), and N, N-diisopropylethylamine (4.9 g, 38.19 mmol) was added. The mixture was replaced with nitrogen three times, and the oil bath was heated to 60°C and stirred for 1 hour. After the reaction was completed (6-LCMS), the mixture was cooled to room temperature, and water (160 mL) was added to dilute the mixture under stirring. The solid precipitated, filtered, and the filter cake was washed with water (40 mL). The filter cake was evaporated to dryness under reduced pressure to obtain int24 (3.1 g). LCMS (ESI) m/z: 304.0 [M+H] + .
中间体int25：
Intermediate int25:
Int25制备方法：Int25 preparation method:
(1)将化合物25a(5.0g，24.22mmol)和化合物25b(17.50g，48.44mmol)和Pd(PPh3)4(280mg，0.24mmol)溶解在无水甲苯(100mL)中，混合物在110℃下搅拌16h。反应结束后旋干溶剂，得到25c粗品7.4g直接用于下一步反应。(1) Compound 25a (5.0 g, 24.22 mmol), compound 25b (17.50 g, 48.44 mmol) and Pd(PPh 3 ) 4 (280 mg, 0.24 mmol) were dissolved in anhydrous toluene (100 mL), and the mixture was stirred at 110° C. for 16 h. After the reaction, the solvent was dried to obtain 7.4 g of crude product 25c which was directly used in the next step.
(2)将25c(粗品7.4g)溶解在稀盐酸(2.0M，100mL)中，在60℃下搅拌2h。反应完毕后，旋干溶剂。加入饱和NaHCO3溶液至反应液pH 7～8，混合物用二氯甲烷萃取，合并有机相所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝9:1)洗脱得25d(2.7g)。(2) 25c (crude product 7.4 g) was dissolved in dilute hydrochloric acid (2.0 M, 100 mL) and stirred at 60°C for 2 h. After the reaction was completed, the solvent was dried by rotary evaporation. Saturated NaHCO 3 solution was added until the pH of the reaction solution was 7-8, and the mixture was extracted with dichloromethane. The organic phases were combined and the residue was purified by column chromatography and eluted with (petroleum ether: ethyl acetate = 9:1) to obtain 25d (2.7 g).
(3)将25d(500mg，2.95mmol)和int2(716mg，3.54mmol，)溶解在冰乙酸(15mL)中，在130℃下搅拌4h。反应结束后旋干溶剂，所得残余物用柱层析纯化，用(DCM:MeOH＝30:1)洗脱得化合物int25(350mg)。LCMS(ESI)m/z:300.1[M+H]+.(3) 25d (500 mg, 2.95 mmol) and int2 (716 mg, 3.54 mmol) were dissolved in glacial acetic acid (15 mL) and stirred at 130°C for 4 h. After the reaction, the solvent was dried and the residue was purified by column chromatography (DCM: MeOH = 30:1) to obtain compound int25 (350 mg). LCMS (ESI) m/z: 300.1 [M+H] + .
中间体int26：
Intermediate int26:
Int26制备方法：Int26 preparation method:
(1)将化合物26a(5.0g，31.45mmol，1.0eq),N,O-邻二甲基羟胺盐酸盐(4.6g，47.17mmol,1.5eq)，HATU(13.2g,34.60mmol,1.1eq)和DIEA(12.2g,94.34mmol,3.0eq)溶解在二氯甲烷(200mL)中，加料完毕后，反应液在室温下搅拌16h。反应完毕后旋干反应液中的溶剂，所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝1:1)洗脱得26b(4.1g)。(1) Compound 26a (5.0 g, 31.45 mmol, 1.0 eq), N,O-dimethylhydroxylamine hydrochloride (4.6 g, 47.17 mmol, 1.5 eq), HATU (13.2 g, 34.60 mmol, 1.1 eq) and DIEA (12.2 g, 94.34 mmol, 3.0 eq) were dissolved in dichloromethane (200 mL). After the addition was completed, the reaction solution was stirred at room temperature for 16 h. After the reaction was completed, the solvent in the reaction solution was dried, and the resulting residue was purified by column chromatography and eluted with (petroleum ether: ethyl acetate = 1:1) to obtain 26b (4.1 g).
(2)将化合物26b(4.0g，19.78mmol，1.0eq)溶解在无水四氢呋喃(40mL)中，反应体系降温至0℃。将MeMgBr(3.0M in THF)(6.6mL，19.78mmol，1.0eq)缓慢滴加到反应液中，滴加完毕后保持0℃搅拌2h。反应完毕后在冰浴条件下向反应液中加入饱和氯化铵溶液，加入乙酸乙酯和水萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝5:1)洗脱得化合物26c(2.5g)。(2) Compound 26b (4.0 g, 19.78 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (40 mL), and the reaction system was cooled to 0°C. MeMgBr (3.0 M in THF) (6.6 mL, 19.78 mmol, 1.0 eq) was slowly added dropwise to the reaction solution, and after the addition was complete, the mixture was stirred at 0°C for 2 h. After the reaction was completed, a saturated ammonium chloride solution was added to the reaction solution under ice bath conditions, and ethyl acetate and water were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography and eluted with (petroleum ether:ethyl acetate = 5:1) to obtain compound 26c (2.5 g).
(3)将26c(500mg，3.18mmol，1eq)，int2(1.0g，4.78mmol，1.5eq)，DIEA(823mg，9.55mmol，3.0eq)溶解在DMSO(20mL)中，反应液在60℃下搅拌30min。反应结束后，加入乙酸乙酯和水萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩所得残余物用柱层析纯化所得(PE/EA＝4/1)纯化得化合物int25(770mg)。LCMS(ESI)m/z:304.1[M+H]+.(3) 26c (500 mg, 3.18 mmol, 1 eq), int2 (1.0 g, 4.78 mmol, 1.5 eq), and DIEA (823 mg, 9.55 mmol, 3.0 eq) were dissolved in DMSO (20 mL), and the reaction solution was stirred at 60°C for 30 min. After the reaction was completed, ethyl acetate and water were added for extraction, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA=4/1) to obtain compound int25 (770 mg). LCMS (ESI) m/z: 304.1 [M+H] + .
中间体int44：
Intermediate int44:
Int44制备方法：Int44 preparation method:
将原料44a(28.2g，256mmol)溶解在乙腈(130mL)和水(130mL)中，加入三氯化铬(13.6g，51.2mmol)，然后80℃搅拌24小时。反应完全后，减压浓缩出大部分乙腈，用二氯甲烷(200mL)溶解残余物，食盐水洗，无水硫酸钠干燥并过滤，将滤液减压浓缩，所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝3:1)洗脱得化合物44b(8g)。将化合物44b(8g，62.5mmol)溶解在二氯甲烷(80mL)中，加入吡啶(14.8g，187mmol)，冰水浴下加入苯甲酰氯(17.56g，125mmol)，加完后室温下搅拌2小时。反应完成后加水淬灭，二氯甲烷(100mL)萃取水相两次，合并有机相，无水硫酸钠干燥过滤，减压浓缩滤液。所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝5:1)洗脱得44c(11g)。将化合物44c(11g，47.4mmol)溶解在超干1，2-二氯乙烷(60mL)中，加入双(2-甲氧基乙基)氨基三氟化硫(BAST，30mL)，氮气保护下50℃搅拌过夜(16小时)。反应结束后，冰水浴搅拌下，将反应液滴加到碳酸氢钠水溶液中。滴完后室温搅拌0.5小时至无气泡冒出，分出有机相，二氯甲烷(80mL)萃取水相两次，合并有机相，无水硫酸钠干燥过滤，减压浓缩滤液。所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝15:1)洗脱得化合物44d(7.8g)。将44d(7.8g，30.7mmol)溶解在甲醇(80mL)和水(20mL)中，加入LiOH(13g，309.5mmol)，室温搅拌过夜(16小时)。反应完成后，加入水和大量二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得粗品44e(4g)。于三口反应瓶中将3b(4.78g，29.3mmol)溶解在超干四氢呋喃(120mL)，氮气置换三次，将反应瓶移至冰水浴中搅拌。将粗品44e(4g，26.6mmol)溶解在超干四氢呋喃(20mL)中，滴入反应液中。然后依次滴加三苯基膦(7.71g，29.3mmol)，偶氮二甲酸二叔丁酯(DBAD，6.75g，29.3mmol)的超干四氢呋喃(14mL)溶液，滴加完成后，将反应液自然升温至室温并搅拌过夜(12小时)。反应结束后加水(100mL)淬灭，搅拌20分钟分出有机相，用二氯甲烷(200mL)萃取水相3次，合并有机相干燥过滤减压浓缩。所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝5:1)洗脱得化44f(2.1g)。将44f(450mg，1.53mmol)溶解在二氯甲烷(10mL)和无水甲醇(1mL)的混合溶剂中，氮气保护下冰水浴降温至0℃，滴加水合肼(98％，153mg，3.05mmol)，滴完后自然升至室温反应2小时。过滤反应液，二氯甲烷(5mL)洗滤饼两次，将稀盐酸(1mol/L，15mL)加入滤液中搅拌0.5小时，分出水相，冻干得化合物int44(280mg，63.97％)。1H NMR(400MHz,DMSO_d6)δ10.91(br.s,2H),4.33–4.27(m,1H),2.62–2.54(m,1H),2.45–2.30(m,1H),2.13–1.91(m,3H),1.77–1.68(m,2H),1.57–1.48(m,3H).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. The obtained residue was purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 3:1) to obtain compound 44b (8 g). Compound 44b (8 g, 62.5 mmol) was dissolved in dichloromethane (80 mL), pyridine (14.8 g, 187 mmol) was added, and benzoyl chloride (17.56 g, 125 mmol) was added under an ice-water bath, and stirred at room temperature for 2 hours after the addition was complete. After the reaction is completed, water is added to quench, the aqueous phase is extracted twice with dichloromethane (100mL), the organic phases are combined, dried and filtered over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 5:1) to obtain 44c (11g). Compound 44c (11g, 47.4mmol) is dissolved in ultra-dry 1,2-dichloroethane (60mL), bis(2-methoxyethyl)aminosulfur trifluoride (BAST, 30mL) is added, and stirred at 50°C overnight (16 hours) under nitrogen protection. After the reaction is completed, the reaction solution is added dropwise to a sodium bicarbonate aqueous solution under stirring in an ice-water bath. After the dripping is completed, the mixture is stirred at room temperature for 0.5 hours until no bubbles emerge, the organic phase is separated, the aqueous phase is extracted twice with dichloromethane (80mL), the organic phases are combined, dried and filtered over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 15: 1) to obtain compound 44d (7.8 g). 44d (7.8 g, 30.7 mmol) was dissolved in methanol (80 mL) and water (20 mL), LiOH (13 g, 309.5 mmol) was added, and the mixture was stirred at room temperature overnight (16 hours). After the reaction was completed, water and a large amount of dichloromethane were added to extract, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product 44e (4 g). 3b (4.78 g, 29.3 mmol) was dissolved in ultra-dry tetrahydrofuran (120 mL) in a three-mouth reaction bottle, nitrogen was replaced three times, and the reaction bottle was moved to an ice-water bath and stirred. The crude product 44e (4 g, 26.6 mmol) was dissolved in ultra-dry tetrahydrofuran (20 mL) and dropped into the reaction solution. Then triphenylphosphine (7.71 g, 29.3 mmol), di-tert-butyl azodicarboxylate (DBAD, 6.75 g, 29.3 mmol) in ultra-dry tetrahydrofuran (14 mL) solution were added dropwise in sequence. After the addition was completed, the reaction solution was naturally warmed to room temperature and stirred overnight (12 hours). After the reaction was completed, water (100 mL) was added to quench, stirred for 20 minutes, and the organic phase was separated. The aqueous phase was extracted 3 times with dichloromethane (200 mL), and the organic phases were combined, dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 5:1) to obtain chemical 44f (2.1 g). 44f (450 mg, 1.53 mmol) was dissolved in a mixed solvent of dichloromethane (10 mL) and anhydrous methanol (1 mL), cooled to 0°C in an ice-water bath under nitrogen protection, and hydrazine hydrate (98%, 153 mg, 3.05 mmol) was added dropwise. After the addition, the temperature was naturally raised to room temperature and reacted for 2 hours. The reaction solution was filtered, and the filter cake was washed twice with dichloromethane (5 mL). Dilute hydrochloric acid (1 mol/L, 15 mL) was added to the filtrate and stirred for 0.5 hours. The aqueous phase was separated and lyophilized to obtain compound int44 (280 mg, 63.97%). 1 H NMR (400 MHz, DMSO_d6) δ10.91 (br.s, 2H), 4.33–4.27 (m, 1H), 2.62–2.54 (m, 1H), 2.45–2.30 (m, 1H), 2.13–1.91 (m, 3H), 1.77–1.68 (m, 2H), 1.57–1.48 (m, 3H).
中间体int27
Intermediate int27
Int27制备方法：Int27 preparation method:
(1)将化合物27a(6g，19.4mmol)、Zn(CN)2(2.73g，23.2mmol)和t-Buxphos Pd G3(307mg，0.39mmol)溶解在THF(50mL)和水(10mL)中。在70℃下搅拌16h。将反应液冷却至室温，加乙酸乙酯(50mL)稀释，再加水(50mL)，用乙酸乙酯萃取(50mL x 3)，合并有机相，用水洗涤2次，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶柱层析纯化，用(乙酸乙酯:石油醚＝1:1)洗脱得化合物27b(2.5g，收率：50.1％)。LCMS(ESI)m/z:258.2[M+H]+.(1) Compound 27a (6 g, 19.4 mmol), Zn(CN) 2 (2.73 g, 23.2 mmol) and t-Buxphos Pd G 3 (307 mg, 0.39 mmol) were dissolved in THF (50 mL) and water (10 mL). The mixture was stirred at 70°C for 16 h. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), and then water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with water twice, dried with sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography and eluted with (ethyl acetate: petroleum ether = 1:1) to obtain compound 27b (2.5 g, yield: 50.1%). LCMS (ESI) m/z: 258.2 [M+H] + .
(2)将化合物27b(2.5g，9.69mmol)溶解在氯化氢/1,4-二氧六环溶液(4M,30mL)中，反应液在室温下搅拌16h。反应结束后减压浓缩得化合物27c(1.5g)。LCMS(ESI)m/z:158.2[M+H]+.(2) Compound 27b (2.5 g, 9.69 mmol) was dissolved in hydrogen chloride/1,4-dioxane solution (4 M, 30 mL), and the reaction solution was stirred at room temperature for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain compound 27c (1.5 g). LCMS (ESI) m/z: 158.2 [M+H] + .
(3)将化合物27c(1g，5.2mmol)、1-(6-氯吡啶-3-基)乙烷-1-酮(800mg，5.2mmol)、对甲苯磺酸(200mg，1.04mmol)溶解在DMF(8mL)中。混合液在氮气保护下60℃搅拌2h，反 应结束后加水(15mL)和乙酸乙酯(15mL)稀释，用乙酸乙酯萃取(15mL x 3)三次，合并有机相，用饱和食盐水洗涤两次，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶柱层析纯化，用(乙酸乙酯:石油醚＝1:1)洗脱得int27(250mg)。LCMS(ESI)m/z:277.2[M+H]+.(3) Compound 27c (1 g, 5.2 mmol), 1-(6-chloropyridin-3-yl)ethan-1-one (800 mg, 5.2 mmol), and p-toluenesulfonic acid (200 mg, 1.04 mmol) were dissolved in DMF (8 mL). The mixture was stirred at 60° C. for 2 h under nitrogen protection. After the reaction was completed, water (15 mL) and ethyl acetate (15 mL) were added to dilute, and ethyl acetate (15 mL x 3) was extracted three times. The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography, and int27 (250 mg) was obtained by elution with (ethyl acetate: petroleum ether = 1:1). LCMS (ESI) m/z: 277.2 [M + H] + .
中间体int28
Intermediate int28
Int28制备方法：Int28 preparation method:
(1)将化合物28a(1.0g，6.66mmol)溶解在四氢呋喃(10.0mL)中，然后加入化合物3b(1.30g，7.99mmol)和三苯基膦(2.62g，9.99mmol)。氮气置换三次，将反应体系温度降低至0℃，滴加偶氮二羧酸二异丙酯(2.0mL，9.99mmol)，滴加完毕后，反应液在室温下搅拌6h。反应结束后，加水淬灭，混合物用乙酸乙酯(10.0mL x 3)萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，合并有机相减压浓缩，所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝4:1)洗脱得化合物28b(1.127g)。(1) Compound 28a (1.0 g, 6.66 mmol) was dissolved in tetrahydrofuran (10.0 mL), and then compound 3b (1.30 g, 7.99 mmol) and triphenylphosphine (2.62 g, 9.99 mmol) were added. The reaction system temperature was lowered to 0°C after nitrogen replacement three times, and diisopropyl azodicarboxylate (2.0 mL, 9.99 mmol) was added dropwise. After the addition was complete, the reaction solution was stirred at room temperature for 6 h. After the reaction was completed, water was added to quench, and the mixture was extracted with ethyl acetate (10.0 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography and eluted with (petroleum ether: ethyl acetate = 4:1) to obtain compound 28b (1.127 g).
(2)将28b(1.0g，3.816mmol)溶解在二氯甲烷(10ml)和甲醇(10ml)的混合溶剂中，氮气置换三次后，在室温下滴加水合肼(382mg,7.633mmol)，反应液在室温下反应2h。反应结束后过滤反应液，然后滤液中加入浓氨水(1ml)和水(10ml)，用二氯甲烷萃取萃取，有机相加无水硫酸钠干燥，过滤。滤液中加入水(20ml)再加浓盐酸调节pH值至酸性，水相用二氯甲烷萃取，取水相冻干，即得int28(1.0g)。1H NMR(400MHz,DMSO_d6)δ3.93(d,J＝6.4Hz,2H),2.02–2.00(m,2H),1.88–1.73(m,4H),1.27–1.18(m,2H).(2) 28b (1.0 g, 3.816 mmol) was dissolved in a mixed solvent of dichloromethane (10 ml) and methanol (10 ml). After nitrogen replacement three times, hydrazine hydrate (382 mg, 7.633 mmol) was added dropwise at room temperature, and the reaction solution was reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was filtered, and then concentrated ammonia (1 ml) and water (10 ml) were added to the filtrate, extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate and filtered. Water (20 ml) was added to the filtrate, and concentrated hydrochloric acid was added to adjust the pH value to acidic. The aqueous phase was extracted with dichloromethane, and the aqueous phase was lyophilized to obtain int28 (1.0 g). 1 H NMR (400 MHz, DMSO_d6) δ 3.93 (d, J = 6.4 Hz, 2H), 2.02–2.00 (m, 2H), 1.88–1.73 (m, 4H), 1.27–1.18 (m, 2H).
中间体int29
Intermediate int29
Int29制备方法：Int29 preparation method:
(1)将化合物29a(15.0g，98.50mmol)溶解在超干二氯甲烷(380mL)中，然后在0℃下加入m-CPBA(51.0g，295.50mmol)。反应液在常温下搅拌16小时。反应结束后，反应液用二氯甲烷和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(DCM:MeOH＝10:1)洗脱得化合物29b(9.0g，收率：54.3％)。LCMS(ESI)m/z:169.1[M+H]+.(1) Compound 29a (15.0 g, 98.50 mmol) was dissolved in ultra-dry dichloromethane (380 mL), and then m-CPBA (51.0 g, 295.50 mmol) was added at 0°C. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was washed with dichloromethane and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (DCM:MeOH=10:1) to obtain compound 29b (9.0 g, yield: 54.3%). LCMS (ESI) m/z: 169.1 [M+H] + .
(2)将29b(8.0g，47.46mmol)溶解在醋酸酐(100mL)中，反应液在150℃下搅拌16小时。反应完成后，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝10:1)洗脱得29c(5.8g，收率：48.3％)。LCMS(ESI)m/z:253.1[M+H]+.(2) 29b (8.0 g, 47.46 mmol) was dissolved in acetic anhydride (100 mL), and the reaction solution was stirred at 150°C for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with (PE:EA=10:1) to obtain 29c (5.8 g, yield: 48.3%). LCMS (ESI) m/z: 253.1 [M+H] + .
(3)将29c(5.8g，22.96mmol)和碳酸钾(9.5g,68.88mmol)溶解在甲醇(100mL)和水(20mL)中，反应液在80℃搅拌4小时。反应结束后，反应液减压浓缩，所得残余物用硅胶柱层析纯化，用(DCM:MeOH＝15:1)洗脱得29d(2.4g，收率：62.1％)。LCMS(ESI)m/z:169.1[M+H]+.(3) 29c (5.8 g, 22.96 mmol) and potassium carbonate (9.5 g, 68.88 mmol) were dissolved in methanol (100 mL) and water (20 mL), and the reaction solution was stirred at 80°C for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with (DCM:MeOH=15:1) to obtain 29d (2.4 g, yield: 62.1%). LCMS (ESI) m/z: 169.1 [M+H] + .
(4)将29d(1.0g，5.93mmol)溶解在超干四氢呋喃(100mL)中，然后加入三甲基硅重氮甲烷(4.5mL，8.90mmol)。混合液在氮气保护下50℃搅拌过夜。监测未反应完全后，需补加两次三甲基硅重氮甲烷(4.5mL，8.90mmol)，并氮气保护下50℃再搅拌2天。反应结束后，反应液用饱和食盐水稀释，用二氯甲烷萃取三次(20mL x 3)，有机相用无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝4:1)洗脱得29e(570mg，收率：52.8％)。LCMS(ESI)m/z:183.1[M+H]+.(4) 29d (1.0 g, 5.93 mmol) was dissolved in ultra-dry tetrahydrofuran (100 mL), and then trimethylsilyldiazomethane (4.5 mL, 8.90 mmol) was added. The mixture was stirred at 50°C overnight under nitrogen protection. After monitoring that the reaction was not complete, trimethylsilyldiazomethane (4.5 mL, 8.90 mmol) was added twice, and the mixture was stirred at 50°C for another 2 days under nitrogen protection. After the reaction was completed, the reaction solution was diluted with saturated brine, extracted with dichloromethane three times (20 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain 29e (570 mg, yield: 52.8%). LCMS (ESI) m/z: 183.1 [M+H] + .
(5)将29e(470mg，2.57mmol)溶解在超干DMF(5mL)中，然后在0℃下加入TFAA(0.4mL，2.72mmol)。混合液在氮气保护下室温搅拌16小时。反应结束后，反应液加水淬灭，析出棕色固体，过滤，所得残余物为29f(1.7g，粗品)。(5) 29e (470 mg, 2.57 mmol) was dissolved in ultra-dry DMF (5 mL), and then TFAA (0.4 mL, 2.72 mmol) was added at 0°C. The mixture was stirred at room temperature for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was quenched with water, and a brown solid was precipitated. The residue was filtered to obtain 29f (1.7 g, crude product).
(6)将29f(1.7g，crude)溶解在20％NaOH(10mL)中。混合液在氮气保护下100℃搅拌16小时。反应结束后，反应液加入浓盐酸调节PH＝3，析出棕褐色固体，过滤、真空干燥后得到29g (380mg)。LCMS(ESI)m/z:225.0[M-H]+.(6) 29f (1.7 g, crude) was dissolved in 20% NaOH (10 mL). The mixture was stirred at 100°C for 16 hours under nitrogen protection. After the reaction was completed, concentrated hydrochloric acid was added to the reaction solution to adjust the pH to 3, and a brown solid was precipitated. After filtration and vacuum drying, 29g (380 mg). LCMS (ESI) m/z: 225.0 [MH] + .
(7)将29g(380mg，1.68mmol)溶解在超干四氢呋喃(5mL)中，然后加入DPPA(0.7mL，3.36mmol)和三乙胺(0.7mL，5.04mmol)。混合液在氮气保护下室温搅拌16小时。反应结束后，反应液减压浓缩，加入甲醇，析出棕色固体，过滤、旋干后所得残余物为29h(420mg，粗品)。LCMS(ESI)m/z:249.9[M-H]+.(7) 29g (380mg, 1.68mmol) was dissolved in ultra-dry tetrahydrofuran (5mL), and then DPPA (0.7mL, 3.36mmol) and triethylamine (0.7mL, 5.04mmol) were added. The mixture was stirred at room temperature for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, methanol was added, and a brown solid was precipitated. The residue obtained after filtration and spin drying was 29h (420mg, crude product). LCMS (ESI) m/z: 249.9 [MH] + .
将29h(420mg，crude)溶解在叔丁醇(5mL)中。混合液在氮气保护下80℃搅拌16小时。反应结束后，反应液减压浓缩，旋干所得残余物用硅胶柱层析纯化，用(PE:EA＝4:1)洗脱得29i(190mg)。LCMS(ESI)m/z:298.1[M+H]+，1H NMR(400MHz,DMSO_d6)δ11.26(s,1H),9.28(s,1H),8.27(s,1H),7.26(s,1H),3.93(s,3H),1.48(s,9H).29h (420 mg, crude) was dissolved in tert-butanol (5 mL). The mixture was stirred at 80 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain 29i (190 mg). LCMS (ESI) m/z: 298.1 [M+H] + , 1 H NMR (400 MHz, DMSO_d6) δ 11.26 (s, 1H), 9.28 (s, 1H), 8.27 (s, 1H), 7.26 (s, 1H), 3.93 (s, 3H), 1.48 (s, 9H).
(8)将29i(190mg，0.64mmol)溶解4M盐酸二氧六环(4mL)中。混合液在室温下搅拌16小时。反应结束后，反应液减压浓缩，旋干所得残余物为int29(150mg)。LCMS(ESI)m/z:198.1[M+H]+.(8) 29i (190 mg, 0.64 mmol) was dissolved in 4 M hydrochloric acid dioxane (4 mL). The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and the residue obtained by spin drying was int29 (150 mg). LCMS (ESI) m/z: 198.1 [M+H] + .
中间体int30
Intermediate int30
Int30制备方法：Int30 preparation method:
(1)将30a(1.0g，4.80mmol)、DMAP(59mg，0.48mmol)和TEA(1.3mL，9.60mmol)溶解在超干DMF(10mL)中，然后在0℃下加入(Boc)2O(3.1g，14.40mmol)。反应液自然升温至室温，并搅拌16小时。反应结束后，反应液加水(30mL)稀释，用乙酸乙酯萃取(20mL x 3)，有机相用饱和食盐水(30mL x 2)洗涤,无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝10:1)洗脱得30b(1.6g)。LCMS(ESI):m/z＝471.0[M+64]+ (1) 30a (1.0 g, 4.80 mmol), DMAP (59 mg, 0.48 mmol) and TEA (1.3 mL, 9.60 mmol) were dissolved in ultra-dry DMF (10 mL), and then (Boc) 2 O (3.1 g, 14.40 mmol) was added at 0°C. The reaction solution was naturally warmed to room temperature and stirred for 16 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (20 mL x 3), and the organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=10:1) to obtain 30b (1.6 g). LCMS (ESI): m/z=471.0 [M+64] +
(2)将30b(1.6g，3.92mmol)、30c(1.7g，4.70mmol)和Pd(PPh3)4(453mg，0.39mmol)溶解在超干甲苯(16mL)中，氮气保护下80℃搅拌16小时。反应结束后，得30d，可直接用于下一步反应。(2) 30b (1.6 g, 3.92 mmol), 30c (1.7 g, 4.70 mmol) and Pd(PPh 3 ) 4 (453 mg, 0.39 mmol) were dissolved in ultra-dry toluene (16 mL) and stirred at 80° C. for 16 hours under nitrogen protection. After the reaction, 30d was obtained, which was directly used in the next reaction.
(3)在上一步中所得反应液中加入4M HCl(20.0mL)，室温下搅拌16小时。反应结束后，反应液加水(30mL)稀释，用乙酸乙酯萃取(20mL x 3)，有机相用饱和食盐水(30mL x 2)洗涤,无水硫酸钠干燥，过滤，减压浓缩,所得残余物用硅胶柱层析纯化，用(PE:EA＝4:1)洗脱得30e(1.2g)。LCMS(ESI):m/z＝435.1[M+64]+ (3) 4M HCl (20.0 mL) was added to the reaction solution obtained in the previous step and stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain 30e (1.2 g). LCMS (ESI): m/z=435.1[M+64] +
(4)将30e(1.0g，2.69mmol)溶解在2M HCl/EA(15.0mL)中，室温下搅拌16小时。反应结束后，反应液减压浓缩得到30f(500mg)。LCMS(ESI):m/z＝172.1[M+1]+ (4) 30e (1.0 g, 2.69 mmol) was dissolved in 2M HCl/EA (15.0 mL) and stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 30f (500 mg). LCMS (ESI): m/z = 172.1 [M+1] +
(5)将30f(500mg，2.91mmol)、30g(1.7g，8.73mmol)溶解在乙醇(12mL)中，加入氢溴酸水溶液(48％)(1.3mL)。混合液在氮气保护下80℃搅拌16小时。反应结束后，减压浓缩得到30h(500mg，粗品)。LCMS(ESI):m/z＝178.1[M+1]+ (5) 30f (500 mg, 2.91 mmol) and 30g (1.7 g, 8.73 mmol) were dissolved in ethanol (12 mL), and aqueous hydrobromic acid solution (48%) (1.3 mL) was added. The mixture was stirred at 80 °C for 16 hours under nitrogen protection. After the reaction was completed, 30h (500 mg, crude product) was obtained by concentration under reduced pressure. LCMS (ESI): m/z = 178.1 [M+1] +
(6)将30h(500mg，crude)溶解在三氯氧磷(10mL)中。混合液在氮气保护下120℃搅拌16小时。反应结束后，减压浓缩。浓缩物加水(10mL)稀释，用乙酸乙酯萃取(10mL x 3)，有机相用饱和食盐水(10mL x 2)洗涤,无水硫酸钠干燥，过滤，减压浓缩得到化合物int30(200mg)。LCMS(ESI):m/z＝196.0[M+1]+ (6) 30h (500 mg, crude) was dissolved in phosphorus oxychloride (10 mL). The mixture was stirred at 120°C for 16 hours under nitrogen protection. After the reaction was completed, it was concentrated under reduced pressure. The concentrate was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), and the organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound int30 (200 mg). LCMS (ESI): m/z = 196.0 [M+1] +
中间体int31
Intermediate int31
Int31的制备方法Preparation method of Int31
(1)将化合物31a(1g，9.1mmol)化合物3b(1.8g，11mmol)和三苯基膦(2.6g，10mmol)溶解在超干四氢呋喃(10mL)中，然后在0℃下加入偶氮二甲酸二叔丁酯(2.3g，10mmol)。反应液自然升温至室温并搅拌4小时。反应结束后，反应液用饱和食盐水稀释，用二氯甲烷萃取三次(20mL x 3)无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝1:1)洗脱得混合物31b(2g)。1H NMR(400MHz,DMSO_d6)δ8.52(dd,J＝4.0，1.2Hz,1H),7.90–7.88(m,1H),7.86(s,4H),7.70(d,J＝8.0Hz,1H),7.41-7.38(m,1H),5.24(s,2H).(1) Compound 31a (1 g, 9.1 mmol), compound 3b (1.8 g, 11 mmol) and triphenylphosphine (2.6 g, 10 mmol) were dissolved in ultra-dry tetrahydrofuran (10 mL), and di-tert-butyl azodicarboxylate (2.3 g, 10 mmol) was then added at 0°C. The reaction solution was naturally warmed to room temperature and stirred for 4 hours. After the reaction was completed, the reaction solution was diluted with saturated brine, extracted with dichloromethane three times (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=1:1) to obtain a mixture 31b (2 g). 1 H NMR (400 MHz, DMSO_d6) δ 8.52 (dd, J = 4.0, 1.2 Hz, 1H), 7.90–7.88 (m, 1H), 7.86 (s, 4H), 7.70 (d, J = 8.0 Hz, 1H), 7.41-7.38 (m, 1H), 5.24 (s, 2H).
(2)将化合物31b(1g，3.9mmol)溶解在二氯甲烷(10mL)和甲醇(1ml)混合液中，然后在室温下滴加水合肼(68％)(394mg，7.9mmol)。反应液在室温下搅拌2小时。反应完成后过滤沉淀，用5N氨水(50ml)冲洗滤液。用二氯甲烷萃取水相两次，有机相用无水硫酸钠干燥,过滤，常温减压浓缩后加入乙醇(10ml)和浓盐酸(1ml)，反应液呈酸性，再次加入纯净水(100ml)，用二氯甲烷(50ml)萃取2次，水相冻干后得到化合物int31(350mg)。1H NMR(400MHz,DMSO_d6)δ8.78(d,J＝4.0Hz,1H),8.28(t,J＝8.0Hz,1H),7.84(d,J＝8.0Hz,1H),7.78–7.75(m,1H),5.37(s,2H).(2) Compound 31b (1 g, 3.9 mmol) was dissolved in a mixture of dichloromethane (10 mL) and methanol (1 ml), and then hydrazine hydrate (68%) (394 mg, 7.9 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the precipitate was filtered and the filtrate was rinsed with 5N ammonia water (50 ml). The aqueous phase was extracted twice with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure at room temperature, and then ethanol (10 ml) and concentrated hydrochloric acid (1 ml) were added. The reaction solution was acidic, and purified water (100 ml) was added again. It was extracted twice with dichloromethane (50 ml), and the aqueous phase was freeze-dried to obtain compound int31 (350 mg). 1 H NMR (400 MHz, DMSO_d6) δ 8.78 (d, J = 4.0 Hz, 1H), 8.28 (t, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.78–7.75 (m, 1H), 5.37 (s, 2H).
中间体int32
Intermediate int32
Int32的制备方法Preparation method of Int32
(1)将化合物32a(5g，49.4mmol)，化合物32b(10.6g，49.4mmol)和碳酸铯(32g，98.9mmol)溶解在超干乙腈(50mL)中。反应液在90℃下搅拌4小时。TLC判断反应结束，反应结束后，反应液过滤，滤饼用二氯甲烷洗涤。滤液加水后，用二氯甲烷萃取三次(50mL x 3),有机相减压浓缩得混合物32c(4g)。(1) Compound 32a (5 g, 49.4 mmol), compound 32b (10.6 g, 49.4 mmol) and cesium carbonate (32 g, 98.9 mmol) were dissolved in ultra-dry acetonitrile (50 mL). The reaction solution was stirred at 90°C for 4 hours. TLC determined that the reaction was complete. After the reaction was complete, the reaction solution was filtered and the filter cake was washed with dichloromethane. After adding water to the filtrate, it was extracted with dichloromethane three times (50 mL x 3), and the organic phase was concentrated under reduced pressure to obtain a mixture 32c (4 g).
(2)将32c(4g，24.2mmol)、3b(4.35g，26.6mmol)和三苯基膦(7g，26.6mmol)溶解在超干四氢呋喃(40mL)中，然后在0℃下加入偶氮二甲酸二叔丁酯(6.1g，26.6mmol)。反应液在0℃下搅拌至常温4小时。反应结束后，反应液加水稀释(100mL)，用二氯甲烷萃取三次(100mL x 3)，有机相减压浓缩所得残余物用硅胶柱层析纯化，用(PE:EA＝1:1)洗脱得混合物32d(2.5g)。1H NMR(400MHz,DMSO_d6)δ7.87–7.84(m,4H),6.28–5.95(m,1H),4.35–4.16(m,1H),2.93–2.64(m,4H),2.38–2.36(m,2H),1.98–1.88(m,2H),1.75–1.64(m,2H).(2) 32c (4 g, 24.2 mmol), 3b (4.35 g, 26.6 mmol) and triphenylphosphine (7 g, 26.6 mmol) were dissolved in ultra-dry tetrahydrofuran (40 mL), and then di-tert-butyl azodicarboxylate (6.1 g, 26.6 mmol) was added at 0°C. The reaction solution was stirred at 0°C until it reached room temperature for 4 hours. After the reaction was completed, the reaction solution was diluted with water (100 mL), extracted with dichloromethane three times (100 mL x 3), and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=1:1) to obtain a mixture 32d (2.5 g). 1 H NMR (400 MHz, DMSO_d6) δ7.87–7.84 (m, 4H), 6.28–5.95 (m, 1H), 4.35–4.16 (m, 1H), 2.93–2.64 (m, 4H), 2.38–2.36 (m, 2H), 1.98–1.88 (m, 2H), 1.75–1.64 (m, 2H).
(3)将32d(2g，3.9mmol)溶解在二氯甲烷(20mL)和甲醇(2ml)混合液中，然后在室温下滴加水合肼(68％)(618mg，12.33mmol)。反应液在室温下搅拌2小时。反应完成后过滤沉淀，用5N氨水(50ml)冲洗滤液。用二氯甲烷萃取水相两次，萃取结束有机相用无水硫酸钠干燥。干燥后常温减压浓缩后加入乙醇(10ml)和浓盐酸(1ml)，反应液呈酸性，再次用纯净水(100ml)和二氯甲烷(100ml)萃取2次，水相冻干后得到int32(300mg)。(3) 32d (2 g, 3.9 mmol) was dissolved in a mixture of dichloromethane (20 mL) and methanol (2 ml), and then hydrazine hydrate (68%) (618 mg, 12.33 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the precipitate was filtered and the filtrate was rinsed with 5N ammonia water (50 ml). The aqueous phase was extracted twice with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate after the extraction. After drying, ethanol (10 ml) and concentrated hydrochloric acid (1 ml) were added after concentration under reduced pressure at room temperature. The 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 int32 (300 mg).
中间体int33
Intermediate int33
Int33的制备方法Preparation method of Int33
(1)将化合物33a(2.3g，22.66mmol)、33b(4g，20.6mmol)和碳酸铯(13.4g，41.2mmol)溶解在超干乙腈(30mL)中。反应液在90℃下搅拌至常温4小时。TLC判断反应结束，反应结束后，将反应液过滤，滤饼用二氯甲烷洗涤。滤液加水后，用二氯甲烷萃取三次(50mL x 3)无水硫酸钠干燥，减压浓缩得粗品33c(800mg)。(1) Compound 33a (2.3 g, 22.66 mmol), 33b (4 g, 20.6 mmol) and cesium carbonate (13.4 g, 41.2 mmol) were dissolved in ultra-dry acetonitrile (30 mL). The reaction solution was stirred at 90°C until it reached room temperature for 4 hours. TLC determined that the reaction was complete. After the reaction was complete, the reaction solution was filtered and the filter cake was washed with dichloromethane. After adding water to the filtrate, it was extracted with dichloromethane three times (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product 33c (800 mg).
(2)将33c(500mg，3.44mmol)、3b(618mg，3.79mmol)和三苯基膦(994mg，3.79mmol)溶解在超干四氢呋喃(5mL)中，然后在0℃下加入偶氮二甲酸二叔丁酯(873mg，3.79mmol)。反应液在0℃下搅拌至常温4小时。点板判断反应结束，反应结束后，将反应液过滤，滤饼用二氯甲烷洗涤。滤液加水后，用二氯甲烷萃取三次(50mL x 3)无水硫酸钠干燥，得粗品33d(2g)。 (2) 33c (500 mg, 3.44 mmol), 3b (618 mg, 3.79 mmol) and triphenylphosphine (994 mg, 3.79 mmol) were dissolved in ultra-dry tetrahydrofuran (5 mL), and then di-tert-butyl azodicarboxylate (873 mg, 3.79 mmol) was added at 0°C. The reaction solution was stirred at 0°C until it reached room temperature for 4 hours. The reaction was judged to be complete by dotting the plate. After the reaction was complete, the reaction solution was filtered and the filter cake was washed with dichloromethane. After adding water to the filtrate, it was extracted with dichloromethane three times (50 mL x 3) and dried over anhydrous sodium sulfate to obtain a crude product 33d (2 g).
(3)将粗品33d(2g)溶解在二氯甲烷(10mL)和甲醇(1ml)混合液中，然后在室温下滴加水合肼(68％)(375mg，6.16mmol)。反应液在室温下搅拌2小时。反应完成后过滤沉淀，用5N氨水(50ml)冲洗滤液。用二氯甲烷萃取水相两次，萃取结束有机相用无水硫酸钠干燥。干燥后常温减压浓缩后加入乙醇(10ml)和浓盐酸(1ml)，反应液呈酸性，再次用纯净水(100ml)和二氯甲烷(100ml)萃取2次，水相冻干后得到int33(600mg)。LCMS(ESI)m/z:163.2[M+H]+.(3) The crude product 33d (2 g) was dissolved in a mixture of dichloromethane (10 mL) and methanol (1 ml), and then hydrazine hydrate (68%) (375 mg, 6.16 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the precipitate was filtered and the filtrate was rinsed with 5N ammonia water (50 ml). The aqueous phase was extracted twice with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate after extraction. After drying, ethanol (10 ml) and concentrated hydrochloric acid (1 ml) were added after concentration under reduced pressure at room temperature. The 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). LCMS (ESI) m/z: 163.2 [M+H] + .
中间体int34
Intermediate int34
Int34的制备方法Preparation method of Int34
(1)将原料34a(800mg，3.58mmol)溶解在甲苯(12mL)中，加入四(三苯基膦)钯(413mg，0.358mmol)和34b(1.55g，4.3mmol)，氮气保护下油浴加热至80℃搅拌反应16小时。反应完全后(TLC显示无原料)，所得反应液即为粗品34c溶液直接用于下一步骤。(1) The raw material 34a (800 mg, 3.58 mmol) was dissolved in toluene (12 mL), and tetrakis(triphenylphosphine)palladium (413 mg, 0.358 mmol) and 34b (1.55 g, 4.3 mmol) were added. The mixture was heated to 80°C in an oil bath under nitrogen protection and stirred for 16 hours. After the reaction was complete (TLC showed no raw material), the resulting reaction solution was the crude product 34c solution, which was directly used in the next step.
(2)盛有34c的混合溶液的反应瓶中加入盐酸水溶液(4mol/L，10mL，40mmol)，反应液在60℃下搅拌2小时。反应完成后冷却至室温，分出有机相，水相用二氯甲烷(50mL)萃取一次。合并有机相，无水硫酸钠干燥有机相过滤后减压浓缩滤液，所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝9:1)洗脱得int34(300mg)。LCMS(ESI)m/z:187.0[M+H]+.(2) Aqueous hydrochloric acid solution (4 mol/L, 10 mL, 40 mmol) was added to the reaction flask containing the mixed solution of 34c, and the reaction solution was stirred 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 once with dichloromethane (50 mL). The organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 9:1) to obtain int34 (300 mg). LCMS (ESI) m/z: 187.0 [M + H] + .
中间体int35
Intermediate int35
Int35的制备方法Preparation method of Int35
(1)将原料35a(5g，25.13mmol)溶解在甲苯(80mL)中，加入催化剂四(三苯基膦)钯(2.91g，2.51mmol)和35b(18.15g，50.25mmol)，反应液在氮气保护下，油浴加热至100℃并搅拌反应16小时。反应完全后(TLC显示无原料)，所得反应液即为粗品35c溶液直接用于下一步骤。(1) The raw material 35a (5 g, 25.13 mmol) was dissolved in toluene (80 mL), and the catalyst tetrakis(triphenylphosphine)palladium (2.91 g, 2.51 mmol) and 35b (18.15 g, 50.25 mmol) were added. The reaction solution was heated to 100° C. in an oil bath under nitrogen protection and stirred for 16 hours. After the reaction was complete (TLC showed no raw material), the resulting reaction solution was the crude product 35c solution, which was directly used in the next step.
(2)向盛有35c(140mL)的混合溶液的反应瓶中加入盐酸水溶液(4mol/L，90mL，360mmol)，反应瓶置于油浴60℃下，快速搅拌2小时。反应完成后冷却至室温，用二氯甲烷(200mL x 2)萃取。合并有机相，无水硫酸钠干燥,有机相过滤后减压浓缩，所得残余物用硅胶柱层析纯化，用(0-10％石油醚:乙酸乙酯)洗脱得35d(2g)。LCMS(ESI)m/z:163.1[M+H]+.(2) Add hydrochloric acid aqueous solution (4 mol/L, 90 mL, 360 mmol) to the reaction flask containing the mixed solution of 35c (140 mL), place the reaction flask in an oil bath at 60°C, and stir rapidly for 2 hours. After the reaction is completed, cool to room temperature and extract with dichloromethane (200 mL x 2). Combine the organic phases, dry over anhydrous sodium sulfate, filter the organic phase, and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography and eluted with (0-10% petroleum ether: ethyl acetate) to obtain 35d (2 g). LCMS (ESI) m/z: 163.1 [M+H] + .
(3)将35d(1.2g，7.41mmol)、CuCl2(1.18g，8.89mmol)、亚硝酸异戊酯(1.04g，8.89mmol)溶解在ACN(25mL)中。混合液在氮气保护下65℃搅拌过夜，反应结束后加水稀释，用乙酸乙酯萃取(30mL x 3)，合并有机相，用饱和食盐水洗涤2次，有机相用无水硫酸钠干燥，过滤并减压浓缩。所得残余物用硅胶柱层析纯化，用(0-30％乙酸乙酯:石油醚)洗脱得int35(1.2g，收率：84.08％)。LCMS(ESI)m/z:182.1[M+H]+.(3) 35d (1.2 g, 7.41 mmol), CuCl 2 (1.18 g, 8.89 mmol), and isoamyl nitrite (1.04 g, 8.89 mmol) were dissolved in ACN (25 mL). The mixture was stirred at 65°C overnight under nitrogen protection. After the reaction was completed, it was diluted with water and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (0-30% ethyl acetate: petroleum ether) to obtain int35 (1.2 g, yield: 84.08%). LCMS (ESI) m/z: 182.1 [M+H] + .
中间体int36
Intermediate int36
Int36的制备方法Preparation method of Int36
(1)在100mL的三口烧瓶中，加入发烟硝酸并降温至0℃,将化合物36a(1g，6.98mmol)分批加入，反应液在0℃下搅拌30min。反应结束后将混合液加入冰水中淬灭反应，产物析出，过滤，滤饼用水洗涤两次，并减压浓缩除去水分，所得粗品36b(0.6g)。(1) In a 100 mL three-necked flask, fuming nitric acid was added and the temperature was lowered to 0°C. Compound 36a (1 g, 6.98 mmol) was added in batches, and the reaction solution was stirred at 0°C for 30 min. After the reaction was completed, the mixture was added into ice water to quench the reaction, the product precipitated, filtered, the filter cake was washed with water twice, and concentrated under reduced pressure to remove water, and the crude product 36b (0.6 g) was obtained.
(2)将粗品36b(0.6g，3.19mmol)溶于HBr(40％)水溶液(6mL)中，然后将SnCl2.2H2O(1.435 g,6.38mmol)加入反应液中，氮气置换三次，在室温条件下反应16小时。反应结束将反应液过滤，再将滤液后减压浓缩，所得粗品(400mg)36c可直接用于下一步。LCMS(ESI)m/z:159.1[M+H]+.(2) The crude product 36b (0.6 g, 3.19 mmol) was dissolved in HBr (40%) aqueous solution (6 mL), and then SnCl 2 .2H 2 O (1.435 g, 6.38 mmol) was added to the reaction solution, replaced with nitrogen three times, and reacted at room temperature for 16 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product (400 mg) 36c was directly used in the next step. LCMS (ESI) m/z: 159.1 [M+H] + .
(3)将36c(400mg，2.53mmol)、1-(6-氯吡啶-3-基)乙烷-1-酮(328mg，2.1mmol)、以及一水合对甲苯磺酸(398mg,2.1mmol)溶解在DMF(8mL)中。氮气保护下混合物于90℃油浴中搅拌4h。反应结束后，将反应液冷却至室温，减压浓缩得到int36(100mg)。LCMS(ESI)m/z:278.2[M+H]+.(3) 36c (400 mg, 2.53 mmol), 1-(6-chloropyridin-3-yl)ethane-1-one (328 mg, 2.1 mmol), and p-toluenesulfonic acid monohydrate (398 mg, 2.1 mmol) were dissolved in DMF (8 mL). The mixture was stirred in an oil bath at 90 °C for 4 h under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain int36 (100 mg). LCMS (ESI) m/z: 278.2 [M+H] + .
中间体int37
Intermediate int37
Int37的制备方法Preparation method of Int37
(1)将37a(4g，2.04mmol)溶解在DMF(30mL)中，加入Zn(CN)2(7.16g，6.12mmol)和Pd(PPh3)4(2.35g,0.204mmol)，反应混合物在氮气保护下，保持100℃反应16h后。将反应液降温到室温，加入水(100mL)，并用乙酸乙酯(150x 3mL)萃取，有机相用饱和食盐水(200mL)洗涤,无水硫酸钠干燥有机相，过滤，减压浓缩所得残余物用硅胶柱层析纯化用石油醚/乙酸乙酯(0％-30％)洗脱得37b(2.2g)。LCMS:m/z＝144.1[M+H]+.(1) 37a (4 g, 2.04 mmol) was dissolved in DMF (30 mL), and Zn(CN) 2 (7.16 g, 6.12 mmol) and Pd(PPh 3 ) 4 (2.35 g, 0.204 mmol) were added. The reaction mixture was kept at 100°C for 16 h under nitrogen protection. The reaction solution was cooled to room temperature, water (100 mL) was added, and extracted with ethyl acetate (150 x 3 mL). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether/ethyl acetate (0%-30%) to obtain 37b (2.2 g). LCMS: m/z=144.1[M+H] + .
(2)将37b(2.0g 1.40mmol)在0℃下加入DMF(10mL)和发烟HNO3(2mL)的混合溶液中，保持0℃搅拌0.5h后，加入冰水混合物(10mL)保持0℃搅拌0.5h，反应完毕后过滤，干燥，得粗品37c(3.5g)直接进行下一步反应。(2) 37b (2.0 g, 1.40 mmol) was added to a mixed solution of DMF (10 mL) and fuming HNO 3 (2 mL) at 0°C, stirred at 0°C for 0.5 h, then added with an ice-water mixture (10 mL) and stirred at 0°C for 0.5 h. After the reaction was completed, the mixture was filtered and dried to obtain a crude product 37c (3.5 g) which was directly used for the next step.
(3)将37c(1g,2.3mmol)和SnCl2(6g,26.6mmol)溶解在氢溴酸水溶液(20mL)中，在0℃下搅拌2h。反应完毕后，过滤，干燥所得红色的固体即为37d(600mg)。LCMS:m/z＝159.0[M+H]+.(3) 37c (1 g, 2.3 mmol) and SnCl 2 (6 g, 26.6 mmol) were dissolved in aqueous hydrobromic acid solution (20 mL) and stirred at 0°C for 2 h. After the reaction was completed, the red solid was filtered and dried to obtain 37d (600 mg). LCMS: m/z = 159.0 [M+H] + .
(4)将37d(600mg,3.79mmol)溶解在DMSO(6mL)中，加入37e(592mg,3.79mmol)和三乙胺(1.2g,11.37mmol)。混合物在60℃下搅拌3h。反应完毕后，将混合物加入水(200mL)和乙酸乙酯(150x 3mL)萃取，有机相用饱和食盐水(200mL)洗涤,无水硫酸钠干燥，过滤，减压浓缩所得残余物用硅胶柱层析纯化用石油醚/乙酸乙酯(0％-50％)洗脱,所得淡黄色色固体即为int37(200mg)。LCMS(ESI)m/z:279.0[M+H]+.(4) 37d (600 mg, 3.79 mmol) was dissolved in DMSO (6 mL), and 37e (592 mg, 3.79 mmol) and triethylamine (1.2 g, 11.37 mmol) were added. The mixture was stirred at 60°C for 3 h. After the reaction was completed, the mixture was extracted with water (200 mL) and ethyl acetate (150 x 3 mL). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether/ethyl acetate (0%-50%). The obtained light yellow solid was int37 (200 mg). LCMS (ESI) m/z: 279.0 [M+H] + .
中间体int38
Intermediate int38
Int38的制备方法Preparation method of Int38
(1)将化合物38a(6g，19.4mmol)、Zn(CN)2(2.73g，23.2mmol)和t-Buxphos Pd G3(307mg，0.39mmol)溶解在THF(50mL)和水(10mL)中。在70℃下搅拌16h。将反应液冷却至室温，加乙酸乙酯稀释，再加水，用乙酸乙酯萃取三次，合并有机相，用水洗涤2次，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶柱层析纯化，用(乙酸乙酯:石油醚＝1:1)洗脱得38b(2.5g，50.1％)。LCMS(ESI)m/z:258.2[M+H]+.(1) Compound 38a (6 g, 19.4 mmol), Zn(CN) 2 (2.73 g, 23.2 mmol) and t-Buxphos Pd G 3 (307 mg, 0.39 mmol) were dissolved in THF (50 mL) and water (10 mL). The mixture was stirred at 70°C for 16 h. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and then water was added. The mixture was extracted with ethyl acetate three times. The organic phases were combined, washed with water twice, dried with sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography and eluted with (ethyl acetate: petroleum ether = 1:1) to obtain 38b (2.5 g, 50.1%). LCMS (ESI) m/z: 258.2 [M+H] + .
(2)将38b(2.5g，9.69mmol)溶解在氯化氢/1,4-二氧六环溶液(4M,30mL)中，反应液在室温下搅拌16h。反应结束后减压浓缩得38c(1.5g)。LCMS(ESI)m/z:158.2[M+H]+.(2) 38b (2.5 g, 9.69 mmol) was dissolved in hydrogen chloride/1,4-dioxane solution (4 M, 30 mL), and the reaction solution was stirred at room temperature for 16 h. After the reaction was completed, the product was concentrated under reduced pressure to obtain 38c (1.5 g). LCMS (ESI) m/z: 158.2 [M+H] + .
(3)将38c(300mg，1.55mmol)、38d(243mg，1.55mmol)、TEA(315mg，3.11mmol)溶解在DMSO(4mL)中。混合液在氮气保护下60℃搅拌2h，反应结束后加水过滤并干燥得int38(200mg)。LCMS(ESI)m/z:278.1[M+H]+.(3) 38c (300 mg, 1.55 mmol), 38d (243 mg, 1.55 mmol), and TEA (315 mg, 3.11 mmol) were dissolved in DMSO (4 mL). The mixture was stirred at 60 °C for 2 h under nitrogen protection. After the reaction, water was added, filtered, and dried to obtain int38 (200 mg). LCMS (ESI) m/z: 278.1 [M+H] + .
中间体int39
Intermediate int39
Int39的制备方法Preparation method of Int39
(1)将39a(1g，4.34mmol)溶解在超干二甲基亚砜(10mL)中，然后在0℃下加入三氟乙酸酐(0.6mL，4.60mmol)。混合液在氮气保护下室温搅拌16小时。反应结束后，反应液加水淬灭，析出棕色固体，过滤，所得残余物为39b(1.7g，粗品)。(1) 39a (1 g, 4.34 mmol) was dissolved in ultra-dry dimethyl sulfoxide (10 mL), and trifluoroacetic anhydride (0.6 mL, 4.60 mmol) was then added at 0°C. The mixture was stirred at room temperature for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was quenched with water, and a brown solid was precipitated. The residue was filtered to obtain 39b (1.7 g, crude product).
(2)将39b(1.7g，crude)溶解在氢氧化钠溶液(20％，10mL)中。混合液在氮气保护下100℃搅拌16小时。反应结束后，反应液加入浓盐酸调节PH＝3，析出棕褐色固体，过滤、旋干后得到39c(640mg)。LCMS(ESI)m/z:273.9[M-H]+.(2) 39b (1.7 g, crude) was dissolved in sodium hydroxide solution (20%, 10 mL). The mixture was stirred at 100°C for 16 hours under nitrogen protection. After the reaction was completed, concentrated hydrochloric acid was added to the reaction solution to adjust the pH to 3, and a brown solid was precipitated. After filtration and spin drying, 39c (640 mg) was obtained. LCMS (ESI) m/z: 273.9 [MH] + .
(3)将39c(640mg，2.33mmol)溶解在超干四氢呋喃(7mL)中，然后加入叠氮磷酸二苯酯(1.0mL，4.66mmol)和三乙胺(1.0mL，6.99mmol)。混合液在氮气保护下室温搅拌16小时。反应结束后，反应液减压浓缩除去大部分溶剂(不要浓缩干)，加入甲醇，析出棕色固体，过滤、旋干后所得残余物为39d(680mg)。LCMS(ESI)m/z:298.8[M-H]+.(3) 39c (640 mg, 2.33 mmol) was dissolved in ultra-dry tetrahydrofuran (7 mL), and then diphenylphosphoryl azide (1.0 mL, 4.66 mmol) and triethylamine (1.0 mL, 6.99 mmol) were added. The mixture was stirred at room temperature for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove most of the solvent (do not concentrate to dryness), methanol was added, and a brown solid was precipitated. After filtering and spin drying, the residue obtained was 39d (680 mg). LCMS (ESI) m/z: 298.8 [MH] + .
(4)将39d(680mg，crude)溶解在叔丁醇(10mL)中。混合液在氮气保护下80℃搅拌16小时。反应结束后，反应液减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝4:1)洗脱得39e(450mg)。LCMS(ESI)m/z:290.9[M-55]+ (4) 39d (680 mg, crude) was dissolved in tert-butyl alcohol (10 mL). The mixture was stirred at 80°C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain 39e (450 mg). LCMS (ESI) m/z: 290.9 [M-55] +
(5)将39e(430mg，1.24mmol)溶解在四氢呋喃(6mL)和水(1.5mL)中，室温下加入氰化锌(176mg，1.50mmol)和t-BuXPhosPdG3(20mg，0.025mmol)。混合液在氮气保护下70℃搅拌16小时。反应结束后，反应液过滤，加水稀释(20mL)，用二氯甲烷萃取三次(20mL x 3)，有机相减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝3:1)洗脱得39f(300mg)。LCMS(ESI)m/z:348.2[M+18+39]+，1H NMR(400MHz,DMSO_d6)δ11.54(s,1H),9.39(s,1H),8.10(s,1H),7.94(s,1H),7.80(s,1H),1.49(s,9H).(5) 39e (430 mg, 1.24 mmol) was dissolved in tetrahydrofuran (6 mL) and water (1.5 mL), and zinc cyanide (176 mg, 1.50 mmol) and t-BuXPhosPdG 3 (20 mg, 0.025 mmol) were added at room temperature. The mixture was stirred at 70°C for 16 hours under nitrogen protection. After the reaction, the reaction solution was filtered, diluted with water (20 mL), and extracted with dichloromethane three times (20 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with (PE:EA=3:1) to obtain 39f (300 mg). LCMS (ESI) m/z: 348.2 [M+18+39] + , 1 H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 9.39 (s, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.80 (s, 1H), 1.49 (s, 9H).
(6)将39f(200mg，0.69mmol)溶解在4M HCl/EA(4mL)中。混合液在室温下搅拌16小时。反应结束后，反应液减压浓缩，减压浓缩所得残余物为int39(160mg)。LCMS(ESI)m/z:192.1[M+H]+.(6) 39f (200 mg, 0.69 mmol) was dissolved in 4M HCl/EA (4 mL). The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain int39 (160 mg). LCMS (ESI) m/z: 192.1 [M+H] + .
中间体int40
Intermediate int40
Int40的制备方法Preparation method of Int40
(1)氮气保护下，将POCl3(4.55g，29.7mmol，1.1eq)滴加到0℃下的N,N-二甲基甲酰胺(40mL)中,在0℃下搅拌0.5h后，常温搅拌1h。将反应体系降到0℃，滴加到反应物40a(5g，27mmol，1eq)的N,N-二甲基甲酰胺(50mL)的溶液中，在0℃下搅拌0.5h后，常温搅拌15h。反应结束后加入冰水淬灭，用NaOH溶液调节PH＝10，过滤，用水冲洗滤饼，得化合物40b(2.71g，收率：47.1％)。LCMS(ESI)m/z:214.0[M+H]+.(1) Under nitrogen protection, POCl 3 (4.55 g, 29.7 mmol, 1.1 eq) was added dropwise to N,N-dimethylformamide (40 mL) at 0°C, stirred at 0°C for 0.5 h, and then stirred at room temperature for 1 h. The reaction system was cooled to 0°C and added dropwise to a solution of reactant 40a (5 g, 27 mmol, 1 eq) in N,N-dimethylformamide (50 mL), stirred at 0°C for 0.5 h, and then stirred at room temperature for 15 h. After the reaction was completed, ice water was added to quench, the pH was adjusted to 10 with NaOH solution, filtered, and the filter cake was rinsed with water to obtain compound 40b (2.71 g, yield: 47.1%). LCMS (ESI) m/z: 214.0 [M+H] + .
(2)将40b(2g，9.4mmol，1eq)和2-甲基-2-丁烯(1.31g，18.8mmol，2eq)溶解在乙腈(30mL)，叔丁醇(30mL)的混合溶液中，在0℃下加入NaClO2(8.4g,94mmol,10eq)和NaH2PO4(13g,94mmol,10eq)的水溶液(50mL)。在室温下搅拌16h。反应完毕后反应液用乙酸乙酯和水进行萃取，合并有机相，减压浓缩所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝3:1)洗脱 得40c(1.5g，收率：69.7％)。LCMS(ESI)m/z:228.0[M-H]- (2) 40b (2 g, 9.4 mmol, 1 eq) and 2-methyl-2-butene (1.31 g, 18.8 mmol, 2 eq) were dissolved in a mixed solution of acetonitrile (30 mL) and tert-butyl alcohol (30 mL). An aqueous solution (50 mL) of NaClO 2 (8.4 g, 94 mmol, 10 eq) and NaH 2 PO 4 (13 g, 94 mmol, 10 eq) was added at 0°C. The mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 3:1). 40c (1.5 g, yield: 69.7%) was obtained. LCMS (ESI) m/z: 228.0 [MH] -
(3)将40c(1.0g，4.36mmol)溶解在无水四氢呋喃(10mL)中，然后将在0℃下加入三乙胺(1.32g，13.1mmol)、叠氮磷酸二苯酯(2.4g，8.73mmol)。反应液在室温下搅拌过夜。反应结束后，减压浓缩除去大部分四氢呋喃，加入甲醇使体系析出固体，抽滤后干燥得到40d(700mg，收率：63.6％)。LCMS(ESI)m/z:253.0[M-H]- (3) 40c (1.0 g, 4.36 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and then triethylamine (1.32 g, 13.1 mmol) and diphenylphosphoryl azide (2.4 g, 8.73 mmol) were added at 0°C. The reaction solution was stirred at room temperature overnight. After the reaction was completed, most of the tetrahydrofuran was removed by concentration under reduced pressure, and methanol was added to precipitate solids in the system. After filtration, solids were obtained by drying to obtain 40d (700 mg, yield: 63.6%). LCMS (ESI) m/z: 253.0 [MH] -
(4)将40d(700mg，2.75mmol)溶解在叔丁醇(7mL)中，混合液在氮气保护下80℃搅拌过夜。反应结束后，将反应液冷却至室温，减压浓缩后，粗品用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝4:1)洗脱得40e(550mg，收率：66％)。LCMS(ESI)m/z:245.0[M-55]+ (4) 40d (700 mg, 2.75 mmol) was dissolved in tert-butyl alcohol (7 mL), and the mixture was stirred at 80°C overnight under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography, eluted with (petroleum ether: ethyl acetate = 4:1) to obtain 40e (550 mg, yield: 66%). LCMS (ESI) m/z: 245.0 [M-55] +
(5)将40e(550mg，1.83mmol)溶解在氯化氢/1,4-二氧六环溶液(4M,2mL)中，反应液在室温下搅拌16h。反应结束后减压浓缩得粗品化合物int40(400mg)。LCMS(ESI)m/z:201.0[M+H]+.(5) 40e (550 mg, 1.83 mmol) was dissolved in a hydrogen chloride/1,4-dioxane solution (4 M, 2 mL), and the reaction solution was stirred at room temperature for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude compound int40 (400 mg). LCMS (ESI) m/z: 201.0 [M+H] + .
中间体int41
Intermediate int41
Int41的制备方法Preparation method of Int41
(1)将原料41a(1g，4.85mmol)溶解在无水甲苯(15mL)中，加入催化剂四(三苯基膦)钯(560mg，0.484mmol)和41b(2.2g，6.09mmol)，氮气保护下油浴加热至110℃搅拌反应16小时。反应完全后(TLC显示无原料)，所得反应液即为粗品41c溶液直接用于下一步骤。(1) The raw material 41a (1 g, 4.85 mmol) was dissolved in anhydrous toluene (15 mL), and the catalyst tetrakis(triphenylphosphine)palladium (560 mg, 0.484 mmol) and 41b (2.2 g, 6.09 mmol) were added. The mixture was heated to 110° C. in an oil bath under nitrogen protection and stirred for 16 hours. After the reaction was complete (TLC showed no raw material), the resulting reaction solution was the crude product 41c solution, which was directly used in the next step.
(2)向盛有41c的混合溶液的反应瓶中加入盐酸水溶液(4mol/L，10mL，40mmol)，室温快速搅拌2小时。反应完成后冷却至室温，分出有机相，水相用二氯甲烷(50mL)萃取一次。合并有机相，无水硫酸钠干燥，过滤后减压浓缩滤液，所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝9:1)洗脱得化合物int41(200mg，24.3％)。LCMS(ESI)m/z:170.1[M+H]+.(2) Add hydrochloric acid aqueous solution (4 mol/L, 10 mL, 40 mmol) to the reaction flask containing the mixed solution of 41c and stir rapidly at room temperature for 2 hours. After the reaction is completed, cool to room temperature, separate the organic phase, and extract the aqueous phase once with dichloromethane (50 mL). Combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography, eluting with (petroleum ether: ethyl acetate = 9:1) to obtain compound int41 (200 mg, 24.3%). LCMS (ESI) m/z: 170.1 [M + H] + .
中间体int42
Intermediate int42
Int42的制备方法Preparation method of Int42
(1)将化合物42a(1.0g,5.376mmol)溶于THF(10ml)，氮气保护下，反应液降温至-45℃，加入DIBAL-H(7.0ml,10.752mmol)，反应液在-45℃下搅拌4h。反应结束，向反应液加入1M HCl(20ml)，搅拌5分钟，再加入DCM(20ml x 3)进行萃取，有机相用饱和的食盐水进行洗涤，再加入无水硫酸钠进行干燥，过滤，有机相减压浓缩，所得粗产品用硅胶柱层析纯化(乙酸乙酯：石油醚＝0-10％)得到产物42b(600mg)。LCMS(ESI)m/z:159.1[M+H]+.(1) Compound 42a (1.0 g, 5.376 mmol) was dissolved in THF (10 ml). Under nitrogen protection, the reaction solution was cooled to -45°C, DIBAL-H (7.0 ml, 10.752 mmol) was added, and the reaction solution was stirred at -45°C for 4 h. After the reaction was completed, 1M HCl (20 ml) was added to the reaction solution, stirred for 5 minutes, and then DCM (20 ml x 3) was added for extraction. The organic phase was washed with saturated brine, and then anhydrous sodium sulfate was added for drying, filtered, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-10%) to obtain product 42b (600 mg). LCMS (ESI) m/z: 159.1 [M+H] + .
(2)将42b(600mg,3.797mmol)溶于DCM(5ml)，将反应液用氮气保护并降温至0℃，然后加入DMP(1.93g,4.556mmol)，缓慢升至室温反应4h。反应结束，过滤掉不溶物，将滤液减压浓缩，所得粗产品用硅胶柱层析纯化(乙酸乙酯：石油醚＝0-20％)得到产物42c(450mg)。1H NMR(400MHz,CDCl3)δ10.03(s,1H),8.70(s,1H),2.69(s,3H).(2) 42b (600 mg, 3.797 mmol) was dissolved in DCM (5 ml), the reaction solution was protected with nitrogen and cooled to 0°C, then DMP (1.93 g, 4.556 mmol) was added, and the temperature was slowly raised to room temperature for 4 h. After the reaction was completed, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-20%) to obtain product 42c (450 mg). 1 H NMR (400 MHz, CDCl 3 ) δ10.03 (s, 1H), 8.70 (s, 1H), 2.69 (s, 3H).
(3)将42c(450mg,2.884mmol)溶于THF(5.0ml)，将反应液用氮气保护并降温至0℃，然后加入EtMgBr(1.92ml,5.769mmol)，缓慢升至室温反应2h。反应结束后，向反应液中加入水(10ml)，再加入乙酸乙酯(10ml x 3)进行萃取，所得有机相用饱和的食盐水进行洗涤，再加入无水硫酸钠进行干燥，过滤，有机相减压蒸馏，所得粗产品用硅胶柱层析纯化(乙酸乙酯：石油醚＝0-10％)得到产物42d(300mg)。1H NMR(400MHz,DMSO-d6)δ8.37(s,1H),5.57(d,J＝4.8Hz,1H),4.58-4.54(m,1H),2.57(s,3H),1.83–1.75(m,1H),1.71–1.60(m,1H),0.86(t,J＝7.2Hz,3H).(3) 42c (450 mg, 2.884 mmol) was dissolved in THF (5.0 ml), the reaction solution was protected with nitrogen and cooled to 0°C, then EtMgBr (1.92 ml, 5.769 mmol) was added, and the temperature was slowly raised to room temperature for 2 h. After the reaction was completed, water (10 ml) was added to the reaction solution, and then ethyl acetate (10 ml x 3) was added for extraction. The obtained organic phase was washed with saturated brine, and then anhydrous sodium sulfate was added for drying, filtered, and the organic phase was distilled under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-10%) to obtain product 42d (300 mg). 1 H NMR (400 MHz, DMSO-d6) δ8.37 (s, 1H), 5.57 (d, J = 4.8 Hz, 1H), 4.58-4.54 (m, 1H), 2.57 (s, 3H), 1.83-1.75 (m, 1H), 1.71-1.60 (m, 1H), 0.86 (t, J = 7.2 Hz, 3H).
(4)将42d(300mg,1.612mmol)溶于DCM(5ml)，将反应液用氮气保护并降温至0℃，然后加入DMP(1.36g,3.225mmol)，缓慢升至室温反应4h。反应结束，过滤掉不溶物，滤液减压蒸馏，所得粗产品用硅胶柱层析纯化(乙酸乙酯：石油醚＝0-20％)得到产物int42(200mg)。LCMS(ESI)m/z:185.1[M+H]+.(4) 42d (300 mg, 1.612 mmol) was dissolved in DCM (5 ml), the reaction solution was protected with nitrogen and cooled to 0°C, then DMP (1.36 g, 3.225 mmol) was added, and the temperature was slowly raised to room temperature for 4 h. After the reaction was completed, the insoluble matter was filtered out, and the filtrate was distilled under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-20%) to obtain the product int42 (200 mg). LCMS (ESI) m/z: 185.1 [M+H] + .
中间体int43
Intermediate int43
Int43的制备方法Preparation method of Int43
(1)将化合物43a(1.0g,3.76mmol)溶于THF(10ml)，反应液在氮气保护下降温至-40℃，加入DIBAL-H(5.0ml,7.52mmol)，反应液在-40℃下搅拌4h。反应结束，向反应液加入1M HCl(20ml)，搅拌5分钟，再加入DCM(20ml x 3)进行萃取，有机相用饱和的食盐水进行洗涤，再加入无水硫酸钠进行干燥，过滤，有机相减压浓缩，所得粗产品用硅胶柱层析纯化(乙酸乙酯：石油醚＝0-10％)得到产物43b(500mg)。1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.99(s,1H).(1) Compound 43a (1.0 g, 3.76 mmol) was dissolved in THF (10 ml), the reaction solution was cooled to -40°C under nitrogen protection, DIBAL-H (5.0 ml, 7.52 mmol) was added, and the reaction solution was stirred at -40°C for 4 h. After the reaction was completed, 1M HCl (20 ml) was added to the reaction solution, stirred for 5 minutes, and then DCM (20 ml x 3) was added for extraction. The organic phase was washed with saturated brine, and then anhydrous sodium sulfate was added for drying, filtered, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-10%) to obtain product 43b (500 mg). 1 H NMR (400 MHz, DMSO-d 6 )δ10.05 (s, 1H), 8.99 (s, 1H).
(2)将43b(500mg,2.11mmol)溶于DCM(5ml)，然后加入TEA.3HF(680mg,4.22mmol)，XtalFluor(725mg,3.165mmol),氮气保护下加热至40℃，反应16h。反应结束，反应液降温到室温，加入饱和碳酸氢钠(10ml)，搅拌5分钟，再加入DCM(20ml X 3)进行萃取，有机相用无水硫酸钠进行干燥，过滤，有机相减压浓缩，所得粗产品用硅胶柱层析纯化(二氯甲烷)得到产物43c(200mg)。1H NMR(400MHz,CDCl3)δ8.55(s,1H),6.75(t,J＝53.2Hz,1H).(2) 43b (500 mg, 2.11 mmol) was dissolved in DCM (5 ml), and then TEA.3HF (680 mg, 4.22 mmol) and XtalFluor (725 mg, 3.165 mmol) were added. The mixture was heated to 40°C under nitrogen protection and reacted for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature, saturated sodium bicarbonate (10 ml) was added, and stirred for 5 minutes. DCM (20 ml x 3) was then added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane) to obtain product 43c (200 mg). 1 H NMR (400 MHz, CDCl 3 ) δ8.55 (s, 1H), 6.75 (t, J=53.2 Hz, 1H).
(3)将43c(200mg,0.826mmol)溶于无水甲苯(5.0ml)，然后加入43d(0.23ml,0.661mmol),和Pd(PPh3)4(95mg,0.0826mmol)，将反应液用氮气保护，然后溶液加热至110℃，反应16h。反应结束，向反应液加入水(10ml)，搅拌5分钟，再加入乙酸乙酯(10ml x 3)进行萃取，有机相减压蒸馏所得粗产品用THF溶解，再加入4M HCl(5ml),然后将溶液升温至60℃，搅拌2h。反应结束后，向反应液中加入水(10ml)，再加入乙酸乙酯(10ml x 3)进行萃取，有机相加入饱和KF(10ml),搅拌30分钟，滤去固体，滤液进行分液，所得有机相用饱和的食盐水进行洗涤，再加入无水硫酸钠进行干燥，过滤，有机相减压浓缩，所得粗产品用硅胶柱层析纯化(乙酸乙酯：石油醚＝0-10％)得到产物int43(100mg)。1H NMR(400MHz,CDCl3)δ9.12(s,1H),6.94(t,J＝53.2Hz,1H),2.75(s,3H).(3) 43c (200 mg, 0.826 mmol) was dissolved in anhydrous toluene (5.0 ml), and then 43d (0.23 ml, 0.661 mmol) and Pd(PPh 3 ) 4 (95 mg, 0.0826 mmol) were added. The reaction solution was protected with nitrogen, and then the solution was heated to 110°C and reacted for 16 h. After the reaction was completed, water (10 ml) was added to the reaction solution, stirred for 5 minutes, and then ethyl acetate (10 ml x 3) was added for extraction. 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. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-10%) to obtain the product int43 (100 mg). 1 H NMR (400 MHz, CDCl 3 ) δ9.12 (s, 1H), 6.94 (t, J = 53.2 Hz, 1H), 2.75 (s, 3H).
中间体int45
Intermediate int45
Int45的制备方法Preparation method of Int45
(1)将45a(4.0g，18.691mmol)溶解在超干四氢呋喃(40mL)中，然后在0℃下滴加三氟乙酸酐(4.16g，19.813mmol)。反应液在常温下搅拌3小时。反应结束后，反应液加水淬灭(100mL)，搅拌半小时有白色固体析出。过滤混合液，合并所得固体，加入20％氢氧化钠水溶液(50mL)。反应液在105℃下反应16小时。反应结束后将反应液冷却至室温，在0℃下分批加入浓盐酸(30mL)，调节PH至6，有白色固体析出。过滤混合液，合并所得固体即为45b(3.2g)。1H NMR(400MHz,DMSO_d6)δ12.22(s,1H),12.15(s,1H),8.19(d,J＝6.8Hz,1H),8.07(d,J＝2.8Hz,1H),7.48(d,J＝9.2Hz,1H).(1) 45a (4.0 g, 18.691 mmol) was dissolved in ultra-dry tetrahydrofuran (40 mL), and trifluoroacetic anhydride (4.16 g, 19.813 mmol) was then added dropwise at 0°C. The reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was quenched with water (100 mL), and stirred for half an hour to precipitate a white solid. The mixed solution was filtered, the obtained solid was combined, and a 20% aqueous sodium hydroxide solution (50 mL) was added. The reaction solution was reacted at 105°C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and concentrated hydrochloric acid (30 mL) was added in batches at 0°C to adjust the pH to 6, and a white solid precipitated. The mixed solution was filtered, and the obtained solid was combined to obtain 45b (3.2 g). 1 H NMR (400 MHz, DMSO_d6) δ 12.22 (s, 1H), 12.15 (s, 1H), 8.19 (d, J = 6.8 Hz, 1H), 8.07 (d, J = 2.8 Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H).
(2)将45b(3.2g，12.403mmol)溶解在超干四氢呋喃(300mL)中，然后在常温下加入DPPA(6.8g，24.806mmol)和三乙胺(3.7g,37.209mmol)。反应液在常温下搅拌16小时。反应结束后,将反应液减压浓缩，混合物加甲醇淬灭(200mL)，搅拌半小时有白色固体析出。过滤混合液，合并所得固体即为45c(2.2g)。LCMS(ESI)m/z:280.9[M+H]- (2) 45b (3.2 g, 12.403 mmol) was dissolved in ultra-dry tetrahydrofuran (300 mL), and then DPPA (6.8 g, 24.806 mmol) and triethylamine (3.7 g, 37.209 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the mixture was quenched with methanol (200 mL). After stirring for half an hour, a white solid precipitated. The mixed solution was filtered and the solid obtained was combined to obtain 45c (2.2 g). LCMS (ESI) m/z: 280.9 [M+H] -
(3)将45c(2.2g，7.829mmol)溶解在叔丁醇(200mL)中，反应液在80℃搅拌16小时。反应结束后，将反应液冷却至室温，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝5:1)洗脱得45d(2.1g)。LCMS(ESI)m/z:331.0[M+H]+.(3) 45c (2.2 g, 7.829 mmol) was dissolved in tert-butyl alcohol (200 mL), and the reaction solution was stirred at 80°C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=5:1) to obtain 45d (2.1 g). LCMS (ESI) m/z: 331.0 [M+H] + .
(4)将45d(1g，3.037mmol)、氰化锌(428mg,3.645mmol)和t-Buxphos Pd G3(48mg,0.060mmol)溶解在四氢呋喃(8mL)和纯净水(2mL)中，然后反应液在70℃下搅拌16小时。反应结束后，冷却至室温。过滤反应液，合并有机相加水稀释(100mL)，用二氯甲烷萃取三次(100mL x 3)，有机相减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝4:1)洗脱得45e(900mg)。1H NMR(400MHz,DMSO_d6)δ11.39(s,1H),9.42(s,1H),8.34(d,J＝6.0Hz,1H),7.59(s,1H),7.36(d,J＝10.4Hz,1H),1.50(s,9H).(4) 45d (1 g, 3.037 mmol), zinc cyanide (428 mg, 3.645 mmol) and t-Buxphos Pd G 3 (48 mg, 0.060 mmol) were dissolved in tetrahydrofuran (8 mL) and purified water (2 mL), and the reaction solution was stirred at 70°C for 16 hours. After the reaction was completed, it was cooled to room temperature. The reaction solution was filtered, the organic phase was combined and diluted with water (100 mL), and extracted with dichloromethane three times (100 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain 45e (900 mg). 1 H NMR (400 MHz, DMSO_d6) δ 11.39 (s, 1H), 9.42 (s, 1H), 8.34 (d, J = 6.0 Hz, 1H), 7.59 (s, 1H), 7.36 (d, J = 10.4 Hz, 1H), 1.50 (s, 9H).
(5)将45e(200mg，0.726mmol)溶解在盐酸乙酸乙酯溶液(5mL,4M)中，反应液在室温下搅拌1小时。反应结束后，将反应液减压浓缩，得int45(140mg)。LCMS(ESI)m/z:176.2[M+H]+.(5) 45e (200 mg, 0.726 mmol) was dissolved in a hydrochloric acid ethyl acetate solution (5 mL, 4 M), and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain int45 (140 mg). LCMS (ESI) m/z: 176.2 [M+H] + .
中间体int46
Intermediate int46
Int46的制备方法Preparation method of Int46
(1)将无水硫酸镁(20.4g，170mmol)加入到DCE(200mL)中，再加入浓H2SO4(2.3mL,42.6mmol)。混合物在常室温下搅拌15min，加入化合物46a(10g，42.6mmol)和叔丁醇(20mL，213mmol)，反应液在室温下反应16h。将混合物加入水(1000mL)和二氯甲烷(1000x 2mL)，萃取，用饱和食盐水(1000mL)洗涤,无水硫酸钠干燥有机相，过滤，减压浓缩所得残余物用柱层析纯化用石油醚/乙酸乙酯(0％-20％)洗脱,所得产物46b(4.5g)。LCMS:m/z＝293.9[M+H]+.(1) Anhydrous magnesium sulfate (20.4 g, 170 mmol) was added to DCE (200 mL), and then concentrated H 2 SO 4 (2.3 mL, 42.6 mmol) was added. The mixture was stirred at room temperature for 15 min, and compound 46a (10 g, 42.6 mmol) and tert-butyl alcohol (20 mL, 213 mmol) were added. The reaction solution was reacted at room temperature for 16 h. The mixture was added with water (1000 mL) and dichloromethane (1000 x 2 mL), extracted, washed with saturated brine (1000 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography and eluted with petroleum ether/ethyl acetate (0%-20%) to obtain product 46b (4.5 g). LCMS: m/z=293.9 [M+H] + .
(2)将化合物46b(10g，34.18mmol)溶解在甲苯(150mL)中，加入催化剂四(三苯基膦)钯(3.9g，3.418mmol)和46c(24.7g，68.36mmol)，反应液氮气保护下油浴加热至110℃搅拌反应16小时。反应完全后(TLC显示无原料)，所得反应液即为粗品46d溶液直接用于下一步骤。(2) Compound 46b (10 g, 34.18 mmol) was dissolved in toluene (150 mL), and catalyst tetrakis(triphenylphosphine)palladium (3.9 g, 3.418 mmol) and 46c (24.7 g, 68.36 mmol) were added. The reaction solution was heated to 110° C. in an oil bath under nitrogen protection and stirred for 16 hours. After the reaction was complete (TLC showed no starting material), the resulting reaction solution was the crude product 46d solution, which was directly used in the next step.
(3)向盛有46d(150mL，34.18mmol)的混合溶液的反应瓶中加入盐酸水溶液(4mol/L，90mL，360mmol)，反应液在油浴60℃下快速搅拌2小时。反应完成后冷却至室温，分出有机相，水相用二氯甲烷(200mL)萃取三次。合并有机相，无水硫酸钠干燥有机相过滤后减压浓缩滤液，所得残余物用硅胶柱层析纯化，用(乙酸乙酯/石油醚＝0％～20％)洗脱得46e(3.5g)。LCMS(ESI)m/z:256.1[M+H]+.(3) 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 residue was purified by silica gel column chromatography and eluted with (ethyl acetate/petroleum ether = 0% to 20%) to obtain 46e (3.5 g). LCMS (ESI) m/z: 256.1 [M+H] + .
(4)将46e(2g,3.79mmol)溶解在DMSO(20mL)中，加入int2(1.6g,9.39mmol)和DIEA(2.0g,15.64mmol)。反应液在25℃下搅拌4h。反应完毕后，向混合物中加入水(100mL),析出固体，过滤，滤饼用水洗涤两次，所得淡黄色色固体即为产物46f(2.5g)。LCMS(ESI)m/z:386.0[M+H]+.(4) 46e (2 g, 3.79 mmol) was dissolved in DMSO (20 mL), and int2 (1.6 g, 9.39 mmol) and DIEA (2.0 g, 15.64 mmol) were added. The reaction solution was stirred at 25 °C for 4 h. After the reaction was completed, water (100 mL) was added to the mixture, and the solid was precipitated. The solid was filtered and the filter cake was washed twice with water. The obtained light yellow solid was the product 46f (2.5 g). LCMS (ESI) m/z: 386.0 [M+H] + .
(5)将46f(2g,5.18mmol)溶解在二氯甲烷(16mL)中,加入三氟乙酸(4mL)，反应液在30℃下搅拌16h。反应完毕后，将反应液减压浓缩，即为产物46g(2.5g)。LCMS(ESI)m/z:330.0[M+H]+.(5) 46f (2 g, 5.18 mmol) was dissolved in dichloromethane (16 mL), trifluoroacetic acid (4 mL) was added, and the reaction solution was stirred at 30°C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the product 46g (2.5 g). LCMS (ESI) m/z: 330.0 [M+H] + .
(6)将化合物46g(500mg，1.5mmol)加入到DMF(5mL)中，再加入甲胺盐酸盐(112mg,1.65mmol),HATU(688g，1.8mmol)和DIEA(581mg，4.5mmol)，反应液在常温下反应4h。向混合物加入水(100mL)和二氯甲烷(100x 2mL)，萃取，有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥，过滤，减压浓缩，所得残余物用柱层析纯化用乙酸乙酯/石油醚(0％-40％)洗脱,所得白色固体即为产物int46(240mg)。LCMS:m/z＝343.0[M+H]+.(6) Compound 46g (500 mg, 1.5 mmol) was added to DMF (5 mL), and then methylamine hydrochloride (112 mg, 1.65 mmol), HATU (688 g, 1.8 mmol) and DIEA (581 mg, 4.5 mmol) were added. The reaction solution was reacted at room temperature for 4 h. Water (100 mL) and dichloromethane (100 x 2 mL) were added to the mixture for extraction. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography and eluted with ethyl acetate/petroleum ether (0%-40%). The obtained white solid was the product int46 (240 mg). LCMS: m/z = 343.0 [M+H] + .
中间体int47
Intermediate int47
Int47制备方法：Int47 preparation method:
(1)将原料47a(500mg，4.94mmol)溶解在乙腈(25mL)中，加入2,2,2-三氟乙基三氟甲烷磺酸酯(1.15g，4.94mmol)和碳酸铯(3.22g，9.89mmol)，氮气保护下油浴加热至85℃搅拌反应2小时。反应完全后将反应液过滤除去固体，减压浓缩滤液至干，二氯甲烷(25mL)溶解残余物，超声溶解三分钟后，过滤除去不溶物，减压浓缩滤液，即得47b(900mg)。1H NMR(400MHz,DMSO_d6)δ4.55(d,J＝4.0Hz,1H),3.50–3.38(m,1H),3.10(q,J＝10.4Hz,2H),2.86–2.74(m,2H),2.41–2.31(m,2H),1.72–1.62(m,2H),1.39–1.35(m,2H).(1) The raw material 47a (500 mg, 4.94 mmol) was dissolved in acetonitrile (25 mL), 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.15 g, 4.94 mmol) and cesium carbonate (3.22 g, 9.89 mmol) were added, and the mixture was heated to 85° C. in an oil bath under nitrogen protection and stirred for 2 hours. After the reaction was complete, the reaction solution was filtered to remove the solid, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in dichloromethane (25 mL), and after ultrasonic dissolution for three minutes, the insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 47b (900 mg). 1 H NMR (400 MHz, DMSO_d6) δ 4.55 (d, J = 4.0 Hz, 1H), 3.50–3.38 (m, 1H), 3.10 (q, J = 10.4 Hz, 2H), 2.86–2.74 (m, 2H), 2.41–2.31 (m, 2H), 1.72–1.62 (m, 2H), 1.39–1.35 (m, 2H).
(2)于三口反应瓶中将47b(300mg，1.64mmol)溶解在超干四氢呋喃(10mL)，加入3b(294mg，1.80mmol)和三苯基膦(516mg，1.96mmol)，氮气保护下,将反应液置于冰水浴中搅拌10分钟。将偶氮二甲酸二叔丁酯(453mg，1.96mmol)溶解在超干四氢呋喃(5mL)中，将此溶液缓慢滴加进上述反应瓶中，滴完后室温搅拌2小时。反应结束后加水(15mL)淬灭，用二氯甲烷(20mL)萃取2次，合并有机相，无水硫酸钠干燥后过滤并减压浓缩。所得残余物用硅胶柱层析 纯化，用(石油醚:乙酸乙酯＝9:1)洗脱得47c(757mg)。1H NMR(400MHz,DMSO_d6)δ7.87(s,4H),4.27–4.21(m,1H),3.19(q,J＝10.4Hz,2H),2.96–2.88(m,2H),2.47(s,2H),1.9–1.92(m,2H),1.76–1.67(m,2H).(2) In a three-necked reaction flask, 47b (300 mg, 1.64 mmol) was dissolved in ultra-dry tetrahydrofuran (10 mL), and 3b (294 mg, 1.80 mmol) and triphenylphosphine (516 mg, 1.96 mmol) were added. Under nitrogen protection, the reaction solution was placed in an ice-water bath and stirred for 10 minutes. Di-tert-butyl azodicarboxylate (453 mg, 1.96 mmol) was dissolved in ultra-dry tetrahydrofuran (5 mL), and the solution was slowly added dropwise to the above reaction flask. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (15 mL) was added to quench the reaction, and the mixture was extracted twice with dichloromethane (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column. Purification was performed and eluted with (petroleum ether:ethyl acetate=9:1) to obtain 47c (757 mg). 1 H NMR (400 MHz, DMSO_d6) δ7.87 (s, 4H), 4.27–4.21 (m, 1H), 3.19 (q, J=10.4 Hz, 2H), 2.96–2.88 (m, 2H), 2.47 (s, 2H), 1.9–1.92 (m, 2H), 1.76–1.67 (m, 2H).
将47c(757mg，1.64mmol)溶解在二氯甲烷(7mL)和甲醇(0.7mL)的混合溶剂中，滴加水合肼(98％，164mg，3.28mmol)，滴完后室温反应2小时。反应结束后，过滤反应液，二氯甲烷(5mL)洗滤饼2次，稀氨水(mol/L，5mL)洗滤饼2次，所得滤液搅拌10分钟后分出有机相，水相用二氯甲烷(5mL)萃取，合并有机相，无水硫酸钠干燥，过滤后减压浓缩(除去氨气)。二氯甲烷(20mL)溶解残余物，将稀盐酸(1mol/L，10mL)加入上述溶液中，搅拌1小时。分出水相，冻干可得int47(268mg)。1H NMR(400MHz,CD3OD)δ4.56–4.48(m,1H),4.33(q,J＝9.2Hz,2H),3.65–3.57(m,4H),2.45–2.37(m,2H),2.29–2.21(m,2H).47c (757 mg, 1.64 mmol) was dissolved in a mixed solvent of dichloromethane (7 mL) and methanol (0.7 mL), and hydrazine hydrate (98%, 164 mg, 3.28 mmol) was added dropwise. After the addition, the mixture was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed twice with dichloromethane (5 mL), and the filter cake was washed twice with dilute ammonia water (mol/L, 5 mL). The obtained filtrate was stirred for 10 minutes and the organic phase was separated. 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). 1 H NMR (400 MHz, CD 3 OD) δ 4.56–4.48 (m, 1H), 4.33 (q, J=9.2 Hz, 2H), 3.65–3.57 (m, 4H), 2.45–2.37 (m, 2H), 2.29–2.21 (m, 2H).
实施例1
Example 1
合成路线：
synthetic route:
(1)化合物C001-1a的合成：将int3(900mg，5.96mmol)和化合物int4(810mg，5.96mmol)溶解在乙腈(5mL)中，然后加入对甲苯磺酸(203.8mg，1.19mmol)。混合液在氮气保护下90℃搅拌4小时。反应结束后，将反应液浓缩。所得残余物用硅胶板层析纯化，用(石油醚:乙酸乙酯＝1:1)洗脱得产物C001-1a(400mg)，1H NMR(400MHz,DMSO)δ10.96(s,1H),9.06(s,1H),8.38(d,J＝36.0Hz,2H),7.90(s,1H),7.80(d,J＝8.0Hz,2H),7.37(d,J＝8.0Hz,1H),7.09(d,J＝8.0Hz,1H),6.82(d,J＝8.0Hz,1H),4.74(d,J＝8.0Hz,2H),2.22(s,3H).(1) Synthesis of compound C001-1a: Int3 (900 mg, 5.96 mmol) and compound int4 (810 mg, 5.96 mmol) were dissolved in acetonitrile (5 mL), and p-toluenesulfonic acid (203.8 mg, 1.19 mmol) was added. The mixture was stirred at 90° C. for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated. The residue was purified by silica gel chromatography and eluted with (petroleum ether: ethyl acetate = 1:1) to give product C001-1a (400 mg). 1 H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 9.06 (s, 1H), 8.38 (d, J = 36.0 Hz, 2H), 7.90 (s, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 4.74 (d, J = 8.0 Hz, 2H), 2.22 (s, 3H).
(2)化合物C001-1b的合成：将C001-1a(100mg，0.43mmol)、化合物int1(151mg，0.39mmol)、t-BuBrettPhos(19mg，0.043mmol)、Pd2(dba)3(37mg，0.043mmol)和磷酸钾(166mg，0.78mmol)溶解在叔丁醇(5mL)中。混合液在氮气保护下120℃搅拌5h。反应结束后，将反应液冷却至室温，加乙酸乙酯稀释，再加水，用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗涤2次，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶板层析纯化，用(石油醚:乙酸乙酯＝3:1)洗脱得产物C001-1b(120mg)，LCMS(ESI)m/z:539.6[M+H]+.(2) Synthesis of compound C001-1b: C001-1a (100 mg, 0.43 mmol), compound int1 (151 mg, 0.39 mmol), t-BuBrettPhos (19 mg, 0.043 mmol), Pd 2 (dba) 3 (37 mg, 0.043 mmol) and potassium phosphate (166 mg, 0.78 mmol) were dissolved in tert-butyl alcohol (5 mL). The mixture was stirred at 120°C for 5 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with ethyl acetate, and then water was added. The mixture was extracted with ethyl acetate three times, the organic phases were combined, washed twice with saturated brine, dried with sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography, and the product C001-1b (120 mg) was obtained by elution with (petroleum ether: ethyl acetate = 3:1). LCMS (ESI) m/z: 539.6 [M+H] + .
(5)化合物C001的合成：将C001-1b(160mg，0.30mmol)溶解在四氢呋喃(2mL)中，再加入氟化铯(137mg，0.90mmol)，反应液在室温下搅拌16h。反应结束后用乙酸乙酯萃取，合并有机相。有机相用盐水洗，无水硫酸钠干燥，真空浓缩，所得残余物经制备分析纯化得化合物C001(5.95mg)。LCMS(ESI)m/z:383.1[M+H]+.1H NMR(400MHz,DMSO)δ10.96(s,1H),9.06(s,1H),8.42(s,1H),8.34(s,0.7H),7.90(s,1H),7.80(d,J＝8.0Hz,2H),7.37(d,J＝8.0Hz,1H),7.09(d,J＝8.0Hz,1H),6.82(d,J＝8.0Hz,1H),4.75-4.73(m,2H),2.22(s,3H).(5) Synthesis of compound C001: C001-1b (160 mg, 0.30 mmol) was dissolved in tetrahydrofuran (2 mL), and cesium fluoride (137 mg, 0.90 mmol) was added. The reaction solution was stirred at room temperature for 16 h. After the reaction was completed, it was extracted with ethyl acetate and the organic phases were combined. The organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by preparative analysis to obtain compound C001 (5.95 mg). LCMS (ESI) m/z: 383.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 9.06 (s, 1H), 8.42 (s, 1H), 8.34 (s, 0.7H), 7.90 (s, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 4.75-4.73 (m, 2H), 2.22 (s, 3H).
实施例2：
Embodiment 2:
合成路线：
synthetic route:
将化合物int 5(100mg，0.35mmol)和化合物int 6(51mg，0.70mmol)溶解在乙腈(2mL)Dissolve compound int 5 (100 mg, 0.35 mmol) and compound int 6 (51 mg, 0.70 mmol) in acetonitrile (2 mL)
中，然后加入对甲苯磺酸(11.98mg，0.07mmol)。混合液在氮气保护下90℃搅拌4小时。反应结束后，将反应液浓缩。所得残余物反相制备纯化得最终产物C002(5.07mg)。LCMS(ESI):m/z＝391.1(M+H)+。1H NMR(400MHz,DMSO_d6)δ10.94(s,1H),9.03(s,1H),8.42(d,J＝4.0Hz,1H),7.90(s,1H),7.84–7.75(m,2H),7.36(d,J＝12.0Hz,1H),7.09(d,J＝8.0Hz,1H),6.82(d,J＝12.0Hz,1H),4.74(s,1H),3.07–2.93(m,2H),2.81–2.69(m,2H),2.20(s,3H).Then p-toluenesulfonic acid (11.98 mg, 0.07 mmol) was added. The mixture was stirred at 90°C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated. The obtained residue was purified by reverse phase preparation to obtain the final product C002 (5.07 mg). LCMS (ESI): m/z = 391.1 (M+H) +. 1 H NMR (400 MHz, DMSO_d6) δ 10.94 (s, 1H), 9.03 (s, 1H), 8.42 (d, J = 4.0 Hz, 1H), 7.90 (s, 1H), 7.84–7.75 (m, 2H), 7.36 (d, J = 12.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 12.0 Hz, 1H), 4.74 (s, 1H), 3.07–2.93 (m, 2H), 2.81–2.69 (m, 2H), 2.20 (s, 3H).
实施例3：
Embodiment 3:
合成路线：
synthetic route:
(1)将化合物C003-3a(5.0g,27.3mmol)置于100mL的单口瓶中，加入甲胺盐酸盐(3.6g,54.6mmol),然后0℃下加入乙腈(50mL)和碳酸钾(11.3g,81.9mmol)，氮气置换3次后室温下搅拌反应过夜。反应完成后，向反应液中加入100mL的水淬灭，用乙酸乙酯萃取(100mL x 3)，合并有机相，有机相用硫酸钠干燥,过滤，减压浓缩。浓缩物用硅胶柱层析纯化(0-20％乙酸乙酯/石油醚)(1) Compound C003-3a (5.0 g, 27.3 mmol) was placed in a 100 mL single-mouth bottle, methylamine hydrochloride (3.6 g, 54.6 mmol) was added, and then acetonitrile (50 mL) and potassium carbonate (11.3 g, 81.9 mmol) were added at 0°C. After nitrogen replacement 3 times, the reaction was stirred at room temperature overnight. After the reaction was completed, 100 mL of water was added to the reaction solution to quench, and it was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (0-20% ethyl acetate/petroleum ether).
得到化合物C003-3b(3.0g)。LCMS(ESI):m/z＝195.1(M+H)+。Compound C003-3b (3.0 g) was obtained. LCMS (ESI): m/z=195.1 (M+H) + .
(2)将化合物C003-3b(3g,15.4mmol)置于100mL的单口瓶中，加入甲醇(40mL),然后加入钯碳(300mg,1.5mmol)，氢气置换2次后，反应液在(氢气球)室温下搅拌反应2小时。反应结束后，将体系在装有硅藻土的砂芯漏斗上过滤，用甲醇(50mL)洗涤固体3次，合并有机相，真空浓缩得到化合物C003-3c(3.0g)。LCMS(ESI):m/z＝165.1(M+H)+。(2) Compound C003-3b (3 g, 15.4 mmol) was placed in a 100 mL single-mouth bottle, methanol (40 mL) was added, and then palladium carbon (300 mg, 1.5 mmol) was added. After hydrogen replacement twice, the reaction solution was stirred (hydrogen balloon) at room temperature for 2 hours. After the reaction was completed, the system was filtered on a sand core funnel filled with diatomaceous earth, the solid was washed 3 times with methanol (50 mL), the organic phases were combined, and vacuum concentrated to obtain compound C003-3c (3.0 g). LCMS (ESI): m/z = 165.1 (M+H) +.
(3)将化合物C003-3c(3.0g,18.3mmol)溶解在甲醇(30mL)中，然后加入溴化氰(2.9g,27.4mmol)，氮气置换3次后室温下搅拌反应1小时。反应完成后加入硅胶减压浓缩，浓缩物用硅胶柱层析纯化(10-50％乙酸乙酯/石油醚)得到化合物C003-3d(2.0g)。LCMS(ESI):m/z＝190.3(M+H)+。(3) Compound C003-3c (3.0 g, 18.3 mmol) was dissolved in methanol (30 mL), and then cyanogen bromide (2.9 g, 27.4 mmol) was added. After nitrogen replacement for 3 times, the mixture was stirred and reacted at room temperature for 1 hour. After the reaction was completed, silica gel was added and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (10-50% ethyl acetate/petroleum ether) to obtain compound C003-3d (2.0 g). LCMS (ESI): m/z = 190.3 (M+H) + .
(4)将化合物C003-3d(900mg，4.8mmol)溶解在乙腈(40mL)中，分别加入化合物int3(657mg,5.7mmol)和对甲苯磺酸一水合物(181mg,0.9mmol),氮气置换3次后升温至90℃下搅拌反应4小时。反应完成后，冷却至室温，反应液中加入50mL的水淬灭，用乙酸乙酯萃取(50mL x 3)，合并有机相，有机相用50mL的饱和食盐水洗涤并用硫酸钠干燥,过滤.减压浓缩。浓缩物用硅胶柱层析纯化(10-40％乙酸乙酯/石油醚)得到化合物C003-3e(800mg)。LCMS(ESI):m/z＝287.2(M+H)+.(4) Compound C003-3d (900 mg, 4.8 mmol) was dissolved in acetonitrile (40 mL), and compound int3 (657 mg, 5.7 mmol) and p-toluenesulfonic acid monohydrate (181 mg, 0.9 mmol) were added respectively. After nitrogen replacement 3 times, the temperature was raised to 90°C and stirred for 4 hours. After the reaction was completed, it was cooled to room temperature, 50 mL of water was added to the reaction solution for quenching, and it was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (10-40% ethyl acetate/petroleum ether) to obtain compound C003-3e (800 mg). LCMS (ESI): m/z=287.2 (M+H) + .
(5)将化合物C003-3e(200mg,0.7mmol)和化合物int1(541g,1.4mmol)溶解在1,4-二氧六环(5mL)中，然后加入磷酸钾(445mg,2.1mmol),t-BuBrettPhos(102mg,0.21mmol)和三(二亚苄基丙酮)二钯(128mg,0.14mmol),氮气置换后120℃下搅拌反应10小时。反应完成后，将体系冷却至室温，向反应液中加入50mL的水淬灭，用乙酸乙酯萃取(50mL x 3)，合并有机相，有机相用50mL的饱和食盐水洗涤并用硫酸钠干燥,过滤.减压浓缩。浓缩物用硅胶柱层析纯化(20-40％乙酸乙酯/石油醚)得到化合物C003-3f(100mg)。LCMS(ESI):m/z＝592.3(M+H)+ (5) Compound C003-3e (200 mg, 0.7 mmol) and compound int1 (541 g, 1.4 mmol) were dissolved in 1,4-dioxane (5 mL), and potassium phosphate (445 mg, 2.1 mmol), t-BuBrettPhos (102 mg, 0.21 mmol) and tris(dibenzylideneacetone)dipalladium (128 mg, 0.14 mmol) were added. After nitrogen substitution, the mixture was stirred at 120°C for 10 hours. After the reaction was completed, the system was cooled to room temperature, 50 mL of water was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (20-40% ethyl acetate/petroleum ether) to obtain compound C003-3f (100 mg). LCMS (ESI): m/z=592.3 (M+H) +
(6)将化合物C003-3f(100mg,0.17mmol)溶解在乙腈(2mL)中，冰浴条件下向体系中加入三乙胺三氟化氢盐(1mL)，加完后升温至室温下搅拌反应2小时。反应完成后，反相制备纯化得到化合物C003(10mg)。LCMS(ESI):m/z＝436.2(M+H)+.1H NMR(400MHz,DMSO)δ12.53(s,1H),11.62(s,1H),7.77(d,J＝12.0Hz,2H),7.62(s,2H),7.52(d,J＝12.0Hz,2H),7.20(d,J＝8.0Hz,1H),4.77(q,J＝8.0Hz,2H),3.82(s,3H),2.27(s,3H). (6) Compound C003-3f (100 mg, 0.17 mmol) was dissolved in acetonitrile (2 mL), and triethylamine trihydrogen fluoride (1 mL) was added to the system under ice bath conditions. After the addition, the temperature was raised to room temperature and stirred for 2 hours. After the reaction was completed, the compound C003 (10 mg) was obtained by reverse phase preparative purification. LCMS (ESI): m/z = 436.2 (M+H) +. 1H NMR (400 MHz, DMSO) δ 12.53 (s, 1H), 11.62 (s, 1H), 7.77 (d, J = 12.0 Hz, 2H), 7.62 (s, 2H), 7.52 (d, J = 12.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 1H), 4.77 (q, J = 8.0 Hz, 2H), 3.82 (s, 3H), 2.27 (s, 3H).
实施例4：
Embodiment 4:
合成路线：
synthetic route:
(1)将化合物C004-4a(25g，222.9mmol)溶解在二氯甲烷(250mL)中，然后加入N,N-二甲基甲酰胺二甲基缩醛(32mL，240.7mmol)反应液在常温下搅拌1小时。反应结束后旋干，将固体溶于乙醇，加入氰乙酰胺(60.55g，719.9mmol)，哌啶(10ml)和N,N-二甲基甲酰胺(200ml)，反应液在80℃下反应过夜。反应液冷却后，用水和冷乙醇过滤冲洗，得化合物C004-4b(28.6g)。LCMS(ESI):m/z＝207.2(M+H)+.(1) Compound C004-4a (25 g, 222.9 mmol) was dissolved in dichloromethane (250 mL), and then N,N-dimethylformamide dimethyl acetal (32 mL, 240.7 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the solid was spin-dried, dissolved in ethanol, and cyanoacetamide (60.55 g, 719.9 mmol), piperidine (10 ml) and N,N-dimethylformamide (200 ml) were added. The reaction solution was reacted at 80°C overnight. After the reaction solution was cooled, it was filtered and rinsed with water and cold ethanol to obtain compound C004-4b (28.6 g). LCMS (ESI): m/z = 207.2 (M+H) + .
(2)将化合物C004-4b(28.6g，138.7mmol)溶于在浓盐酸(500mL)中，在100℃下搅拌6小时。反应完成后用水和乙醇过滤冲洗，收集固体干燥，得化合物C004-4c(28.21g)。LCMS(ESI):m/z＝208.2(M+H)+.(2) Compound C004-4b (28.6 g, 138.7 mmol) was dissolved in concentrated hydrochloric acid (500 mL) and stirred at 100°C for 6 hours. After the reaction was completed, the mixture was filtered and rinsed with water and ethanol, and the solid was collected and dried to obtain compound C004-4c (28.21 g). LCMS (ESI): m/z = 208.2 (M+H) + .
(3)将化合物C004-4c(1g，4.82mmol)加热至320℃反应1小时，得到化合物C004-4d粗品(610mg)。LCMS(ESI):m/z＝164.1(M+H)+,(3) Compound C004-4c (1 g, 4.82 mmol) was heated to 320°C for 1 hour to obtain a crude compound C004-4d (610 mg). LCMS (ESI): m/z = 164.1 (M+H) + ,
(4)将化合物C004-4d(1g，6.12mmol)、三氯氧磷(2ml，23.9mmol)溶于乙腈(10ml)，反应液在90℃下反应2小时。反应结束后，用氨水中和反应液，乙酸乙酯萃取得有机相，无水硫酸钠干燥后，旋干，浓缩物用硅胶柱层析纯化(0-30％乙酸乙酯/石油醚)得到化合物C004-4e(300mg)。LCMS(ESI):m/z＝182.2(M+H)+,(4) Compound C004-4d (1 g, 6.12 mmol) and phosphorus oxychloride (2 ml, 23.9 mmol) were dissolved in acetonitrile (10 ml), and the reaction solution was reacted at 90° C. for 2 hours. After the reaction was completed, the reaction solution was neutralized with ammonia water, and the organic phase was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the organic phase was spin-dried, and the concentrate was purified by silica gel column chromatography (0-30% ethyl acetate/petroleum ether) to obtain compound C004-4e (300 mg). LCMS (ESI): m/z=182.2 (M+H)+,
(5)将化合物C004-4e(100mg，0.55mmol)、化合物int 2(92mg，0.55mmol)和对甲苯磺酸(94.8mg，0.55mmol)溶解在N,N-二甲基甲酰胺(2mL)中，反应液在120℃下搅拌16h。反应结束后用乙酸乙酯萃取，无水硫酸钠干燥，真空浓缩，所得残余物用硅胶板纯化，浓缩物用硅胶柱层析纯化(0-30％乙酸乙酯/石油醚)得到化合物C004-4f(90mg)。LCMS(ESI):m/z＝312.1(M+H)+,(5) Compound C004-4e (100 mg, 0.55 mmol), compound int 2 (92 mg, 0.55 mmol) and p-toluenesulfonic acid (94.8 mg, 0.55 mmol) were dissolved in N,N-dimethylformamide (2 mL), and the reaction solution was stirred at 120° C. for 16 h. After the reaction was completed, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel plate, and the concentrate was purified by silica gel column chromatography (0-30% ethyl acetate/petroleum ether) to obtain compound C004-4f (90 mg). LCMS (ESI): m/z=312.1 (M+H) + ,
(6)将化合物C004-4f(90mg，0.28mmol)、化合物int 3(89mg，0.77mmol)和对甲苯磺酸(22mg，0.12mmol)溶解在乙腈(2mL)中，反应液在90℃下搅拌4h。反应结束后将反应液浓缩，所得残余物经反相制备分析纯化得化合物最终产物(9.68mg)。LCMS(ESI):m/z＝409.1(M+H)+.1H NMR(400MHz,DMSO_d6)δ10.92(s,1H),9.10(s,1H),8.00(s,1H),7.87–7.84(m,2H),7.36(d,J＝8.0Hz,1H),7.10(d,J＝4.0Hz,1H),6.71(d,J＝8.0Hz,1H),4.70(q,J＝12.0Hz,2H),2.78(t,J＝8.0Hz,2H),2.70(t,J＝8.0Hz,2H),1.86–1.83(m,2H).(6) Compound C004-4f (90 mg, 0.28 mmol), compound int 3 (89 mg, 0.77 mmol) and p-toluenesulfonic acid (22 mg, 0.12 mmol) were dissolved in acetonitrile (2 mL), and the reaction solution was stirred at 90° C. for 4 h. After the reaction was completed, the reaction solution was concentrated, and the obtained residue was purified by reverse phase preparative analysis to obtain the final compound product (9.68 mg). LCMS (ESI): m/z = 409.1 (M+H) + . 1 H NMR (400 MHz, DMSO_d6) δ 10.92 (s, 1H), 9.10 (s, 1H), 8.00 (s, 1H), 7.87-7.84 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 4.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 4.70 (q, J = 12.0 Hz, 2H), 2.78 (t, J = 8.0 Hz, 2H), 2.70 (t, J = 8.0 Hz, 2H), 1.86-1.83 (m, 2H).
实施例5：
Embodiment 5:
合成路线：
synthetic route:
将化合物int 5(200mg,0.7mmol)和化合物int 7(128mg,0.84mmol)溶解在乙腈(2mL)中，加入对甲苯磺酸(27mg,0.14mmol)，加完后升温至90℃搅拌反应4小时。反应完成后，反相制备纯化得到最终产物C005(10mg)。LCMS(ESI):m/z＝419.2(M+H)+.1H NMR(400MHz,DMSO_d6)δ11.12(s,1H),8.34–8.28(m,1H),7.95-7.93(m,1H),7.86(s,1H),7.73(s,1H),7.49–7.39(m,1H),7.13–7.10(m,1H),6.89(s,1H),4.36–4.29(m,1H),2.18(s,3H),2.07–1.84(m,8H).Compound int 5 (200 mg, 0.7 mmol) and compound int 7 (128 mg, 0.84 mmol) were dissolved in acetonitrile (2 mL), p-toluenesulfonic acid (27 mg, 0.14 mmol) was added, and the temperature was raised to 90°C and stirred for 4 hours. After the reaction was completed, the final product C005 (10 mg) was obtained by reverse phase preparative purification. LCMS (ESI): m/z = 419.2 (M+H) +. 1H NMR (400 MHz, DMSO_d6) δ 11.12 (s, 1H), 8.34–8.28 (m, 1H), 7.95-7.93 (m, 1H), 7.86 (s, 1H), 7.73 (s, 1H), 7.49–7.39 (m, 1H), 7.13–7.10 (m, 1H), 6.89 (s, 1H), 4.36–4.29 (m, 1H), 2.18 (s, 3H), 2.07–1.84 (m, 8H).
实施例6：
Embodiment 6:
合成路线：
synthetic route:
(1)将化合物C006-6a(1.0g，7.17mmol，1eq)和化合物int2(1.6g，7.88mmol，1.1eq)和对甲苯磺酸水合物(1.5g，7.88mmol，1.1eq)溶解在N,N-二甲基甲酰胺(25.0mL)中，在120℃下搅拌5h。反应结束后旋干溶剂，用乙酸乙酯萃取反应物并用水洗涤，合并有机相所得残余物用柱层析纯化，浓缩物用硅胶柱层析纯化(0-50％乙酸乙酯/石油醚)得化合物C006-6b(1.5g)。LCMS(ESI):m/z＝270.0(M+H)+,(1) Compound C006-6a (1.0 g, 7.17 mmol, 1 eq) and compound int2 (1.6 g, 7.88 mmol, 1.1 eq) and p-toluenesulfonic acid hydrate (1.5 g, 7.88 mmol, 1.1 eq) were dissolved in N,N-dimethylformamide (25.0 mL) and stirred at 120° C. for 5 h. After the reaction, the solvent was dried, the reactant was extracted with ethyl acetate and washed with water, the organic phases were combined and the residue was purified by column chromatography, and the concentrate was purified by silica gel column chromatography (0-50% ethyl acetate/petroleum ether) to obtain compound C006-6b (1.5 g). LCMS (ESI): m/z=270.0 (M+H)+,
(2)将化合物C006-6b(400mg，1.48mmol，1eq)溶解在超干四氢呋喃(3.0mL)中，置换氮气，在0℃下搅拌20min，将甲基溴化镁(4.44mL，4.44mmol，3eq)缓慢滴加到溶液中。滴加完毕后，升温至45℃，搅拌16h。反应结束后，加入饱和氯化铵溶液淬灭，混合物用乙酸乙酯萃取，合并有机相所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝2:1)洗脱得化合物C006-6c(250mg)。LCMS(ESI):m/z＝287.0(M+H)+.(2) Compound C006-6b (400 mg, 1.48 mmol, 1 eq) was dissolved in ultra-dry tetrahydrofuran (3.0 mL), nitrogen was replaced, and the mixture was stirred at 0°C for 20 min. Methylmagnesium bromide (4.44 mL, 4.44 mmol, 3 eq) was slowly added dropwise to the solution. After the addition was complete, the temperature was raised to 45°C and stirred for 16 h. After the reaction was completed, saturated ammonium chloride solution was added to quench the mixture, and the mixture was extracted with ethyl acetate. The residue obtained by combining the organic phases was purified by column chromatography and eluted with (petroleum ether: ethyl acetate = 2:1) to obtain compound C006-6c (250 mg). LCMS (ESI): m/z = 287.0 (M+H) + .
(3)将化合物C006-6c(200mg，0.70mmol，1eq)，化合物int3(127mg，0.84mmol，1.2eq)和对甲苯磺酸水合物(26mg，0.14mmol，0.2eq)溶解在乙腈(5.0mL)中，在90℃下搅拌4h。反应结束后，过滤反应液，用乙腈洗涤，合并有机相所得残余物经反相制备纯化得最终产物C006(33.48mg)。LCMS(ESI):m/z＝383.9(M+H)+.1H NMR(400MHz,DMSO_d6)δ11.07(s,1H),9.38(s,1H),8.04(d,J＝4.0Hz,1H),7.84(s,1H),7.77(d,J＝12.0Hz,1H),7.39(d,J＝12.0Hz,1H),7.18(d,J＝8.0Hz,1H),7.13(d,J＝4.0Hz,1H),7.11(d,J＝4.0Hz,1H),4.84(q,J＝8.0Hz,2H),2.38(s,3H).(3) Compound C006-6c (200 mg, 0.70 mmol, 1 eq), compound int3 (127 mg, 0.84 mmol, 1.2 eq) and p-toluenesulfonic acid hydrate (26 mg, 0.14 mmol, 0.2 eq) were dissolved in acetonitrile (5.0 mL) and stirred at 90° C. for 4 h. After the reaction was completed, the reaction solution was filtered and washed with acetonitrile. The organic phases were combined and the residues were purified by reverse phase preparative purification to obtain the final product C006 (33.48 mg). LCMS (ESI): m/z = 383.9 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.38 (s, 1H), 8.04 (d, J = 4.0 Hz, 1H), 7.84 (s, 1H), 7.77 (d, J = 12.0 Hz, 1H), 7.39 (d, J = 12.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 4.0 Hz, 1H), 7.11 (d, J = 4.0 Hz, 1H), 4.84 (q, J = 8.0 Hz, 2H), 2.38 (s, 3H).
实施例7：
Embodiment 7:
合成路线：
synthetic route:
(1)将化合物C007-7a(4.5g,37.8mmol)置于100mL的单口瓶中，加入四氢呋喃(40mL),氮气置换3次后，在0℃下滴加MeMgBr(1M in THF,114mmol,114mL)，控制反应温度在0℃-5℃反应2小时。反应完成后，将反应液中倒入100mL冰水淬灭，用乙酸乙酯萃取(100mL x 3)，合并有机相，有机相用硫酸钠干燥,过滤，减压浓缩。浓缩物用硅胶柱层析纯化(0-30％乙酸乙酯/石油醚)得到化合物C007-7b(3.5g)。LCMS(ESI):m/z＝137.1(M+H)+.(1) Compound C007-7a (4.5 g, 37.8 mmol) was placed in a 100 mL single-mouth bottle, tetrahydrofuran (40 mL) was added, and after nitrogen replacement 3 times, MeMgBr (1M in THF, 114 mmol, 114 mL) was added dropwise at 0°C, and the reaction temperature was controlled at 0°C-5°C for 2 hours. After the reaction was completed, 100 mL of ice water was poured into the reaction solution to quench, and it was extracted with ethyl acetate (100 mL x 3), and the organic phases were combined, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (0-30% ethyl acetate/petroleum ether) to obtain compound C007-7b (3.5 g). LCMS (ESI): m/z=137.1 (M+H) + .
(2)将化合物C007-7b(1.1g,8.3mmol)和化合物int 3(800mg,6.96mmol)置于100mL的单口瓶中，加入乙腈(40mL),然后加入对甲苯磺酸(265mg,1.39mmol)，氮气置换2次后，反应液在90℃搅拌反应4小时。反应结束后，将反应液降温至室温，加入硅胶，浓缩物用硅胶柱层析纯化(0-30％乙酸乙酯/石油醚)得到化合物C007-7c(300mg)。LCMS(ESI):m/z＝234.1(M+H)+.(2) Compound C007-7b (1.1 g, 8.3 mmol) and compound int 3 (800 mg, 6.96 mmol) were placed in a 100 mL single-mouth bottle, acetonitrile (40 mL) was added, and then p-toluenesulfonic acid (265 mg, 1.39 mmol) was added. After nitrogen replacement twice, the reaction solution was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, silica gel was added, and the concentrate was purified by silica gel column chromatography (0-30% ethyl acetate/petroleum ether) to obtain compound C007-7c (300 mg). LCMS (ESI): m/z = 234.1 (M+H) + .
(3)将化合物C007-7c(260mg,1.2mmol)和化合物int 1(516mg,1.34mmol)溶解在叔丁醇(5mL)中，然后加入磷酸钾(710mg,3.35mmol),t-BuBreetPhos(108mg,0.22mmol)和三(二亚苄基丙酮)二钯(102mg,0.11mmol),氮气置换后120℃下搅拌反应10小时。反应完成后，将体系冷却至室温，向反应液中加入50mL的水淬灭，用乙酸乙酯萃取(50mL x 3)，合并有机相，有机相用50mL的饱和食盐水洗涤并用硫酸钠干燥,过滤.减压浓缩。浓缩物用硅胶柱层析纯化(10-30％乙酸乙酯/石油醚)得到化合物C007-7d(200mg)。LCMS(ESI):m/z＝539.2(M+H)+.(3) Compound C007-7c (260 mg, 1.2 mmol) and compound int 1 (516 mg, 1.34 mmol) were dissolved in tert-butyl alcohol (5 mL), and potassium phosphate (710 mg, 3.35 mmol), t-BuBreetPhos (108 mg, 0.22 mmol) and tris(dibenzylideneacetone)dipalladium (102 mg, 0.11 mmol) were added. After nitrogen substitution, the mixture was stirred at 120°C for 10 hours. After the reaction was completed, the system was cooled to room temperature, 50 mL of water was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (10-30% ethyl acetate/petroleum ether) to obtain compound C007-7d (200 mg). LCMS (ESI): m/z = 539.2 (M+H) + .
(4)将化合物C007-7d(150mg,0.28mmol)溶解在四氢呋喃(5mL)中，冰浴条件下向体系中加入CsF(127mg,0.84mmol)，加完后室温下搅拌反应16小时。反应完成后，反相制备纯化得最终产物C007(10mg)。LCMS(ESI):m/z＝383.1(M+H)+.1H NMR(400MHz,DMSO_d6)δ11.19(s,1H),8.18(s,1H),8.15(d,J＝4.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.47(d,J＝4.0Hz,1H),7.42-7.40(m,2H),7.13-7.08(m,2H),4.76(q,J＝8.0Hz,2H),2.25(s,3H).(4) Compound C007-7d (150 mg, 0.28 mmol) was dissolved in tetrahydrofuran (5 mL), and CsF (127 mg, 0.84 mmol) was added to the system under ice bath conditions. After the addition, the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the final product C007 (10 mg) was obtained by reverse phase preparative purification. LCMS (ESI): m/z = 383.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 8.18 (s, 1H), 8.15 (d, J = 4.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 4.0 Hz, 1H), 7.42-7.40 (m, 2H), 7.13-7.08 (m, 2H), 4.76 (q, J = 8.0 Hz, 2H), 2.25 (s, 3H).
实施例8：
Embodiment 8:
合成路线：
synthetic route:
(1)将化合物C008-8a(4.0g，31.2mmol，1.1eq)，化合物3b(4.6g，28.4mmol，1.0eq)和三苯基磷(8.2g，31.2mmol，1.1eq)在四氢呋喃(100mL)中，反应体系降温至0℃。将DBAD(7.2g，31.2mmol，1.1eq)溶于四氢呋喃(100mL)，缓慢滴到反应液中，滴加完毕后温度升至室温搅拌6h。反应完毕后旋干得到的混合物用二氯甲烷和水进行萃取，合并有机相，所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝3:1)洗脱得化合物C008-8b(4.2g)。LCMS(ESI):m/z＝273.1(M+H)+.1H NMR(400MHz,DMSO_d6)δ7.87(s,4H),4.22(t,J＝8.0Hz,2H),2.58–2.52(m,2H),1.93–1.86(m,2H).(1) Compound C008-8a (4.0 g, 31.2 mmol, 1.1 eq), compound 3b (4.6 g, 28.4 mmol, 1.0 eq) and triphenylphosphine (8.2 g, 31.2 mmol, 1.1 eq) were placed in tetrahydrofuran (100 mL), and the reaction system was cooled to 0°C. DBAD (7.2 g, 31.2 mmol, 1.1 eq) was dissolved in tetrahydrofuran (100 mL) and slowly dripped into the reaction solution. After the addition was complete, the temperature was raised to room temperature and stirred for 6 h. After the reaction was completed, the mixture was dried and extracted with dichloromethane and water. The organic phases were combined, and the residue was purified by column chromatography and eluted with (petroleum ether: ethyl acetate = 3:1) to obtain compound C008-8b (4.2 g). LCMS (ESI): m/z = 273.1 (M+H) + . 1 H NMR (400 MHz, DMSO_d6) δ 7.87 (s, 4H), 4.22 (t, J = 8.0 Hz, 2H), 2.58-2.52 (m, 2H), 1.93-1.86 (m, 2H).
(2)将化合物C008-8b(1g，3.66mmol，1eq)溶解在(二氯甲烷/甲醇＝10/1)(10mL)中，逐步滴加68％水合肼(0.5mL，7.32mmol，2eq)，在室温下搅拌2h。反应结束后过滤，用氨水冲洗滤液，用二氯甲烷和水萃取，合并有机相，旋蒸后加入乙醇，滴加浓盐酸呈酸性有固体析出，过滤得到化合物C008-8c(500mg)。1H NMR(400MHz,DMSO_d6)δ11.14(s,2H),4.09(t,J＝8.0Hz,2H),2.41–2.28(m,2H),1.87–1.80(m,2H).(2) Compound C008-8b (1 g, 3.66 mmol, 1 eq) was dissolved in (dichloromethane/methanol = 10/1) (10 mL), and 68% hydrazine hydrate (0.5 mL, 7.32 mmol, 2 eq) was gradually added dropwise, and stirred at room temperature for 2 h. After the reaction was completed, the mixture was filtered, and the filtrate was washed with ammonia water, extracted with dichloromethane and water, and the organic phases were combined, and ethanol was added after rotary evaporation. Concentrated hydrochloric acid was added dropwise to make the mixture acidic and solid precipitated. Compound C008-8c (500 mg) was obtained by filtration. 1 H NMR (400 MHz, DMSO_d6) δ11.14 (s, 2H), 4.09 (t, J = 8.0 Hz, 2H), 2.41–2.28 (m, 2H), 1.87–1.80 (m, 2H).
(3)将化合物C008-8c(100mg，0.56mmol，1eq)，化合物int 5(191mg，0.67mmol，1.2eq) 和对甲苯磺酸水合物(21mg，0.11mmol，0.2eq)溶解在乙腈(3.0mL)中，在90℃下搅拌4h。反应结束后，过滤反应液，用乙腈洗涤，合并有机相所得残余物经制备分析纯化得最终产物C008(9.30mg)。LCMS(ESI):m/z＝411.1(M+H)+.1H NMR(400MHz,DMSO_d6)δ10.93(s,1H),8.99(s,1H),8.40(d,J＝2.0Hz,1H),7.90(d,J＝2.0Hz,1H),7.81(d,J＝8.0Hz,1H),7.80(s,1H),7.36(d,J＝8.0Hz,1H),7.10-7.07(m,1H),6.81(d,J＝8.0Hz,1H),4.15(t,J＝8.0Hz,2H),2.39–2.32(m,2H),2.17(s,3H),1.92–1.85(m,2H).(3) Compound C008-8c (100 mg, 0.56 mmol, 1 eq) and compound int 5 (191 mg, 0.67 mmol, 1.2 eq) were added. and p-toluenesulfonic acid hydrate (21 mg, 0.11 mmol, 0.2 eq) were dissolved in acetonitrile (3.0 mL) and stirred at 90° C. for 4 h. After the reaction was completed, the reaction solution was filtered and washed with acetonitrile, and the residue obtained by combining the organic phases was purified by preparative analysis to obtain the final product C008 (9.30 mg). LCMS (ESI): m/z = 411.1 (M+H) + . 1 H NMR (400 MHz, DMSO_d6) δ 10.93 (s, 1H), 8.99 (s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.10-7.07 (m, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.15 (t, J = 8.0 Hz, 2H), 2.39-2.32 (m, 2H), 2.17 (s, 3H), 1.92-1.85 (m, 2H).
实施例9：
Embodiment 9:
合成路线：
synthetic route:
(1)将化合物3c(4g，15.43mmol)溶解在二氯甲烷(40mL)和甲醇(4ml)混合液中，然后在室温下滴加水合肼(68％)(1.5ml)。反应液在室温下搅拌2小时。反应完成后过滤沉淀，滤液加入5N氨水(100ml)搅拌后静置分液，水相用二氯甲烷(50mL)萃取三次，有机相用无水硫酸钠干燥。干燥后常温减压浓缩后加入乙醇(20ml)和浓盐酸(2ml)，反应液呈酸性，减压浓缩后得到int3·HCl(2g)。1H NMR(400MHz,DMSO_d6)δ4.31(d,J＝8.0Hz,2H),2.82–2.74(m,2H).(1) Compound 3c (4 g, 15.43 mmol) was dissolved in a mixture of dichloromethane (40 mL) and methanol (4 ml), and then hydrazine hydrate (68%) (1.5 ml) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the precipitate was filtered, and the filtrate was added with 5N ammonia water (100 ml) and stirred, and then allowed to stand for separation. The aqueous phase was extracted three times with dichloromethane (50 mL), and the organic phase was dried over anhydrous sodium sulfate. After drying, ethanol (20 ml) and concentrated hydrochloric acid (2 ml) were added to the mixture under reduced pressure at room temperature. The reaction solution was acidic and concentrated under reduced pressure to obtain int3·HCl (2 g). 1 H NMR (400 MHz, DMSO_d6) δ4.31 (d, J＝8.0 Hz, 2H), 2.82–2.74 (m, 2H).
(2)将int5(200mg，0.70mmol)和int3·HCl(101.65mg，1.05mmol)溶解在乙腈(10mL)中，然后加入对甲苯磺酸(18mg，0.14mmol)。混合液在氮气保护下90℃搅拌4小时。反应结束后，将反应液浓缩。所得残余物反相制备分析纯化得化合物C009(38.91mg)。LCMS(ESI)m/z:397.0[M+H]+；1H NMR(400MHz,DMSO_d6)δ10.94(s,1H),9.01(s,1H),8.42(d,J＝4.0Hz,1H),7.90(d,J＝4.0Hz,1H),7.84(dd,J＝8.0,2.0Hz,1H),7.79(d,J＝4.0Hz,1H),7.37(d,J＝8.0Hz,1H),7.09(dd,J＝4.0,4.0Hz,1H),6.80(d,J＝8.0Hz,1H),4.3(d,J＝8.0Hz,2H),2.75–2.67(m,2H),2.16(s,3H).(2) Int5 (200 mg, 0.70 mmol) and int3·HCl (101.65 mg, 1.05 mmol) were dissolved in acetonitrile (10 mL), and p-toluenesulfonic acid (18 mg, 0.14 mmol) was then added. The mixture was stirred at 90°C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated. The obtained residue was purified by reverse phase preparative analysis to obtain compound C009 (38.91 mg). LCMS (ESI) m/z: 397.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.01 (s, 1H), 8.42 (d, J = 4.0 Hz, 1H), 7.90 (d, J = 4.0 Hz, 1H), 7.84 (dd, J = 8.0, 2.0 Hz, 1H), 7.79 (d, J = 4.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.09 (dd, J = 4.0, 4.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 4.3 (d, J = 8.0 Hz, 2H), 2.75-2.67 (m, 2H), 2.16 (s, 3H).
实施例10：
Embodiment 10:
合成路线：
synthetic route:
(1)将int5(220mg，0.708mmol)和int7(135mg,0.849mmol)溶解在ACN(5mL)中，加入对甲苯磺酸水合物(26mg，0.141mmol),在60℃下搅拌4h。反应结束后，将反应液减压浓缩，所得残余物经反相制备分析纯化得化合物C010(22.75mg)。LCMS(ESI)m/z:416.2[M+H]+；1H NMR(400MHz,CD3OD)δ8.49(d,J＝4.0Hz,1H),8.20(d,J＝4.0Hz,1H),7.49(s,1H),7.36–7.35(m,2H),7.10(dd,J＝2.0Hz,8.0Hz,1H),4.79–4.76(m,1H),2.99–2.90(m,2H),2.82–2.69(m,2H),2.2(s, 3H).(1) Int5 (220 mg, 0.708 mmol) and int7 (135 mg, 0.849 mmol) were dissolved in ACN (5 mL), p-toluenesulfonic acid hydrate (26 mg, 0.141 mmol) was added, and the mixture was stirred at 60° C. for 4 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase preparative analysis to obtain compound C010 (22.75 mg). LCMS (ESI) m/z: 416.2 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ8.49 (d, J=4.0 Hz, 1H), 8.20 (d, J=4.0 Hz, 1H), 7.49 (s, 1H), 7.36–7.35 (m, 2H), 7.10 (dd, J=2.0 Hz, 8.0 Hz, 1H), 4.79–4.76 (m, 1H), 2.99–2.90 (m, 2H), 2.82–2.69 (m, 2H), 2.2 (s, 3H).
实施例11：
Embodiment 11:
合成路线：
synthetic route:
(1)于三口反应瓶中将C011-1a(19g，141.66mmol)溶解在二氯甲烷(380mL)中，将三氟化硼乙醚溶液(23.2mL，184.16mmol)溶解在二氯甲烷(95mL)中作为备用溶液a，置于恒压滴液漏斗，将重氮乙酸乙酯C011-11b(21g，184.16mmol)溶解在二氯甲烷(95mL)中作为备用溶b，置于另一恒压滴液漏斗。氮气置换反应体系后，降温至-10℃。搅拌15分钟后，开始滴加备用溶液a，滴加完成后保持温度-10℃，搅拌10分钟。滴加备用溶液b，滴加完成后保持温度-10℃，搅拌1小时。撤去冰盐浴，自然升至室温。反应完全后，用碳酸钾水溶液(30wt％，190mL)淬灭反应，分出有机相，用饱和盐水洗一遍，干燥并过滤，将滤液减压浓缩，所得粗品C011-11c(30g)可直接用于下一步。(1) In a three-necked reaction flask, C011-1a (19 g, 141.66 mmol) was dissolved in dichloromethane (380 mL), and a boron trifluoride ether solution (23.2 mL, 184.16 mmol) was dissolved in dichloromethane (95 mL) as a standby solution a, and placed in a constant pressure dropping funnel. Ethyl diazoacetate C011-11b (21 g, 184.16 mmol) was dissolved in dichloromethane (95 mL) as a standby solution b, and placed in another constant pressure dropping funnel. After nitrogen substitution, the reaction system was cooled to -10°C. After stirring for 15 minutes, standby solution a was added dropwise. After the addition was completed, the temperature was maintained at -10°C and stirred for 10 minutes. Standby solution b was added dropwise. After the addition was completed, the temperature was maintained at -10°C and stirred for 1 hour. The ice-salt bath was removed and the mixture was naturally warmed to room temperature. After the reaction is completed, the reaction is quenched with aqueous potassium carbonate solution (30wt%, 190mL), the organic phase is separated, washed once with saturated brine, dried and filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product C011-11c (30g) which can be directly used in the next step.
(2)在1L反应瓶中，将粗品C011-11c(30g，141.66mmol)加入到盐酸(3mol/L,285mL)溶液中。反应体系搅拌加热至100℃，并回流4小时。反应完成后冷却至室温，二氯甲烷(100mL)萃取两次，合并有机相干燥过滤减压浓缩，所得残余物用硅胶柱层析纯化，(石油醚:乙酸乙酯＝20:1)洗脱得化合物C011-11d(6.96g)。(2) In a 1L reaction bottle, the crude product C011-11c (30 g, 141.66 mmol) was added to a hydrochloric acid solution (3 mol/L, 285 mL). The reaction system was stirred and heated to 100°C and refluxed for 4 hours. After the reaction was completed, it was cooled to room temperature and extracted twice with dichloromethane (100 mL). The organic phases were combined, dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain compound C011-11d (6.96 g).
(3)将C011-11d(6.96g，46.97mmol)溶解在无水甲醇(70mL)中，氮气保护下降温冷却至0℃。分多次加入硼氢化钠(2.13g，56.36mmol)，加完后不撤冰浴，反应液自然升温至室温。反应结束后，用饱和食盐水(70mL)淬灭反应，减压浓缩出甲醇后。用乙酸乙酯(70mL)萃取3次，有机相用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化，(石油醚:乙酸乙酯＝10:1)洗脱得化合物C011-11e(4.96g)。(3) C011-11d (6.96 g, 46.97 mmol) was dissolved in anhydrous methanol (70 mL) and cooled to 0°C under nitrogen protection. Sodium borohydride (2.13 g, 56.36 mmol) was added in several portions. After the addition, the ice bath was not removed and the reaction solution was naturally heated to room temperature. After the reaction was completed, the reaction was quenched with saturated brine (70 mL) and the methanol was concentrated under reduced pressure. It was extracted with ethyl acetate (70 mL) three times, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound C011-11e (4.96 g).
(4)将偶氮二甲酸二叔丁酯(DBAD，8.1g，35.16mmol)溶解在无水四氢呋喃(100mL)中，作为备用溶液a。将C011-11e(4.8g，31.96mmol)、化合物3b(5.74g，35.16mmol)和三苯基膦(9.23g，35.16mmol)溶解在无水甲苯(177mL)中，氮气保护下降温至0℃搅拌，滴加备用溶液a，滴完后自然升至室温。反应结束后加水(100mL)，用二氯甲烷(100mL)萃取3次，合并有机相干燥过滤减压浓缩。所得残余物用硅胶柱层析纯化，(石油醚:乙酸乙酯＝10:1)洗脱得化合物C011-11f(2.246g)。(4) Di-tert-butyl azodicarboxylate (DBAD, 8.1 g, 35.16 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) as a standby solution a. C011-11e (4.8 g, 31.96 mmol), compound 3b (5.74 g, 35.16 mmol) and triphenylphosphine (9.23 g, 35.16 mmol) were dissolved in anhydrous toluene (177 mL), cooled to 0°C under nitrogen protection and stirred, and standby solution a was added dropwise. After the addition was completed, the temperature was naturally raised to room temperature. After the reaction was completed, water (100 mL) was added, and the mixture was extracted with dichloromethane (100 mL) for 3 times. The organic phases were combined, dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound C011-11f (2.246 g).
(5)将C011-11f(2.246g，7.61mmol)溶解在二氯甲烷(22mL)和无水甲醇(2.2mL)的混合溶剂中，氮气保护下冰水浴降温至0℃，滴加水合肼(98％，771mg，15.1mmol)，滴完后自然升至室温反应2小时。过滤反应液，二氯甲烷(20mL)洗滤饼，氨水(20mL)洗滤饼2次。水相用二氯甲烷(20mL)萃取3次，合并有机相，无水硫酸钠干燥，过滤，常温减压浓缩滤液，加入无 水乙醇(10mL)溶解后用浓盐酸调至酸性(pH＝3)，减压浓缩至干，得到化合物C011-11g。(5) C011-11f (2.246 g, 7.61 mmol) was dissolved in a mixed solvent of dichloromethane (22 mL) and anhydrous methanol (2.2 mL). The mixture was cooled to 0°C in an ice-water bath under nitrogen protection. Hydrazine hydrate (98%, 771 mg, 15.1 mmol) was added dropwise. After the addition was complete, the mixture was naturally heated to room temperature and reacted for 2 hours. The reaction solution was filtered, and the filter cake was washed with dichloromethane (20 mL) and ammonia water (20 mL) twice. The aqueous phase was extracted three times with dichloromethane (20 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at room temperature. Anhydrous After dissolving in water and ethanol (10 mL), the mixture was adjusted to acidity (pH=3) with concentrated hydrochloric acid and concentrated to dryness under reduced pressure to obtain compound C011-11g.
(6)将C011-11g(315mg，1.1mmol)、int5(142mg，0.7mmol)和一水合对甲苯磺酸(27mg，0.14mmol)溶解在乙腈(4.8mL)中，氮气保护下90℃搅拌4小时。反应完成后降至室温，减压浓缩。经反相制备分析纯化得化合物C011(23mg)。LCMS(ESI)m/z:433.3[M+H]+；1H NMR(400MHz,DMSO_d6)δ10.94(s,1H),8.99(s,1H),8.40(d,J＝2.0Hz,1H),7.91(s,1H),7.84–7.78(m,2H),7.37(d,J＝8.4Hz,1H),7.09(dd,J＝8.0,2.0Hz,1H),6.81(d,J＝8.0Hz,1H),4.37–4.31(m,1H),2.20(s,3H),2.19–1.92(m,9H),1.87–1.74(m,2H),1.70–1.60(m,1H),1.55–1.43(m,1H).(6) C011-11g (315 mg, 1.1 mmol), int5 (142 mg, 0.7 mmol) and p-toluenesulfonic acid monohydrate (27 mg, 0.14 mmol) were dissolved in acetonitrile (4.8 mL) and stirred at 90°C for 4 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. Compound C011 (23 mg) was obtained by reverse phase preparative analysis and purification. LCMS (ESI) m/z: 433.3 [M+H] + ; 1 H NMR (400 MHz, DMSO_d6) δ 10.94 (s, 1H), 8.99 (s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 7.91 (s, 1H), 7.84-7.78 (m, 2H), 7.37 (d, J = 8.4 Hz, 1H), 7.09 (dd, J = 8.0, 2.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.37-4.31 (m, 1H), 2.20 (s, 3H), 2.19-1.92 (m, 9H), 1.87-1.74 (m, 2H), 1.70-1.60 (m, 1H), 1.55-1.43 (m, 1H).
实施例12和实施例13：
Example 12 and Example 13:
合成路线：化合物C011经手性SFC拆分为化合物C012和化合物C013。Synthesis route: Compound C011 was separated into compound C012 and compound C013 by chiral SFC.
系统：Waters SFC 150；柱：柱尺寸：250*25mm 10m；流动相A：超临界CO2；流动相B：MEOH(+0.1％7.0mol/l氨在MEOH中)；A:B＝70:30；波长：214nm；流速：100ml/min；柱温：室温；背压：100bar；注射：1mL；循环时间：5.1分钟；溶剂：甲醇：再蒸馏级，超临界CO2：食品级；样品溶液的制备：将样品溶解在约30mL MeOH中。System: Waters SFC 150; Column: Column size: 250*25mm 10m; mobile phase A: supercritical CO2; mobile phase B: MEOH (+0.1% 7.0 mol/l ammonia in MEOH); A:B=70:30; wavelength: 214nm; flow rate: 100ml/min; column temperature: room temperature; back pressure: 100bar; injection: 1mL; cycle time: 5.1 minutes; solvent: methanol: redistilled grade, supercritical CO2 : food grade; preparation of sample solution: dissolve the sample in about 30mL MeOH.
实施例14：
Embodiment 14:
合成路线：
synthetic route:
(1)将C004-4f(100mg，0.32mmol)、int6(78mg，0.64mmol)和对甲苯磺酸(12mg，0.06mmol)溶解在乙腈(2mL)中，反应液在90℃下搅拌4h。反应结束后将反应液减压浓缩，所得残余物经反相制备分析纯化得化合物C014(11.56mg)。LCMS(ESI)m/z:417.2[M+H]+；1H NMR(400MHz,DMSO_d6)δ10.91(s,1H),9.07(s,1H),8.00(s,1H),7.92–7.82(m,2H),7.36(d,J＝8.0Hz,1H),7.09(dd,J＝12.0,4.0Hz,1H),6.71(d,J＝8.0Hz,1H),4.70(m,1H),2.99(m,2H),2.79–2.66(m,6H),1.89–1.79(m,2H).(1) C004-4f (100 mg, 0.32 mmol), int6 (78 mg, 0.64 mmol) and p-toluenesulfonic acid (12 mg, 0.06 mmol) were dissolved in acetonitrile (2 mL), and the reaction solution was stirred at 90° C. for 4 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase preparative analysis to obtain compound C014 (11.56 mg). LCMS (ESI) m/z: 417.2 [M+H] + ; 1 H NMR (400 MHz, DMSO_d6) δ 10.91 (s, 1H), 9.07 (s, 1H), 8.00 (s, 1H), 7.92–7.82 (m, 2H), 7.36 (d, J=8.0 Hz, 1H), 7.09 (dd, J=12.0, 4.0 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 4.70 (m, 1H), 2.99 (m, 2H), 2.79–2.66 (m, 6H), 1.89–1.79 (m, 2H).
实施例15：
Embodiment 15:
合成路线：
synthetic route:
将int6(200mg，0.667mmol)和int8(98mg，0.801mmol)溶解在乙腈(4mL)中，然后加入对甲苯磺酸(22.9mg，0.133mmol)。混合液在氮气保护下70℃搅拌4小时。反应结束后，将反应液浓缩。所得残余物经制备分析纯化得化合物C015(29.95mg)。1H NMR(400MHz,DMSO_d6)δ10.96(s,1H),9.05(s,1H),8.41(s,1H),7.92(s,1H),7.85–7.79(m,2H),7.36(d,J＝12.0Hz,1H),7.09(d,J＝2.0,1H),7.08(d,J＝2.0Hz,1H),6.83(d,J＝8.0Hz,1H),4.76–4.74(m,1H),3.01–2.98(m,2H),2.77–2.64(m,4H),1.07(t,J＝8.0Hz,3H).Int6 (200 mg, 0.667 mmol) and int8 (98 mg, 0.801 mmol) were dissolved in acetonitrile (4 mL), and then p-toluenesulfonic acid (22.9 mg, 0.133 mmol) was added. The mixture was stirred at 70°C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated. The obtained residue was purified by preparative analysis to obtain compound C015 (29.95 mg). 1 H NMR (400 MHz, DMSO_d6) δ 10.96 (s, 1H), 9.05 (s, 1H), 8.41 (s, 1H), 7.92 (s, 1H), 7.85–7.79 (m, 2H), 7.36 (d, J = 12.0 Hz, 1H), 7.09 (d, J = 2.0, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 4.76–4.74 (m, 1H), 3.01–2.98 (m, 2H), 2.77–2.64 (m, 4H), 1.07 (t, J = 8.0 Hz, 3H).
实施例16和实施例17：
Example 16 and Example 17:
合成路线：
synthetic route:
(1)在氮气保护下，将C016-16a(5g，24.99mmol,1eq)溶解于四氢呋喃(20ml)中，降温至0℃，滴加乙基溴化镁溶液(19ml,37.49mmol,2M,1.5eq)，然后升温至45℃，搅拌16h。反应结束后，反应液用饱和氯化铵淬灭，混合物用乙酸乙酯萃取三次(30mL x 3)，有机相用饱和食盐水洗涤，无水硫酸钠干燥，合并有机相所得残余物用柱层析纯化，(PE:AE＝4:1)洗脱，得到C016-16b(2.5g,54,48％)。LCMS(ESI)m/z:184.1[M+H]+.(1) Under nitrogen protection, C016-16a (5 g, 24.99 mmol, 1 eq) was dissolved in tetrahydrofuran (20 ml), cooled to 0 ° C, ethyl magnesium bromide solution (19 ml, 37.49 mmol, 2 M, 1.5 eq) was added dropwise, and then the temperature was raised to 45 ° C and stirred for 16 h. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride, the mixture was extracted with ethyl acetate three times (30 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the residue obtained by combining the organic phases was purified by column chromatography (PE:AE = 4:1) to obtain C016-16b (2.5 g, 54, 48%). LCMS (ESI) m/z: 184.1 [M + H] + .
(2)将C016-16b(1g，5.46mmol，1eq.)和int2(1.3g,6.56mmol，1.2eq)溶解在醋酸中，在130℃下搅拌4h,反应结束后，将反应液减压浓缩，滴加氨水调节PH至弱碱性，将残余物用柱层析纯化，用(PE:AE＝3:1)洗脱，得到C016-16b(650mg)。LCMS(ESI)m/z:314.1[M+H]+.(2) C016-16b (1 g, 5.46 mmol, 1 eq.) and int2 (1.3 g, 6.56 mmol, 1.2 eq.) were dissolved in acetic acid and stirred at 130°C for 4 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and ammonia water was added dropwise to adjust the pH to weak alkalinity. The residue was purified by column chromatography and eluted with (PE:AE=3:1) to obtain C016-16b (650 mg). LCMS (ESI) m/z: 314.1 [M+H] + .
(3)将C016-16b(400mg,1.28mmol,1eq)和int6(334mg，1.91mmol，1.5eq)和对甲苯磺酸(49mg，0.26mmol，0.2eq.)溶解在N,N-二甲基甲酰胺(3mL)中，在氮气保护下，升温至120℃，搅拌4h。反应结束后，将反应液减压浓缩，所得残余物用柱层析纯化，用(PE:AE＝3:1)洗脱得到产物，取100mg经SFC拆分后得化合物C016(7.1mg)和化合物C017(55.91mg)。(3) C016-16b (400 mg, 1.28 mmol, 1 eq) and int6 (334 mg, 1.91 mmol, 1.5 eq) and p-toluenesulfonic acid (49 mg, 0.26 mmol, 0.2 eq.) were dissolved in N,N-dimethylformamide (3 mL), and the temperature was raised to 120° C. under nitrogen protection, and stirred for 4 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography, and the product was eluted with (PE:AE=3:1). 100 mg was taken and separated by SFC to obtain compound C016 (7.1 mg) and compound C017 (55.91 mg).
SFC拆分方法：系统：Waters SFC 150；柱：柱尺寸：250*25mm 10m；流动相A：超临界CO2，流动相B：MEOH(+0.1％7.0mol/l氨在MEOH中)；A:B:80:20；波长：214nm；流速：100ml/min；柱温：室温；背压：100bar；注射：3mL；循环时间：4.1分钟；溶剂：甲醇：再蒸馏级，超临界CO2：食品级；样品溶液的制备：将样品溶解在约20mL MeOH中。 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.
C016&C017：LCMS(ESI)m/z:419.2[M+H]+；1H NMR(400MHz,CD3OD)δ8.27(d,J＝2.2Hz,1H),7.69(dd,J＝8.8,2.0Hz,1H),7.51(s,1H),7.44(d,J＝2.0Hz,1H),7.34(d,J＝8.4Hz,1H),7.09(dd,J＝8.0,2.0Hz,1H),6.63(d,J＝8.0Hz,1H),4.66–4.59(m,1H),2.92-2.85(m,2H),2.71–2.51(m,2H),2.53(t,J＝8.0Hz,2H),1.55–1.45(m,2H),0.92(t,J＝8.0Hz,3H)./LCMS(ESI)m/z:419.3[M+H]+；1H NMR(400MHz,CD3OD)δ8.27(d,J＝4.0Hz,1H),7.79(dd,J＝8.0,2.0Hz,1H),7.51(s,1H),7.43(d,J＝2.0Hz,1H),7.34(d,J＝8.0Hz,1H),7.09(dd,J＝8.0,2.0Hz,1H),6.63(d,J＝8.0Hz,1H),4.76–4.69(m,1H),2.97-2.88(m,2H),2.77–2.69(m,2H),1.63–1.53(m,2H),1.55–1.45(m,2H),0.97(t,J＝8.0Hz,3H).C016 & C017: LCMS (ESI) m/z: 419.2 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ8.27 (d, J = 2.2 Hz, 1H), 7.69 (dd, J = 8.8, 2.0 Hz, 1H), 7.51 (s, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.09 (dd, J = 8.0, 2.0 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 4.66-4.59 (m, 1H), 2.92-2.85 (m, 2H), 2.71-2.51 (m, 2H), 2.53 (t, J = 8.0 Hz, 2H), 1.55-1.45 (m, 2H), 0.92 (t, J = 8.0 Hz, 3H)./LCMS (ESI) m/z: 419.3 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ8.27 (d, J=4.0 Hz, 1H), 7.79 (dd, J=8.0, 2.0 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.09 (dd, J=8.0, 2.0 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 4.76-4.69 (m, 1H), 2.97-2.88 (m, 2H), 2.77-2.69 (m, 2H), 1.63-1.53 (m, 2H), 1.55-1.45 (m, 2H), 0.97 (t, J=8.0 Hz, 3H).
实施例18：
Embodiment 18:
合成路线：
synthetic route:
(1)将2-氯-1-甲基-1H-咪唑(10g，85.8mmol)加到THF(50mL)中，将体系降温至-70℃，滴加正丁基锂(36mL，2.5mmol/L in THF)。将混合物在-70℃下搅拌1h，滴加DMF(6.58g，90.1mmol)，滴加完将反应自然升温至室温并在室温下搅拌2h。反应结束后用饱和氯化铵水溶液淬灭，并用二氯甲烷(50mL)萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化，(PE:EA＝10:1)洗脱得C018-18b(7g)。(1) 2-Chloro-1-methyl-1H-imidazole (10 g, 85.8 mmol) was added to THF (50 mL), the system was cooled to -70 °C, and n-butyl lithium (36 mL, 2.5 mmol/L in THF) was added dropwise. The mixture was stirred at -70 °C for 1 h, and DMF (6.58 g, 90.1 mmol) was added dropwise. After the addition, the reaction was naturally warmed to room temperature and stirred at room temperature for 2 h. After the reaction was completed, it was quenched with saturated aqueous ammonium chloride solution and extracted three times with dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=10:1) to obtain C018-18b (7 g).
(2)将C018-18b(7g，48.6mmol)溶解在THF(70mL)中。将体系降温至-70℃，滴加甲基溴化镁(19.4mL，3mmol/L in THF)。将混合物在-70℃下搅拌2h。反应结束后用饱和氯化铵水溶液淬灭，并用二氯甲烷(50mL)萃取，合并有机相，无水硫酸钠干燥，过滤,减压浓缩，所得残余物用硅胶柱层析纯化，(乙酸乙酯:石油醚＝1:1)洗脱得C018-18c(3g)。(2) C018-18b (7 g, 48.6 mmol) was dissolved in THF (70 mL). The system was cooled to -70 °C and methylmagnesium bromide (19.4 mL, 3 mmol/L in THF) was added dropwise. The mixture was stirred at -70 °C for 2 h. After the reaction was completed, it was quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain C018-18c (3 g).
(3)将C018-18c(3g，18.57mmol)溶解在DCM(50mL)中，加入DMP(8.35g，19.69mmol)并在室温下搅拌2h。反应结束后用水洗涤二氯甲烷相，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶柱层析纯化，(乙酸乙酯:石油醚＝1:1)洗脱得C018-18d(1.05g)。(3) C018-18c (3 g, 18.57 mmol) was dissolved in DCM (50 mL), and DMP (8.35 g, 19.69 mmol) was added and stirred at room temperature for 2 h. After the reaction was completed, the dichloromethane phase was washed with water, and the organic phase was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain C018-18d (1.05 g).
(4)将C018-18d(500mg，3.16mmol)溶解在对二甲苯(10mL)中，加入int2(703mg，3.48mmol)和对甲苯磺酸(19mg，0.32mmol)并在150℃下搅拌16h。反应结束后加入甲醇并用硅胶柱层析纯化，(二氯甲烷：甲醇＝9:1)洗脱得C018-18e(300mg)。(4) C018-18d (500 mg, 3.16 mmol) was dissolved in p-xylene (10 mL), and int2 (703 mg, 3.48 mmol) and p-toluenesulfonic acid (19 mg, 0.32 mmol) were added and stirred at 150° C. for 16 h. After the reaction, methanol was added and purified by silica gel column chromatography (dichloromethane: methanol = 9:1) to obtain C018-18e (300 mg).
(5)将C018-18e(200mg，0.69mmol)溶解在乙腈(5mL)中，加入int6(94mg，0.76mmol)和对甲苯磺酸一水合物(26mg，0.14mmol)并在60℃下搅拌4h。反应结束后反相制备纯化得化合物C018(9.01mg)。LCMS(ESI)m/z:394.2[M+H]+；1H NMR(400MHz,DMSO_d6)δ10.85(s,1H),8.22(s,1H),8.12(s,1H),7.77(s,1H),7.70(s,1H),7.34(d,J＝12.0Hz,1H),7.12(s,1H),7.06(dd,J＝8.4,2.0Hz,1H),4.75–4.73(m,1H),3.74(s,3H),3.01–2.98(m,2H),2.82–2.77(m,2H),2.12(s,3H).(5) C018-18e (200 mg, 0.69 mmol) was dissolved in acetonitrile (5 mL), and int6 (94 mg, 0.76 mmol) and p-toluenesulfonic acid monohydrate (26 mg, 0.14 mmol) were added and stirred at 60° C. for 4 h. After the reaction, the compound C018 (9.01 mg) was obtained by reverse phase preparation and purification. LCMS (ESI) m/z: 394.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 7.77 (s, 1H), 7.70 (s, 1H), 7.34 (d, J = 12.0 Hz, 1H), 7.12 (s, 1H), 7.06 (dd, J = 8.4, 2.0 Hz, 1H), 4.75-4.73 (m, 1H), 3.74 (s, 3H), 3.01-2.98 (m, 2H), 2.82-2.77 (m, 2H), 2.12 (s, 3H).
实施例19：
Embodiment 19:
合成路线：
synthetic route:
(1)将4-氯-3-硝基苯乙酮(10g，50.1mmol)和甲胺盐酸盐(5.07g，75.2mmol)添加到乙腈(150mL)中，添加碳酸钾(27.7g，200.4mmol)。将混合物在室温下搅拌过夜。反应结束后，反应液加水稀释，用乙酸乙酯(50mL)萃取三次，合并有机相。有机相用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化，(PE:EA＝10:1)洗脱得C019-19b(8.5g)。(1) 4-Chloro-3-nitroacetophenone (10 g, 50.1 mmol) and methylamine hydrochloride (5.07 g, 75.2 mmol) were added to acetonitrile (150 mL), and potassium carbonate (27.7 g, 200.4 mmol) was added. The mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was diluted with water, extracted three times with ethyl acetate (50 mL), and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=10:1) to obtain C019-19b (8.5 g).
(2)将C019-19b(8.5g，43.81mmol)溶解在甲醇(120mL)中，然后将雷尼镍加入到溶液中。在室温下搅拌过夜。反应结束后将反应液过滤，将滤液旋干得C019-19c(5.6g，70.98％)。LCMS(ESI)m/z:165.2[M+H]+.(2) C019-19b (8.5 g, 43.81 mmol) was dissolved in methanol (120 mL), and then Raney nickel was added to the solution. The mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was filtered and the filtrate was dried to obtain C019-19c (5.6 g, 70.98%). LCMS (ESI) m/z: 165.2 [M+H] + .
(3)将C019-19c(5.6g，34.1mmol)和溴化氰(5.43g，51.2mmol)溶解在甲醇(100mL)中。混合液在室温下搅拌1h。反应结束后，加水稀释，用乙酸乙酯(100mL)萃取三次，合并有机相，用饱和食盐水洗涤2次，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶柱层析纯化，(二氯甲烷:甲醇＝10:1)洗脱得C019-19d(3.1g)。LCMS(ESI)m/z:190.1[M+H]+.(3) C019-19c (5.6 g, 34.1 mmol) and cyanogen bromide (5.43 g, 51.2 mmol) were dissolved in methanol (100 mL). The mixture was stirred at room temperature for 1 h. After the reaction was completed, it was diluted with water and extracted three times with ethyl acetate (100 mL). The organic phases were combined and washed twice with saturated brine. The organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain C019-19d (3.1 g). LCMS (ESI) m/z: 190.1 [M+H] + .
(4)将C019-19d(2g，10.5mmol)、int1(4.89g，12.6mmol)、t-BuBrettphos(1.026g，2.12mmol)、Pd2(dba)3(968mg，1.05mmol)、磷酸钾(6.73g，31.7mmol)溶解在二氧六环(50mL)中。混合液在氮气保护下120℃搅拌16小时。将反应液冷却至室温，加乙酸乙酯(50mL)稀释，再加水(50mL)，用乙酸乙酯(30mL)萃取三次，合并有机相，用饱和食盐水洗涤2次，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶柱层析纯化，(乙酸乙酯:石油醚＝1:1)洗脱得C019-19f(1.0g)。LCMS(ESI)m/z:495.3[M+H]+.(4) C019-19d (2 g, 10.5 mmol), int1 (4.89 g, 12.6 mmol), t-BuBrettphos (1.026 g, 2.12 mmol), Pd 2 (dba) 3 (968 mg, 1.05 mmol), and potassium phosphate (6.73 g, 31.7 mmol) were dissolved in dioxane (50 mL). The mixture was stirred at 120°C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), and then added with water (50 mL). It was extracted three times with ethyl acetate (30 mL), the organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain C019-19f (1.0 g). LCMS (ESI) m/z: 495.3 [M+H] + .
(5)将C019-19f(1g，2.02mmol)溶解在三乙胺氢氟酸盐(5mL)和乙腈(10mL)的混合溶液中并在室温下搅拌1h。反应结束后过滤，反相制备纯化得C019-19g(180mg，26.3％)。LCMS(ESI)m/z:339.2[M+H]+.(5) C019-19f (1 g, 2.02 mmol) was dissolved in a mixed solution of triethylamine hydrofluoride (5 mL) and acetonitrile (10 mL) and stirred at room temperature for 1 h. After the reaction was completed, the mixture was filtered and purified by reverse phase preparation to obtain C019-19g (180 mg, 26.3%). LCMS (ESI) m/z: 339.2 [M+H] + .
(6)将C019-19g(120mg，0.355mmol)和int6(66mg，0.533mmol)、对甲苯磺酸一水合物(14mg，0.071mmol)溶解在乙腈(2mL)中。混合液在90℃下搅拌5h。反应结束后，反应液减压浓缩。所得残余物经制备纯化，得化合物C019(13.81mg)。LCMS(ESI)m/z:444.3[M+H]+；1H NMR(400MHz,DMSO_d6)δ11.01(s,1H),8.65(s,1H),8.14(s,1H),7.95(s,1H),7.87(s,1H),7.59(s,1H),7.39(d,J＝8.0Hz,2H),7.27(d,J＝8.0Hz,1H),7.10(dd,J＝8.0,2.0Hz,1H),4.81–4.71(m,1H),3.75(s,3H),3.03-2.98(m,2H),2.82–2.75(m,2H),2.27(s,3H).(6) C019-19g (120 mg, 0.355 mmol), int6 (66 mg, 0.533 mmol) and p-toluenesulfonic acid monohydrate (14 mg, 0.071 mmol) were dissolved in acetonitrile (2 mL). The mixture was stirred at 90° C. for 5 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by preparative purification to obtain compound C019 (13.81 mg). LCMS (ESI) m/z: 444.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.65 (s, 1H), 8.14 (s, 1H), 7.95 (s, 1H), 7.87 (s, 1H), 7.59 (s, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 1H), 7.10 (dd, J = 8.0, 2.0 Hz, 1H), 4.81-4.71 (m, 1H), 3.75 (s, 3H), 3.03-2.98 (m, 2H), 2.82-2.75 (m, 2H), 2.27 (s, 3H).
实施例20：
Embodiment 20:
合成路线：
synthetic route:
(1)将3-氨基-6-氰基吡啶(4.5g，37.8mmol)加到THF(40mL)中，将体系降温至0℃，滴加甲基溴化镁(114mL，1mmol/L in THF)。将混合物在0℃下搅拌2h。反应结束后用饱和氯化铵水溶液淬灭，乙酸乙酯(50mL)萃取三次，合并有机相。有机相用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化，(PE:EA＝10:1)洗脱得C020-20b(3.5g，68.06％)。LCMS(ESI)m/z:137.4[M+H]+.(1) Add 3-amino-6-cyanopyridine (4.5 g, 37.8 mmol) to THF (40 mL), cool the system to 0°C, and drop methylmagnesium bromide (114 mL, 1 mmol/L in THF). Stir the mixture at 0°C for 2 h. After the reaction is completed, quench with saturated aqueous ammonium chloride solution, extract three times with ethyl acetate (50 mL), and combine the organic phases. The organic phase is washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (PE:EA=10:1) to obtain C020-20b (3.5 g, 68.06%). LCMS (ESI) m/z: 137.4 [M+H] + .
(2)将C020-20b(670mg，4.92mmol)、int6(909mg，7.39mmol)和对甲苯磺酸一水合物(187mg，0.99mmol)溶解在乙腈(10mL)中。在90℃下搅拌4h。将反应液冷却至室温，加乙酸乙酯(10mL)稀释，再加水(30mL)，用乙酸乙酯(20mL)萃取三次，合并有机相，用饱和食盐水洗涤2次，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶柱层析纯化，(乙酸乙酯:石油醚＝1:1)洗脱得C020-20c(200mg)。LCMS(ESI)m/z:242.3[M+H]+.(2) C020-20b (670 mg, 4.92 mmol), int6 (909 mg, 7.39 mmol) and p-toluenesulfonic acid monohydrate (187 mg, 0.99 mmol) were dissolved in acetonitrile (10 mL). Stir at 90 ° C for 4 h. The reaction solution was cooled to room temperature, diluted with ethyl acetate (10 mL), and then added with water (30 mL). It was extracted three times with ethyl acetate (20 mL), the organic phases were combined, washed twice with saturated brine, and the organic phases were dried with sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain C020-20c (200 mg). LCMS (ESI) m/z: 242.3 [M + H] + .
(3)将C020-20c(108mg，0.448mmol)、C019-19e(207mg，0.54mmol)、t-BuBrettphos(43mg，0.089mmol)、Pd2(dba)3(41mg，0.049mmol)、磷酸钾(285mg，1.34mmol)溶解在叔丁醇(5mL)中。混合液在氮气保护下120℃搅拌5h，将反应液冷却至室温，加乙酸乙酯(20mL)稀释，再加水(20mL)，用乙酸乙酯(10mL)萃取三次，合并有机相，用饱和食盐水洗涤2次，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶柱层析纯化，(乙酸乙酯:石油醚＝1:1)洗脱得C020-20d(100mg)。LCMS(ESI)m/z:547.4[M+H]+.(3) C020-20c (108 mg, 0.448 mmol), C019-19e (207 mg, 0.54 mmol), t-BuBrettphos (43 mg, 0.089 mmol), Pd 2 (dba) 3 (41 mg, 0.049 mmol), potassium phosphate (285 mg, 1.34 mmol) were dissolved in tert-butyl alcohol (5 mL). The mixture was stirred at 120° C. for 5 h under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate (20 mL), and then water (20 mL) was added. It was extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain C020-20d (100 mg). LCMS (ESI) m/z: 547.4 [M+H] + .
(4)将C020-20d(80mg，0.15mmol)溶解在三乙胺氢氟酸盐(1mL)和乙腈(2mL)的混合溶液中并在室温下搅拌1h。反应结束后过滤，反相制备纯化得化合物C020(19.95mg)。LCMS(ESI)m/z:391.2[M+H]+；1H NMR(400MHz,DMSO_d6)δ11.20(s,1H),8.17–8.13(m,2H),7.66(d,J＝8.0Hz,1H),7.47–7.40(m,3H),7.14–7.09(m,2H),4.76–4.74(m,1H),3.04–2.97(m,2H),2.81-2.73(m,2H),2.22(s,3H).(4) C020-20d (80 mg, 0.15 mmol) was dissolved in a mixed solution of triethylamine hydrofluoride (1 mL) and acetonitrile (2 mL) and stirred at room temperature for 1 h. After the reaction was completed, the mixture was filtered and purified by reverse phase preparation to obtain compound C020 (19.95 mg). LCMS (ESI) m/z: 391.2 [M+H] + ; 1 H NMR (400 MHz, DMSO_d6) δ 11.20 (s, 1H), 8.17–8.13 (m, 2H), 7.66 (d, J=8.0 Hz, 1H), 7.47–7.40 (m, 3H), 7.14–7.09 (m, 2H), 4.76–4.74 (m, 1H), 3.04–2.97 (m, 2H), 2.81-2.73 (m, 2H), 2.22 (s, 3H).
实施例21：
Embodiment 21:
合成路线：
synthetic route:
(1)将3-氟-4-硝基苯乙酮(5g，27.3mmol)和甲胺盐酸盐(2.77g，41.0mmol)添加到乙腈(100mL)中，添加碳酸钾(15.1g，109.21mmol)。将混合物在室温下搅拌过夜。反应结束后，加水稀释，用乙酸乙酯(50mL)萃取三次，合并有机相。有机相用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，(PE:EA＝1:1)洗脱得C021-21b(5g，94.32％)。(1) 3-Fluoro-4-nitroacetophenone (5 g, 27.3 mmol) and methylamine hydrochloride (2.77 g, 41.0 mmol) were added to acetonitrile (100 mL), and potassium carbonate (15.1 g, 109.21 mmol) was added. The mixture was stirred at room temperature overnight. After the reaction was completed, it was diluted with water, extracted three times with ethyl acetate (50 mL), and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=1:1) to obtain C021-21b (5 g, 94.32%).
(2)将C021-21b(5g，25.77mmol)溶解在甲醇(60mL)中，然后将雷尼镍加入到溶液中。在室温下搅拌过夜。反应结束后将反应液过滤，将滤液旋干得到C021-21c(4.2g)。(2) C021-21b (5 g, 25.77 mmol) was dissolved in methanol (60 mL), and then Raney nickel was added to the solution. The mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was filtered and the filtrate was dried to obtain C021-21c (4.2 g).
(3)将C021-21c(3.5g，21.34mmol)溶解在THF(50mL)中，加入三乙胺(4.3g，42.68mmol)和CDI(10.38g，64.02mmol)。混合液在60℃下搅拌3h。反应结束后，加乙酸乙酯(50mL)稀释，再加水(80mL)，用乙酸乙酯(50mL)萃取三次，合并有机相，用饱和食盐水洗涤2次，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶柱层析纯化，(乙酸乙酯:石油醚＝1:1)洗脱得C021-21d(1.9g)。(3) C021-21c (3.5 g, 21.34 mmol) was dissolved in THF (50 mL), and triethylamine (4.3 g, 42.68 mmol) and CDI (10.38 g, 64.02 mmol) were added. The mixture was stirred at 60°C for 3 h. After the reaction was completed, ethyl acetate (50 mL) was added for dilution, and water (80 mL) was added. The mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain C021-21d (1.9 g).
(4)将C021-21d(1.9g，10mmol)溶解在POCl3(50mL)中。混合液在氮气保护下100℃搅拌15h，将反应液冷却至室温，将三氯氧磷旋干，加乙酸乙酯(50mL)稀释，再加水(50mL)，用乙酸乙酯(30mL)萃取三次，合并有机相，用饱和食盐水洗涤2次，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶柱层析纯化，(乙酸乙酯:石油醚＝1:1)洗脱得C021-21e(900mg)。LCMS(ESI)m/z:209.1[M+H]+.(4) C021-21d (1.9 g, 10 mmol) was dissolved in POCl 3 (50 mL). The mixture was stirred at 100°C for 15 h under nitrogen protection. The reaction solution was cooled to room temperature, phosphorus oxychloride was dried, diluted with ethyl acetate (50 mL), and then water (50 mL) was added. It was extracted three times with ethyl acetate (30 mL). The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain C021-21e (900 mg). LCMS (ESI) m/z: 209.1 [M+H] + .
(5)将C021-21e(340mg，1.63mmol)溶解在对二甲苯(10mL)中，加入int2(363mg，1.80mmol)和对甲苯磺酸一水合物(31mg，0.16mmol)并在150℃下搅拌16h。反应结束后加入甲醇并用硅胶柱层析纯化，用(二氯甲烷：甲醇＝9:1)洗脱得C021-21f(300mg)。LCMS(ESI)m/z:339.0[M+H]+.(5) C021-21e (340 mg, 1.63 mmol) was dissolved in p-xylene (10 mL), int2 (363 mg, 1.80 mmol) and p-toluenesulfonic acid monohydrate (31 mg, 0.16 mmol) were added and stirred at 150°C for 16 h. After the reaction, methanol was added and purified by silica gel column chromatography, and C021-21f (300 mg) was obtained by elution with (dichloromethane: methanol = 9:1). LCMS (ESI) m/z: 339.0 [M+H] + .
(6)将C021-21f(270mg，0.797mmol)和int6(108mg，0.88mmol)、对甲苯磺酸(30mg，0.16mmol)溶解在乙腈(5mL)中。混合液在90℃下搅拌5h。反应结束后，反应液减压浓缩。所得残余物经反相制备纯化，得到化合物C021(25.89mg)。LCMS(ESI)m/z:444.4[M+H]+；1H NMR(400MHz,DMSO_d6)δ11.02(s,1H),8.68(s,1H),8.15(s,1H),7.93(s,1H),7.86(s,1H),7.55(s,1H),7.39(d,J＝8.0Hz,2H),7.26(d,J＝8.0Hz,1H),7.10(d,J＝8.0Hz,1H),4.79–4.77(m,1H),3.77(s,3H),3.05-3.02(m,2H),2.80–2.74(m,2H),2.29(s,3H).(6) C021-21f (270 mg, 0.797 mmol), int6 (108 mg, 0.88 mmol) and p-toluenesulfonic acid (30 mg, 0.16 mmol) were dissolved in acetonitrile (5 mL). The mixture was stirred at 90°C for 5 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by reverse phase preparative reaction to obtain compound C021 (25.89 mg). LCMS (ESI) m/z: 444.4 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.68 (s, 1H), 8.15 (s, 1H), 7.93 (s, 1H), 7.86 (s, 1H), 7.55 (s, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 4.79-4.77 (m, 1H), 3.77 (s, 3H), 3.05-3.02 (m, 2H), 2.80-2.74 (m, 2H), 2.29 (s, 3H).
实施例22：
Embodiment 22:
合成路线：
synthetic route:
(1)将4a(234mg，1.50mmol)和int2(366mg，1.80mmol)溶解在冰醋酸(5.8mL)中。将混合物在130℃下搅拌2小时。反应结束后减压浓缩至干，所得残余物即为粗品C022-22b可直接用于下一步。(1) 4a (234 mg, 1.50 mmol) and int2 (366 mg, 1.80 mmol) were dissolved in glacial acetic acid (5.8 mL). The mixture was stirred at 130°C for 2 hours. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure. The resulting residue was the crude product C022-22b, which was directly used in the next step.
(2)将C022-22b(423mg，1.50mmol)、int9(214mg，1.23mmol)和对甲苯磺酸(47mg，0.247mmol)溶解在乙腈(6mL)中。反应液在60℃下反应12小时。反应结束后减压浓缩干，DMF溶解后经制备分析纯化得化合物C022(13.29mg)。(2) C022-22b (423 mg, 1.50 mmol), int9 (214 mg, 1.23 mmol) and p-toluenesulfonic acid (47 mg, 0.247 mmol) were dissolved in acetonitrile (6 mL). The reaction solution was reacted at 60° C. for 12 hours. After the reaction was completed, the solution was concentrated to dryness under reduced pressure, dissolved in DMF, and purified by preparative analysis to obtain compound C022 (13.29 mg).
1H NMR(400MHz,CD3OD)δ8.31(d,J＝2.0Hz,1H),7.84(dd,J＝8.8,2.4Hz,1H),7.53(s,1H),7.45(d,J＝2.0Hz,1H),7.36(d,J＝8.4Hz,1H),7.11(dd,J＝8.4,2.0Hz,1H),6.65(d,J＝8.8Hz,1H),4.84(s,1H),2.44–2.34(m,3H),2.20(s,3H),2.17–2.10(m,3H). 1 H NMR (400 MHz, CD 3 OD) δ8.31 (d, J=2.0 Hz, 1H), 7.84 (dd, J=8.8, 2.4 Hz, 1H), 7.53 (s, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.11 (dd, J=8.4, 2.0 Hz, 1H), 6.65 (d, J=8.8 Hz, 1H), 4.84 (s, 1H), 2.44-2.34 (m, 3H), 2.20 (s, 3H), 2.17-2.10 (m, 3H).
实施例23：
Embodiment 23:
合成路线
synthetic route
(1)将int10(2g，7.00mmol)、int6(1.68g，10.5mmol)、对甲苯磺酸(241.1mg，1.40mmol)加入乙腈(20ml)中。氮气保护下混合物于60℃油浴中搅拌12h。反应结束后，将反应液冷却至室温，减压浓缩。所得残余物用TLC纯化，用(石油醚:乙酸乙酯＝4:1)得化合物C023(18.31mg)。(1) Add int10 (2 g, 7.00 mmol), int6 (1.68 g, 10.5 mmol), and p-toluenesulfonic acid (241.1 mg, 1.40 mmol) to acetonitrile (20 ml). Stir the mixture in a 60°C oil bath under nitrogen protection for 12 h. After the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by TLC and (petroleum ether: ethyl acetate = 4:1) to obtain compound C023 (18.31 mg).
1H NMR(400MHz,CD3OD)δ8.24(d,J＝2.0Hz,1H),7.79(dd,J＝8.0,2.0Hz,1H),7.39(s,1H),7.32(d,J＝8.0Hz,1H),7.06(t,J＝8.0Hz,1H),6.96(d,J＝4.0Hz,1H),6.51(d,J＝8.0Hz,1H),4.76-4.67(m,1H),2.98–2.87(m,2H),2.78–2.66(m,2H),2.19(s,3H). 1 H NMR (400 MHz, CD 3 OD) δ8.24 (d, J=2.0 Hz, 1H), 7.79 (dd, J=8.0, 2.0 Hz, 1H), 7.39 (s, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.06 (t, J=8.0 Hz, 1H), 6.96 (d, J=4.0 Hz, 1H), 6.51 (d, J=8.0 Hz, 1H), 4.76-4.67 (m, 1H), 2.98-2.87 (m, 2H), 2.78-2.66 (m, 2H), 2.19 (s, 3H).
实施例24：
Embodiment 24:
合成路线
synthetic route
(1)将粗品int11(200mg)，int6(172mg，0.55mmol)和对甲苯磺酸水合物(26mg，0.10mmol)溶解在乙腈(2.5mL)中，在90℃下搅拌4h。反应结束后，过滤反应液，用乙腈洗涤，合并有机相所得残余物经制备分析纯化得C024(12.39mg)。(1) Crude int11 (200 mg), int6 (172 mg, 0.55 mmol) and p-toluenesulfonic acid hydrate (26 mg, 0.10 mmol) were dissolved in acetonitrile (2.5 mL) and stirred at 90°C for 4 h. After the reaction was completed, the reaction solution was filtered and washed with acetonitrile. The organic phases were combined to obtain the residue, which was purified by preparative analysis to obtain C024 (12.39 mg).
1H NMR(400MHz,DMSO_d6)δ10.90(s,1H),9.00(s,1H),8.41(d,J＝2.0Hz,1H),7.87(d,J＝2.0Hz,1H),7.82(dd,J＝8.0Hz,2.0Hz,1H),7.67(dd,J＝12.0Hz,8.0Hz,1H),7.35(dd,J＝12.0Hz,6.0Hz,1H),6.80(d,J＝8.0Hz,1H),4.74–4.72(m,1H),3.04-2.95(m,2H),2.81–2.73(m,2H),2.19(s,3H). 1 H NMR (400 MHz, DMSO_d6) δ 10.90 (s, 1H), 9.00 (s, 1H), 8.41 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.67 (dd, J = 12.0 Hz, 8.0 Hz, 1H), 7.35 (dd, J = 12.0 Hz, 6.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 4.74–4.72 (m, 1H), 3.04–2.95 (m, 2H), 2.81–2.73 (m, 2H), 2.19 (s, 3H).
实施例25：
Embodiment 25:
合成路线
synthetic route
(1)将C025-25a(500mg，3.19mmol，1eq)和int2(980mg，4.79mmol，1.5eq)和Pd2(dba)3(290mg，0.319mmol，0.1eq)和tBuBretterPhos(310mg，0.638mmol，0.2eq)和K3PO4(2.03g，9.57mmol，3eq)溶解在叔丁醇(40mL)中，置换氮气，在120℃下搅拌2h。反应结束后旋干溶剂，所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝1:1)洗脱得C025-25b(213mg，23.3％)。(1) C025-25a (500 mg, 3.19 mmol, 1 eq), int2 (980 mg, 4.79 mmol, 1.5 eq), Pd 2 (dba) 3 (290 mg, 0.319 mmol, 0.1 eq), tBuBretterPhos (310 mg, 0.638 mmol, 0.2 eq), and K 3 PO 4 (2.03 g, 9.57 mmol, 3 eq) were dissolved in tert-butyl alcohol (40 mL), replaced with nitrogen, and stirred at 120° C. for 2 h. After the reaction was completed, the solvent was dried and the residue was purified by column chromatography and eluted with (petroleum ether: ethyl acetate = 1:1) to obtain C025-25b (213 mg, 23.3%).
(2)将C025-25b(213mg，0.743mmol，1eq)，int6(138mg，1.121mmol，1.5eq)和对甲苯磺酸水合物(29mg，0.152mmol，0.2eq)溶解在乙腈(5.0mL)中，在90℃下搅拌4h。反应结束后，过滤反应液，用乙腈洗涤，合并有机相所得残余物通过薄层色谱纯化得C025(18.8mg)。(2) C025-25b (213 mg, 0.743 mmol, 1 eq), int6 (138 mg, 1.121 mmol, 1.5 eq) and p-toluenesulfonic acid hydrate (29 mg, 0.152 mmol, 0.2 eq) were dissolved in acetonitrile (5.0 mL) and stirred at 90° C. for 4 h. After the reaction was completed, the reaction solution was filtered and washed with acetonitrile. The organic phases were combined and the residue was purified by thin layer chromatography to obtain C025 (18.8 mg).
1H NMR(400MHz,DMSO_d6)δ11.02(s,1H),9.85(s,1H),8.72(s,2H),7.95(d,J＝2.0Hz,1H),7.86(d,J＝2.0Hz,1H),7.36(d,J＝8.4Hz,1H),7.08(dd,J＝8.4,2.0Hz,1H),4.76(s,1H),3.01–2.78(m,2H),2.51–2.50(m,2H),2.21(s,3H). 1 H NMR (400 MHz, DMSO_d6) δ 11.02 (s, 1H), 9.85 (s, 1H), 8.72 (s, 2H), 7.95 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.08 (dd, J = 8.4, 2.0 Hz, 1H), 4.76 (s, 1H), 3.01–2.78 (m, 2H), 2.51–2.50 (m, 2H), 2.21 (s, 3H).
实施例26：
Embodiment 26:
合成路线
synthetic route
(1)将化合物C026-26a(800mg，5.14mmol，1eq)，int2(1.25g，6.17mmol，1.2eq)溶解在冰乙酸(15mL)中，在130℃下搅拌2h。反应结束后，旋干反应液，所得残余物用柱色谱(DCM/MeOH＝50/1)纯化得C026-26b粗品(900mg)。(1) Compound C026-26a (800 mg, 5.14 mmol, 1 eq) and int2 (1.25 g, 6.17 mmol, 1.2 eq) were dissolved in glacial acetic acid (15 mL) and stirred at 130° C. for 2 h. After the reaction was completed, the reaction solution was dried and the residue was purified by column chromatography (DCM/MeOH=50/1) to obtain a crude product of C026-26b (900 mg).
(2)将C026-26b(900mg，3.16mmol，1eq)，int14(603mg，3.79mmol，1.2eq)和对甲 苯磺酸水合物(120mg，0.63mmol，0.2eq)溶解在乙腈(12.0mL)中，在90℃下搅拌4h。反应结束后，过滤反应液，用乙腈洗涤，合并有机相所得残余物经制备分析纯化得C026，手性制备得C026-A(23.4mg，1.9％)和C026-B(23.2mg，1.9％)。(2) C026-26b (900 mg, 3.16 mmol, 1 eq), int14 (603 mg, 3.79 mmol, 1.2 eq) and Benzenesulfonic acid hydrate (120 mg, 0.63 mmol, 0.2 eq) was dissolved in acetonitrile (12.0 mL) and stirred at 90°C for 4 h. After the reaction was completed, the reaction solution was filtered, washed with acetonitrile, and the residue obtained by combining the organic phases was purified by preparative analysis to obtain C026, and chiral preparations were obtained to obtain C026-A (23.4 mg, 1.9%) and C026-B (23.2 mg, 1.9%).
C026：1H NMR(400MHz,DMSO_d6)δ10.94(s,1H),9.00(s,1H),8.42(d,J＝2.0Hz,1H),7.94–7.77(m,3H),7.36(d,J＝8.4Hz,1H),7.09(dd,J＝8.4,2.0Hz,1H),6.81(d,J＝8.8Hz,1H),4.26–4.16(m,1H),4.14–4.03(m,1H),2.18(s,3H),2.15–2.10(m,1H),1.73–1.61(m,1H),1.46–1.34(m,1H).C026: 1 H NMR (400 MHz, DMSO_d6) δ 10.94 (s, 1H), 9.00 (s, 1H), 8.42 (d, J = 2.0 Hz, 1H), 7.94–7.77 (m, 3H), 7.36 (d, J = 8.4 Hz, 1H), 7.09 (dd, J = 8.4, 2.0 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 4.26–4.16 (m, 1H), 4.14–4.03 (m, 1H), 2.18 (s, 3H), 2.15–2.10 (m, 1H), 1.73–1.61 (m, 1H), 1.46–1.34 (m, 1H).
实施例27：
Embodiment 27:
合成路线
synthetic route
(1)将6-氯烟酸(26.5g，162.49mmol)加到二氯甲烷(500mL)中，再加入二甲羟胺盐酸盐(18.1g，178.74mmol)，HATU(70.4g，178.74mmol)和DIEA(94mL，487.46mmol)。将混合物在室温下搅拌16h。反应结束后用水和二氯甲烷萃取，合并有机相。有机相用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝4:1)洗脱得C027-27b(28g)。(1) Add 6-chloronicotinic acid (26.5 g, 162.49 mmol) to dichloromethane (500 mL), and then add dimethylhydroxylamine hydrochloride (18.1 g, 178.74 mmol), HATU (70.4 g, 178.74 mmol) and DIEA (94 mL, 487.46 mmol). Stir the mixture at room temperature for 16 h. After the reaction is completed, extract with water and dichloromethane, and combine the organic phases. Wash the organic phase with water and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain C027-27b (28 g).
(2)将C027-27b(4g，20mmol)溶解在THF(50mL)中,将体系降温至0℃，滴加异丙基溴化镁(30mL，1mmol/L in THF)。将混合物在室温下搅拌16h。反应结束后用饱和氯化铵水溶液淬灭，并用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤2次，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶柱层析纯化，用(乙酸乙酯:石油醚＝1:1)洗脱得C027-27c(1.5g)。(2) C027-27b (4 g, 20 mmol) was dissolved in THF (50 mL), the system was cooled to 0°C, and isopropylmagnesium bromide (30 mL, 1 mmol/L in THF) was added dropwise. The mixture was stirred at room temperature for 16 h. After the reaction was completed, it was quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography and eluted with (ethyl acetate: petroleum ether = 1:1) to obtain C027-27c (1.5 g).
(3)将C027-27c(500mg，2.76mmol)、int2(506mg，3.04mmol)溶解在乙酸(8mL)中。混合液在氮气保护下100℃搅拌2h，反应结束后将乙酸旋干，加乙酸乙酯稀释，再加水，用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗涤2次，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶柱层析纯化，用(乙酸乙酯:石油醚＝1:1)洗脱得C027-27d(300mg)。(3) C027-27c (500 mg, 2.76 mmol) and int2 (506 mg, 3.04 mmol) were dissolved in acetic acid (8 mL). The mixture was stirred at 100 °C for 2 h under nitrogen protection. After the reaction, the acetic acid was dried, diluted with ethyl acetate, and then water was added. The mixture was extracted with ethyl acetate three times. The organic phases were combined, washed twice with saturated brine, dried with sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography and eluted with (ethyl acetate: petroleum ether = 1:1) to obtain C027-27d (300 mg).
(4)将C027-27d(300mg，0.96mmol)溶解在乙腈(5mL)中，加入int6(142mg，1.16mmol)和对甲苯磺酸(37mg，1.93mmol)并在90℃下搅拌4h。反应结束后过滤，反相纯化得化合物C027(15.19mg)。(4) C027-27d (300 mg, 0.96 mmol) was dissolved in acetonitrile (5 mL), and int6 (142 mg, 1.16 mmol) and p-toluenesulfonic acid (37 mg, 1.93 mmol) were added and stirred at 90° C. for 4 h. After the reaction was completed, the mixture was filtered and purified by reverse phase to obtain compound C027 (15.19 mg).
1H NMR(400MHz,DMSO_d6)δ10.96(s,1H),9.01(s,1H),8.17–8.12(m,1H),7.87(d,J＝2.0Hz,1H),7.78(s,1H),7.56(d,J＝7.2Hz,1H),7.37(d,J＝8.4Hz,1H),7.09(dd,J＝8.4,2.0Hz,1H),6.80(d,J＝8.8Hz,1H),4.82–4.63(m,1H),3.12–2.93(m,2H),2.80–2.66(m,2H),2.13–2.10(m,1H),0.97–0.92(m,2H),0.66–0.63(m,2H). 1 H NMR (400 MHz, DMSO_d6) δ 10.96 (s, 1H), 9.01 (s, 1H), 8.17–8.12 (m, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.78 (s, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.09 (dd, J = 8.4, 2.0 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 4.82–4.63 (m, 1H), 3.12–2.93 (m, 2H), 2.80–2.66 (m, 2H), 2.13–2.10 (m, 1H), 0.97–0.92 (m, 2H), 0.66–0.63 (m, 2H).
实施例28：
Embodiment 28:
合成路线
synthetic route
(1)在一个50mL的封口瓶中加入化合物C028-28a(100mg,0.642mmol)化合物int2(154mg，0.770mmol)和Pd2(dba)3(58mg，0.064mmol),碳酸铯(418mg，1.284mmol)和t-Bubrettphos(62mg,0.128mmol)溶于二氧六环(4mL)中，于100℃下反应2小时。反应冷却后，反应液用乙酸乙酯和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得C028-28b(200mg)。(1) Compound C028-28a (100 mg, 0.642 mmol), compound int2 (154 mg, 0.770 mmol), Pd 2 (dba) 3 (58 mg, 0.064 mmol), cesium carbonate (418 mg, 1.284 mmol) and t-Bubrettphos (62 mg, 0.128 mmol) were added to a 50 mL sealed bottle and reacted at 100°C for 2 hours. After the reaction was cooled, the reaction solution was washed with ethyl acetate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain C028-28b (200 mg).
(2)将C028-28b(100mg，0.35mmol)和int6(51mg，0.42mmol)溶解在乙腈(2mL)中，然后加入对甲苯磺酸(11.98mg，0.07mmol)。混合液在氮气保护下90℃搅拌4小时。反应结束后，将反应液浓缩。所得残余物经制备分析纯化得化合物C028(37.42mg)。(2) C028-28b (100 mg, 0.35 mmol) and int6 (51 mg, 0.42 mmol) were dissolved in acetonitrile (2 mL), and p-toluenesulfonic acid (11.98 mg, 0.07 mmol) was then added. The mixture was stirred at 90°C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated. The residue was purified by preparative analysis to obtain compound C028 (37.42 mg).
1H NMR(400MHz,DMSO_d6)δ10.85(s,1H),8.90(s,1H),8.15(d,J＝8.0Hz,1H),7.91(s,1H),7.83(s,1H)7.35(d,J＝8.0Hz,1H),7.09–7.06(m,2H),6.88(d,J＝4.0Hz,1H),4.83–4.79(m,1H),3.07–2.98(m,2H),2.83–2.74(m,2H),2.19(s,3H). 1 H NMR (400 MHz, DMSO_d6) δ 10.85 (s, 1H), 8.90 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.91 (s, 1H), 7.83 (s, 1H) 7.35 (d, J = 8.0 Hz, 1H), 7.09–7.06 (m, 2H), 6.88 (d, J = 4.0 Hz, 1H), 4.83–4.79 (m, 1H), 3.07–2.98 (m, 2H), 2.83–2.74 (m, 2H), 2.19 (s, 3H).
实施例29：
Embodiment 29:
合成路线
synthetic route
(1)将C029-29a(800mg，5.14mmol)、int2(1.246g，6.17mmol)、t-BuBrettphos(499mg，1.03mmol)、Pd2(dba)3(470mg，0.514mmol)磷酸钾(3.27g，15.4mmol)溶解在叔丁醇(15mL)中。混合液在氮气保护下120℃搅拌5h，反应结束后加乙酸乙酯稀释，再加水，用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗涤2次，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶柱层析纯化，用(乙酸乙酯:石油醚＝1:1)洗脱得C029-29b(300mg)。(1) C029-29a (800 mg, 5.14 mmol), int2 (1.246 g, 6.17 mmol), t-BuBrettphos (499 mg, 1.03 mmol), Pd2(dba)3 (470 mg, 0.514 mmol) and potassium phosphate (3.27 g, 15.4 mmol) were dissolved in tert-butyl alcohol (15 mL). The mixture was stirred at 120°C for 5 h under nitrogen protection. After the reaction was completed, ethyl acetate was added to dilute the mixture, and water was added. The mixture was extracted with ethyl acetate three times. The organic phases were combined, washed twice with saturated brine, dried with sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography and eluted with (ethyl acetate: petroleum ether = 1:1) to obtain C029-29b (300 mg).
(2)将C029-29b(200mg，0.70mmol)溶解在乙腈(5mL)中，加入int6(95mg，0.77mmol)和对甲苯磺酸(27mg，0.14mmol)并在90℃下搅拌4h。反应结束后过滤，反相纯化得化合物C029(24.73mg)。(2) C029-29b (200 mg, 0.70 mmol) was dissolved in acetonitrile (5 mL), and int6 (95 mg, 0.77 mmol) and p-toluenesulfonic acid (27 mg, 0.14 mmol) were added and stirred at 90° C. for 4 h. After the reaction was completed, the mixture was filtered and purified by reverse phase to obtain compound C029 (24.73 mg).
1H NMR(400MHz,DMSO_d6)δ10.87(s,1H),8.88(s,1H),7.93(d,J＝2.0Hz,1H),7.86(d,J＝2.0Hz,1H),7.56–7.50(m,1H),7.35(d,J＝8.4Hz,1H),7.14–7.06(m,2H),6.85(d,J＝8.0Hz,1H),4.83–4.79(m,1H),3.08–3.01(m,2H),2.81–2.76(m,2H),2.31(s,3H). 1 H NMR (400 MHz, DMSO_d6) δ 10.87 (s, 1H), 8.88 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.56–7.50 (m, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.14–7.06 (m, 2H), 6.85 (d, J = 8.0 Hz, 1H), 4.83–4.79 (m, 1H), 3.08–3.01 (m, 2H), 2.81–2.76 (m, 2H), 2.31 (s, 3H).
实施例31：
Embodiment 31:
合成路线
synthetic route
(1)将int5(400mg，1.39mmol，1eq)，O-苄基羟胺(267mg，1.67mmol，1.2eq)和对甲苯磺酸水合物(48mg，0.279mmol，0.2eq)溶解在乙腈(3.0mL)中，在90℃下搅拌4h。反应结束后，过滤反应液，用乙腈洗涤，合并有机相,减压浓缩，所得残余物反相制备分析纯化得化合物C031(17.02mg)。(1) Int5 (400 mg, 1.39 mmol, 1 eq), O-benzylhydroxylamine (267 mg, 1.67 mmol, 1.2 eq) and p-toluenesulfonic acid hydrate (48 mg, 0.279 mmol, 0.2 eq) were dissolved in acetonitrile (3.0 mL) and stirred at 90° C. for 4 h. After the reaction was completed, the reaction solution was filtered, washed with acetonitrile, the organic phases were combined, and concentrated under reduced pressure. The obtained residue was purified by reverse phase preparative analysis to obtain compound C031 (17.02 mg).
1H NMR(400MHz,DMSO_d6)δ10.94(s,1H),9.00(s,1H),8.39(d,J＝4.0Hz,1H),7.90(d,J＝4.0Hz,1H),7.80–7.78(m,2H),7.40–7.35(m,6H),7.08(dd,J＝8.0,2.0Hz,1H),6.80(d,J＝8.0Hz,1H),5.16(s,2H),2.19(s,3H). 1 H NMR (400 MHz, DMSO_d6) δ 10.94 (s, 1H), 9.00 (s, 1H), 8.39 (d, J = 4.0 Hz, 1H), 7.90 (d, J = 4.0 Hz, 1H), 7.80–7.78 (m, 2H), 7.40–7.35 (m, 6H), 7.08 (dd, J = 8.0, 2.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 5.16 (s, 2H), 2.19 (s, 3H).
实施例32：
Embodiment 32:
合成路线
synthetic route
将int12(220mg，0.40mmol)溶解在乙腈(5mL)中，加入int6(58mg，0.475mmol)和对甲苯磺酸(15mg，0.08mmol)并在90℃下搅拌4h。反应结束后过滤，反相纯化得化合物C032(22.71mg)。Int12 (220 mg, 0.40 mmol) was dissolved in acetonitrile (5 mL), and int6 (58 mg, 0.475 mmol) and p-toluenesulfonic acid (15 mg, 0.08 mmol) were added and stirred at 90° C. for 4 h. After the reaction was completed, the mixture was filtered and purified by reverse phase to obtain compound C032 (22.71 mg).
1H NMR(400MHz,DMSO_d6)δ10.99(s,1H),9.11(s,1H),8.43(d,J＝2.0Hz,1H),7.96–7.92(m,3H),7.82(d,J＝2.0Hz,1H),7.35(d,J＝12.0Hz,1H),6.84(d,J＝8.8Hz,1H),4.75–7.72(m,1H),3.04–2.97(m,2H),2.78–2.73(m,2H),2.20(s,3H). 1 H NMR (400 MHz, DMSO_d6) δ 10.99 (s, 1H), 9.11 (s, 1H), 8.43 (d, J = 2.0 Hz, 1H), 7.96–7.92 (m, 3H), 7.82 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 12.0 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.75–7.72 (m, 1H), 3.04–2.97 (m, 2H), 2.78–2.73 (m, 2H), 2.20 (s, 3H).
实施例33：
Embodiment 33:
合成路线
synthetic route
将int13(100mg，0.348mmol)、int6(50mg，0.418mmol)、PTSA(15mg,0.05mmol),依次加入乙腈(5mL)中。氮气保护下混合物于60℃油浴中搅拌4h。反应结束后，将反应液冷却至室温，减压浓缩。所得残余物用反相制备纯化得化合物C033(2.7mg)。Int13 (100 mg, 0.348 mmol), int6 (50 mg, 0.418 mmol), and PTSA (15 mg, 0.05 mmol) were added to acetonitrile (5 mL) in sequence. The mixture was stirred in a 60°C oil bath under nitrogen protection for 4 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was purified by reverse phase preparation to obtain compound C033 (2.7 mg).
1H NMR(400MHz,DMSO_d6)δ11.64(s,1H),9.37(s,1H),8.37(s,1H),8.23(s,2H),7.99(d,J＝4.0Hz,1H),7.91(d,J＝8.0Hz,1H),6.88(d,J＝8.0Hz,1H),4.77–4.75(m,1H),3.02-2.95(m,2H),2.84–2.71(m,2H),2.20(s,3H). 1 H NMR (400 MHz, DMSO_d6) δ 11.64 (s, 1H), 9.37 (s, 1H), 8.37 (s, 1H), 8.23 (s, 2H), 7.99 (d, J = 4.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.77–4.75 (m, 1H), 3.02-2.95 (m, 2H), 2.84–2.71 (m, 2H), 2.20 (s, 3H).
实施例34：
Embodiment 34:
合成路线
synthetic route
(1)将C034-34a(100mg，0.528mmol)、int2(212mg，1.05mmol)以及DIEA(0.1mL，1.05mmol)溶解在DMSO(10mL)中。氮气保护下混合物于90℃油浴中搅拌3h。反应结束后，将反应液冷却至室温，减压浓缩。所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝1:1)洗脱得C034-34b(50mg)。(1) C034-34a (100 mg, 0.528 mmol), int2 (212 mg, 1.05 mmol) and DIEA (0.1 mL, 1.05 mmol) were dissolved in DMSO (10 mL). The mixture was stirred in an oil bath at 90°C for 3 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 1:1) to obtain C034-34b (50 mg).
(2)将C034-34b(50mg，0.156mmol)、int6(30mg，0.372mmol)和PTSA(12mg,0.062mmol),依次加入乙腈(5mL)中。氮气保护下混合物于60℃油浴中搅拌4h。反应结束后，将反应液冷却至室温，减压浓缩。所得残余物用反相制备纯化得化合物C034(2.7mg)。(2) C034-34b (50 mg, 0.156 mmol), int6 (30 mg, 0.372 mmol) and PTSA (12 mg, 0.062 mmol) were added to acetonitrile (5 mL) in sequence. The mixture was stirred in an oil bath at 60°C for 4 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase preparative reaction to obtain compound C034 (2.7 mg).
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),8.43(s,1H),8.27(d,J＝4.0Hz,1H),7.97(d,J＝4.0Hz,1H),7.65(d,J＝4.0Hz,1H),7.49(s,1H),7.39(d,J＝8.0Hz,1H),7.12–7.04(m,1H),4.76–4.74(m,1H),3.06–2.95(m,2H),2.78–2.73(m,2H),2.18(s,3H). 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.43 (s, 1H), 8.27 (d, J = 4.0 Hz, 1H), 7.97 (d, J = 4.0 Hz, 1H), 7.65 (d, J = 4.0 Hz, 1H), 7.49 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.12–7.04 (m, 1H), 4.76–4.74 (m, 1H), 3.06–2.95 (m, 2H), 2.78–2.73 (m, 2H), 2.18 (s, 3H).
实施例35：
Embodiment 35:
合成路线
synthetic route
将int24(2.17g，7.14mmol)、int6(1.37g，8.57mmol)和对甲苯磺酸(272mg，1.43mmol)溶解在乙腈(39mL)中。反应液在80℃下反应2小时。反应结束后冷却至室温，过滤，将滤饼转移至250mL单口反应瓶中，加入乙酸乙酯(100mL)和水(40mL)，搅拌下滴加浓氨水(0.1mL)。待有机层溶清后分出有机相，乙酸乙酯(20mL)萃取水相一次，合并有机相，干燥过滤浓缩后，经高效液相制备分析纯化得化合物C035(698.80mg)。Dissolve int24 (2.17 g, 7.14 mmol), int6 (1.37 g, 8.57 mmol) and p-toluenesulfonic acid (272 mg, 1.43 mmol) in acetonitrile (39 mL). The reaction solution was reacted at 80 ° C for 2 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the filter cake was transferred to a 250 mL single-mouth reaction bottle, ethyl acetate (100 mL) and water (40 mL) were added, and concentrated ammonia (0.1 mL) was added dropwise under stirring. After the organic layer was dissolved, the organic phase was separated, and the aqueous phase was extracted once with ethyl acetate (20 mL), and the organic phases were combined, dried, filtered, and concentrated, and purified by high-performance liquid preparative analysis to obtain compound C035 (698.80 mg).
1H NMR(400MHz,DMSO_d6)δ11.04(s,1H),8.91(s,1H),8.22(s,1H),7.86(d,J＝2.4Hz,1H),7.82(d,J＝2.0Hz,1H),7.73(dd,J＝12.8,2.0Hz,1H),7.37(d,J＝8.8Hz,1H),7.08(dd,J＝8.4,2.0Hz,1H),4.79–4.72(m,1H),3.03–2.99(m,2H),2.79–2.74(m,2H),2.20(s,3H). 1 H NMR (400 MHz, DMSO_d6) δ 11.04 (s, 1H), 8.91 (s, 1H), 8.22 (s, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 12.8, 2.0 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.08 (dd, J = 8.4, 2.0 Hz, 1H), 4.79–4.72 (m, 1H), 3.03–2.99 (m, 2H), 2.79–2.74 (m, 2H), 2.20 (s, 3H).
实施例36：
Embodiment 36:
合成路线
synthetic route
(1)将化合物C036-36a(500mg，3.19mmol)和int2(649mg，3.19mmol)溶解在N，N-二甲基甲酰胺(15mL)中，添加三乙胺(970mg，9.58mmol)。将混合物在120℃下搅拌2小时。反应结束后减压浓缩，用乙酸乙酯打浆，得C036-36b可直接用于下一步。(1) Compound C036-36a (500 mg, 3.19 mmol) and int2 (649 mg, 3.19 mmol) were dissolved in N,N-dimethylformamide (15 mL), and triethylamine (970 mg, 9.58 mmol) was added. The mixture was stirred at 120°C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and slurried with ethyl acetate to obtain C036-36b, which was directly used in the next step.
(2)将C036-36b(100mg，0.34mmol)、int6(108mg，0.68mmol)和对甲苯磺酸(13mg，0.068mmol)溶解在乙腈(2mL)中。反应液在90℃下反应4小时。反应结束后用乙酸乙酯萃取，合并有机相。有机相用盐水洗，无水硫酸钠干燥，真空浓缩后，所得残余物经制备分析纯化得化合物C036(2.2mg)。1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.58(s,1H),8.57(d,J＝4.0Hz,1H),8.25(d,J＝4.0Hz,1H),7.90(dd,J＝36.0,2.1Hz,2H),7.39(d,J＝8.0Hz,1H),7.12(dd,J＝8.0,2.0Hz,1H),4.80(s,1H),3.02(dt,J＝20.0,7.5Hz,2H),2.80(tt,J＝12,7.2Hz,2H),2.23(s,3H).(2) C036-36b (100 mg, 0.34 mmol), int6 (108 mg, 0.68 mmol) and p-toluenesulfonic acid (13 mg, 0.068 mmol) were dissolved in acetonitrile (2 mL). The reaction solution was reacted at 90° C. for 4 hours. After the reaction was completed, it was extracted with ethyl acetate and the organic phases were combined. The organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by preparative analysis to obtain compound C036 (2.2 mg). 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.58 (s, 1H), 8.57 (d, J = 4.0 Hz, 1H), 8.25 (d, J = 4.0 Hz, 1H), 7.90 (dd, J = 36.0, 2.1 Hz, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.12 (dd, J = 8.0, 2.0 Hz, 1H), 4.80 (s, 1H), 3.02 (dt, J = 20.0, 7.5 Hz, 2H), 2.80 (tt, J = 12, 7.2 Hz, 2H), 2.23 (s, 3H).
实施例37：
Embodiment 37:
合成路线
synthetic route
将int21(138mg，0.461mmol)和int6(68mg,0.554mmol)溶解在ACN(2mL)中，加入对甲苯磺酸水合物(15mg，0.092mmol),氮气保护下在90℃下搅拌4h。反应结束后，过滤,滤饼用用乙腈洗涤，合并有机相所得残余物经反相制备分析纯化得化合物C037(25.53mg)。Int21 (138 mg, 0.461 mmol) and int6 (68 mg, 0.554 mmol) were dissolved in ACN (2 mL), p-toluenesulfonic acid hydrate (15 mg, 0.092 mmol) was added, and stirred at 90°C for 4 h under nitrogen protection. After the reaction was completed, the mixture was filtered, the filter cake was washed with acetonitrile, and the residue obtained by combining the organic phases was purified by reverse phase preparative analysis to obtain compound C037 (25.53 mg).
1H NMR(400MHz,DMSO_d6)δ10.97(s,1H),8.93(s,1H),7.91(s,1H),7.76(s,1H),7.48(s,1H),7.38(d,J＝8.8Hz,1H),7.11–7.08(m,1H),6.66(s,1H),6.65(d,J＝8.4Hz,1H),4.74–4.72(m,1H),3.09–2.95(m,2H),2.77–2.31(m,2H),2.46(s,1H),2.15(s,1H). 1 H NMR (400 MHz, DMSO_d6) δ 10.97 (s, 1H), 8.93 (s, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 7.48 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.11–7.08 (m, 1H), 6.66 (s, 1H), 6.65 (d, J = 8.4 Hz, 1H), 4.74–4.72 (m, 1H), 3.09–2.95 (m, 2H), 2.77–2.31 (m, 2H), 2.46 (s, 1H), 2.15 (s, 1H).
实施例38：
Embodiment 38:
合成路线
synthetic route
将化合物int25(150mg，0.50mmol)，int6(80mg，0.55mmol，)和对甲苯磺酸水合物(19mg，0.10mmol)溶解在乙腈(5.0mL)中，在90℃下搅拌4h。反应结束后，过滤反应液，用乙腈洗涤，合并有机相所得残余物经制备分析纯化得C038(18.69mg)。Compound int25 (150 mg, 0.50 mmol), int6 (80 mg, 0.55 mmol,) and p-toluenesulfonic acid hydrate (19 mg, 0.10 mmol) were dissolved in acetonitrile (5.0 mL) and stirred at 90° C. for 4 h. After the reaction was completed, the reaction solution was filtered and washed with acetonitrile, and the residue obtained by combining the organic phases was purified by preparative analysis to obtain C038 (18.69 mg).
1H NMR(400MHz,DMSO_d6)δ10.92(s,1H),8.79(s,1H),8.39(s,1H),8.07(s,1H),7.84(d,J＝2.0Hz,1H),7.76(d,J＝2.0Hz,1H),7.36(d,J＝8.6Hz,1H),7.09–7.07(m,1H),6.63(s,1H),4.81–4.62(m,1H),3.04–2.93(m,2H),2.82–2.68(m,2H),2.26(s,3H),2.17(s,3H). 1 H NMR (400 MHz, DMSO_d6) δ 10.92 (s, 1H), 8.79 (s, 1H), 8.39 (s, 1H), 8.07 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.09–7.07 (m, 1H), 6.63 (s, 1H), 4.81–4.62 (m, 1H), 3.04–2.93 (m, 2H), 2.82–2.68 (m, 2H), 2.26 (s, 3H), 2.17 (s, 3H).
实施例39：
Embodiment 39:
合成路线
synthetic route
将int26(200mg，0.66mmol，1eq)、int6(126mg，0.79mmol，1.2eq)和对甲苯磺酸水合物(25mg，0.13mmol，0.2eq)溶解在DMF(5.0mL)中，在120℃下搅拌4h。反应结束后，旋干反应液，所得残余物用柱色谱(PE/EA＝4/1)纯化得C039(70mg)。Int26 (200 mg, 0.66 mmol, 1 eq), int6 (126 mg, 0.79 mmol, 1.2 eq) and p-toluenesulfonic acid hydrate (25 mg, 0.13 mmol, 0.2 eq) were dissolved in DMF (5.0 mL) and stirred at 120° C. for 4 h. After the reaction was completed, the reaction solution was spin-dried and the residue was purified by column chromatography (PE/EA=4/1) to obtain C039 (70 mg).
1H NMR(400MHz,DMSO_d6)δ11.05(s,1H),9.34(s,1H),7.81–7.75(m,3H),7.39(d,J＝8.4Hz,1H),7.11(dd,J＝8.4,2.0Hz,1H),6.70(d,J＝8.0Hz,1H),4.79–4.70(m,1H),3.03–2.96(m,2H),2.80–2.73(m,2H),2.18(d,J＝2.4Hz,3H). 1 H NMR (400 MHz, DMSO_d6) δ 11.05 (s, 1H), 9.34 (s, 1H), 7.81–7.75 (m, 3H), 7.39 (d, J = 8.4 Hz, 1H), 7.11 (dd, J = 8.4, 2.0 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 4.79–4.70 (m, 1H), 3.03–2.96 (m, 2H), 2.80–2.73 (m, 2H), 2.18 (d, J = 2.4 Hz, 3H).
实施例40：
Embodiment 40:
合成路线
synthetic route
将int15(400mg，1.27mmol)，int6(187mg，1.52mmol)和对甲苯磺酸水合物(48mg，0.25mmol)溶解在乙腈(5.0mL)中，在90℃下搅拌4小时。反应结束后，浓缩反应液，用二氯甲烷萃取，合并有机相所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝4:1)洗脱，得到化合物C040-a(45mg)和C40-b(40mg)。Int15 (400 mg, 1.27 mmol), int6 (187 mg, 1.52 mmol) and p-toluenesulfonic acid hydrate (48 mg, 0.25 mmol) were dissolved in acetonitrile (5.0 mL) and stirred at 90° C. for 4 hours. After the reaction was completed, the reaction solution was concentrated and extracted with dichloromethane, and the residue obtained by combining the organic phases was purified by column chromatography and eluted with (petroleum ether: ethyl acetate = 4:1) to obtain compounds C040-a (45 mg) and C40-b (40 mg).
C040-a：1H NMR(400MHz,CD3OD)δ8.07(d,J＝4.0Hz,1H),7.50–7.49(m,2H),7.44(d,J＝4.0Hz,1H),7.33(d,J＝12.0Hz,1H),7.09(dd,J＝8.0,4.0Hz,1H),6.64(d,J＝12.0Hz,1H),4.62–4.60(m,1H),2.93–2.78(m,3H),2.71–2.59(m,2H),1.13(d,J＝8.0Hz,6H).C040-a: 1 H NMR (400 MHz, CD 3 OD) δ 8.07 (d, J = 4.0 Hz, 1H), 7.50-7.49 (m, 2H), 7.44 (d, J = 4.0 Hz, 1H), 7.33 (d, J = 12.0 Hz, 1H), 7.09 (dd, J = 8.0, 4.0 Hz, 1H), 6.64 (d, J = 12.0 Hz, 1H), 4.62-4.60 (m, 1H), 2.93-2.78 (m, 3H), 2.71-2.59 (m, 2H), 1.13 (d, J = 8.0 Hz, 6H).
C40-b：1H NMR(400MHz,CD3OD)δ8.10–8.06(m,1H),7.59(dd,J＝8.0,2.0Hz,1H),7.49(s,1H),7.42(d,J＝4.0Hz,1H),7.34(d,J＝8.0Hz,1H),7.09(dd,J＝8.0,2.0Hz,1H),6.62(d,J＝8.0Hz,1H),4.75–4.64(m,1H),3.42–3.28(m,1H),3.02–2.86(m,2H),2.79–2.62(m,2H),1.23(d,J＝8.0Hz,6H).C40-b: 1 H NMR (400 MHz, CD 3 OD) δ 8.10–8.06 (m, 1H), 7.59 (dd, J=8.0, 2.0 Hz, 1H), 7.49 (s, 1H), 7.42 (d, J=4.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.09 (dd, J=8.0, 2.0 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 4.75–4.64 (m, 1H), 3.42–3.28 (m, 1H), 3.02–2.86 (m, 2H), 2.79–2.62 (m, 2H), 1.23 (d, J=8.0 Hz, 6H).
实施例41：
Embodiment 41:
合成路线
synthetic route
将int5(500mg，1.74mmol)和int16(300mg，2.5mmol)溶解在乙腈(5mL)中，然后加入对甲苯磺酸(50mg，0.26mmol)。混合液在氮气保护下90℃搅拌4小时。反应结束后，将反应液浓缩。所得残余物反相制备分析纯化得化合物C041(13.16mg)。Int5 (500 mg, 1.74 mmol) and int16 (300 mg, 2.5 mmol) were dissolved in acetonitrile (5 mL), and then p-toluenesulfonic acid (50 mg, 0.26 mmol) was added. The mixture was stirred at 90°C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated. The obtained residue was purified by reverse phase preparative analysis to obtain compound C041 (13.16 mg).
1H NMR(400MHz,DMSO_d6)δ10.94(s,1H),8.99(s,1H),8.40(d,J＝4.0Hz,1H),7.90(d,J＝4.0Hz,1H),7.86–7.77(m,2H),7.36(d,J＝8.0Hz,1H),7.09(dd,J＝8.0,2.0Hz,1H),6.81(d,J＝8.0Hz,1H),4.33–4.28(m,1H),3.87–3.78(m,2H),3.48–3.42(m,2H),2.18(s,3H),1.99-1.96(m,2H),1.65–1.56(m,2H). 1 H NMR (400 MHz, DMSO_d6) δ 10.94 (s, 1H), 8.99 (s, 1H), 8.40 (d, J = 4.0 Hz, 1H), 7.90 (d, J = 4.0 Hz, 1H), 7.86–7.77 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.09 (dd, J = 8.0, 2.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.33–4.28 (m, 1H), 3.87–3.78 (m, 2H), 3.48–3.42 (m, 2H), 2.18 (s, 3H), 1.99-1.96 (m, 2H), 1.65–1.56 (m, 2H).
实施例42：
Embodiment 42:
合成路线
synthetic route
(1)将6-羟基烟酸(5g，35.94mmol)加到水(10mL)和甲醇(70mL)中，再加入碘甲烷(21mL.359.43mmol)。将混合物在100℃下搅拌16h。反应结束后用水(200mL)和二氯甲烷(100mL x 3)萃取，合并有机相。有机相用无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝4:1)洗脱得C042-42b(2.1g)。(1) Add 6-hydroxynicotinic acid (5 g, 35.94 mmol) to water (10 mL) and methanol (70 mL), and then add iodomethane (21 mL. 359.43 mmol). The mixture was stirred at 100°C for 16 h. After the reaction was completed, it was extracted with water (200 mL) and dichloromethane (100 mL x 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain C042-42b (2.1 g).
(2)将C042-42b(5.1g，33.3mmol)加到乙腈(100mL)中，再加入二甲羟胺盐酸盐(3.9g，39.9mmol)，T3P(32g，49.9mmol,50％in DMF)和吡啶(7.9g，99.9mmol)。将混合物在室温下搅拌16h。反应结束后用水(200mL)和二氯甲烷(100mL x 3)萃取，合并有机相。有机相用无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝8:1)洗脱得C042-42c(1.9g)。(2) C042-42b (5.1 g, 33.3 mmol) was added to acetonitrile (100 mL), and then dimethylhydroxylamine hydrochloride (3.9 g, 39.9 mmol), T 3 P (32 g, 49.9 mmol, 50% in DMF) and pyridine (7.9 g, 99.9 mmol) were added. The mixture was stirred at room temperature for 16 h. After the reaction was completed, it was extracted with water (200 mL) and dichloromethane (100 mL x 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=8:1) to obtain C042-42c (1.9 g).
(3)将C042-42c(1.5g，7.65mmol)溶解在THF(15mL)中,将体系降温至0℃，滴加甲基溴化镁(4mL，3mmol/L in THF)。将混合物在室温下搅拌16h。反应结束后用饱和氯化铵水溶液(5mL)淬灭，加水(50mL)稀释后，用二氯甲烷(30mL x 3)萃取，合并有机相，用饱和食盐水洗涤2次，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶柱层析纯化，用乙酸乙酯洗脱得C042-42d(490mg)。(3) C042-42c (1.5 g, 7.65 mmol) was dissolved in THF (15 mL), the system was cooled to 0 °C, and methylmagnesium bromide (4 mL, 3 mmol/L in THF) was added dropwise. The mixture was stirred at room temperature for 16 h. After the reaction was completed, it was quenched with saturated aqueous ammonium chloride solution (5 mL), diluted with water (50 mL), and extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography and eluted with ethyl acetate to obtain C042-42d (490 mg).
(4)将C042-42d(420mg，2.78mmol)加到DMF(10mL)中，再加入NCS(371mg，2.78mmol)。将混合物在50℃下搅拌2h。反应结束后加水(50mL)稀释，用二氯甲烷(30mL x 3)萃取合并有机相。有机相用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝2:1)洗脱得C042-42e(360mg)。(4) C042-42d (420 mg, 2.78 mmol) was added to DMF (10 mL), and NCS (371 mg, 2.78 mmol) was added. The mixture was stirred at 50 °C for 2 h. After the reaction was completed, water (50 mL) was added to dilute it, and the organic phases were extracted and combined with dichloromethane (30 mL x 3). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=2:1) to obtain C042-42e (360 mg).
(5)将C042-42e(270mg，1.45mmol)、int2(244mg，1.21mmol)、t-BuBrettphos(117mg，0.24mmol)、Pd2(dba)3(111mg，0.12mmol)和磷酸钾(769mg，3.63mmol)溶解在叔丁醇(5mL)中。混合液在氮气保护下120℃搅拌5h，反应结束后加乙酸乙酯(30mL)稀释，再加水(30mL)，用乙酸乙酯萃取(30mL x 3)，合并有机相，用饱和食盐水洗涤2次，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶柱层析纯化，用(乙酸乙酯:石油醚＝1:1)洗脱得化合物C042-42f(330mg)。(5) C042-42e (270 mg, 1.45 mmol), int2 (244 mg, 1.21 mmol), t-BuBrettphos (117 mg, 0.24 mmol), Pd 2 (dba) 3 (111 mg, 0.12 mmol) and potassium phosphate (769 mg, 3.63 mmol) were dissolved in tert-butyl alcohol (5 mL). The mixture was stirred at 120° C. for 5 h under nitrogen protection. After the reaction was completed, ethyl acetate (30 mL) was added for dilution, and water (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography and eluted with (ethyl acetate: petroleum ether = 1:1) to obtain compound C042-42f (330 mg).
(6)将C042-42f(170mg，0.54mmol)溶解在乙腈(5mL)中，加入int6(73mg，0.59mmol)和对甲苯磺酸(21mg，0.11mmol)并在90℃下搅拌4h。反应结束后，减压浓缩，所得残余物用高效液相纯化得化合物C042(11.1mg)。1H NMR(400MHz,DMSO_d6)δ11.20(s,1H),7.42–7.40(m,3H),7.30(s,1H),7.11(d,J＝6.8Hz,1H),6.24–6.19(m,2H),4.76(br.s,1H),3.50(s,3H),3.05–2.95(m,2H),2.77–2.66(m,2H),2.13(s,3H).(6) C042-42f (170 mg, 0.54 mmol) was dissolved in acetonitrile (5 mL), int6 (73 mg, 0.59 mmol) and p-toluenesulfonic acid (21 mg, 0.11 mmol) were added and stirred at 90°C for 4 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain compound C042 (11.1 mg). 1 H NMR (400 MHz, DMSO_d6) δ 11.20 (s, 1H), 7.42–7.40 (m, 3H), 7.30 (s, 1H), 7.11 (d, J=6.8 Hz, 1H), 6.24–6.19 (m, 2H), 4.76 (br. s, 1H), 3.50 (s, 3H), 3.05–2.95 (m, 2H), 2.77–2.66 (m, 2H), 2.13 (s, 3H).
实施例43：
Embodiment 43:
合成路线
synthetic route
将int22(89mg，0.755mmol)和int5(180mg，0.629mmol)溶解在乙腈(2mL)中，然后加入对甲苯磺酸(10mg，0.063mmol)。混合液在氮气保护下70℃搅拌4小时。反应结束后，将反应液浓缩。所得残余物经制备分析纯化得化合物C043(13.67mg)。Int22 (89 mg, 0.755 mmol) and int5 (180 mg, 0.629 mmol) were dissolved in acetonitrile (2 mL), and then p-toluenesulfonic acid (10 mg, 0.063 mmol) was added. The mixture was stirred at 70 ° C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated. The obtained residue was purified by preparative analysis to obtain compound C043 (13.67 mg).
1H NMR(400MHz,CD3OD)δ8.27(d,J＝2.0Hz,1H),7.80(dd,J＝8.0,2.0Hz,1H),7.50(s,1H),7.42(d,J＝2.0Hz,1H),7.33(d,J＝8.0Hz,1H),7.08(dd,J＝4.0,4.0Hz,1H),6.62(d,J＝8.0Hz,1H),4.82–4.77(m,1H),4.43(dd,J＝8.0,4.0Hz,2H),2.66–2.57(m,1H),2.39–2.24(m,4H),2.17(s,3H). 1 H NMR (400 MHz, CD 3 OD) δ8.27 (d, J=2.0 Hz, 1H), 7.80 (dd, J=8.0, 2.0 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.08 (dd, J=4.0, 4.0 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 4.82-4.77 (m, 1H), 4.43 (dd, J=8.0, 4.0 Hz, 2H), 2.66-2.57 (m, 1H), 2.39-2.24 (m, 4H), 2.17 (s, 3H).
实施例44：
Embodiment 44:
合成路线
synthetic route
将int17(183mg，0.645mmol)、int5(114mg，0.774mmol)、PTSA(25mg,0.129mmol),依次加入乙腈(5mL)中。氮气保护下混合物于60℃油浴中搅拌4h。反应结束后，将反应液冷却至室温，减压浓缩。所得残余物用反向制备纯化得化合物C044(2.1mg)。Int17 (183 mg, 0.645 mmol), int5 (114 mg, 0.774 mmol), and PTSA (25 mg, 0.129 mmol) were added to acetonitrile (5 mL) in sequence. The mixture was stirred in a 60°C oil bath under nitrogen protection for 4 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was purified by reverse preparation to obtain compound C044 (2.1 mg).
1H NMR(400MHz,CDCl3)δ8.36(d,J＝4.0Hz,1H),8.14(s,1H),7.79(dd,J＝8.0,2.0Hz,1H),7.40(d,J＝12.0Hz,2H),7.33(d,J＝8.0Hz,1H),7.20(dd,J＝8.0,4.0Hz,1H),6.73(s,1H),6.47(d,J＝8.0Hz,1H),5.12–4.81(m,1H),3.21–3.16(m,1H),2.76–2.69(m,2H),2.68–2.61(m,2H),2.20(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.36 (d, J = 4.0 Hz, 1H), 8.14 (s, 1H), 7.79 (dd, J = 8.0, 2.0 Hz, 1H), 7.40 (d, J = 12.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.0, 4.0 Hz, 1H), 6.73 (s, 1H), 6.47 (d, J = 8.0 Hz, 1H), 5.12–4.81 (m, 1H), 3.21–3.16 (m, 1H), 2.76–2.69 (m, 2H), 2.68–2.61 (m, 2H), 2.20 (s, 3H).
实施例45：
Embodiment 45:
合成路线
synthetic route
将化合物int18(100mg，3.03mmol)，化合物int5(566mg，3.64mmol)溶解在醋酸(5.0mL)中，在130℃下搅拌4小时。反应结束后，浓缩反应液得化合物C045(600mg)。Compound int18 (100 mg, 3.03 mmol) and compound int5 (566 mg, 3.64 mmol) were dissolved in acetic acid (5.0 mL) and stirred at 130° C. for 4 hours. After the reaction was completed, the reaction solution was concentrated to obtain compound C045 (600 mg).
1H NMR(400MHz,CD3OD)δ8.26(s,1H),7.80(dd,J＝8.0,2.0Hz,1H),7.49(s,1H),7.42(s,1H),7.33(d,J＝8.0Hz,1H),7.09(d,J＝8.0Hz,1H),6.62(d,J＝8.0Hz,1H),4.74–4.69(m,1H),2.32–2.26(m,2H),2.18(s,3H),2.16–2.08(m,2H),1.79–1.62(m,2H). 1 H NMR (400 MHz, CD3OD) δ8.26 (s, 1H), 7.80 (dd, J = 8.0, 2.0 Hz, 1H), 7.49 (s, 1H), 7.42 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 4.74–4.69 (m, 1H), 2.32–2.26 (m, 2H), 2.18 (s, 3H), 2.16–2.08 (m, 2H), 1.79–1.62 (m, 2H).
实施例46：
Embodiment 46:
步骤1：step 1:
于1L三口反应瓶中将氢化钠(1.72g，43.1mmol)溶解在超干四氢呋喃(350mL)中，氮气保护下用冰水浴降温至0℃。将C046-1(5.00g，43.1mmol)溶解在超干四氢呋喃(50mL)中，缓慢滴入反应瓶中(约20分钟)。滴加完后，反应液在0℃下搅拌1小时。将溴化苄(7.37g，43.1mmol)滴入反应液，滴完后在氮气保护下迅速倒入四丁基碘化铵(1.59g，4.31mmol)，继续冰水浴10分钟，然后室温搅拌12小时。反应完全后，用饱和氯化铵水溶液(17mL)淬灭反应，减压浓缩除去大部分四氢呋喃，用二氯甲烷(200mL)溶解残余物，食盐水(100mL)洗一遍，无水硫酸钠干燥并过滤，将滤液减压浓缩，所得残余物用硅胶柱层析纯化，用石油醚:乙酸乙酯(3:1)洗脱，得化合物C046-2(4.3g，48.43％)，为无色液体Dissolve sodium hydride (1.72 g, 43.1 mmol) in ultra-dry tetrahydrofuran (350 mL) in a 1L three-necked reaction bottle, and cool to 0°C in an ice-water bath under nitrogen protection. Dissolve C046-1 (5.00 g, 43.1 mmol) in ultra-dry tetrahydrofuran (50 mL) and slowly drip into the reaction bottle (about 20 minutes). After the addition is complete, stir the reaction solution at 0°C for 1 hour. Drop benzyl bromide (7.37 g, 43.1 mmol) into the reaction solution, and after the addition is complete, quickly pour tetrabutylammonium iodide (1.59 g, 4.31 mmol) under nitrogen protection, continue ice-water bath for 10 minutes, and then stir at room temperature for 12 hours. After the reaction was complete, the reaction was quenched with saturated aqueous ammonium chloride solution (17 mL), and most of the tetrahydrofuran was removed by concentration under reduced pressure. The residue was dissolved with dichloromethane (200 mL), washed once with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with petroleum ether: ethyl acetate (3:1) to obtain compound C046-2 (4.3 g, 48.43%) as a colorless liquid.
1H NMR(400MHz,DMSO_d6)δ7.35–7.24(m,5H),4.60–4.58(m,1H),4.49(s,2H),3.38–3.25(m,2H),2.25–2.21(m,1H),1.96–1.93(m,1H),1.77–1.75(m,1H),1.68–1.64(m,1H),1.13–0.98(m,4H). 1 H NMR (400 MHz, DMSO_d6) δ7.35–7.24 (m, 5H), 4.60–4.58 (m, 1H), 4.49 (s, 2H), 3.38–3.25 (m, 2H), 2.25–2.21 (m, 1H), 1.96–1.93 (m, 1H), 1.77–1.75 (m, 1H), 1.68–1.64 (m, 1H), 1.13–0.98 (m, 4H).
步骤2:Step 2:
将化合物C046-2(4.3g，20.87mmol)溶解在二氯甲烷(120mL)中，冰水浴下加入戴斯-马汀试剂(10.62g，25.04mmol)，加完后在0℃下搅拌2小时。反应完成后，将反应液过滤，二氯甲烷(50mL)润洗滤饼两次，减压浓缩滤液，所得残余物用硅胶柱层析纯化，用石油醚:乙酸乙酯(10:1)洗脱，得化合物C046-3(3.8g，90.09％)，为无色液体。Compound C046-2 (4.3 g, 20.87 mmol) was dissolved in dichloromethane (120 mL), and Dess-Martin reagent (10.62 g, 25.04 mmol) was added under an ice-water bath, and stirred at 0°C for 2 hours after the addition. After the reaction was completed, the reaction solution was filtered, the filter cake was rinsed twice with dichloromethane (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether: ethyl acetate (10:1) to obtain compound C046-3 (3.8 g, 90.09%) as a colorless liquid.
1H NMR(400MHz,DMSO_d6)δ7.36–7.25(m,5H),4.50–4.43(m,2H),3.93–3.89(m,1H),2.64–2.60(m,1H),2.45–2.40(m,1H),2.31–2.19(m,2H),1.91–1.85(m,3H),1.71–1.62(m,1H). 1 H NMR (400 MHz, DMSO_d6) δ7.36–7.25 (m, 5H), 4.50–4.43 (m, 2H), 3.93–3.89 (m, 1H), 2.64–2.60 (m, 1H), 2.45–2.40 (m, 1H), 2.31–2.19 (m, 2H), 1.91–1.85 (m, 3H), 1.71–1.62 (m, 1H).
步骤3:Step 3:
将化合物C046-3(3.8g，18.62mmol)溶解在无水1,2-二氯乙烷(12mL)中，加入双(2-甲氧基乙基)氨基三氟化硫(BAST，5mL，27.12mmol)，氮气保护下在90℃搅拌过夜(16小时)。反应结束后，冷却到室温，将反应液缓慢滴加到提前冷却到0℃的饱和碳酸氢钠水溶液中。滴完后室温搅拌0.5小时至无气泡冒出，分出有机相，用二氯甲烷(30mL)萃取水相两次。合并有机相，无水硫酸钠干燥，过滤，减压浓缩滤液。所得残余物用硅胶柱层析纯化，用石油醚:乙酸乙酯(20:1)洗脱，得化合物C046-4(2.7g，64％)，为无色液体。 Compound C046-3 (3.8 g, 18.62 mmol) was dissolved in anhydrous 1,2-dichloroethane (12 mL), bis(2-methoxyethyl)aminosulfur trifluoride (BAST, 5 mL, 27.12 mmol) was added, and stirred at 90 ° C overnight (16 hours) under nitrogen protection. After the reaction was completed, it was cooled to room temperature, and the reaction solution was slowly added dropwise to a saturated sodium bicarbonate aqueous solution cooled to 0 ° C in advance. After the drop was completed, it was stirred at room temperature for 0.5 hours until no bubbles emerged, the organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography and eluted with petroleum ether: ethyl acetate (20:1) to obtain compound C046-4 (2.7 g, 64%) as a colorless liquid.
1H NMR(400MHz,DMSO_d6)δ7.38–7.25(m,5H),4.56–4.46(m,2H),3.58–3.53(m,1H),2.44–2.31(m,1H),2.00–1.69(m,5H),0.88-0.82(m,2H). 1 H NMR (400 MHz, DMSO_d6) δ7.38–7.25 (m, 5H), 4.56–4.46 (m, 2H), 3.58–3.53 (m, 1H), 2.44–2.31 (m, 1H), 2.00–1.69 (m, 5H), 0.88-0.82 (m, 2H).
步骤4:Step 4:
将化合物C046-4(2.7g，11.94mmol)溶解在甲醇(36mL)中，加入醋酸(7.2mL)和10％湿钯碳(1.1g)，混合物置于高压反应釜内，氢气置换四次，调整高压反应釜内氢气压强为50psi，室温搅拌过夜(16小时)。反应完成后，将反应液过滤并用甲醇(10mL)润洗滤饼，常压90℃下蒸馏，蒸出甲醇(顶温下降至40℃)。用无水乙醚(50mL)稀释冷却后的剩余溶液，搅拌下加入碳酸钠粉末(11g)，氮气保护(不置换)下搅拌2小时。过滤并用无水乙醚(10mL)润洗滤饼3次，常压40℃下蒸馏以除去无水乙醚，得粗品化合物C046-5(1.5g)。Compound C046-4 (2.7 g, 11.94 mmol) was dissolved in methanol (36 mL), acetic acid (7.2 mL) and 10% wet palladium carbon (1.1 g) were added, and the mixture was placed in a high-pressure reactor, replaced with hydrogen four times, and the hydrogen pressure in the high-pressure reactor was adjusted to 50 psi, and stirred at room temperature overnight (16 hours). After the reaction was completed, the reaction solution was filtered and the filter cake was rinsed with methanol (10 mL), and distilled at 90 ° C at normal pressure to distill methanol (the top temperature dropped to 40 ° C). The remaining solution after cooling was diluted with anhydrous ether (50 mL), and sodium carbonate powder (11 g) was added under stirring, and stirred for 2 hours under nitrogen protection (without replacement). Filter and rinse the filter cake with anhydrous ether (10 mL) 3 times, and distill at 40 ° C at normal pressure to remove anhydrous ether to obtain crude compound C046-5 (1.5 g).
1H NMR(400MHz,DMSO_d6)δ4.95(br.s,1H),3.68–3.61(m,6H),2.30–2.19(m,1H),1.98–1.83(m,2H),1.80–1.59(m,3H),1.44–1.33(m,1H),1.31–1.16(m,1H). 1 H NMR (400 MHz, DMSO_d6) δ 4.95 (br.s, 1H), 3.68–3.61 (m, 6H), 2.30–2.19 (m, 1H), 1.98–1.83 (m, 2H), 1.80–1.59 (m, 3H), 1.44–1.33 (m, 1H), 1.31–1.16 (m, 1H).
步骤5:Step 5:
于三口反应瓶中将化合物C046-6(3.6g，22.05mmol)溶解在无水甲苯(50mL)中，氮气置换并保护下，于0℃下依次滴加粗品化合物C046-5(1.5g，11.025mmol)的无水四氢呋喃(15mL)溶液、三苯基膦(5.78g，22.05mmol)的无水四氢呋喃(60mL)溶液和偶氮二甲酸二叔丁酯(DBAD，5.07g，22.05mmol)的无水四氢呋喃(50mL)溶液。滴加完成后，将反应液自然升温至室温，搅拌过夜(12小时)。反应结束后加水(40mL)淬灭，搅拌20分钟，然后分出有机相，用二氯甲烷(40mL)萃取水相3次。合并有机相，干燥、过滤、减压浓缩。所得残余物用硅胶柱层析纯化，用石油醚:乙酸乙酯(10:1)洗脱，得化合物C046-7(515mg，收率16.14％)，为白色固体。Compound C046-6 (3.6 g, 22.05 mmol) was dissolved in anhydrous toluene (50 mL) in a three-necked reaction flask. Under nitrogen replacement and protection, a solution of crude compound C046-5 (1.5 g, 11.025 mmol) in anhydrous tetrahydrofuran (15 mL), a solution of triphenylphosphine (5.78 g, 22.05 mmol) in anhydrous tetrahydrofuran (60 mL), and a solution of di-tert-butyl azodicarboxylate (DBAD, 5.07 g, 22.05 mmol) in anhydrous tetrahydrofuran (50 mL) were added dropwise at 0°C. After the addition was completed, the reaction solution was naturally warmed to room temperature and stirred overnight (12 hours). After the reaction was completed, water (40 mL) was added to quench the reaction, stirred for 20 minutes, and then the organic phase was separated, and the aqueous phase was extracted 3 times with dichloromethane (40 mL). The organic phases were combined, dried, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using petroleum ether:ethyl acetate (10:1) as eluent to obtain compound C046-7 (515 mg, yield 16.14%) as a white solid.
1H NMR(400MHz,DMSO_d6)δ7.86(s,4H),4.35–4.28(m,1H),2.18–1.82(m,4H),1.64–1.56(m,1H),1.44–1.34(m,3H). 1 H NMR (400 MHz, DMSO_d6) δ7.86 (s, 4H), 4.35–4.28 (m, 1H), 2.18–1.82 (m, 4H), 1.64–1.56 (m, 1H), 1.44–1.34 (m, 3H).
步骤6:Step 6:
将化合物C046-7(515mg，1.83mmol)溶解在二氯甲烷(4mL)和甲醇(0.4mL)的混合溶剂中，氮气保护下冰水浴降温至0℃，滴加水合肼(98％，183.21mg，3.66mmol)，滴完后自然升至室温反应2小时。过滤反应液，二氯甲烷(5mL)洗滤饼两次，将稀盐酸(1mol/L，15mL)加入滤液中搅拌0.5小时，分出水相，冻干，得化合物C046-8(192mg，59.47％)。Compound C046-7 (515 mg, 1.83 mmol) was dissolved in a mixed solvent of dichloromethane (4 mL) and methanol (0.4 mL), cooled to 0°C in an ice-water bath under nitrogen protection, and hydrazine hydrate (98%, 183.21 mg, 3.66 mmol) was added dropwise. After the addition was complete, the temperature was naturally raised to room temperature for 2 hours. The reaction liquid was filtered, and the filter cake was washed twice with dichloromethane (5 mL). Dilute hydrochloric acid (1 mol/L, 15 mL) was added to the filtrate and stirred for 0.5 hours. The aqueous phase was separated and freeze-dried to obtain compound C046-8 (192 mg, 59.47%).
1H NMR(400MHz,DMSO_d6)δ11.2(br.s,3H),4.34–4.28(m,1H),2.07–1.77(m,6H),1.55–1.38(m,2H). 1 H NMR (400 MHz, DMSO_d6) δ 11.2 (br.s, 3H), 4.34–4.28 (m, 1H), 2.07–1.77 (m, 6H), 1.55–1.38 (m, 2H).
步骤7:Step 7:
将化合物C046-9(400mg，2.571mmol)和化合物C046-10(626mg，3.085mmol)溶解在冰醋酸(10mL)中。将混合物在130℃下搅拌2小时。反应结束后减压浓缩至干，所得残余物即为粗品化合物C046-11，其可直接用于下一步。Compound C046-9 (400 mg, 2.571 mmol) and compound C046-10 (626 mg, 3.085 mmol) were dissolved in glacial acetic acid (10 mL). The mixture was stirred at 130°C for 2 hours. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure. The resulting residue was the crude compound C046-11, which was directly used in the next step.
LCMS(ESI)m/z:286.0[M+H]+。LCMS (ESI) m/z: 286.0 [M+H] + .
步骤8:Step 8:
将化合物C046-11(436mg，1.525mmol)、化合物C046-8(192mg，1.27mmol)和对甲苯磺酸(48mg，0.254mmol)溶解在乙腈(6mL)中。反应液在60℃下反应12小时。反应结束后减压浓缩干，DMF溶解后经制备分析纯化，得化合物C046(3.85mg)，为白色固体。Compound C046-11 (436 mg, 1.525 mmol), compound C046-8 (192 mg, 1.27 mmol) and p-toluenesulfonic acid (48 mg, 0.254 mmol) were dissolved in acetonitrile (6 mL). The reaction solution was reacted at 60°C for 12 hours. After the reaction was completed, it was concentrated to dryness under reduced pressure, dissolved in DMF and purified by preparative analysis to obtain compound C046 (3.85 mg) as a white solid.
LCMS(ESI)m/z:419.0[M+H]+。LCMS (ESI) m/z: 419.0 [M+H] + .
实施例47：
Embodiment 47:
合成路线
synthetic route
将化合物int5(600mg，2.10mmol)、C047-47a(400mg，2.26mmol)和对甲苯磺酸水合物(72mg，0.42mmol)溶解在乙腈(10.0mL)中，在70℃下搅拌4h。反应结束后，将反应液浓缩，所得残余物经制备分析纯化得C047(24.10mg)。Compound int5 (600 mg, 2.10 mmol), C047-47a (400 mg, 2.26 mmol) and p-toluenesulfonic acid hydrate (72 mg, 0.42 mmol) were dissolved in acetonitrile (10.0 mL) and stirred at 70° C. for 4 h. After the reaction was completed, the reaction solution was concentrated and the obtained residue was purified by preparative analysis to obtain C047 (24.10 mg).
1H NMR(400MHz,DMSO_d6)δ10.94(s,1H),9.01(s,1H),8.39(d,J＝2.4Hz,1H),7.90(s,1H),7.79–7.76(m,2H),7.48–7.44(m,2H),7.36(d,J＝8.4Hz,1H),7.22–7.18(m,2H),7.08(dd,J＝8.4,2.0Hz,1H),6.80(d,J＝8.8Hz,1H),5.14(s,2H),2.18(s,3H). 1 H NMR (400 MHz, DMSO_d6) δ 10.94 (s, 1H), 9.01 (s, 1H), 8.39 (d, J = 2.4 Hz, 1H), 7.90 (s, 1H), 7.79–7.76 (m, 2H), 7.48–7.44 (m, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.22–7.18 (m, 2H), 7.08 (dd, J = 8.4, 2.0 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 5.14 (s, 2H), 2.18 (s, 3H).
实施例48：
Embodiment 48:
合成路线
synthetic route
将化合物int5(194mg，0.68mmol)和int19(130mg，0.81mmol)溶解在乙腈(3mL)中，然后加入对甲苯磺酸(27mg，0.14mmol)。混合液在氮气保护下60℃搅拌4小时。反应结束后，将反应液浓缩。所得残余物反相制备分析纯化得化合物C048(30.19mg)。Compounds int5 (194 mg, 0.68 mmol) and int19 (130 mg, 0.81 mmol) were dissolved in acetonitrile (3 mL), and p-toluenesulfonic acid (27 mg, 0.14 mmol) was then added. The mixture was stirred at 60°C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated. The obtained residue was purified by reverse phase preparative analysis to obtain compound C048 (30.19 mg).
1H NMR(400MHz,DMSO_d6)δ10.94(s,1H),9.01(s,1H),8.56(d,J＝4.0Hz,2H),8.39(d,J＝2.0Hz,1H),8.18(s,0.36H),7.89(d,J＝4.0Hz,1H),7.78–7.75(m,2H),7.38–7.35(m,3H),7.08(dd,J＝8.0,4.0Hz,1H),6.79(d,J＝8.0Hz,1H),5.22(s,2H),2.26(s,3H). 1 H NMR (400 MHz, DMSO_d6) δ 10.94 (s, 1H), 9.01 (s, 1H), 8.56 (d, J = 4.0 Hz, 2H), 8.39 (d, J = 2.0 Hz, 1H), 8.18 (s, 0.36H), 7.89 (d, J = 4.0 Hz, 1H), 7.78–7.75 (m, 2H), 7.38–7.35 (m, 3H), 7.08 (dd, J = 8.0, 4.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 5.22 (s, 2H), 2.26 (s, 3H).
实施例49：
Embodiment 49:
合成路线
synthetic route
将int5(260mg，0.640mmol)和int23(154mg,0.770mmol)溶解在ACN(2mL)中，加入对甲苯磺酸水合物(25mg，0.130mmol),氮气保护下在90℃下搅拌4h。反应结束后，过滤反应液，用乙腈洗涤，合并有机相所得残余物经制备分析纯化得化合物C049(44.15mg)。Int5 (260 mg, 0.640 mmol) and int23 (154 mg, 0.770 mmol) were dissolved in ACN (2 mL), p-toluenesulfonic acid hydrate (25 mg, 0.130 mmol) was added, and stirred at 90°C for 4 h under nitrogen protection. After the reaction was completed, the reaction solution was filtered and washed with acetonitrile, and the residue obtained by combining the organic phases was purified by preparative analysis to obtain compound C049 (44.15 mg).
1H NMR(400MHz,DMSO_d6)δ10.94(s,1H)，9.01(s,1H)，8.41(s,1H),8.29(s,1H)，7.94–7.65(m,5H),7.37(d,J＝12.0Hz,1H),7.10(d,J＝2.0Hz,1H),6.82(d,J＝8.0Hz,1H),5.06(s,2H). 1 H NMR (400 MHz, DMSO_d6) δ 10.94 (s, 1H), 9.01 (s, 1H), 8.41 (s, 1H), 8.29 (s, 1H), 7.94–7.65 (m, 5H), 7.37 (d, J = 12.0 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 5.06 (s, 2H).
实施例50：
Embodiment 50:
合成路线
synthetic route
(1)将化合物C050-50a(100mg，0.613mmol，1eq)，化合物int2(148mg，0.735mmol，1.2eq)溶解在二甲基亚砜(2mL)中，加入DIEA(0.2ml，1.225mmol,2.0eq)在90℃下搅拌4h。反应结束后，二氯甲烷和水萃取，无水硫酸钠干燥减压旋干，所得残余物硅胶柱分离(DCM/MeOH＝50/1)纯化得化合物C050-50b(143mg)。(1) Compound C050-50a (100 mg, 0.613 mmol, 1 eq) and compound int2 (148 mg, 0.735 mmol, 1.2 eq) were dissolved in dimethyl sulfoxide (2 mL), and DIEA (0.2 ml, 1.225 mmol, 2.0 eq) was added and stirred at 90° C. for 4 h. After the reaction was completed, the mixture was extracted with dichloromethane and water, dried over anhydrous sodium sulfate, and dried under reduced pressure. The residue was separated by silica gel column (DCM/MeOH=50/1) and purified to obtain compound C050-50b (143 mg).
(2)将C050-50b(143mg，0.461mmol，1eq)，化合物int6(68mg，0.553mmol，1.2eq)和对甲苯磺酸水合物(15.8mg，0.092mmol，0.2eq)溶解在乙腈(3.0mL)中，在60℃下搅拌4h。反应结束后，过滤反应液，用乙腈洗涤，合并有机相所得残余物反相制备分析纯化得化合物C050(41.59mg)。(2) C050-50b (143 mg, 0.461 mmol, 1 eq), compound int6 (68 mg, 0.553 mmol, 1.2 eq) and p-toluenesulfonic acid hydrate (15.8 mg, 0.092 mmol, 0.2 eq) were dissolved in acetonitrile (3.0 mL) and stirred at 60° C. for 4 h. After the reaction was completed, the reaction solution was filtered and washed with acetonitrile. The organic phases were combined and the residues were purified by reverse phase preparative analysis to obtain compound C050 (41.59 mg).
1H NMR(400MHz,DMSO_d6)δ11.36(s,1H),8.54(s,1H),8.25(s,1H),7.81(d,J＝4.0Hz,1H),7.67–7.64(m,1H),7.45–7.43(m,2H),7.24(s,1H),7.13(dd,J＝8.0,4.0Hz,1H),6.57(d,J＝8.0Hz,1H),4.75–4.67(m,1H),3.00–2.97(m,2H),2.75–2.70(m,2H),2.16(s,3H). 1 H NMR (400 MHz, DMSO_d6) δ 11.36 (s, 1H), 8.54 (s, 1H), 8.25 (s, 1H), 7.81 (d, J = 4.0 Hz, 1H), 7.67–7.64 (m, 1H), 7.45–7.43 (m, 2H), 7.24 (s, 1H), 7.13 (dd, J = 8.0, 4.0 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 4.75–4.67 (m, 1H), 3.00–2.97 (m, 2H), 2.75–2.70 (m, 2H), 2.16 (s, 3H).
实施例51：
Embodiment 51:
合成路线
synthetic route
将化合物int5(310mg，1.10mmol)和化合物int20(227mg，1.32mmol)溶解在乙腈(5mL)中，然后加入对甲苯磺酸(42mg，0.22mmol)。混合液在氮气保护下60℃搅拌4小时。反应结束后，将反应液浓缩。所得残余物高效液相制备分析纯化得化合物C051(32.93mg)。Compound int5 (310 mg, 1.10 mmol) and compound int20 (227 mg, 1.32 mmol) were dissolved in acetonitrile (5 mL), and then p-toluenesulfonic acid (42 mg, 0.22 mmol) was added. The mixture was stirred at 60°C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated. The obtained residue was purified by high performance liquid phase preparative analysis to obtain compound C051 (32.93 mg).
1H NMR(400MHz,CD3OD)δ8.28(d,J＝4.0Hz,1H),7.81(dd,J＝8.0,4.0Hz,1H),7.50(s,1H),7.42(s,1H),7.33(d,J＝8.0Hz,1H),7.09(dd,J＝8.0,4.0Hz,1H),6.63(d,J＝8.0Hz,1H),4.18(d,J＝8.0Hz,2H),2.72–2.51(m,3H),2.49–2.35(m,2H),2.18(s,3H). 1 H NMR (400 MHz, CD 3 OD) δ8.28 (d, J=4.0 Hz, 1H), 7.81 (dd, J=8.0, 4.0 Hz, 1H), 7.50 (s, 1H), 7.42 (s, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.09 (dd, J=8.0, 4.0 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 4.18 (d, J=8.0 Hz, 2H), 2.72-2.51 (m, 3H), 2.49-2.35 (m, 2H), 2.18 (s, 3H).
实施例52：
Embodiment 52:
合成路线
synthetic route
将int5(220mg，0.77mmol)、int44(140mg，0.85mmol)和对甲苯磺酸(30mg，0.15mmol)溶解在乙腈(6mL)中。反应液在60℃下反应4小时。反应结束后，将反应液减压浓缩，所得残余物用高效液相纯化得化合物C052(57.06mg)。Int5 (220 mg, 0.77 mmol), int44 (140 mg, 0.85 mmol) and p-toluenesulfonic acid (30 mg, 0.15 mmol) were dissolved in acetonitrile (6 mL). The reaction solution was reacted at 60°C for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain compound C052 (57.06 mg).
1H NMR(400MHz,DMSO_d6)δ10.94(s,1H),9.02(s,1H),8.40(d,J＝2.0Hz,1H),7.92(d,J＝2.0Hz,1H),7.83–7.81(m,2H),7.37(d,J＝8.4Hz,1H),7.09(dd,J＝8.4,2.0Hz,1H),6.83(d,J＝8.8Hz,1H),4.36–4.31(m,1H),2.64–2.51(m,1H),2.47–2.30(m,1H),2.16(s,3H),2.13–1.93(m,3H),1.82–1.73(m,2H),1.58(s,3H). 1 H NMR (400 MHz, DMSO_d6) δ 10.94 (s, 1H), 9.02 (s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.83–7.81 (m, 2H), 7.37 (d, J = 8.4 Hz, 1H), 7.09 (dd, J = 8.4, 2.0 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.36–4.31 (m, 1H), 2.64–2.51 (m, 1H), 2.47–2.30 (m, 1H), 2.16 (s, 3H), 2.13–1.93 (m, 3H), 1.82–1.73 (m, 2H), 1.58 (s, 3H).
实施例53：
Embodiment 53:
合成路线
synthetic route
将int26(100mg，0.33mmol)，int7(60mg，0.39mmol，)和对甲苯磺酸水合物(12mg，0.06mmol)溶解在DMF(2.0mL)中，在120℃下搅拌4h。反应结束后，过滤反应液,高效液相制备分析纯化得C053(24.34mg)。1H NMR(400MHz,CD3OD)δ7.75–7.70(m,1H),7.66(s,1H),7.55(s,1H),7.32(d,J＝8.0Hz,1H),7.09(dd,J＝8.0,2.0Hz,1H),6.53(d,J＝8.0Hz,1H),4.33(br.s,1H),2.22(d,J＝4.0Hz,3H),2.08–1.88(m,8H).Int26 (100 mg, 0.33 mmol), int7 (60 mg, 0.39 mmol) and p-toluenesulfonic acid hydrate (12 mg, 0.06 mmol) were dissolved in DMF (2.0 mL) and stirred at 120°C for 4 h. After the reaction was completed, the reaction solution was filtered and purified by HPLC to obtain C053 (24.34 mg). 1 H NMR (400 MHz, CD 3 OD) δ7.75–7.70 (m, 1H), 7.66 (s, 1H), 7.55 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.09 (dd, J = 8.0, 2.0 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), 4.33 (br. s, 1H), 2.22 (d, J = 4.0 Hz, 3H), 2.08–1.88 (m, 8H).
实施例54：
Embodiment 54:
合成路线
synthetic route
将int21(250mg，0.84mmol)，int7(127mg，0.84mmol，)和对甲苯磺酸水合物(32mg，0.17mmol)溶解在DMF(5.0mL)中，在120℃下搅拌4h。反应结束后，反应液直接用高效液相制备分析纯化得C054(40mg)。Int21 (250 mg, 0.84 mmol), int7 (127 mg, 0.84 mmol) and p-toluenesulfonic acid hydrate (32 mg, 0.17 mmol) were dissolved in DMF (5.0 mL) and stirred at 120° C. for 4 h. After the reaction was completed, the reaction solution was directly purified by HPLC to obtain C054 (40 mg).
1H NMR(400MHz,CD3OD)δ7.55(s,1H),7.43(s,1H),7.38–7.31(m,2H),7.08(d,J＝8.8Hz,1H),6.42(d,J＝9.2Hz,1H),4.30(br.s,1H),2.45(d,J＝2.0Hz,3H),2.17(d,J＝2.0Hz,3H),2.10–1.76(m,8H). 1 H NMR (400 MHz, CD 3 OD) δ7.55 (s, 1H), 7.43 (s, 1H), 7.38–7.31 (m, 2H), 7.08 (d, J=8.8 Hz, 1H), 6.42 (d, J=9.2 Hz, 1H), 4.30 (br. s, 1H), 2.45 (d, J=2.0 Hz, 3H), 2.17 (d, J=2.0 Hz, 3H), 2.10–1.76 (m, 8H).
实施例55：
Embodiment 55:
合成路线
synthetic route
(1)于250mL单口反应瓶中将C055-a(4.50g，24.38mmol)溶解在甲苯(72mL)中，加入催化剂四(三苯基膦)钯(2.54g，2.44mmol)和C055-b(15.3mL，48.76mmol)，氮气保护下油浴加热至110℃搅拌反应16小时。反应完全后(TLC显示无原料)，减压浓缩为粗品C055-c直接用于下一步骤。(1) C055-a (4.50 g, 24.38 mmol) was dissolved in toluene (72 mL) in a 250 mL single-mouth reaction bottle, and the catalyst tetrakis(triphenylphosphine)palladium (2.54 g, 2.44 mmol) and C055-b (15.3 mL, 48.76 mmol) were added. The mixture was heated to 110° C. in an oil bath under nitrogen protection and stirred for 16 hours. After the reaction was complete (TLC showed no starting material), the mixture was concentrated under reduced pressure to give a crude product C055-c, which was directly used in the next step.
(2)向盛有粗品C055-c(7.0g，24.38mmol)的单口瓶中加入盐酸水溶液(2mol/L，60mL，120mmol)，油浴60℃搅拌2小时。反应完成后冷却至室温，二氯甲烷(50mL)萃取两次，无水硫酸钠干燥有机相过滤后减压浓缩滤液，所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝1:1)洗脱得C055-d(2.6g)。1H NMR(400MHz,DMSO_d6)δ9.08(s,2H),2.59(s,6H).(2) Add hydrochloric acid aqueous solution (2 mol/L, 60 mL, 120 mmol) to a single-mouth bottle containing crude product C055-c (7.0 g, 24.38 mmol) and stir in an oil bath at 60°C for 2 hours. After the reaction is completed, cool to room temperature, extract twice with dichloromethane (50 mL), dry the organic phase with anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography, eluting with (petroleum ether: ethyl acetate = 1:1) to obtain C055-d (2.6 g). 1 H NMR (400 MHz, DMSO_d6) δ9.08 (s, 2H), 2.59 (s, 6H).
(3)将C055-d(2.6g，15.46mmol)溶解在无水二氯甲烷(42mL)中，冰水浴搅拌下分批加入间氯过氧苯甲酸(3.5g，20.28mmol)。加完后继续冰水浴搅拌2小时。反应结束后，冰水浴下滴入碳酸氢钠水溶液中和至pH＝7～8，滴入亚硫酸氢钠水溶液消耗掉过量的间氯过氧苯甲酸。分出有机相，二氯甲烷(30mL)萃取水相两次，合并有机相，无水硫酸钠干燥过滤，减压浓缩滤液。所得残余物用硅胶柱层析纯化，用(二氯甲烷:甲醇＝9:1)洗脱得C055-e(1.6g)。LCMS(ESI)m/z:185.0[M+H]+。(3) C055-d (2.6 g, 15.46 mmol) was dissolved in anhydrous dichloromethane (42 mL), and m-chloroperbenzoic acid (3.5 g, 20.28 mmol) was added in batches under ice-water bath stirring. After the addition, the mixture was stirred in an ice-water bath for 2 hours. After the reaction was completed, sodium bicarbonate aqueous solution was added dropwise under ice-water bath to neutralize to pH=7-8, and sodium bisulfite aqueous solution was added dropwise to consume the excess m-chloroperbenzoic acid. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (dichloromethane: methanol = 9:1) to obtain C055-e (1.6 g). LCMS (ESI) m/z: 185.0 [M+H] + .
(4)将C055-e(1.0g，5.43mmol)溶解在1,4-二氧六环(24mL)中，加入int2(919mg，4.52mmol)和N,N-二异丙基乙胺(1.75g，13.57mmol)，60℃搅拌2小时。反应完成后(7-LCMS)，将反应液减压浓缩至干，乙酸乙酯(10mL)打浆，过滤即得化合物C055-f。LCMS(ESI)m/z:287.0 [M+H]+。(4) C055-e (1.0 g, 5.43 mmol) was dissolved in 1,4-dioxane (24 mL), int2 (919 mg, 4.52 mmol) and N,N-diisopropylethylamine (1.75 g, 13.57 mmol) were added, and stirred at 60°C for 2 hours. After the reaction was completed (7-LCMS), the reaction solution was concentrated to dryness under reduced pressure, slurried with ethyl acetate (10 mL), and filtered to obtain compound C055-f. LCMS (ESI) m/z: 287.0 [M+H] + .
(5)将C055-f(200mg，0.698mmol)、int7(158mg，0.837mmol)和一水合对甲苯磺酸(27mg，0.140mmol)溶解在乙腈(4.6mL)中。反应液在60℃下反应4小时。反应结束后过滤，滤饼用DMF溶解后经高效液相制备分析纯化得化合物C055(107.85mg)。LCMS(ESI)m/z:420.3[M+H]+。(5) C055-f (200 mg, 0.698 mmol), int7 (158 mg, 0.837 mmol) and p-toluenesulfonic acid monohydrate (27 mg, 0.140 mmol) were dissolved in acetonitrile (4.6 mL). The reaction solution was reacted at 60° C. for 4 hours. After the reaction was completed, the filter cake was dissolved in DMF and purified by high performance liquid chromatography preparative analysis to obtain compound C055 (107.85 mg). LCMS (ESI) m/z: 420.3 [M+H] + .
实施例56：
Embodiment 56:
合成路线
synthetic route
(1)将化合物C056-56a(500mg，3.19mmol)和化合物C056-56b(649mg，3.19mmol)溶解在N，N-二甲基甲酰胺(15mL)中，添加三乙胺(970mg，9.58mmol)。将混合物在120℃下搅拌2小时。反应结束后减压浓缩，用乙酸乙酯打浆，所得产物C056-56c可直接用于下一步(450mg)。(1) Compound C056-56a (500 mg, 3.19 mmol) and compound C056-56b (649 mg, 3.19 mmol) were dissolved in N,N-dimethylformamide (15 mL), and triethylamine (970 mg, 9.58 mmol) was added. The mixture was stirred at 120°C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and slurried with ethyl acetate. The obtained product C056-56c was directly used in the next step (450 mg).
(2)将C056-56c(217mg，0.757mmol)、int7(163mg，0.869mmol)和对甲苯磺酸(30mg，0.158mmol)溶解在乙腈(4mL)中。反应液在60℃下反应4小时。反应结束后减压浓缩干，DMF溶解后高效液相制备分析纯化得化合物C056(33.78mg)。(2) C056-56c (217 mg, 0.757 mmol), int7 (163 mg, 0.869 mmol) and p-toluenesulfonic acid (30 mg, 0.158 mmol) were dissolved in acetonitrile (4 mL). The reaction solution was reacted at 60° C. for 4 hours. After the reaction was completed, the solution was concentrated to dryness under reduced pressure, dissolved in DMF and purified by high performance liquid chromatography to obtain compound C056 (33.78 mg).
1H NMR(400MHz,CD3OD)δ8.53(s,1H),8.11(s,1H),7.74(s,1H),7.59(s,1H),7.34(d,J＝8.0Hz,1H),7.11(d,J＝8.0Hz,1H),4.40–4.37(m,1H),2.25(s,3H),2.08–1.95(m,8H). 1 H NMR (400 MHz, CD 3 OD) δ8.53 (s, 1H), 8.11 (s, 1H), 7.74 (s, 1H), 7.59 (s, 1H), 7.34 (d, J＝8.0 Hz, 1H), 7.11 (d, J＝8.0 Hz, 1H), 4.40–4.37 (m, 1H), 2.25 (s, 3H), 2.08–1.95 (m, 8H).
实施例57：
Embodiment 57:
合成路线
synthetic route
将C038(100mg，0.33mmol)，int7(60mg，0.40mmol)和对甲苯磺酸水合物(13mg，0.07mmol)溶解在乙腈(3.0mL)中，在60℃下搅拌4小时。反应结束后，过滤反应液，用乙腈洗涤， 合并有机相所得残余物经制备分析纯化得化合物C057(20.23mg)。C038 (100 mg, 0.33 mmol), int7 (60 mg, 0.40 mmol) and p-toluenesulfonic acid hydrate (13 mg, 0.07 mmol) were dissolved in acetonitrile (3.0 mL) and stirred at 60°C for 4 hours. After the reaction was completed, the reaction solution was filtered and washed with acetonitrile. The residue obtained by combining the organic phases was purified by preparative analysis to obtain compound C057 (20.23 mg).
1H NMR(400MHz,DMSO_d6)δ10.91(s,1H),8.75(s,1H),8.05(s,1H),7.84(s,1H),7.76(s,1H),7.36(d,J＝8.0Hz,1H),7.08(d,J＝8.0Hz,1H),6.62(s,1H),4.30–4.28(m,1H),2.26(s,3H),2.16(s,3H),1.99–1.87(m,8H). 1 H NMR (400 MHz, DMSO_d6) δ 10.91 (s, 1H), 8.75 (s, 1H), 8.05 (s, 1H), 7.84 (s, 1H), 7.76 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.62 (s, 1H), 4.30–4.28 (m, 1H), 2.26 (s, 3H), 2.16 (s, 3H), 1.99–1.87 (m, 8H).
实施例58：
Embodiment 58:
合成路线
synthetic route
(1)将化合物C058-a(5.0g，37.0mmol)和硝酸银(6.9g，40.70mmol)溶解在ACN(50mL)中，氮气保护下在0℃滴加苯甲酰氯(4.7ml，40.698mmol)，然后反应液在0℃恒温搅拌0.5h。反应结束后，加水(50mL)淬灭，用乙酸乙酯(50mL x 3)萃取，饱和食盐水洗涤，无水硫酸钠干燥，合并有机相所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝2:1)洗脱得化合物C058-b(4.0g，收率：60.02％)。LCMS(ESI)m/z:181.1[M+H]+.(1) Compound C058-a (5.0 g, 37.0 mmol) and silver nitrate (6.9 g, 40.70 mmol) were dissolved in ACN (50 mL), and benzoyl chloride (4.7 ml, 40.698 mmol) was added dropwise at 0°C under nitrogen protection, and then the reaction solution was stirred at 0°C for 0.5 h. After the reaction was completed, water (50 mL) was added to quench, extracted with ethyl acetate (50 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phases were combined to obtain the residue, which was purified by column chromatography and eluted with (petroleum ether: ethyl acetate = 2:1) to obtain compound C058-b (4.0 g, yield: 60.02%). LCMS (ESI) m/z: 181.1 [M+H] + .
(2)将化合物C058-b(1.5g，8.327mmol)和二氯化锡二水合物(7.894g，41.634mmol)溶解在醋酸(15mL)中，置换氮气，氮气保护下在80℃反应2h。反应结束后，将反应液降温至0℃,滴加饱和碳酸氢钠水溶液调节pH值至弱碱性(PH＝8)。然后用DCM(50mL x 5)萃取，饱和食盐水洗涤，无水硫酸钠干燥，直接旋干溶剂得粗品C058-c(915mg)。LCMS(ESI)m/z:151.1[M+H]+.(2) Compound C058-b (1.5 g, 8.327 mmol) and tin dichloride dihydrate (7.894 g, 41.634 mmol) were dissolved in acetic acid (15 mL), nitrogen was replaced, and the mixture was reacted at 80 °C for 2 h under nitrogen protection. After the reaction, the reaction solution was cooled to 0 °C, and a saturated sodium bicarbonate aqueous solution was added dropwise to adjust the pH value to a weak alkaline state (PH = 8). Then, the mixture was extracted with DCM (50 mL x 5), washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was directly dried to obtain a crude product C058-c (915 mg). LCMS (ESI) m/z: 151.1 [M+H] + .
(3)将C058-c(800mg，5.333mmol)和1-(6-氯吡啶-3-基)乙烷-1-酮(200mg，5.333mmol)溶解在醋酸(8mL)中，置换氮气后在100℃下反应4h。反应结束后,反应液加水稀释，乙酸乙酯(50mL x 5)萃取，饱和食盐水洗涤，无水硫酸钠干燥，合并有机相旋干溶剂得粗品C058-d(200mg)。LCMS(ESI)m/z:270.1[M+H]+.(3) C058-c (800 mg, 5.333 mmol) and 1-(6-chloropyridin-3-yl)ethane-1-one (200 mg, 5.333 mmol) were dissolved in acetic acid (8 mL), and the mixture was reacted at 100 °C for 4 h after nitrogen replacement. After the reaction, the reaction solution was diluted with water, extracted with ethyl acetate (50 mL x 5), washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phases were combined and the solvent was dried to obtain crude product C058-d (200 mg). LCMS (ESI) m/z: 270.1 [M+H] + .
(4)将C058-d(200mg，0.742mmol)和int7(139mg，0.742溶mmol)溶解在DMF(2ml)中，再加入PTSA(169mg，0.891mmol)。置换氮气后在60℃下反应4h。反应结束后，过滤反应液，取滤液经制备分析纯化得化合物C058(2.18mg，收率：7.3％)。LCMS(ESI)m/z:403.3[M+H]+.(4) C058-d (200 mg, 0.742 mmol) and int7 (139 mg, 0.742 mmol) were dissolved in DMF (2 ml), and PTSA (169 mg, 0.891 mmol) was added. After nitrogen was replaced, the mixture was reacted at 60°C for 4 h. After the reaction, the reaction solution was filtered, and the filtrate was purified by preparative analysis to obtain compound C058 (2.18 mg, yield: 7.3%). LCMS (ESI) m/z: 403.3 [M+H] + .
实施例59：
Embodiment 59:
合成路线
synthetic route
将化合物int27(250mg，0.91mmol)溶解在DMF(5mL)中，加入int7(139mg，0.91mmol)和对甲苯磺酸(35mg，0.2mmol)并在60℃下搅拌4h。反应结束后过滤，反相纯化得化合物C059(27.09mg，7.34％)。LCMS(ESI)m/z:410.3[M+H]+.Compound int27 (250 mg, 0.91 mmol) was dissolved in DMF (5 mL), int7 (139 mg, 0.91 mmol) and p-toluenesulfonic acid (35 mg, 0.2 mmol) were added and stirred at 60°C for 4 h. After the reaction was completed, the mixture was filtered and purified by reverse phase to obtain compound C059 (27.09 mg, 7.34%). LCMS (ESI) m/z: 410.3 [M+H] + .
实施例60：
Embodiment 60:
合成路线
synthetic route
(1)将化合物C060-a(6g，19.35mmol)、Pd(OAc)2(434mg，1.94mmol)xantphos(2.24g，3.87mmol)、TEA(5.87g，58.06mmol)溶解在甲醇(10mL)和DMF(50mL)中。在CO气体中，100℃下搅拌16h。将反应液冷却至室温，加乙酸乙酯稀释，再加水，用乙酸乙酯萃取三次，合并有机相，用水洗涤2次，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶柱层析纯化，用(乙酸乙酯:石油醚＝1:1)洗脱得C060-b(1.5g，26.7％)。LCMS(ESI)m/z:291.2[M+H]+.(1) Compound C060-a (6 g, 19.35 mmol), Pd(OAc) 2 (434 mg, 1.94 mmol), xantphos (2.24 g, 3.87 mmol), and TEA (5.87 g, 58.06 mmol) were dissolved in methanol (10 mL) and DMF (50 mL). The mixture was stirred at 100°C for 16 h in CO gas. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and then water was added. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed twice with water, dried with sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography and eluted with (ethyl acetate: petroleum ether = 1:1) to obtain C060-b (1.5 g, 26.7%). LCMS (ESI) m/z: 291.2 [M+H] + .
(2)将C060-b(1.6g，5.5mmol)和KOH(3.09g，55mmol)溶解在甲醇(20mL)和水(5mL)中，反应液在30℃下搅拌16h。反应结束后用HCl水溶液调节pH为酸性，DCM/MeOH萃取，有机相减压浓缩得C060-c(1.0g)。LCMS(ESI)m/z:221.1[M-56]+ (2) C060-b (1.6 g, 5.5 mmol) and KOH (3.09 g, 55 mmol) were dissolved in methanol (20 mL) and water (5 mL), and the reaction solution was stirred at 30°C for 16 h. After the reaction, the pH was adjusted to acidic with HCl aqueous solution, extracted with DCM/MeOH, and the organic phase was concentrated under reduced pressure to obtain C060-c (1.0 g). LCMS (ESI) m/z: 221.1 [M-56] +
(3)将C060-c(1.3g，4.35mmol)、二甲胺四氢呋喃溶液(2.4mL，4.78mmol)、HATU(1.8g，4.78mmol)和DIEA(1.68g，13.04mmol)溶解在DMF(15mL)中。混合液在氮气保护下室温搅拌过夜，反应结束后加水，加乙酸乙酯稀释，再加水，用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗涤2次，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶柱层析纯化，用(乙酸乙酯:石油醚＝1:2)洗脱得C060-d(1.2g)。将C060-d(1.2g，3.96mmol)溶解在氯化氢/1,4-二氧六环溶液(4M,15mL)中，反应液在室温下搅拌16h。反应结束后减压浓缩得C060-e。LCMS(ESI)m/z:204.1[M+H]+.(3) C060-c (1.3 g, 4.35 mmol), dimethylamine tetrahydrofuran solution (2.4 mL, 4.78 mmol), HATU (1.8 g, 4.78 mmol) and DIEA (1.68 g, 13.04 mmol) were dissolved in DMF (15 mL). The mixture was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, water was added, diluted with ethyl acetate, and water was added again. The mixture was extracted with ethyl acetate three times, the organic phases were combined, washed with saturated brine twice, dried with sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography and eluted with (ethyl acetate: petroleum ether = 1:2) to obtain C060-d (1.2 g). C060-d (1.2 g, 3.96 mmol) was dissolved in hydrogen chloride/1,4-dioxane solution (4 M, 15 mL), and the reaction solution was stirred at room temperature for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain C060-e. LCMS (ESI) m/z: 204.1 [M+H] + .
(4)将C060-e(500mg，2.45mmol)、1-(6-氯吡啶-3-基)乙烷-1-酮(348mg，2.23mmol)、对甲苯磺酸(88mg，0.45mmol)溶解在DMF(8mL)中。混合液在氮气保护下100℃搅拌2h，反应结束后加水，加乙酸乙酯稀释，再加水，用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗涤2次，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶柱层析纯化，用(乙酸乙酯:石油醚＝2:1)洗脱得C060-f(250mg，35.11％)。LCMS(ESI)m/z:323.1[M+H]+. (4) C060-e (500 mg, 2.45 mmol), 1-(6-chloropyridin-3-yl)ethane-1-one (348 mg, 2.23 mmol), and p-toluenesulfonic acid (88 mg, 0.45 mmol) were dissolved in DMF (8 mL). The mixture was stirred at 100 ° C for 2 h under nitrogen protection. After the reaction was completed, water was added, diluted with ethyl acetate, and water was added again. It was extracted with ethyl acetate three times, the organic phases were combined, washed twice with saturated brine, and the organic phases were dried with sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography and eluted with (ethyl acetate: petroleum ether = 2:1) to obtain C060-f (250 mg, 35.11%). LCMS (ESI) m/z: 323.1 [M+H] + .
(5)将C060-f(200mg，0.62mmol)溶解在DMF(5mL)中，加入int7(114mg，0.75mmol)和对甲苯磺酸(24mg，0.12mmol)并在60℃下搅拌4h。反应结束后过滤，反相纯化得化合物C060(5.04mg，1.78％)。LCMS(ESI)m/z:456.4[M+H]+.(5) C060-f (200 mg, 0.62 mmol) was dissolved in DMF (5 mL), int7 (114 mg, 0.75 mmol) and p-toluenesulfonic acid (24 mg, 0.12 mmol) were added and stirred at 60°C for 4 h. After the reaction was completed, the mixture was filtered and purified by reverse phase to obtain compound C060 (5.04 mg, 1.78%). LCMS (ESI) m/z: 456.4 [M+H] + .
实施例61：
Embodiment 61:
合成路线
synthetic route
(1)将int5(1.1g，3.86mmol，1.2eq)，C061-61a(350mg，3.2mmol，1eq)和对甲苯磺酸水合物(121.6mg，0.64mmol，0.2eq)溶解在乙腈(16mL)中，在60℃下搅拌4h。反应完成后，减压浓缩。所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝1:1)洗脱得C061-61b(260mg)。(1) Int5 (1.1 g, 3.86 mmol, 1.2 eq), C061-61a (350 mg, 3.2 mmol, 1 eq) and p-toluenesulfonic acid hydrate (121.6 mg, 0.64 mmol, 0.2 eq) were dissolved in acetonitrile (16 mL) and stirred at 60 ° C for 4 h. After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was purified by column chromatography and eluted with (petroleum ether: ethyl acetate = 1:1) to obtain C061-61b (260 mg).
(2)将C061-61b(260mg，0.724mmol，1eq)和C061-61c(175mg，1.448mmol，2eq)和HATU(412.9mg，1.086mmol)溶解在DMF(5mL)中，添加N，N-二异丙基乙胺(280mg，2.172mmol),置换氮气三次，反应液在室温下搅拌16h。反应完成后，反应液直接经反相制备分析纯化得化合物C061(20.55mg)。(2) C061-61b (260 mg, 0.724 mmol, 1 eq) and C061-61c (175 mg, 1.448 mmol, 2 eq) and HATU (412.9 mg, 1.086 mmol) were dissolved in DMF (5 mL), N,N-diisopropylethylamine (280 mg, 2.172 mmol) was added, and nitrogen was replaced three times. The reaction solution was stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was directly purified by reverse phase preparative analysis to obtain compound C061 (20.55 mg).
1H NMR(400MHz,CD3OD)δ8.31(dd,J＝9.2,2.0Hz,1H),7.89(s,1H),7.57(s,1H),7.57–7.43(m,2H),7.21(dd,J＝8.8,2.0Hz,1H),7.15(d,J＝8.0Hz,1H),4.95(s,2H),3.72–3.64(m,4H),2.23(s,3H),2.08–1.93(m,4H). 1 H NMR (400 MHz, CD 3 OD) δ8.31 (dd, J=9.2, 2.0 Hz, 1H), 7.89 (s, 1H), 7.57 (s, 1H), 7.57-7.43 (m, 2H), 7.21 (dd, J=8.8, 2.0 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 4.95 (s, 2H), 3.72-3.64 (m, 4H), 2.23 (s, 3H), 2.08-1.93 (m, 4H).
实施例62：
Embodiment 62:
合成路线
synthetic route
(1)将原料C062-a(1g，3.21mmol)溶解在1，4-二氧六环(3.6mL)和水(0.9mL)中，加入C062-b(857mg，3.86mmol)以及催化剂[1,1-双(二苯基膦)二茂铁]二氯化钯(236mg，0.32mmol)和碳酸钾(1.33g，9.64mmol)。氮气保护下油浴加热至120℃搅拌反应12小时。反应完全后，将反应液减压浓缩，所得残余物用硅胶柱层析纯化，用(0-100％乙酸乙酯/石油醚)洗脱得C062-c(670mg)。LCMS(ESI)m/z:327.2[M+H]+.(1) The raw material C062-a (1 g, 3.21 mmol) was dissolved in 1,4-dioxane (3.6 mL) and water (0.9 mL), and C062-b (857 mg, 3.86 mmol) and the catalyst [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (236 mg, 0.32 mmol) and potassium carbonate (1.33 g, 9.64 mmol) were added. The mixture was heated to 120°C in an oil bath under nitrogen protection and stirred for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with (0-100% ethyl acetate/petroleum ether) to obtain C062-c (670 mg). LCMS (ESI) m/z: 327.2 [M+H] + .
(2)向单口烧瓶中加入C062-c(670mg，2.05mmol)和盐酸二氧六环溶液(4mol/L，10.5mL)室温搅拌2小时。反应完成后浓缩至干即得C062-d(532mg)。(2) C062-c (670 mg, 2.05 mmol) and dioxane hydrochloride solution (4 mol/L, 10.5 mL) were added to a single-necked flask and stirred at room temperature for 2 hours. After the reaction was completed, the solution was concentrated to dryness to obtain C062-d (532 mg).
(3)将C062-d(532mg，2.03mmol)和C062-e(318mg，2.03mmol)溶解在N，N-二甲基甲酰胺(9mL)中，添加三乙胺(615mg，6.08mmol)。将混合物在120℃下搅拌2小时。反应结束后减压浓缩，用乙酸乙酯打浆，所得残余物即为粗品C062-f(238mg)。可直接用于下一步。LCMS(ESI)m/z:347.1[M+H]+.(3) C062-d (532 mg, 2.03 mmol) and C062-e (318 mg, 2.03 mmol) were dissolved in N, N-dimethylformamide (9 mL), and triethylamine (615 mg, 6.08 mmol) was added. The mixture was stirred at 120°C for 2 hours. After the reaction was completed, it was concentrated under reduced pressure and slurried with ethyl acetate. The resulting residue was the crude product C062-f (238 mg). It can be used directly in the next step. LCMS (ESI) m/z: 347.1 [M+H] + .
(4)将C062-f(238mg，0.69mmol)、int7(155mg，0.83mmol)和对甲苯磺酸(27mg，0.14mmol)溶解在N，N-二甲基甲酰胺(4mL)中。反应液在60℃下反应2小时。反应结束后，反应液经反相制备分析纯化得化合物C062(30.83mg，9.32％)。LCMS(ESI)m/z:480.4[M+H]+.(4) C062-f (238 mg, 0.69 mmol), int7 (155 mg, 0.83 mmol) and p-toluenesulfonic acid (27 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (4 mL). The reaction solution was reacted at 60°C for 2 hours. After the reaction, the reaction solution was purified by reverse phase preparative analysis to obtain compound C062 (30.83 mg, 9.32%). LCMS (ESI) m/z: 480.4 [M+H] + .
实施例63：
Embodiment 63:
合成路线
synthetic route
(1)将int28(300mg，1.493mmol)、C056-56c(428mg,1.493mmol)和一水合对甲苯磺酸(340mg，1.792mmol)溶解在N,N-二甲基甲酰胺(5mL)中。氮气保护下反应液于90℃油浴中搅拌4h。反应结束后，过滤反应液，取滤液反相制备分析纯化得化合物C063(23.60mg)。LCMS(ESI) m/z:434.3[M+H]+.(1) Int28 (300 mg, 1.493 mmol), C056-56c (428 mg, 1.493 mmol) and p-toluenesulfonic acid monohydrate (340 mg, 1.792 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was stirred in a 90°C oil bath under nitrogen protection for 4 h. After the reaction was completed, the reaction solution was filtered and the filtrate was purified by reverse phase preparative analysis to obtain compound C063 (23.60 mg). LCMS (ESI) m/z:434.3[M+H] + .
实施例64：
Embodiment 64:
合成路线
synthetic route
(1)将C064-a(2.0g，14.80mmol)溶解在N,N-二甲基甲酰胺(20mL)中，在0℃下滴加三氟乙酸酐(3.42g，16.28mmol)。反应液在室温搅拌3小时后，将混合物倒入50ml水中，固体析出，抽滤得到沉淀物并在20％NaOH(30ml)中加热回流过夜。反应液冷却到室温后用二氯甲烷萃取三次(30ml/次)，水相用盐酸酸化，产物析出，过滤并真空干燥得到C064-b(2.2g)。LCMS(ESI)m/z:178.2[M-H]+.(1) C064-a (2.0 g, 14.80 mmol) was dissolved in N,N-dimethylformamide (20 mL), and trifluoroacetic anhydride (3.42 g, 16.28 mmol) was added dropwise at 0°C. After the reaction solution was stirred at room temperature for 3 hours, the mixture was poured into 50 ml of water, and solid precipitated. The precipitate was filtered and heated under reflux in 20% NaOH (30 ml) overnight. After the reaction solution was cooled to room temperature, it was extracted three times with dichloromethane (30 ml/times), the aqueous phase was acidified with hydrochloric acid, the product precipitated, filtered and vacuum dried to obtain C064-b (2.2 g). LCMS (ESI) m/z: 178.2 [MH] + .
(2)将C064-b(1.0g，5.58mmol)溶解在四氢呋喃(10mL)中，然后将在0℃下依次加入三乙胺(1.69g，16.74mmol)、叠氮磷酸二苯酯(2.4g，11.16mmol)。反应液在室温下搅拌过夜。反应结束后，将反应液减压浓缩，用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝4:1)洗脱得C064-c(500mg)。LCMS(ESI)m/z:203.0[M-H]+.(2) C064-b (1.0 g, 5.58 mmol) was dissolved in tetrahydrofuran (10 mL), and then triethylamine (1.69 g, 16.74 mmol) and diphenylphosphoryl azide (2.4 g, 11.16 mmol) were added in sequence at 0°C. The reaction solution was stirred overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography, and C064-c (500 mg) was obtained by elution with (petroleum ether: ethyl acetate = 4:1). LCMS (ESI) m/z: 203.0 [MH] + .
(3)将C064-c(500mg，2.45mmol)溶解在叔丁醇(8mL)中，混合液在氮气保护下80℃搅拌过夜。反应结束后，将反应液冷却至室温，减压浓缩后用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝4:1)洗脱得C064-d(420mg)。LCMS(ESI)m/z:251.1[M+H]+.(3) C064-c (500 mg, 2.45 mmol) was dissolved in tert-butyl alcohol (8 mL), and the mixture was stirred at 80°C overnight under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography, and eluted with (petroleum ether: ethyl acetate = 4:1) to obtain C064-d (420 mg). LCMS (ESI) m/z: 251.1 [M+H] + .
(4)将C064-d(420mg，1.68mmol)溶解在氯化氢/1,4-二氧六环溶液(4M,5mL)中，反应液在室温下搅拌16h。反应结束后减压浓缩得C064-e(300mg)。LCMS(ESI)m/z:151.2[M+H]+.(4) C064-d (420 mg, 1.68 mmol) was dissolved in hydrogen chloride/1,4-dioxane solution (4 M, 5 mL), and the reaction solution was stirred at room temperature for 16 h. After the reaction was completed, the solution was concentrated under reduced pressure to obtain C064-e (300 mg). LCMS (ESI) m/z: 151.2 [M+H] + .
(5)将C064-e(300mg，1.61mmol)，1-(5-氯吡嗪-2-基)乙烷-1-酮(202mg，1.29mmol)和N,N-二异丙基乙胺(333mg，2.58mmol)溶解在二甲基亚砜(3.0mL)中，在90℃下搅拌4小时。反应结束后，混合物用二氯甲烷和水萃取，合并有机相减压浓缩得粗品C064-f(300mg)。LCMS(ESI)m/z:271.1[M+H]+.(5) C064-e (300 mg, 1.61 mmol), 1-(5-chloropyrazin-2-yl)ethane-1-one (202 mg, 1.29 mmol) and N,N-diisopropylethylamine (333 mg, 2.58 mmol) were dissolved in dimethyl sulfoxide (3.0 mL) and stirred at 90° C. for 4 hours. After the reaction was completed, the mixture was extracted with dichloromethane and water, and the organic phases were combined and concentrated under reduced pressure to obtain a crude product C064-f (300 mg). LCMS (ESI) m/z: 271.1 [M+H] + .
(6)将C064-f(100mg，0.37mmol)，化合物8(66.5mg，0.44mmol)和一水合对甲苯磺酸水合物(13.3mg，0.07mmol)溶解在N,N-二甲基甲酰胺(2.0mL)中，反应液在60℃下搅拌4小时。反应结束后，将反应液过滤，滤液反相制备分析纯化得C064(18.01mg，收率：12.1％)。LCMS(ESI)m/z:404.1[M+H]+.(6) C064-f (100 mg, 0.37 mmol), compound 8 (66.5 mg, 0.44 mmol) and p-toluenesulfonic acid monohydrate (13.3 mg, 0.07 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), and the reaction solution was stirred at 60°C for 4 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was purified by reverse phase preparative analysis to obtain C064 (18.01 mg, yield: 12.1%). LCMS (ESI) m/z: 404.1 [M+H] + .
实施例65：
Embodiment 65:
合成路线
synthetic route
(1)将C065-a(1g，7.345mmol)在0℃下分批加入发烟硝酸(7.3ml)中，反应液在0℃下搅拌0.5小时。反应结束后，将反应液缓慢滴加入冰水中，固体析出，过滤，真空干燥得粗品C065-b(1.4g)。(1) C065-a (1 g, 7.345 mmol) was added to fuming nitric acid (7.3 ml) in batches at 0°C, and the reaction solution was stirred at 0°C for 0.5 hours. After the reaction was completed, the reaction solution was slowly added dropwise to ice water, and the solid precipitated, filtered, and vacuum dried to obtain a crude product C065-b (1.4 g).
(2)将C065-b(1g，5.52mmol)溶解在氢溴酸水溶液(40％)(10mL)中，然后在常温下加入二氯化锡(6.23g，27.6mmol)。反应液在30℃下搅拌过夜。反应完成后,反应液加水(30mL)稀释，用二氯甲烷萃取(20mL x 3),有机相用无水硫酸钠干燥,过滤，减压浓缩。所得残留物用硅胶柱层析纯化(0-10％甲醇/二氯甲烷)得到C065-c(700mg)。LCMS(ESI)m/z:152.1[M+H]+.(2) C065-b (1 g, 5.52 mmol) was dissolved in a hydrobromic acid aqueous solution (40%) (10 mL), and then tin dichloride (6.23 g, 27.6 mmol) was added at room temperature. The reaction solution was stirred at 30°C overnight. After the reaction was completed, the reaction solution was diluted with water (30 mL), extracted with dichloromethane (20 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-10% methanol/dichloromethane) to obtain C065-c (700 mg). LCMS (ESI) m/z: 152.1 [M+H] + .
(3)将C065-c(500mg，3.31mmol)，1-(5-氯吡嗪-2-基)乙烷-1-酮(517mg，3.31mmol)溶解在二甲基亚砜(2mL)中，加入N,N-二异丙基乙胺(1ml，6.62mmol)，反应液在90℃下搅拌4h。反应结束后，将反应液过滤，所得滤液用反相色谱柱(0.1％FA)纯化得C065-d(200mg)。LCMS(ESI)m/z:272.1[M+H]+.(3) C065-c (500 mg, 3.31 mmol) and 1-(5-chloropyrazin-2-yl)ethane-1-one (517 mg, 3.31 mmol) were dissolved in dimethyl sulfoxide (2 mL), and N,N-diisopropylethylamine (1 ml, 6.62 mmol) was added. The reaction solution was stirred at 90°C for 4 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was purified by reverse phase chromatography (0.1% FA) to obtain C065-d (200 mg). LCMS (ESI) m/z: 272.1 [M+H] + .
(4)将C065-d(200mg，0.737mmol)，int7(122mg，0.811mmol)和一水合对甲苯磺酸水合物(25mg，0.147mmol)溶解在乙腈(3.0mL)中，反应液在60℃下搅拌4h。反应结束后，将反应液过滤，滤饼用乙腈洗涤，合并有机相，减压浓缩。所得残余物用高效液相制备分析纯化得C065(8.52mg)。LCMS(ESI)m/z:405.3[M+H]+.(4) C065-d (200 mg, 0.737 mmol), int7 (122 mg, 0.811 mmol) and p-toluenesulfonic acid monohydrate (25 mg, 0.147 mmol) were dissolved in acetonitrile (3.0 mL), and the reaction solution was stirred at 60°C for 4 h. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with acetonitrile, the organic phases were combined, and concentrated under reduced pressure. The obtained residue was purified by high performance liquid chromatography preparative analysis to obtain C065 (8.52 mg). LCMS (ESI) m/z: 405.3 [M+H] + .
实施例66：
Embodiment 66:
合成路线
synthetic route
(1)将C056-5c(233mg，0.81mmol)、C066-a(228mg，0.97mmol)和一水合对甲苯磺酸(31mg，0.16mmol)溶解在N，N-二甲基甲酰胺(5mL)中。反应液在60℃下反应2小时。反应结束后加一滴氨水晃匀后高效液相制备分析纯化得化合物C066(25.47mg)。LCMS(ESI)m/z:467.3[M+H]+.(1) C056-5c (233 mg, 0.81 mmol), C066-a (228 mg, 0.97 mmol) and p-toluenesulfonic acid monohydrate (31 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was reacted at 60°C for 2 hours. After the reaction was completed, a drop of ammonia water was added and shaken well, and then purified by high-performance liquid chromatography preparative analysis to obtain compound C066 (25.47 mg). LCMS (ESI) m/z: 467.3 [M+H] + .
实施例67：
Embodiment 67:
合成路线
synthetic route
(1)将原料C067-a(5g，25.13mmol)溶解在甲苯(80mL)中，加入四(三苯基膦)钯(2.91g，2.51mmol)和C067-b(18.15g，50.25mmol)，氮气保护下油浴加热至100℃搅拌反应16小时。反应完全后(TLC显示无原料)，所得C067-c反应液直接用于下一步反应。(1) The raw material C067-a (5 g, 25.13 mmol) was dissolved in toluene (80 mL), tetrakis(triphenylphosphine)palladium (2.91 g, 2.51 mmol) and C067-b (18.15 g, 50.25 mmol) were added, and the mixture was heated to 100° C. in an oil bath under nitrogen protection and stirred for 16 hours. After the reaction was complete (TLC showed no raw material), the obtained C067-c reaction solution was directly used for the next step reaction.
(2)向盛有C067-c(140mL，25.13mmol)的混合溶液的反应瓶中加入盐酸水溶液(4mol/L，90mL，360mmol)，油浴60℃搅拌2小时。反应完成后冷却至室温，分出有机相，水相用二氯甲烷(200mL)萃取一次。合并有机相，无水硫酸钠干燥，过滤，减压浓缩滤液，所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝9:1)洗脱得C067-d(2g)。LCMS(ESI)m/z:163.1[M+H]+.(2) Add hydrochloric acid aqueous solution (4 mol/L, 90 mL, 360 mmol) to the reaction bottle containing the mixed solution of C067-c (140 mL, 25.13 mmol) and stir in an oil bath at 60°C for 2 hours. After the reaction is completed, cool to room temperature, separate the organic phase, and extract the aqueous phase once with dichloromethane (200 mL). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 9:1) to obtain C067-d (2 g). LCMS (ESI) m/z: 163.1 [M+H] + .
(3)将C067-d(1.2g，7.41mmol)、氯化铜(1.18g，8.89mmol)、亚硝酸异戊酯(1.04g，8.89mmol)溶解在乙腈(25mL)中。混合液在氮气保护下65℃搅拌过夜，反应结束后加水(50mL)和乙酸乙酯(25mL)稀释，用乙酸乙酯萃取三次(25mL x 3)，合并有机相，用饱和食盐水洗涤2次，硫酸钠干燥，过滤并减压浓缩。所得残余物用硅胶柱层析纯化，用(乙酸乙酯:石油醚＝1:2)洗脱得C067-e(1.2g)。(3) C067-d (1.2 g, 7.41 mmol), cupric chloride (1.18 g, 8.89 mmol), and isoamyl nitrite (1.04 g, 8.89 mmol) were dissolved in acetonitrile (25 mL). The mixture was stirred at 65 °C overnight under nitrogen protection. After the reaction was completed, water (50 mL) and ethyl acetate (25 mL) were added to dilute the mixture, and the mixture was extracted with ethyl acetate three times (25 mL x 3). The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (ethyl acetate: petroleum ether = 1:2) to obtain C067-e (1.2 g).
(4)将C067-e(300mg，1.66mmol)、int2(368mg，1.82mmol)、(4) C067-e (300 mg, 1.66 mmol), int2 (368 mg, 1.82 mmol),
N,N-二异丙基乙胺(641mg，4.97mmol)溶解在二甲基亚砜(7mL)中。混合液在氮气保护下室温搅拌2h，反应结束后加水，加乙酸乙酯稀释，用乙酸乙酯萃取三次(10mL x 3)，合并有机相，用饱和食盐水洗涤2次，有机相用硫酸钠干燥，过滤并减压浓缩。所得残余物用硅胶柱层析纯化，用(乙酸乙酯:石油醚＝1:1)洗脱得C067-f(200mg)。LCMS(ESI)m/z:312.1[M+H]+.N,N-diisopropylethylamine (641 mg, 4.97 mmol) was dissolved in dimethyl sulfoxide (7 mL). The mixture was stirred at room temperature for 2 h under nitrogen protection. After the reaction was completed, water was added, diluted with ethyl acetate, extracted with ethyl acetate three times (10 mL x 3), the organic phases were combined, washed twice with saturated brine, dried with sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography and eluted with (ethyl acetate: petroleum ether = 1:1) to obtain C067-f (200 mg). LCMS (ESI) m/z: 312.1 [M + H] + .
(5)将C067-f(200mg，0.64mmol)溶解在DMF(5mL)中，加入int7(108mg，0.71mmol)和一水合对甲苯磺酸(25mg，0.13mmol)，反应液在60℃下搅拌4h。反应结束后，将反应液过滤，滤液反相制备纯化得化合物C067(24.60mg，收率：8.62％)。LCMS(ESI)m/z:445.3[M+H]+.(5) C067-f (200 mg, 0.64 mmol) was dissolved in DMF (5 mL), int7 (108 mg, 0.71 mmol) and p-toluenesulfonic acid monohydrate (25 mg, 0.13 mmol) were added, and the reaction solution was stirred at 60°C for 4 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was purified by reverse phase preparation to obtain compound C067 (24.60 mg, yield: 8.62%). LCMS (ESI) m/z: 445.3 [M+H] + .
实施例68：
Embodiment 68:
合成路线
synthetic route
(1)将int29(80mg，crude)、1-(5-氯吡嗪-2-基)乙烷-1-酮(44mg，0.28mmol)和DIEA(72mg，0.56mmol)溶解在二甲基亚砜(1mL)中。混合液在氮气保护下90℃搅拌4小时。反应结束后，反应液加水稀释，用二氯甲烷萃取，萃取结束后，合并有机相旋干后得C068-a(100mg，粗品)。LCMS(ESI)m/z:318.0[M+H]+.(1) Int29 (80 mg, crude), 1-(5-chloropyrazin-2-yl)ethane-1-one (44 mg, 0.28 mmol) and DIEA (72 mg, 0.56 mmol) were dissolved in dimethyl sulfoxide (1 mL). The mixture was stirred at 90 °C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water and extracted with dichloromethane. After the extraction was completed, the organic phases were combined and dried to obtain C068-a (100 mg, crude). LCMS (ESI) m/z: 318.0 [M+H] + .
(2)将C068-a(100mg，crude)、int7(70mg，0.37mmol)和对甲苯磺酸(6mg，0.031mmol)溶解在乙腈(2mL)中。混合液在氮气保护下70℃搅拌4小时。反应结束后，反应液减压浓缩，并用二氯甲烷和水萃取，萃取结束后，合并有机相旋干所得残余物经制备分析纯化得化合物C068(4.17mg)。(2) C068-a (100 mg, crude), int7 (70 mg, 0.37 mmol) and p-toluenesulfonic acid (6 mg, 0.031 mmol) were dissolved in acetonitrile (2 mL). The mixture was stirred at 70°C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and extracted with dichloromethane and water. After the extraction was completed, the organic phases were combined and the residue was dried by spin drying and purified by preparative analysis to obtain compound C068 (4.17 mg).
实施例69和70：
Examples 69 and 70:
合成路线
synthetic route
(1)将int30(100mg，0.51mmol)和int2(119mg，0.61mmol)溶解在超干二甲基亚砜(2mL)中，然后加入DIEA(0.2mL，1.02mmol)。混合液在氮气保护下40℃搅拌4小时。反应结束后，反应液加水析出大量固体，过滤、减压浓缩，所得残余物为化合物C069-a(150mg，收率：43.9％)。LCMS(ESI):m/z＝326.0[M+1]+，1H NMR(400MHz,DMSO_d6)δ11.38(s,1H),10.51(s,1H),9.02(s,1H),8.60(s,1H),8.04(d,J＝2.4Hz,1H),7.96(s,1H),7.83(s,1H),7.50(d,J＝8.4Hz,1H),7.20(dd,J＝8.8,2.0Hz,1H),2.66(s,3H).(1) Int30 (100 mg, 0.51 mmol) and int2 (119 mg, 0.61 mmol) were dissolved in ultra-dry dimethyl sulfoxide (2 mL), and then DIEA (0.2 mL, 1.02 mmol) was added. The mixture was stirred at 40°C for 4 hours under nitrogen protection. After the reaction was completed, water was added to the reaction solution to precipitate a large amount of solid, which was filtered and concentrated under reduced pressure to obtain the residue of compound C069-a (150 mg, yield: 43.9%). LCMS (ESI): m/z=326.0 [M+1] + , 1 H NMR (400 MHz, DMSO-d6) δ11.38 (s, 1H), 10.51 (s, 1H), 9.02 (s, 1H), 8.60 (s, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.20 (dd, J=8.8, 2.0 Hz, 1H), 2.66 (s, 3H).
(2)将C069-a(210mg，0.61mmol)、int6(117mg，0.73mmol)和对甲苯磺酸(12mg，0.061mmol)溶解在超干DMF(3mL)中。混合液在氮气保护下60℃搅拌4小时。反应结束后，反应液过滤后用高效液相制备分析纯化得化合物C069(36.70mg，收率：14.0％)LCMS(ESI):m/z＝431.2[M+1]+，和C070(1.29mg)LCMS(ESI):m/z＝431.2[M+1]+。(2) C069-a (210 mg, 0.61 mmol), int6 (117 mg, 0.73 mmol) and p-toluenesulfonic acid (12 mg, 0.061 mmol) were dissolved in ultra-dry DMF (3 mL). The mixture was stirred at 60° C. for 4 hours under nitrogen protection. After the reaction, the reaction solution was filtered and purified by high performance liquid chromatography preparative analysis to obtain compound C069 (36.70 mg, yield: 14.0%) LCMS (ESI): m/z=431.2[M+1] + , and C070 (1.29 mg) LCMS (ESI): m/z=431.2[M+1] + .
实施例71：
Embodiment 71:
合成路线
synthetic route
(1)将int5(350mg，1.22mmol)和int31(76mg，0.61mmol)溶解在乙腈(3mL)中，然后加入一水合对甲苯磺酸(23mg，0.12mmol)。混合液在氮气保护下60℃搅拌4小时。反应结束后，将反应液浓缩。所得残余物用高效液相制备分析纯化得化合物C071(12.74mg，5.32％)。LCMS(ESI)m/z:392.2[M+H]+.(1) Dissolve int5 (350 mg, 1.22 mmol) and int31 (76 mg, 0.61 mmol) in acetonitrile (3 mL), and then add p-toluenesulfonic acid monohydrate (23 mg, 0.12 mmol). The mixture was stirred at 60°C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated. The obtained residue was purified by high performance liquid chromatography preparative analysis to obtain compound C071 (12.74 mg, 5.32%). LCMS (ESI) m/z: 392.2 [M+H] + .
实施例72：
Embodiment 72:
合成路线
synthetic route
(1)在500mL的三口烧瓶中加入化合物C072-a(11g，42.292mmol)，氮气置换三次后，在0℃下滴加硼烷四氢呋喃(100ml，1M in THF)，反应液在氮气保护下搅拌2小时。反应结束后，将反应液降温到0℃，缓慢滴加甲醇(20ml)淬灭反应，滴加完毕，升至室温继续搅拌半小时，直到没有气体产生。将反应液减压浓缩。所得残余物用硅胶柱层析纯化，用(PE in EA＝0to 5％to 10％to 25％)洗脱得C072-b(3g)。LCMS(ESI)m/z:223.9[M+H]+.(1) Compound C072-a (11 g, 42.292 mmol) was added to a 500 mL three-necked flask. After nitrogen replacement three times, borane tetrahydrofuran (100 ml, 1 M in THF) was added dropwise at 0°C. The reaction solution was stirred for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to 0°C and methanol (20 ml) was slowly added dropwise to quench the reaction. After the addition was completed, the temperature was raised to room temperature and stirred for half an hour until no gas was generated. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE in EA = 0 to 5% to 10% to 25%) to obtain C072-b (3 g). LCMS (ESI) m/z: 223.9 [M + H] + .
(2)将C072-b(2.8g，12.585mmol,1.0eq)，TBSCl(3.7g,25.171mmol,2.0eq)和咪唑(2.5g,37.755mmol,3.0eq)溶解在乙腈(50mL)中。反应液在35℃下搅拌10h。TLC显示反应完成后过滤，滤液用二氯甲烷(100ml)稀释，并用饱和食盐水(100ml)萃取两次，萃取结束有机相用无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化(PE in EA＝0to 5％to 10％)得到C072-c(3.2g)。LCMS(ESI)m/z:338.0[M+H]+. (2) C072-b (2.8 g, 12.585 mmol, 1.0 eq), TBSCl (3.7 g, 25.171 mmol, 2.0 eq) and imidazole (2.5 g, 37.755 mmol, 3.0 eq) were dissolved in acetonitrile (50 mL). The reaction solution was stirred at 35 ° C for 10 h. After TLC showed that the reaction was completed, the filtrate was filtered, and the filtrate was diluted with dichloromethane (100 ml) and extracted twice with saturated brine (100 ml). After the extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE in EA = 0 to 5% to 10%) to obtain C072-c (3.2 g). LCMS (ESI) m/z: 338.0 [M + H] + .
(3)将C072-c(1g，2.969mmol,1.0eq),三丁基(1-乙氧基乙烯基)锡(2.35g，6.533mmol,2.2eq)和四(三苯基膦)钯(343mg,0.296mmol,0.1eq)溶解在无水甲苯(10mL)中，在110℃下搅拌4h。反应结束后，将反应液减压浓缩，所得混合物加入2M盐酸水溶液(5ml)于60℃下反应2h。反应结束后，将反应液冷却至室温，加水稀释，用乙酸乙酯(100ml)萃取两次，有机相用饱和食盐水(100ml)洗涤一次，加入氟化钾水溶液搅拌1小时后过滤。所得滤液用分液漏斗分离出有机相，加入无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化(PE in EA＝0to 5％to15％)得C072-d(200mg)。1H NMR(400MHz,DMSO_d6)δ8.90(d,J＝2.0Hz,1H),8.34(s,1H),4.78(s,2H),2.63(s,3H),0.94(s,9H),0.13(s,6H).(3) C072-c (1 g, 2.969 mmol, 1.0 eq), tributyl (1-ethoxyvinyl) tin (2.35 g, 6.533 mmol, 2.2 eq) and tetrakis (triphenylphosphine) palladium (343 mg, 0.296 mmol, 0.1 eq) were dissolved in anhydrous toluene (10 mL) and stirred at 110°C for 4 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting mixture was added with 2M aqueous hydrochloric acid solution (5 ml) and reacted at 60°C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water, extracted twice with ethyl acetate (100 ml), and the organic phase was washed once with saturated brine (100 ml), and potassium fluoride aqueous solution was added and stirred for 1 hour and filtered. The resulting filtrate was separated into an organic phase with a separatory funnel, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE in EA = 0 to 5% to 15%) to give C072-d (200 mg). 1 H NMR (400 MHz, DMSO_d6) δ 8.90 (d, J = 2.0 Hz, 1H), 8.34 (s, 1H), 4.78 (s, 2H), 2.63 (s, 3H), 0.94 (s, 9H), 0.13 (s, 6H).
(4)将C072-d(700mg，2.334mmol,1.0eq)，int2(388mg，2.334mmol,1.0eq)和一水合对甲苯磺酸水合物(77mg，0.466mmol)溶解在N,N-二甲基甲酰胺(8.0mL)中，在120℃下搅拌2h。反应结束后，将反应液冷却到室温，加水稀释，用乙酸乙酯(100ml x 2)萃取两次,有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥,过滤，减压浓缩，所得残余物用硅胶柱层析纯化(DCM在MeOH中约为0到5％)，得C072-e粗品(200mg)。LCMS(ESI)m/z:316.1[M+H]+.(4) C072-d (700 mg, 2.334 mmol, 1.0 eq), int2 (388 mg, 2.334 mmol, 1.0 eq) and p-toluenesulfonic acid monohydrate (77 mg, 0.466 mmol) were dissolved in N,N-dimethylformamide (8.0 mL) and stirred at 120°C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water, extracted twice with ethyl acetate (100 ml x 2), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM in MeOH is about 0 to 5%) to obtain C072-e crude product (200 mg). LCMS (ESI) m/z: 316.1 [M+H] + .
(5)将C072-e(200mg，0.634mmol,1.0eq)，int6(93mg，0.761mmol,1.2eq)和一水合对甲苯磺酸水合物(21mg，0.126mmol，0.2eq)溶解在N,N-二甲基甲酰胺(5.0mL)中，在60℃下搅拌4h。反应结束后过滤反应液，所得滤液用高效液相制备分析纯化得C072(3.29mg)。LCMS(ESI)m/z:421.2[M+H]+.(5) C072-e (200 mg, 0.634 mmol, 1.0 eq), int6 (93 mg, 0.761 mmol, 1.2 eq) and p-toluenesulfonic acid monohydrate (21 mg, 0.126 mmol, 0.2 eq) were dissolved in N,N-dimethylformamide (5.0 mL) and stirred at 60°C for 4 h. After the reaction was completed, the reaction solution was filtered and the filtrate was purified by high performance liquid chromatography to obtain C072 (3.29 mg). LCMS (ESI) m/z: 421.2 [M+H] + .
实施例73：
Embodiment 73:
合成路线
synthetic route
(1)将化合物C073-a(10.0g，43.10mmol)、C073-b(4.6g，47.41mmol)和HATU(18.0g，47.41mmol)溶解在超干二氯甲烷(300mL)中，然后在常温下加入DIEA(17.8g，137.92mmol)。反应液在常温下搅拌16小时。反应结束后，反应液加水稀释(300mL)，用二氯甲烷萃取三次(100mL x 3)，有机相减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝4:1)洗脱得C073-c(11.4g)。LCMS(ESI)m/z:275.0[M+H]+.(1) Compound C073-a (10.0 g, 43.10 mmol), C073-b (4.6 g, 47.41 mmol) and HATU (18.0 g, 47.41 mmol) were dissolved in ultra-dry dichloromethane (300 mL), and then DIEA (17.8 g, 137.92 mmol) was added at room temperature. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with water (300 mL), extracted with dichloromethane three times (100 mL x 3), and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain C073-c (11.4 g). LCMS (ESI) m/z: 275.0 [M+H] + .
(2)将C073-c(11.4g，41.40mmol)溶解在超干四氢呋喃(120mL)中，然后在0℃下滴加甲基溴化镁溶液(28mL，82.80mmol，3M))。反应液在搅拌下自然升温至室温，继续搅拌2小时。反应完成后，用饱和氯化铵水溶液(50mL)淬灭反应，并加水(120mL)稀释，用二氯甲烷萃取(100mL x 3)。有机相用减压浓缩得到C073-d(9.0g)。LCMS(ESI)m/z:230.0[M+H]+.(2) C073-c (11.4 g, 41.40 mmol) was dissolved in ultra-dry tetrahydrofuran (120 mL), and then methylmagnesium bromide solution (28 mL, 82.80 mmol, 3 M) was added dropwise at 0°C. The reaction solution was naturally warmed to room temperature under stirring and continued to stir for 2 hours. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride solution (50 mL), diluted with water (120 mL), and extracted with dichloromethane (100 mL x 3). The organic phase was concentrated under reduced pressure to obtain C073-d (9.0 g). LCMS (ESI) m/z: 230.0 [M+H] + .
(3)将C073-d(1.0g，4.35mmol)、双联频哪醇酯(1.7g，6.53mmol)、醋酸钾(854mg,8.70mmol)和Pd(dppf)Cl2(322mg,0.44mmol)溶解在超干二氧六环(20mL)中，氮气保护下90℃搅拌16小时。反应结束后，反应液加水稀释(20mL)，用二氯甲烷萃取三次(20mL x 3)，有机相减压浓缩，所得残余物用硅胶柱层析纯化，用(DCM:MeOH＝20:1)洗脱得C073-e(870mg)。LCMS(ESI)m/z:196.1[M+H]+.，1H NMR(400MHz,DMSO_d6)δ8.91(d,J＝2.8Hz,1H),8.37(d,J＝2.4Hz,1H),3.95(s,3H),2.56(s,3H),1.30(s,12H). (3) C073-d (1.0 g, 4.35 mmol), bis-pinacol ester (1.7 g, 6.53 mmol), potassium acetate (854 mg, 8.70 mmol) and Pd(dppf)Cl 2 (322 mg, 0.44 mmol) were dissolved in ultra-dry dioxane (20 mL) and stirred at 90° C. for 16 hours under nitrogen protection. After the reaction, the reaction solution was diluted with water (20 mL), extracted with dichloromethane three times (20 mL x 3), and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (DCM:MeOH=20:1) to obtain C073-e (870 mg). LCMS (ESI) m/z: 196.1 [M+H] + . , 1 H NMR (400 MHz, DMSO_d6) δ 8.91 (d, J = 2.8 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H), 3.95 (s, 3H), 2.56 (s, 3H), 1.30 (s, 12H).
(4)将C073-e(400mg，1.44mmol)和C073-f(280mg，1.73mmol)溶解在二氧六环(5mL)和水(1mL)中，然后加入Pd(dppf)Cl2(105mg，0.14mmol)和碳酸钾(597mg,4.32mmol)。混合液在氮气保护下120℃搅拌3小时。反应结束后，反应液加水稀释(20mL)，用二氯甲烷萃取三次(20mL x 3)，有机相减压浓缩，所得残余物用硅胶柱层析纯化，用(DCM:MeOH＝20:1)洗脱得C073-g(120mg)。LCMS(ESI)m/z:233.1[M+H]+，1H NMR(400MHz,DMSO_d6)δ8.88(d,J＝2.4Hz,1H),8.64(d,J＝2.4Hz,1H),8.58(s,1H),4.04(s,3H),3.95(s,3H),2.61(s,3H).(4) C073-e (400 mg, 1.44 mmol) and C073-f (280 mg, 1.73 mmol) were dissolved in dioxane (5 mL) and water (1 mL), and then Pd(dppf)Cl 2 (105 mg, 0.14 mmol) and potassium carbonate (597 mg, 4.32 mmol) were added. The mixture was stirred at 120° C. for 3 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water (20 mL), extracted with dichloromethane three times (20 mL x 3), and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (DCM:MeOH=20:1) to obtain C073-g (120 mg). LCMS (ESI) m/z: 233.1 [M+H] + , 1 H NMR (400 MHz, DMSO_d6) δ 8.88 (d, J = 2.4 Hz, 1H), 8.64 (d, J = 2.4 Hz, 1H), 8.58 (s, 1H), 4.04 (s, 3H), 3.95 (s, 3H), 2.61 (s, 3H).
(5)将C073-g(290mg，1.25mmol)溶解在氯仿(5mL)中，然后加入TMSI(750mg，3.75mmol)。混合液在氮气保护下55℃搅拌1小时。反应结束后，反应液用甲醇淬灭，减压浓缩，所得残余物为C073-h(300mg，粗品)。LCMS(ESI)m/z:219.1[M+H]+.(5) C073-g (290 mg, 1.25 mmol) was dissolved in chloroform (5 mL), and then TMSI (750 mg, 3.75 mmol) was added. The mixture was stirred at 55 °C for 1 hour under nitrogen protection. After the reaction was completed, the reaction solution was quenched with methanol and concentrated under reduced pressure to obtain C073-h (300 mg, crude product). LCMS (ESI) m/z: 219.1 [M+H] + .
(6)将C073-h(300mg，crude)溶解在氧氯化磷(5mL)中。混合液在氮气保护下80℃搅拌1小时。反应结束后，反应液减压浓缩，残留物加水(1mL)淬灭，水相旋干后用硅胶板纯化得到C073-i(20mg)。LCMS(ESI)m/z:237.1[M+H]+.，1H NMR(400MHz,CDCl3)δ8.95(d,J＝2.4Hz,1H),8.76(d,J＝2.4Hz,1H),8.18(s,1H),4.04(s,3H),2.66(s,3H).(6) C073-h (300 mg, crude) was dissolved in phosphorus oxychloride (5 mL). The mixture was stirred at 80 °C for 1 hour under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was quenched with water (1 mL). The aqueous phase was spin-dried and purified on a silica gel plate to obtain C073-i (20 mg). LCMS (ESI) m/z: 237.1 [M+H] + . , 1 H NMR (400 MHz, CDCl3) δ 8.95 (d, J = 2.4 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.18 (s, 1H), 4.04 (s, 3H), 2.66 (s, 3H).
(7)将C073-i(20mg，0.085mmol)、int2(21mg，0.10mmol)和DIEA(20mg，0.085mmol)溶解在二甲基亚砜(0.5mL)中。混合液在氮气保护下60℃搅拌16小时。反应结束后，反应液加水稀释(10mL)，用二氯甲烷萃取三次(10mL x 3)，合并有机相减压浓缩所得残余物为C073-j(30mg，粗品)。LCMS(ESI)m/z:367.1[M+H]+.(7) C073-i (20 mg, 0.085 mmol), int2 (21 mg, 0.10 mmol) and DIEA (20 mg, 0.085 mmol) were dissolved in dimethyl sulfoxide (0.5 mL). The mixture was stirred at 60 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water (10 mL), extracted with dichloromethane three times (10 mL x 3), and the organic phases were combined and concentrated under reduced pressure to obtain the residue C073-j (30 mg, crude product). LCMS (ESI) m/z: 367.1 [M+H] + .
(8)将C073-j(30mg，crude)、int6(16mg，0.098mmol)和对甲苯磺酸(3mg，0.016mmol)溶解在乙腈(1mL)中。混合液在氮气保护下70℃搅拌4小时。反应结束后，反应液减压浓缩所得残余用物高效液相制备分析纯化得化合物C073(6.17mg)。LCMS(ESI)m/z:472.2[M+H]+.(8) C073-j (30 mg, crude), int6 (16 mg, 0.098 mmol) and p-toluenesulfonic acid (3 mg, 0.016 mmol) were dissolved in acetonitrile (1 mL). The mixture was stirred at 70°C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and the obtained residue was purified by high performance liquid chromatography to obtain compound C073 (6.17 mg). LCMS (ESI) m/z: 472.2 [M+H] + .
实施例74：
Embodiment 74:
合成路线
synthetic route
(1)将C074-a(5.8g，24.9mmol)溶解在甲苯(60mL)中，加入催化剂四(三苯基膦)钯(2.89g，2.49mmol)和C074-b(19.9g，54.9mmol)，氮气保护下油浴加热至110℃搅拌反应16小时。反应完全后，所得反应液即为粗品C074-c溶液直接用于下一步骤。(1) C074-a (5.8 g, 24.9 mmol) was dissolved in toluene (60 mL), and catalyst tetrakis(triphenylphosphine)palladium (2.89 g, 2.49 mmol) and C074-b (19.9 g, 54.9 mmol) were added. The mixture was heated to 110° C. in an oil bath under nitrogen protection and stirred for 16 hours. After the reaction was complete, the resulting reaction solution was the crude C074-c solution, which was directly used in the next step.
(2)向盛有C074-c(60mL，24.9mmol)的混合溶液的反应瓶中加入盐酸水溶液(4mol/L，60mL，240mmol)，油浴60℃快速搅拌2小时。反应完成后冷却至室温，分出有机相，水相用二氯甲烷(200mL)萃取三次。合并有机相，无水硫酸钠干燥有机相过滤后减压浓缩滤液，所得残余物用硅胶柱层析纯化，用(乙酸乙酯/石油醚＝0％～20％)洗脱得C074-d(2.3g)。LCMS(ESI)m/z:196.2[M+H]+.(2) Add hydrochloric acid aqueous solution (4 mol/L, 60 mL, 240 mmol) to the reaction bottle containing the mixed solution of C074-c (60 mL, 24.9 mmol), and stir rapidly in an oil bath at 60°C for 2 hours. After the reaction is completed, cool to room temperature, separate the organic phase, and extract the aqueous phase three times with dichloromethane (200 mL). Combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure. The resulting residue is purified by silica gel column chromatography and eluted with (ethyl acetate/petroleum ether = 0% to 20%) to obtain C074-d (2.3 g). LCMS (ESI) m/z: 196.2 [M+H] + .
(3)将C074-d(1.75g,8.97mmol)溶解在ACN(25mL)中，加入亚硝酸异戊酯(1.37g,11.67mmol)和CuCl2(1.55g,11.67mmol)。混合液在氮气保护下65℃搅拌过夜，反应结束后加水，加乙酸乙酯稀释，再加水，用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗涤2次，有机相用硫酸钠干燥，过滤并浓缩。所得残余物用硅胶柱层析纯化，用(乙酸乙酯:石油醚＝1:2)洗脱得C074-e(300mg)。LCMS(ESI)m/z:215.2[M+H]+.(3) C074-d (1.75 g, 8.97 mmol) was dissolved in ACN (25 mL), and isoamyl nitrite (1.37 g, 11.67 mmol) and CuCl 2 (1.55 g, 11.67 mmol) were added. The mixture was stirred at 65°C overnight under nitrogen protection. After the reaction was completed, water was added, and ethyl acetate was added to dilute it. Water was added again, and it was extracted with ethyl acetate three times. The organic phases were combined, washed with saturated brine twice, and the organic phases were dried with sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography and eluted with (ethyl acetate: petroleum ether = 1:2) to obtain C074-e (300 mg). LCMS (ESI) m/z: 215.2 [M+H] + .
(4)将C074-e(300mg,1.40mmol)溶解在DMSO(5mL)中，int2(256mg,1.54mmol)和DIEA(284mg,2.80mmol)。在60℃下搅拌2h。反应完毕后，将混合物加入水(20mL),过滤，干 燥固体，得产物C074-f(410mg)。LCMS(ESI)m/z:345.1[M+H]+.(4) C074-e (300 mg, 1.40 mmol) was dissolved in DMSO (5 mL), int2 (256 mg, 1.54 mmol) and DIEA (284 mg, 2.80 mmol). The mixture was stirred at 60 °C for 2 h. After the reaction was completed, water (20 mL) was added to the mixture, filtered, and dried. The solid was dried to obtain product C074-f (410 mg). LCMS (ESI) m/z: 345.1 [M+H] + .
(5)C074-f(410mg,1.19mmol)溶解在甲醇：水(4mL:1mL)中,加入一水合氢氧化锂(100mg,2.38mmol)在室温下搅拌2h。反应完毕后，减压浓缩除去大部分甲醇，用2M HCl水溶液调节pH＝1-2，过滤得到产物C074-g(220mg)。LCMS(ESI)m/z:329.0[M-H]+.(5) C074-f (410 mg, 1.19 mmol) was dissolved in methanol: water (4 mL: 1 mL), and lithium hydroxide monohydrate (100 mg, 2.38 mmol) was added and stirred at room temperature for 2 h. After the reaction was completed, most of the methanol was removed by concentration under reduced pressure, and the pH was adjusted to 1-2 with 2M HCl aqueous solution, and the product C074-g (220 mg) was obtained by filtration. LCMS (ESI) m/z: 329.0 [MH] + .
(6)将C074-g(200mg，0.61mmol)加入到DMF(5mL)中，再加入甲胺盐酸盐(45mg,0.67mmol),HATU(253mg，0.67mmol)和DIEA(235mg，1.82mmol)保持常温反应16h。将混合物加入水(30mL)和二氯甲烷(10x 2mL)萃取，用饱和食盐水(20mL)洗涤,无水硫酸钠干燥有机相，过滤，减压浓缩所得残余物用硅胶柱层析纯化用乙酸乙酯/石油醚(0％-40％)洗脱得产物C074-h(140mg)。LCMS:m/z＝344.1[M+H]+.(6) C074-g (200 mg, 0.61 mmol) was added to DMF (5 mL), and then methylamine hydrochloride (45 mg, 0.67 mmol), HATU (253 mg, 0.67 mmol) and DIEA (235 mg, 1.82 mmol) were added and the reaction was maintained at room temperature for 16 h. The mixture was extracted with water (30 mL) and dichloromethane (10 x 2 mL), washed with saturated brine (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (0%-40%) to obtain the product C074-h (140 mg). LCMS: m/z = 344.1 [M+H] + .
(7)将粗品C074-h(140mg,0.41mmol)，int6(55mg，0.45mmol)和一水合对甲苯磺酸水合物(16mg，0.08mmol)溶解在乙腈(2mL)中，在60℃下搅拌4h。反应结束后，过滤反应液，用乙腈洗涤，合并有机相所得残余物用高效液相制备分析纯化得C074(32.25mg)。LCMS(ESI)m/z:449.2[M+H]+.(7) The crude product C074-h (140 mg, 0.41 mmol), int6 (55 mg, 0.45 mmol) and p-toluenesulfonic acid monohydrate (16 mg, 0.08 mmol) were dissolved in acetonitrile (2 mL) and stirred at 60°C for 4 h. After the reaction was completed, the reaction solution was filtered and washed with acetonitrile. The organic phases were combined and the residue was purified by high performance liquid chromatography to obtain C074 (32.25 mg). LCMS (ESI) m/z: 449.2 [M+H] + .
实施例75：
Embodiment 75:
合成路线
synthetic route
(1)将中间体C074-g(200mg，0.61mmol)加入到DMF(5mL)中，再加入二甲胺盐酸盐(54mg,0.67mmol),HATU(253mg，0.67mmol)和DIEA(235mg，1.82mmol)，混合物保持常温反应16h。将混合物加入水(30mL)，用二氯甲烷(10x 2mL)萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化用乙酸乙酯/石油醚(0％-40％)洗脱得产物C075-a(110mg)。LCMS:m/z＝358.1[M+H]+.(1) The intermediate C074-g (200 mg, 0.61 mmol) was added to DMF (5 mL), and then dimethylamine hydrochloride (54 mg, 0.67 mmol), HATU (253 mg, 0.67 mmol) and DIEA (235 mg, 1.82 mmol) were added, and the mixture was kept at room temperature for 16 h. The mixture was added to water (30 mL), extracted with dichloromethane (10 x 2 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (0%-40%) to obtain the product C075-a (110 mg). LCMS: m/z=358.1[M+H] + .
(2)将粗品C075-a(110mg,0.31mmol)，int6(42mg，0.34mmol)和一水合对甲苯磺酸水合物(12mg，0.06mmol)溶解在乙腈(2mL)中，在60℃下搅拌4h。反应结束后，过滤反应液，用乙腈洗涤，合并有机相所得残余物用高效液相制备分析纯化得C075(52.90mg)。LCMS(ESI)m/z:463.3[M+H]+.(2) Dissolve the crude product C075-a (110 mg, 0.31 mmol), int6 (42 mg, 0.34 mmol) and p-toluenesulfonic acid monohydrate (12 mg, 0.06 mmol) in acetonitrile (2 mL) and stir at 60°C for 4 h. After the reaction, filter the reaction solution, wash with acetonitrile, combine the organic phases, and purify the residue by high performance liquid chromatography to obtain C075 (52.90 mg). LCMS (ESI) m/z: 463.3 [M+H] + .
实施例76：
Embodiment 76:
合成路线
synthetic route
(1)将int46(500mg，1.5mmol)加入到DMF(5mL)中，再加入二甲胺盐酸盐(135mg,1.65 mmol),HATU(688g，1.8mmol)和DIEA(581mg，4.5mmol)，反应液在常温下反应4h。将混合物加入水(100mL)和二氯甲烷(100x 2mL)，萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩所得残余物用柱层析纯化用乙酸乙酯/石油醚(0％-40％)洗脱,所得产物C076-b(210mg，收率39.2％)。LCMS:m/z＝357.0[M+H]+.(1) Int46 (500 mg, 1.5 mmol) was added to DMF (5 mL), and then dimethylamine hydrochloride (135 mg, 1.65 mmol), HATU (688g, 1.8mmol) and DIEA (581mg, 4.5mmol), the reaction solution was reacted at room temperature for 4h. The mixture was added with water (100mL) and dichloromethane (100x 2mL), extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography and eluted with ethyl acetate/petroleum ether (0%-40%) to obtain the product C076-b (210mg, yield 39.2%). LCMS: m/z=357.0[M+H] + .
(2)将粗品C076-b(200mg 0.56mmol)，int6(98mg，0.62mmol，)和一水合对甲苯磺酸水合物(21mg，0.11mmol)溶解在乙腈(2mL)中，反应液在60℃下搅拌4h。反应结束后，将反应液过滤，用乙腈洗涤，合并有机相所得残余物经高效液相制备分析纯化得83.62mg化合物C076。LCMS(ESI)m/z:462.2[M+H]+.(2) The crude product C076-b (200 mg, 0.56 mmol), int6 (98 mg, 0.62 mmol) and p-toluenesulfonic acid monohydrate (21 mg, 0.11 mmol) were dissolved in acetonitrile (2 mL), and the reaction solution was stirred at 60°C for 4 h. After the reaction was completed, the reaction solution was filtered and washed with acetonitrile. The organic phases were combined and the residue was purified by high performance liquid chromatography preparative analysis to obtain 83.62 mg of compound C076. LCMS (ESI) m/z: 462.2 [M+H] + .
实施例77：
Embodiment 77:
合成路线
synthetic route
(1)在一个100mL的封口瓶中加入38d(940mg,6mmol)、int2(1g，6mmol)溶于DMF(1ml)中，加入三乙胺(1.8g,18mmol)于120℃下反应2h。反应冷却后，减压浓缩，得粗品C077-b(200mg)，直接用于下一步反应。LCMS(ESI)m/z:287.0[M+H]+.(1) Add 38d (940 mg, 6 mmol) and int2 (1 g, 6 mmol) to a 100 mL sealed bottle and dissolve in DMF (1 ml). Add triethylamine (1.8 g, 18 mmol) and react at 120 °C for 2 h. After the reaction is cooled, it is concentrated under reduced pressure to obtain a crude product C077-b (200 mg), which is directly used in the next step. LCMS (ESI) m/z: 287.0 [M+H] + .
(2)将粗品C077-b(100mg，0.35mmol)和int32(63mg，0.35mmol)溶解在乙腈(1mL)中，然后加入一水合对甲苯磺酸(12mg，0.07mmol)。混合液在氮气保护下60℃搅拌4小时。反应结束后，将反应液浓缩。所得残余物经制备分析纯化得化合物C077(7.13mg)。LCMS(ESI)m/z:449.3[M+H]+.(2) The crude product C077-b (100 mg, 0.35 mmol) and int32 (63 mg, 0.35 mmol) were dissolved in acetonitrile (1 mL), and then p-toluenesulfonic acid monohydrate (12 mg, 0.07 mmol) was added. The mixture was stirred at 60°C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated. The obtained residue was purified by preparative analysis to obtain compound C077 (7.13 mg). LCMS (ESI) m/z: 449.3 [M+H] + .
实施例78：
Embodiment 78:
合成路线
synthetic route
将C077-b(400mg，1.39mmol)和int33(270mg，1.67mmol)溶解在乙腈(4mL)中，然后加入一水合对甲苯磺酸(53mg，0.28mmol)。混合液在氮气保护下60℃搅拌4小时。反应结束后，将反应液浓缩。所得残余物经高效液相制备分析纯化得化合物C078(5.94mg)。LCMS(ESI)m/z:431.3[M+H]+.C077-b (400 mg, 1.39 mmol) and int33 (270 mg, 1.67 mmol) were dissolved in acetonitrile (4 mL), and then p-toluenesulfonic acid monohydrate (53 mg, 0.28 mmol) was added. The mixture was stirred at 60 ° C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated. The obtained residue was purified by high-performance liquid chromatography preparative analysis to obtain compound C078 (5.94 mg). LCMS (ESI) m/z: 431.3 [M+H] + .
实施例79：
Embodiment 79:
合成路线
synthetic route
(1)将C079-a(1.0g，4.524mmol)溶解在无水DCM(10mL)中，反应液降温至0℃，然后加入DAST(2ml，18.10mmol)，反应液缓慢升至室温，并在室温下搅拌16h。反应结束，将反应液缓慢加入水(20ml)中，搅拌5分钟，再加入DCM(20ml x 3)进行萃取，合并后的有机相加入无水硫酸钠进行干燥，过滤，减压浓缩，所得粗产品用柱层析纯化(乙酸乙酯：石油醚＝0-20％)得到产物C079-b(500mg)。1H NMR(400MHz,DMSO_d6)δ8.81(d,J＝1.2Hz,1H),5.60(d,J＝48.0Hz,2H).(1) C079-a (1.0 g, 4.524 mmol) was dissolved in anhydrous DCM (10 mL), the reaction solution was cooled to 0°C, and then DAST (2 ml, 18.10 mmol) was added. The reaction solution was slowly warmed to room temperature and stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was slowly added to water (20 ml), stirred for 5 minutes, and then DCM (20 ml x 3) was added for extraction. The combined organic phase was added with anhydrous sodium sulfate for drying, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 0-20%) to obtain the product C079-b (500 mg). 1 H NMR (400 MHz, DMSO_d6) δ8.81 (d, J = 1.2 Hz, 1H), 5.60 (d, J = 48.0 Hz, 2H).
(2)将C079-b(500mg,2.23mmol)溶于甲苯(5.0ml)中，然后加入二丁基(1-乙氧基乙烯基)(乙基)锡烷(1.2ml,3.345mmol)和Pd(PPh3)4(257mg,0.223mmol),将反应液用氮气置换三次，并在110℃下反应16h。反应结束，向反应液加入水(10ml)，搅拌5分钟，再加入乙酸乙酯(10ml x 3)进行萃取，有机相减压浓缩所得粗产品用THF溶解，再加入2M HCl(5ml),然后将溶液升温至60℃，搅拌2h。反应结束后，向反应液中加入水(10ml)，再加入乙酸乙酯(10ml x 3)进行萃取，有机相加入饱和KF(10ml),搅拌30分钟，滤去固体，滤液进行分液，所得有机相用饱和的食盐水进行洗涤，再加入无水硫酸钠进行干燥，过滤，有机相减压浓缩，所得粗产品用硅胶柱层析纯化(乙酸乙酯：石油醚＝0-10％)得到产物C079-c(210mg)。1H NMR(400MHz,DMSO_d6)δ8.97(s,1H),5.70(d,J＝48.0Hz,2H),2.65(s,3H).(2) C079-b (500 mg, 2.23 mmol) was dissolved in toluene (5.0 ml), and then dibutyl (1-ethoxyvinyl) (ethyl) stannane (1.2 ml, 3.345 mmol) and Pd (PPh 3 ) 4 (257 mg, 0.223 mmol) were added. The reaction solution was replaced with nitrogen three times and reacted at 110° C. for 16 h. After the reaction was completed, water (10 ml) was added to the reaction solution, stirred for 5 minutes, and then ethyl acetate (10 ml x 3) was added for extraction. The organic phase was concentrated under reduced pressure and the obtained crude product was dissolved in THF, and 2M 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. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-10%) to obtain the product C079-c (210 mg). 1 H NMR (400 MHz, DMSO_d6) δ8.97 (s, 1H), 5.70 (d, J = 48.0 Hz, 2H), 2.65 (s, 3H).
(3)先将C079-c(210mg,1.117mmol)，int2(451mg,2.234mmol)溶于DMSO(5ml)，然后加入DIEA(0.36ml,2.234mmol),将反应液用氮气保护，并加热至60℃，反应4h。反应结束，将反应 液降温到室温，加入水，过滤所得粗品C079-d(250mg)可直接用于下一步。LCMS(ESI)m/z:319.0[M+H]+.(3) C079-c (210 mg, 1.117 mmol) and int2 (451 mg, 2.234 mmol) were first dissolved in DMSO (5 ml), and then DIEA (0.36 ml, 2.234 mmol) was added. The reaction solution was protected with nitrogen and heated to 60°C for 4 h. The solution was cooled to room temperature, water was added, and the crude product C079-d (250 mg) obtained by filtration was directly used in the next step. LCMS (ESI) m/z: 319.0 [M+H] + .
(4)将C079-d(150mg，0.471mmol)，int7(176mg，0.943mmol)和一水合对甲苯磺酸水合物(8.9mg，0.0471mmol)溶解在乙腈(5.0mL)中，反应液在60℃下搅拌4h。反应结束后，过滤反应液，用乙腈洗涤滤饼，合并有机相，减压浓缩，所得残余物用高效液相制备分析纯化得C079(8.62mg)。LCMS(ESI)m/z:452.2[M+H]+.(4) C079-d (150 mg, 0.471 mmol), int7 (176 mg, 0.943 mmol) and p-toluenesulfonic acid monohydrate (8.9 mg, 0.0471 mmol) were dissolved in acetonitrile (5.0 mL), and the reaction solution was stirred at 60°C for 4 h. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with acetonitrile, the organic phases were combined, and concentrated under reduced pressure. The obtained residue was purified by high performance liquid chromatography preparative analysis to obtain C079 (8.62 mg). LCMS (ESI) m/z: 452.2 [M+H] + .
实施例80：
Embodiment 80:
合成路线
synthetic route
将int28(200mg，0.72mmol)溶解在DMF(4mL)中，加入int28(131mg，0.79mmol)和一水合对甲苯磺酸(27mg，0.214mmol)并在60℃下搅拌4h。反应结束后，将反应液过滤，滤液用高效液相制备纯化得化合物C080(3.61mg)。LCMS(ESI)m/z:425.3[M+H]+.Int28 (200 mg, 0.72 mmol) was dissolved in DMF (4 mL), and int28 (131 mg, 0.79 mmol) and p-toluenesulfonic acid monohydrate (27 mg, 0.214 mmol) were added and stirred at 60°C for 4 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography to obtain compound C080 (3.61 mg). LCMS (ESI) m/z: 425.3 [M+H] + .
实施例81：
Embodiment 81:
合成路线
synthetic route
将化合物C080-d(200mg，0.72mmol)溶解在DMF(4mL)中，加入int20(109mg，0.79mmol)和一水合对甲苯磺酸(27mg，0.214mmol)，反应液氮气保护下，在60℃下搅拌4h。反应结束后，将反应液过滤，滤液用高效液相色谱纯化得化合物C081(10.93mg，收率：3.82％)。LCMS(ESI)m/z:397.3[M+H]+.Compound C080-d (200 mg, 0.72 mmol) was dissolved in DMF (4 mL), int20 (109 mg, 0.79 mmol) and p-toluenesulfonic acid monohydrate (27 mg, 0.214 mmol) were added, and the reaction liquid was stirred at 60°C for 4 h under nitrogen protection. After the reaction, the reaction liquid was filtered, and the filtrate was purified by high performance liquid chromatography to obtain compound C081 (10.93 mg, yield: 3.82%). LCMS (ESI) m/z: 397.3 [M+H] + .
实施例82：
Embodiment 82:
合成路线
synthetic route
(1)将int35(300mg，1.66mmol)、int2(368mg，1.82mmol)、DIEA(641mg，4.97mmol)溶解在DMSO(7mL)中。混合液在氮气保护下室温搅拌2h，反应结束后加水和乙酸乙酯稀释，分出有机相，水相用乙酸乙酯萃取(20mL x 3)，合并有机相，用饱和食盐水洗涤2次，有机相用硫酸钠干燥，过滤并减压浓缩。所得残余物用硅胶柱层析纯化，用(0-50％乙酸乙酯:石油醚)洗脱得化合物C082-a(200mg，收率：38.79％)。LCMS(ESI)m/z:312.1[M+H]+.(1) Int35 (300 mg, 1.66 mmol), int2 (368 mg, 1.82 mmol), and DIEA (641 mg, 4.97 mmol) were dissolved in DMSO (7 mL). The mixture was stirred at room temperature for 2 h under nitrogen protection. After the reaction was completed, water and ethyl acetate were added to dilute the mixture. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (0-50% ethyl acetate: petroleum ether) to obtain compound C082-a (200 mg, yield: 38.79%). LCMS (ESI) m/z: 312.1 [M+H] + .
(2)将C082-a(200mg，0.64mmol)溶解在DMF(5mL)中，加入int28(117mg，0.71mmol)和一水合对甲苯磺酸(25mg，0.13mmol)并在60℃下搅拌4h。反应结束后过滤，反相纯化得化合物C082(27.37mg，收率：9.29％)。LCMS(ESI)m/z:459.3[M+H]+.(2) C082-a (200 mg, 0.64 mmol) was dissolved in DMF (5 mL), int28 (117 mg, 0.71 mmol) and p-toluenesulfonic acid monohydrate (25 mg, 0.13 mmol) were added and stirred at 60°C for 4 h. After the reaction was completed, the mixture was filtered and purified by reverse phase to obtain compound C082 (27.37 mg, yield: 9.29%). LCMS (ESI) m/z: 459.3 [M+H] + .
实施例83：
Embodiment 83:
合成路线
synthetic route
(1)将C034-34c(200mg,1.058mmol)，27c(250mg,1.587mmol)溶于DMSO(2ml)，然后加入DIEA(0.3ml,2.116mmol),将反应液氮气保护，加热至90℃，反应4h。反应结束，将反应加入水，过滤所得C083-d(200mg)，直接用于下一步反应。LCMS(ESI)m/z:311.0[M+H]+.(1) C034-34c (200 mg, 1.058 mmol) and 27c (250 mg, 1.587 mmol) were dissolved in DMSO (2 ml), and then DIEA (0.3 ml, 2.116 mmol) was added. The reaction liquid was protected by nitrogen and heated to 90 °C for 4 h. After the reaction was completed, water was added to the reaction mixture, and the obtained C083-d (200 mg) was filtered and used directly in the next step. LCMS (ESI) m/z: 311.0 [M+H] + .
(2)将粗品C083-d(200mg，0.645mmol),int6(150mg，0.967mmol)溶于乙腈(5ml)中，然后将对甲苯磺酸一水合物(15mg,0.0793mmol)加入反应液中,升温90℃，反应4h。反应完毕后加水(5ml)产物析出来，过滤，滤饼再用TLC(石油醚:乙酸乙酯＝3:1)纯化得化合物C083(21.56mg)。LCMS(ESI)m/z:M＝416.2[M+H]+.(2) The crude product C083-d (200 mg, 0.645 mmol) and int6 (150 mg, 0.967 mmol) were dissolved in acetonitrile (5 ml), and then p-toluenesulfonic acid monohydrate (15 mg, 0.0793 mmol) was added to the reaction solution, and the temperature was raised to 90°C and the reaction was carried out for 4 hours. After the reaction was completed, water (5 ml) was added to precipitate the product, which was filtered and the filter cake was purified by TLC (petroleum ether: ethyl acetate = 3:1) to obtain compound C083 (21.56 mg). LCMS (ESI) m/z: M = 416.2 [M+H] + .
实施例84：
Embodiment 84:
合成路线
synthetic route
(1)将24d(150mg，0.954mmol，1.0eq)，27c(164mg，1.049mmol，1.1eq)溶解在N,N-二甲基甲酰胺(4mL)中，常温下加入N,N-二异丙基乙胺(0.5ml,2.862mmol,3.0eq),反应液在60℃下搅拌2h。反应结束后，降温，加水析出，过滤旋干得C084-b粗品(250mg)。LCMS(ESI)m/z:295.0[M+H]+.(1) 24d (150 mg, 0.954 mmol, 1.0 eq) and 27c (164 mg, 1.049 mmol, 1.1 eq) were dissolved in N,N-dimethylformamide (4 mL), and N,N-diisopropylethylamine (0.5 ml, 2.862 mmol, 3.0 eq) was added at room temperature. The reaction solution was stirred at 60°C for 2 h. After the reaction was completed, the temperature was lowered, water was added to precipitate, and the crude product C084-b (250 mg) was obtained by filtration and spin drying. LCMS (ESI) m/z: 295.0 [M+H] + .
(2)将C084-b(200mg，0.679mmol，1.0eq)，int6(92mg，0.747mmol，1.1eq)和对甲苯磺酸一水合物(23mg，0.136mmol，0.2eq)溶解在N.N-二甲基甲酰胺(4.0mL)中，反应液在70℃下搅拌4h。反应结束后，降温过滤，洗涤，合并有机相用高效液相色谱纯化得C084(66mg，收率：24.3％)。LCMS(ESI)m/z:400.2[M+H]+.(2) C084-b (200 mg, 0.679 mmol, 1.0 eq), int6 (92 mg, 0.747 mmol, 1.1 eq) and p-toluenesulfonic acid monohydrate (23 mg, 0.136 mmol, 0.2 eq) were dissolved in NN-dimethylformamide (4.0 mL), and the reaction solution was stirred at 70°C for 4 h. After the reaction was completed, the temperature was lowered, filtered, washed, and the organic phases were combined and purified by high performance liquid chromatography to obtain C084 (66 mg, yield: 24.3%). LCMS (ESI) m/z: 400.2 [M+H] + .
实施例85：
Embodiment 85:
合成路线
synthetic route
将int27(200mg，0.723mmol，1.0eq)，int6(97mg，0.796mmol，1.1eq)和对甲苯磺酸水合物(29mg，0.144mmol，0.2eq)溶解在N.N-二甲基甲酰胺(4.0mL)中，反应液在70℃下搅拌4h。反应结束后，降温过滤合并有机相所得残余物经制备分析纯化得C085(14.02mg，收率：5.08％)。LCMS(ESI)m/z:382.1[M+H]+.Int27 (200 mg, 0.723 mmol, 1.0 eq), int6 (97 mg, 0.796 mmol, 1.1 eq) and p-toluenesulfonic acid hydrate (29 mg, 0.144 mmol, 0.2 eq) were dissolved in NN-dimethylformamide (4.0 mL), and the reaction solution was stirred at 70 ° C for 4 h. After the reaction was completed, the organic phase was cooled and filtered to obtain the residue, which was purified by preparative analysis to obtain C085 (14.02 mg, yield: 5.08%). LCMS (ESI) m/z: 382.1 [M + H] + .
实施例86：
Embodiment 86:
合成路线
synthetic route
将int36(100mg，0.361mmol)、int7(81mg，0.433mmol)、一水合对甲苯磺酸(14mg,0.07mmol),依次加入乙腈(2mL)中。氮气保护下混合物于60℃油浴中搅拌4h。反应完成后，将反应液减压浓缩，所得粗品用高效液相色谱纯化得化合物C086(2.81mg)。LCMS(ESI)m/z:411.1[M+H]+.Int36 (100 mg, 0.361 mmol), int7 (81 mg, 0.433 mmol), p-toluenesulfonic acid monohydrate (14 mg, 0.07 mmol) were added to acetonitrile (2 mL) in sequence. The mixture was stirred in a 60°C oil bath under nitrogen protection for 4 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography to obtain compound C086 (2.81 mg). LCMS (ESI) m/z: 411.1 [M+H] + .
实施例87：
Embodiment 87:
合成路线
synthetic route
(1)将int36(100mg，0.361mmol)、int6(69mg，0.433mmol)和一水合对甲苯磺酸(14mg,0.07mmol)依次加入DMF(2mL)中。氮气保护下，混合物于60℃油浴中搅拌2h。反应完成后，将反应液减压浓缩。所得残留物用高效液相色谱制备分析纯化得化合物C087(37.07mg)。LCMS(ESI)m/z:383.0[M+H]+.(1) Int36 (100 mg, 0.361 mmol), int6 (69 mg, 0.433 mmol) and p-toluenesulfonic acid monohydrate (14 mg, 0.07 mmol) were added to DMF (2 mL) in sequence. Under nitrogen protection, the mixture was stirred in a 60°C oil bath for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by high performance liquid chromatography preparative analysis to obtain compound C087 (37.07 mg). LCMS (ESI) m/z: 383.0 [M+H] + .
实施例88：
Embodiment 88:
合成路线
synthetic route
(1)将36c(400mg，2.53mmol)、原料C088-a(358mg，2.3mmol)以及三乙胺(696mg,6.9mmol)溶解在DMSO(8mL)中。氮气保护下,混合物于60℃油浴中搅拌2h。反应结束后，将反应液冷却至室温，反应液加水析出固体，过滤并用水洗涤得粗品C088-b(100mg)，可直接用于下一步。LCMS(ESI)m/z:279.0[M+H]+.(1) 36c (400 mg, 2.53 mmol), raw material C088-a (358 mg, 2.3 mmol) and triethylamine (696 mg, 6.9 mmol) were dissolved in DMSO (8 mL). Under nitrogen protection, the mixture was stirred in a 60°C oil bath for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, water was added to the reaction solution to precipitate solids, which were filtered and washed with water to obtain crude product C088-b (100 mg), which was directly used in the next step. LCMS (ESI) m/z: 279.0 [M+H] + .
(2)将粗品C088-b(100mg，0.359mmol)、int28(86mg，0.431mmol)和一水合对甲苯磺酸(14mg,0.07mmol),依次加入DMF(2mL)中。氮气保护下，混合物于60℃油浴中搅拌2h。反应完成后减压浓缩。浓缩物用高效液相色谱制备得化合物C088(2.05mg)。LCMS(ESI)m/z:426.0[M+H]+.(2) Crude C088-b (100 mg, 0.359 mmol), int28 (86 mg, 0.431 mmol) and p-toluenesulfonic acid monohydrate (14 mg, 0.07 mmol) were added to DMF (2 mL) in sequence. Under nitrogen protection, the mixture was stirred in an oil bath at 60°C for 2 h. After the reaction was completed, it was concentrated under reduced pressure. The concentrate was used for high performance liquid chromatography to obtain compound C088 (2.05 mg). LCMS (ESI) m/z: 426.0 [M+H] + .
实施例89：
Embodiment 89:
合成路线
synthetic route
(1)将C089-a(1.0g,5.128mmol)，氰化锌(1.8g,15.384mmol)和四(三苯基膦)钯(600mg,0.512mmol)溶于N,N-二甲基甲酰胺(20ml)中，混合液在氮气保护下80℃搅拌过夜。反应完成后,反应液加水(60mL)稀释，用二氯甲烷萃取(40mL x 3),有机相用无水硫酸钠干燥,过滤，减压浓缩。所得残留物用硅胶柱层析纯化(0-5％甲醇/二氯甲烷)得到C089-b(500mg)。LCMS(ESI)m/z:144.1[M+H]+.(1) C089-a (1.0 g, 5.128 mmol), zinc cyanide (1.8 g, 15.384 mmol) and tetrakis(triphenylphosphine)palladium (600 mg, 0.512 mmol) were dissolved in N,N-dimethylformamide (20 ml), and the mixture was stirred at 80°C overnight under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water (60 mL), extracted with dichloromethane (40 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% methanol/dichloromethane) to obtain C089-b (500 mg). LCMS (ESI) m/z: 144.1 [M+H] + .
(2)将C089-b(500mg，3.496mmol)在0℃下分批加入到发烟硝酸(5.2ml)中，反应液在0℃下搅拌0.5小时。反应结束后，将反应液缓慢滴加入冰水中，固体析出，过滤，真空干燥得粗品C089-c(400mg)。LCMS(ESI)m/z:189.1[M+H]+.(2) C089-b (500 mg, 3.496 mmol) was added to fuming nitric acid (5.2 ml) in batches at 0°C, and the reaction solution was stirred at 0°C for 0.5 hours. After the reaction was completed, the reaction solution was slowly added dropwise to ice water, and the solid precipitated, filtered, and vacuum dried to obtain a crude product C089-c (400 mg). LCMS (ESI) m/z: 189.1 [M+H] + .
(3)将C089-c(350mg，1.861mmol)溶解在氢溴酸水溶液(40％)(10mL)中，然后在常温下加入二氯化锡(2.1g，9.308mmol)。反应液在30℃下搅拌过夜。反应完成后,反应液加水(10mL)稀释，用二氯甲烷萃取(10mL x 3),有机相用无水硫酸钠干燥,过滤，减压浓缩。所得残留物用硅胶柱层析纯化(0-10％甲醇/二氯甲烷)得到C089-d(200mg)。LCMS(ESI)m/z:159.1[M+H]+.(3) C089-c (350 mg, 1.861 mmol) was dissolved in a hydrobromic acid aqueous solution (40%) (10 mL), and then tin dichloride (2.1 g, 9.308 mmol) was added at room temperature. The reaction solution was stirred at 30°C overnight. After the reaction was completed, the reaction solution was diluted with water (10 mL), extracted with dichloromethane (10 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-10% methanol/dichloromethane) to obtain C089-d (200 mg). LCMS (ESI) m/z: 159.1 [M+H] + .
(4)将C089-d(150mg，0.887mmol)和38d(125mg,0.806mmol)溶解在二甲基亚砜(5mL)中，然后在常温下加入N,N-二异丙基乙胺(114mg，0.887mmol)。反应液在60℃下搅拌4小时。反应完成后降温至常温，反应液加水(10mL)搅拌5分钟，固体析出，过滤得C089-e粗品(120mg)。LCMS(ESI)m/z:279.0[M+H]+.(4) C089-d (150 mg, 0.887 mmol) and 38d (125 mg, 0.806 mmol) were dissolved in dimethyl sulfoxide (5 mL), and then N, N-diisopropylethylamine (114 mg, 0.887 mmol) was added at room temperature. The reaction solution was stirred at 60°C for 4 hours. After the reaction was completed, the temperature was lowered to room temperature, and water (10 mL) was added to the reaction solution and stirred for 5 minutes. Solids precipitated and were filtered to obtain a crude product of C089-e (120 mg). LCMS (ESI) m/z: 279.0 [M+H] + .
(5)将C089-e(120mg，0.431mmol)和int28(104mg,0.517mmol)溶解在N,N-二甲基甲酰胺(5mL)中，然后在常温下加入一水合对甲苯磺酸水合物(14mg，0.086mmol)。反应液在60℃下搅拌4小时。反应完成后降温至常温，用二氯甲烷(30ml)和水(30ml)萃取两次，所得有机相加入无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶板进行纯化，溶剂比例为二氯甲烷(100ml)和甲醇(10ml)，得到产物C089(10mg)。LCMS(ESI)m/z:426.2[M+H]+.(5) C089-e (120 mg, 0.431 mmol) and int28 (104 mg, 0.517 mmol) were dissolved in N,N-dimethylformamide (5 mL), and then p-toluenesulfonic acid monohydrate (14 mg, 0.086 mmol) was added at room temperature. The reaction solution was stirred at 60°C for 4 hours. After the reaction was completed, the temperature was lowered to room temperature, and the mixture was extracted twice with dichloromethane (30 ml) and water (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel plate with a solvent ratio of dichloromethane (100 ml) and methanol (10 ml) to obtain the product C089 (10 mg). LCMS (ESI) m/z: 426.2 [M+H] + .
实施例90：
Embodiment 90:
合成路线
synthetic route
(1)将int37(200mg 0.72mmol)，int28(142mg，0.86mmol，)和一水合对甲苯磺酸水合物(27mg，0.14mmol)溶解在乙腈(2mL)中，在60℃下搅拌4h。反应结束后，过滤反应液，用乙腈洗涤，合并有机相所得残余物用高效液相制备分析纯化得C090(11.36mg)。LCMS(ESI)m/z:426.1[M+H]+. (1) Int37 (200 mg, 0.72 mmol), int28 (142 mg, 0.86 mmol) and p-toluenesulfonic acid monohydrate (27 mg, 0.14 mmol) were dissolved in acetonitrile (2 mL) and stirred at 60°C for 4 h. After the reaction was completed, the reaction solution was filtered and washed with acetonitrile. The organic phases were combined and the residue was purified by high performance liquid chromatography to obtain C090 (11.36 mg). LCMS (ESI) m/z: 426.1 [M+H] + .
实施例91：
Embodiment 91:
合成路线
synthetic route
将int38(200mg，0.72mmol)溶解在DMF(3mL)中，加入int7(110mg，0.72mmol)和对甲苯磺酸(27mg，0.14mmol)并在60℃下搅拌4h。反应结束后过滤，反相纯化得化合物C091(30.74mg，10.38％)。LCMS(ESI)m/z:411.2[M+H]+.Int38 (200 mg, 0.72 mmol) was dissolved in DMF (3 mL), and int7 (110 mg, 0.72 mmol) and p-toluenesulfonic acid (27 mg, 0.14 mmol) were added and stirred at 60°C for 4 h. After the reaction was completed, the mixture was filtered and purified by reverse phase to obtain compound C091 (30.74 mg, 10.38%). LCMS (ESI) m/z: 411.2 [M+H] + .
实施例92：
Embodiment 92:
合成路线
synthetic route
将int38(250mg，0.90mmol)溶解在DMF(4mL)中，加入int6(144mg，0.90mmol)和一水合对甲苯磺酸(34mg，0.18mmol)，反应液并在60℃下搅拌4h。反应结束后，将反应液过滤，滤液用高效液相制备纯化得化合物C092(26.31mg，收率：7.63％)。LCMS(ESI)m/z:383.2[M+H]+.Int38 (250 mg, 0.90 mmol) was dissolved in DMF (4 mL), and int6 (144 mg, 0.90 mmol) and p-toluenesulfonic acid monohydrate (34 mg, 0.18 mmol) were added, and the reaction solution was stirred at 60°C for 4 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography to obtain compound C092 (26.31 mg, yield: 7.63%). LCMS (ESI) m/z: 383.2 [M+H] + .
实施例93：
Embodiment 93:
合成路线
synthetic route
(1)将C093-a(25g，133.9mmol，1eq)溶解在四氢呋喃：水＝5:1(250mL)中，然后加入一水合氢氧化锂(28.1g，669.8mmol，5.0eq)，在室温下搅拌2h。反应结束后加盐酸(1M，50ml)淬灭反应，浓缩除去大部分四氢呋喃，再加入盐酸(1M)，调节PH值至1-2，过滤得到C093-b粗品17g，直接用于下一步反应。LCMS(ESI)m/z:170.9[M-H]-，1H NMR(400MHz,DMSO_d6)δ13.69(s,1H),8.85(d,J＝2.8Hz,1H),2.65(d,J＝1.2Hz,3H).(1) C093-a (25 g, 133.9 mmol, 1 eq) was dissolved in tetrahydrofuran: water = 5:1 (250 mL), and then lithium hydroxide monohydrate (28.1 g, 669.8 mmol, 5.0 eq) was added and stirred at room temperature for 2 h. After the reaction was completed, hydrochloric acid (1 M, 50 ml) was added to quench the reaction, and most of the tetrahydrofuran was removed by concentration. Hydrochloric acid (1 M) was then added, and the pH value was adjusted to 1-2. 17 g of crude C093-b was obtained by filtration and used directly in the next step. LCMS (ESI) m/z: 170.9 [MH] - , 1 H NMR (400 MHz, DMSO_d6) δ 13.69 (s, 1H), 8.85 (d, J = 2.8 Hz, 1H), 2.65 (d, J = 1.2 Hz, 3H).
(2)将C093-b(6.1g，35.5mmol，1eq)、盐酸羟胺(6.9g，70.9mmol，2.0eq)和DIEA(13.7g，106.5mmol，3.0eq)加入无水乙腈(150mL)中，0℃搅拌下分批加入HATU(20.2g，53.25mmol，1.5eq)并于室温下搅拌反应3h。反应结束后加入水(100mL)淬灭反应，混合物用二氯甲烷(50mL x3)萃取，合并有机相,减压浓缩，所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝20:1到5:1)洗脱得C093-c(4.8g)。LCMS(ESI)m/z:216.1[M+H]+，1H NMR(400MHz,CDCl3)δ8.53(s,1H),3.76(s,3H),3.40(s,3H),2.71(s,3H).(2) C093-b (6.1 g, 35.5 mmol, 1 eq), hydroxylamine hydrochloride (6.9 g, 70.9 mmol, 2.0 eq) and DIEA (13.7 g, 106.5 mmol, 3.0 eq) were added to anhydrous acetonitrile (150 mL), and HATU (20.2 g, 53.25 mmol, 1.5 eq) was added in batches under stirring at 0°C and stirred at room temperature for 3 h. After the reaction was completed, water (100 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography and eluted with (petroleum ether: ethyl acetate = 20:1 to 5:1) to obtain C093-c (4.8 g). LCMS (ESI) m/z: 216.1 [M+H] + , 1 H NMR (400 MHz, CDCl 3 ) δ 8.53 (s, 1H), 3.76 (s, 3H), 3.40 (s, 3H), 2.71 (s, 3H).
(3)在氮气保护下，将C093-c(4g，1eq)溶解在四氢呋喃(50mL)中，在0℃下搅拌滴加MeMgBr(12.4ml，3mmol/ml，2eq)移至室温下反应2h。反应完毕后，将反应液用冰浴降温，并滴加饱和NH4Cl溶液至反应液pH＝7～8，混合物用二氯甲烷萃取(50mL x 3)，合并有机相所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝30:1至10:1)洗脱得C093-d(1.5g)，用于下一步反应。LCMS(ESI)m/z:171.1[M+H]+，1H NMR(400MHz,CDCl3)δ8.83(s,1H),2.73(s,3H),2.69(s,3H).(3) Under nitrogen protection, C093-c (4 g, 1 eq) was dissolved in tetrahydrofuran (50 mL), and MeMgBr (12.4 ml, 3 mmol/ml, 2 eq) was added dropwise at 0°C with stirring, and the mixture was moved to room temperature for 2 h. After the reaction was completed, the reaction solution was cooled with an ice bath, and a saturated NH 4 Cl solution was added dropwise until the pH of the reaction solution was 7-8. The mixture was extracted with dichloromethane (50 mL x 3), and the residue obtained by combining the organic phases was purified by column chromatography, and eluted with (petroleum ether: ethyl acetate = 30:1 to 10:1) to obtain C093-d (1.5 g), which was used for the next reaction. LCMS (ESI) m/z: 171.1 [M+H] + , 1 H NMR (400 MHz, CDCl 3 ) δ 8.83 (s, 1H), 2.73 (s, 3H), 2.69 (s, 3H).
(4)将C093-d(1.5g，8.79mmol，1eq)、int2(2.1g，10.55mmol，1.2eq)和DIEA(3.4g，26.37mmol，3.0eq)溶解在DMSO(15mL)中，在90℃下搅拌2h。TLC监测反应结束后降至室温，加入水，析出固体，过滤。析出的固体再用柱层析纯化，用(二氯甲烷:甲醇＝100:1至10:1)洗脱得C093-e(1.5g)，用于下一步反应。LCMS(ESI)m/z:301.1[M+H]+.(4) C093-d (1.5 g, 8.79 mmol, 1 eq), int2 (2.1 g, 10.55 mmol, 1.2 eq) and DIEA (3.4 g, 26.37 mmol, 3.0 eq) were dissolved in DMSO (15 mL) and stirred at 90°C for 2 h. After the reaction was completed, the mixture was cooled to room temperature and water was added to precipitate a solid, which was then filtered. The precipitated solid was purified by column chromatography and eluted with (dichloromethane:methanol=100:1 to 10:1) to obtain C093-e (1.5 g), which was used for the next step. LCMS (ESI) m/z: 301.1 [M+H] + .
(5)将C093-e(1.5g，5mmol，1eq)，int7(1.1g，6mmol，1.2eq)和对甲苯磺酸水合物(190mg，1mmol，0.2eq)溶解在DMF(15mL)中，在60℃下搅拌2h。TLC监测反应结束后，直接经制备分析纯化得C093(607mg，28％)。LCMS(ESI)m/z:434.2[M+H]+.(5) C093-e (1.5 g, 5 mmol, 1 eq), int7 (1.1 g, 6 mmol, 1.2 eq) and p-toluenesulfonic acid hydrate (190 mg, 1 mmol, 0.2 eq) were dissolved in DMF (15 mL) and stirred at 60°C for 2 h. After the reaction was completed by TLC monitoring, C093 (607 mg, 28%) was directly purified by preparative analysis. LCMS (ESI) m/z: 434.2 [M+H] + .
实施例94：
Embodiment 94:
合成路线
synthetic route
(1)将C094-a(200mg，0.851mmol)和int2(204mg，1.02mmol)和Pd(OAc)2(20mg，0.085mmol)和Xantphos(96mg，0.17mmol)和Cs2CO3(548mg，1.7mmol)溶解在甲苯(8mL)中，氮气置换三次，反应液在100℃下搅拌3h。反应结束后，将反应液减压浓缩，所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝1:1)洗脱得C094-b(110mg，收率：40.2％)。LCMS(ESI)m/z:321.0[M+H]+.(1) C094-a (200 mg, 0.851 mmol), int2 (204 mg, 1.02 mmol), Pd(OAc) 2 (20 mg, 0.085 mmol), Xantphos (96 mg, 0.17 mmol), and Cs 2 CO 3 (548 mg, 1.7 mmol) were dissolved in toluene (8 mL), replaced with nitrogen three times, and the reaction solution was stirred at 100° C. for 3 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, and eluted with (petroleum ether: ethyl acetate = 1:1) to obtain C094-b (110 mg, yield: 40.2%). LCMS (ESI) m/z: 321.0 [M+H] + .
(2)将C094-b(110mg，0.343mmol)、int6(65mg，0.411mmol)和一水合对甲苯磺酸水合物(13mg，0.068mmol)溶解在DMF(2.0mL)中，在60℃下搅拌2h。反应结束后，过滤反应液，滤液用高效液相制备纯化得C094(10.94mg，收率：7.5％)。LCMS(ESI)m/z:426[M+H]+.(2) C094-b (110 mg, 0.343 mmol), int6 (65 mg, 0.411 mmol) and p-toluenesulfonic acid monohydrate (13 mg, 0.068 mmol) were dissolved in DMF (2.0 mL) and stirred at 60°C for 2 h. After the reaction, the reaction solution was filtered and the filtrate was purified by high performance liquid chromatography to obtain C094 (10.94 mg, yield: 7.5%). LCMS (ESI) m/z: 426 [M+H] + .
实施例95：
Embodiment 95:
合成路线
synthetic route
(1)将C095-a(500mg，2.5mmol)，int2(1.01g，5.0mmol)溶解在二甲基亚砜(20mL)中，加入N,N-二异丙基乙胺(0.8ml，5.0mmol)，反应液在室温下搅拌4h。反应结束后，向反应液加入水(10ml)，固体析出，过滤所得固体，干燥得到C095-b(200mg，收率：24.24％)。LCMS(ESI)m/z:Rt＝1.849min,M＝331.0[M+H]+.(1) C095-a (500 mg, 2.5 mmol) and int2 (1.01 g, 5.0 mmol) were dissolved in dimethyl sulfoxide (20 mL), and N,N-diisopropylethylamine (0.8 ml, 5.0 mmol) was added. The reaction solution was stirred at room temperature for 4 h. After the reaction was completed, water (10 ml) was added to the reaction solution, and a solid precipitated. The obtained solid was filtered and dried to obtain C095-b (200 mg, yield: 24.24%). LCMS (ESI) m/z: Rt = 1.849 min, M = 331.0 [M + H] + .
(2)将C095-b(200mg，0.606mmol)溶解在四氢呋喃(10mL)中，然后在常温下加入Pd/C(100mg)。在氢气的氛围下(15psi)反应30分钟。反应完成后,将反应液过滤，滤液减压浓缩，得到C095-c(100mg)。LCMS(ESI)m/z:301.1[M+H]+.(2) C095-b (200 mg, 0.606 mmol) was dissolved in tetrahydrofuran (10 mL), and then Pd/C (100 mg) was added at room temperature. The reaction was carried out for 30 minutes under a hydrogen atmosphere (15 psi). After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain C095-c (100 mg). LCMS (ESI) m/z: 301.1 [M+H] + .
(3)将C095-c(200mg，0.333mmol)、int7(124mg，0.666mmol)和一水合对甲苯磺酸水合物(5mg，0.0333mmol)溶解在DMF(3.0mL)中，反应液在60℃下搅拌4h。反应结束后，将反应液过滤，滤饼用DMF洗涤，合并有机相，减压浓缩。所得残余物用高效液相制备分析纯化得 C095(22.6mg)。LCMS(ESI)m/z:434.2[M+H]+.(3) C095-c (200 mg, 0.333 mmol), int7 (124 mg, 0.666 mmol) and p-toluenesulfonic acid monohydrate (5 mg, 0.0333 mmol) were dissolved in DMF (3.0 mL), and the reaction solution was stirred at 60° C. for 4 h. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with DMF, the organic phases were combined, and concentrated under reduced pressure. The obtained residue was purified by high performance liquid chromatography preparative analysis to obtain C095 (22.6 mg). LCMS (ESI) m/z: 434.2 [M+H] + .
实施例96：
Embodiment 96:
合成路线
synthetic route
(1)将C096-a(1.0g，4.80mmol)、DMAP(59mg，0.48mmol)和TEA(1.3mL，9.60mmol)溶解在超干DMF(10mL)中，然后在0℃下加入(Boc)2O(3.1g，14.40mmol)。反应液自然升温至室温，并搅拌16小时。反应结束后，反应液加水(30mL)稀释，用乙酸乙酯萃取(20mL x 3)，有机相用饱和食盐水(30mL x 2)洗涤,无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝10:1)洗脱得C096-b(1.6g)。LCMS(ESI):m/z＝471.0[M+64]+ (1) C096-a (1.0 g, 4.80 mmol), DMAP (59 mg, 0.48 mmol) and TEA (1.3 mL, 9.60 mmol) were dissolved in ultra-dry DMF (10 mL), and then (Boc) 2 O (3.1 g, 14.40 mmol) was added at 0°C. The reaction solution was naturally warmed to room temperature and stirred for 16 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (20 mL x 3), and the organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=10:1) to obtain C096-b (1.6 g). LCMS (ESI): m/z=471.0 [M+64] +
(2)将C096-b(1.6g，3.92mmol)、C096-c(1.7g，4.70mmol)和Pd(PPh3)4(453mg，0.39mmol)溶解在超干甲苯(16mL)中，氮气保护下80℃搅拌16小时。反应结束后得C096-d可直接用于下一步反应。(2) C096-b (1.6 g, 3.92 mmol), C096-c (1.7 g, 4.70 mmol) and Pd(PPh 3 ) 4 (453 mg, 0.39 mmol) were dissolved in ultra-dry toluene (16 mL) and stirred at 80° C. for 16 hours under nitrogen protection. After the reaction, C096-d was obtained and used directly in the next step.
(3)在上一步中所得反应液中加入4M HCl(20.0mL)，室温下搅拌16小时。反应结束后，反应液加水(30mL)稀释，用乙酸乙酯萃取(20mL x 3)，有机相用饱和食盐水(30mL x 2)洗涤,无水硫酸钠干燥，过滤，减压浓缩,所得残余物用硅胶柱层析纯化，用(PE:EA＝4:1)洗脱得C096-e(1.2g，收率：81％)。LCMS(ESI):m/z＝435.1[M+64]+ (3) 4M HCl (20.0 mL) was added to the reaction solution obtained in the previous step and stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain C096-e (1.2 g, yield: 81%). LCMS (ESI): m/z=435.1[M+64] +
(4)将C096-e(200mg，0.54mmol)和int2(130mg，0.65mmol)溶解在超干二甲基亚砜(4mL)中，然后加入DIEA(0.2mL，1.08mmol)。混合液在氮气保护下60℃搅拌4小时。反应液加水(30mL)稀释，用乙酸乙酯萃取(20mL x 3)，有机相用饱和食盐水(30mL x 2)洗涤,无水硫酸钠干燥，过滤，减压浓缩,所得残余物用硅胶柱层析纯化用(DCM:MeOH＝20:1)洗脱得C096-f(40mg,收率：14.8％)。LCMS(ESI):m/z＝502.2[M+1]+ (4) C096-e (200 mg, 0.54 mmol) and int2 (130 mg, 0.65 mmol) were dissolved in ultra-dry dimethyl sulfoxide (4 mL), and DIEA (0.2 mL, 1.08 mmol) was added. The mixture was stirred at 60 °C for 4 hours under nitrogen protection. The reaction solution was diluted with water (30 mL), extracted with ethyl acetate (20 mL x 3), and the organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (DCM: MeOH = 20: 1) to obtain C096-f (40 mg, yield: 14.8%). LCMS (ESI): m/z = 502.2 [M+1] +
(5)将C096-f(40mg，0.080mmol)、int28(19mg，0.096mmol)和一水合对甲苯磺酸(2mg，0.0080mmol)溶解在超干DMF(1mL)中。混合液在氮气保护下70℃搅拌4小时。反应结束后，反应液过滤，滤液用高效液相制备分析纯化得化合物C096(1.36mg)。LCMS(ESI):m/z＝449.2[M+1]+ (5) C096-f (40 mg, 0.080 mmol), int28 (19 mg, 0.096 mmol) and p-toluenesulfonic acid monohydrate (2 mg, 0.0080 mmol) were dissolved in ultra-dry DMF (1 mL). The mixture was stirred at 70° C. for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was filtered and the filtrate was purified by high performance liquid chromatography to obtain compound C096 (1.36 mg). LCMS (ESI): m/z=449.2 [M+1] +
实施例97：
Embodiment 97:
合成路线
synthetic route
(1)向150mL耐压瓶中依次加入3-溴氧杂环丁烷(1.89g，13.81mmol)、碘化镍(864mg，2.76mmol)、4,4’-二叔丁基2,2’-二吡啶(742mg，2.76mmol)、无水氯化镁(1.32g，13.81mmol)、锰粉(3.04g，55.25mmol)、原料C097-a(4.50g，15.19mmol)和溶剂N,N-二甲基乙酰胺(67mL)。最后滴入4-乙基吡啶(1.19g，11.05mmol)，氩气鼓气30秒后封口。80℃油浴加热24小时后，将冷却至室温的反应液滴入400mL水中，用乙酸乙酯(300mL)萃取三次，有机相用饱和氯化钠(150mL)洗涤三次，无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝9:1)洗脱得C097-b(2.2g，收率：58％)。(1) 3-bromooxetane (1.89 g, 13.81 mmol), nickel iodide (864 mg, 2.76 mmol), 4,4'-di-tert-butyl 2,2'-bipyridine (742 mg, 2.76 mmol), anhydrous magnesium chloride (1.32 g, 13.81 mmol), manganese powder (3.04 g, 55.25 mmol), raw material C097-a (4.50 g, 15.19 mmol) and solvent N,N-dimethylacetamide (67 mL) were added to a 150 mL pressure bottle in sequence. Finally, 4-ethylpyridine (1.19 g, 11.05 mmol) was added dropwise, and the bottle was sealed after argon gas was blown for 30 seconds. After heating in an oil bath at 80°C for 24 hours, the reaction solution cooled to room temperature was added dropwise to 400 mL of water, extracted three times with ethyl acetate (300 mL), and the organic phase was washed three times with saturated sodium chloride (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography and eluted with (petroleum ether:ethyl acetate=9:1) to obtain C097-b (2.2 g, yield: 58%).
(2)向盛有C097-b(2.2g，8.05mmol)的250mL单口瓶中加入碳酸钾(3.34g，24.15mmol)、甲醇(110mL)和水(37mL)，氮气保护下油浴加热至70℃搅拌16小时。反应完成后冷却至室温，减压浓缩至有大量固体析出(旋出大部分甲醇)。用二氯甲烷(200mL)萃取一次，二氯甲烷(30mL)再萃两次，合并有机相，无水硫酸钠干燥并过滤减压浓缩滤液即得粗品C097-c(1.379g)，可直接用于下一步。LCMS(ESI)m/z:174.0[M+H]+.(2) Add potassium carbonate (3.34 g, 24.15 mmol), methanol (110 mL) and water (37 mL) to a 250 mL single-mouth bottle containing C097-b (2.2 g, 8.05 mmol), heat to 70 ° C in an oil bath under nitrogen protection and stir for 16 hours. After the reaction is completed, cool to room temperature and concentrate under reduced pressure until a large amount of solid precipitates (most of the methanol is spun out). Extract once with dichloromethane (200 mL), extract twice with dichloromethane (30 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure to obtain crude C097-c (1.379 g), which can be used directly in the next step. LCMS (ESI) m/z: 174.0 [M+H] + .
(3)将C097-c(1.38g，7.96mmol)溶解在超干溶剂N,N-二甲基甲酰胺(14mL)中，冰水浴搅拌下缓慢滴加三氟乙酸酐(1.77g，8.44mmol)，加完后室温搅拌16小时。反应结束后，于冰水浴中将反应液滴入水(100mL)中，用乙酸乙酯(50mL)萃取三次。合并有机相并用饱和氯化钠(30mL)洗涤一次。有机相用无水硫酸钠干燥，过滤并减压浓缩滤液，即得粗品C097-d(2.41g)。LCMS(ESI)m/z:269.1[M+H]+.(3) C097-c (1.38 g, 7.96 mmol) was dissolved in an ultra-dry solvent N,N-dimethylformamide (14 mL), and trifluoroacetic anhydride (1.77 g, 8.44 mmol) was slowly added dropwise under stirring in an ice-water bath. After the addition, the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was added dropwise into water (100 mL) in an ice-water bath and extracted three times with ethyl acetate (50 mL). The organic phases were combined and washed once with saturated sodium chloride (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product C097-d (2.41 g). LCMS (ESI) m/z: 269.1 [M+H] + .
(4)向盛有C097-d(2.41g，7.96mmol)的100mL单口瓶中加入氢氧化钠水溶液(20wt％，36mL)，油浴100℃搅拌1小时。反应结束后冷却至室温并置于冰水浴中，边搅拌边滴加盐酸溶液直至溶液pH≈6。用二氯甲烷与甲醇的混合溶剂(DCM：MeOH＝10：1)萃取水相三次(可以先减压浓缩水相再萃取)，合并所有有机相，无水硫酸钠干燥后过滤，减压浓缩滤液即得粗品C097-e(1.19g)。LCMS(ESI)m/z:216.2[M-H]- (4) Add sodium hydroxide aqueous solution (20wt%, 36mL) to a 100mL single-mouth bottle containing C097-d (2.41g, 7.96mmol) and stir in an oil bath at 100℃ for 1 hour. After the reaction is completed, cool to room temperature and place in an ice water bath, and add hydrochloric acid solution dropwise while stirring until the solution pH is ≈ 6. Extract the aqueous phase three times with a mixed solvent of dichloromethane and methanol (DCM:MeOH=10:1) (the aqueous phase can be concentrated under reduced pressure before extraction), combine all organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product C097-e (1.19g). LCMS (ESI) m/z: 216.2 [MH] -
(5)向盛有粗品C097-e(1.19g，5.48mmol)的100mL单口瓶中加入超干溶剂甲苯(19mL)、DPPA(1.5mL，6.90mmol)和三乙胺(0.95mL，5.98mmol)，氮气置换三次，室温搅拌过夜。反应完全后即得C097-f的甲苯溶液，可直接用于下一步。LCMS(ESI)m/z:241.1[M-H]- (5) Add ultra-dry solvent toluene (19 mL), DPPA (1.5 mL, 6.90 mmol) and triethylamine (0.95 mL, 5.98 mmol) to a 100 mL single-necked bottle containing crude product C097-e (1.19 g, 5.48 mmol), replace with nitrogen three times, and stir at room temperature overnight. After the reaction is complete, a toluene solution of C097-f is obtained, which can be directly used in the next step. LCMS (ESI) m/z: 241.1 [MH] -
(6)向盛有C097-f甲苯溶液(23mL，5.48mmol)的100mL单口瓶中加入苯甲醇(1.31mL，12.66mmol)，油浴110℃搅拌6小时。反应结束后冷却至室温，减压浓缩干，所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝3:2)洗脱得C097-g(752mg，收率：42％)。LCMS(ESI)m/z:323.0[M+H]+.(6) Add benzyl alcohol (1.31 mL, 12.66 mmol) to a 100 mL single-mouth bottle containing a toluene solution of C097-f (23 mL, 5.48 mmol) and stir in an oil bath at 110°C for 6 hours. After the reaction is completed, cool to room temperature, concentrate under reduced pressure, and purify the residue by silica gel column chromatography, eluting with (petroleum ether: ethyl acetate = 3:2) to obtain C097-g (752 mg, yield: 42%). LCMS (ESI) m/z: 323.0 [M+H] + .
(7)将C097-g(610mg，1.89mmol)溶于无水甲醇(60mL)中，并加入催化剂湿钯碳(61mg)。氢气置换三次并在氢气保护下(15psi)，室温搅拌过夜。反应结束后,将反应液过滤，滤液低温减压浓缩干，即得粗品C097-h，可直接用于下一步。LCMS(ESI)m/z:189.2[M+H]+.(7) C097-g (610 mg, 1.89 mmol) was dissolved in anhydrous methanol (60 mL), and wet palladium carbon (61 mg) was added as catalyst. The mixture was replaced with hydrogen three times and stirred at room temperature overnight under hydrogen protection (15 psi). After the reaction, the reaction solution was filtered, and the filtrate was concentrated to dryness under low temperature and reduced pressure to obtain crude product C097-h, which was directly used in the next step. LCMS (ESI) m/z: 189.2 [M+H] + .
(8)向盛有粗品C097-h(1.89mmol)的100mL单口瓶中加入化合物38d(296mg，1.89mmol)、超干溶剂二甲基亚砜(7.6mL)和N,N-二异丙基乙胺(0.94mL，5.68mmol)，氮气置换三次，油浴60℃搅拌2小时。反应结束后冷却至室温，将反应液滴入水(50mL)中，析出大量固体，过滤，真空干燥滤饼至干。即得粗品C097-i(513mg)。LCMS(ESI)m/z:308.9[M+H]+.(8) Compound 38d (296 mg, 1.89 mmol), ultra-dry solvent dimethyl sulfoxide (7.6 mL) and N,N-diisopropylethylamine (0.94 mL, 5.68 mmol) were added to a 100 mL single-mouth bottle containing crude C097-h (1.89 mmol), replaced with nitrogen three times, and stirred in an oil bath at 60°C for 2 hours. After the reaction was completed, it was cooled to room temperature and the reaction solution was dropped into water (50 mL). A large amount of solid was precipitated, filtered, and the filter cake was vacuum dried to dryness. The crude product C097-i (513 mg) was obtained. LCMS (ESI) m/z: 308.9 [M+H] + .
(9)向盛有粗品C097-i(513mg，1.66mmol)的100mL单口瓶中加入int20(578mg，3.33mmol)、超干溶剂乙腈(40mL)和一水合对甲苯磺酸(32mg，0.17mmol)，氮气置换三次，油浴60℃搅 拌1小时。反应结束后冷却至室温，减压浓缩干后，所得残余物经高效液相制备分析纯化得化合物C097(13.97mg)。LCMS(ESI)m/z:428.2[M+H]+.(9) Int20 (578 mg, 3.33 mmol), ultra-dry solvent acetonitrile (40 mL) and p-toluenesulfonic acid monohydrate (32 mg, 0.17 mmol) were added to a 100 mL single-necked bottle containing the crude product C097-i (513 mg, 1.66 mmol). The atmosphere was replaced with nitrogen three times and stirred in an oil bath at 60 °C. Stir for 1 hour. After the reaction was completed, the mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was purified by high performance liquid chromatography preparative analysis to obtain compound C097 (13.97 mg). LCMS (ESI) m/z: 428.2 [M+H] + .
实施例98：
Embodiment 98:
合成路线
synthetic route
(1)依次将int34(100mg，0.537mmol)，int2(130mg，0.645mmol)以及N,N-二异丙基乙胺(138mg,1.075mmol)溶解在二甲基亚砜(2mL)中。氮气保护下混合物于90℃油浴中搅拌4h。反应结束后，将反应液冷却至室温，反应液加水析出粗品C098-a(150mg)，直接用于下一步。LCMS(ESI)m/z:317.0[M+H]+.(1) Dissolve int34 (100 mg, 0.537 mmol), int2 (130 mg, 0.645 mmol) and N,N-diisopropylethylamine (138 mg, 1.075 mmol) in dimethyl sulfoxide (2 mL) in turn. Stir the mixture in a 90°C oil bath under nitrogen protection for 4 h. After the reaction, the reaction solution was cooled to room temperature, and water was added to the reaction solution to precipitate the crude product C098-a (150 mg), which was directly used in the next step. LCMS (ESI) m/z: 317.0 [M+H] + .
(2)将C098-a(150mg，0.474mmol)、int7(107mg，0.568mmol)和一水合对甲苯磺酸(18mg，0.094mmol)溶解在N,N-二甲基甲酰胺(6mL)中。反应液在60℃下反应4小时。反应结束后将反应液反相制备分析纯化得化合物C098(50.81mg，收率：23.8％)。LCMS(ESI)m/z:450.0[M+H]+.(2) C098-a (150 mg, 0.474 mmol), int7 (107 mg, 0.568 mmol) and p-toluenesulfonic acid monohydrate (18 mg, 0.094 mmol) were dissolved in N,N-dimethylformamide (6 mL). The reaction solution was reacted at 60°C for 4 hours. After the reaction, the reaction solution was purified by reverse phase preparative analysis to obtain compound C098 (50.81 mg, yield: 23.8%). LCMS (ESI) m/z: 450.0 [M+H] + .
实施例99：
Embodiment 99:
合成路线
synthetic route
(1)将C099-a(154mg，0.820mmol，1.0eq)，int2(200mg，0.984mmol，1.2eq)和N,N-二异丙基乙胺(0.3ml,1.641mmol,2.0eq)溶解在二甲基亚砜(4mL)中，在90℃下搅拌4h。反应结束后，降温，加水固体析出，过滤，滤饼用水洗涤，真空干燥得C099-b粗品(240mg)。LCMS(ESI)m/z:320.0[M+H]+.(1) C099-a (154 mg, 0.820 mmol, 1.0 eq), int2 (200 mg, 0.984 mmol, 1.2 eq) and N,N-diisopropylethylamine (0.3 ml, 1.641 mmol, 2.0 eq) were dissolved in dimethyl sulfoxide (4 mL) and stirred at 90 ° C for 4 h. After the reaction was completed, the temperature was lowered, and water was added to precipitate the solid, which was filtered, and the filter cake was washed with water and vacuum dried to obtain C099-b crude product (240 mg). LCMS (ESI) m/z: 320.0 [M+H] + .
(2)将C099-b(100mg，0.312mmol，1.0eq)，int32(81.2mg，0.374mmol，1.2eq)和一水合对甲苯磺酸水合物(10mg，0.062mmol，0.2eq)溶解在N.N-二甲基甲酰胺(3.0mL)中，在70℃下搅拌4h。反应结束后，反应液有固体析出，降温过滤得粗产品77mg。用二氯甲烷溶解，二氯甲烷甲醇10：1层析板纯化，得C099(32.68mg，收率：21.7％)。LCMS(ESI)m/z:482.3[M+H]+.(2) C099-b (100 mg, 0.312 mmol, 1.0 eq), int32 (81.2 mg, 0.374 mmol, 1.2 eq) and p-toluenesulfonic acid monohydrate (10 mg, 0.062 mmol, 0.2 eq) were dissolved in NN-dimethylformamide (3.0 mL) and stirred at 70°C for 4 h. After the reaction, solids precipitated from the reaction solution, which was cooled and filtered to obtain 77 mg of crude product. The product was dissolved in dichloromethane and purified by dichloromethane-methanol 10:1 chromatography plate to obtain C099 (32.68 mg, yield: 21.7%). LCMS (ESI) m/z: 482.3 [M+H] + .
实施例100：
Embodiment 100:
合成路线
synthetic route
(1)在氮气保护下，将C100-a(5.0g，26.7mmol，1eq)，化合物3b(4.8g，28.68mmol，1.1eq)和三苯基膦(7.5g，28.68mmol，1.1eq)溶解在四氢呋喃(80mL)中，在0℃下将溶于四氢呋喃(20ml)的DBAD(6.6g，28.68mmol，1.1eq)滴加入体系中，滴加完毕后将体系移至室温搅拌16h。反应结束后加水(50ml)淬灭反应，用二氯甲烷(100ml x 3)萃取，合并有机相，并用无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝4:1)洗脱得C100-b(7.8g)。LCMS(ESI)m/z:277.1[M-55]+ (1) Under nitrogen protection, C100-a (5.0 g, 26.7 mmol, 1 eq), compound 3b (4.8 g, 28.68 mmol, 1.1 eq) and triphenylphosphine (7.5 g, 28.68 mmol, 1.1 eq) were dissolved in tetrahydrofuran (80 mL), and DBAD (6.6 g, 28.68 mmol, 1.1 eq) dissolved in tetrahydrofuran (20 ml) was added dropwise to the system at 0°C. After the addition was complete, the system was moved to room temperature and stirred for 16 h. After the reaction was completed, water (50 ml) was added to quench the reaction, and the mixture was extracted with dichloromethane (100 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain C100-b (7.8 g). LCMS (ESI) m/z: 277.1 [M-55] +
(2)将C100-b(7.8g，23.5mmol)溶解在盐酸二氧六环(40ml,4M)溶液中。反应液在室温下搅拌1小时。反应完成后,将反应液减压浓缩，加入二氯甲烷(40ml)，搅拌打浆10min,过滤，滤液用二氯甲烷淋洗，得C100-c(5.8g)。LCMS(ESI)m/z:233.0[M+H]+.(2) C100-b (7.8 g, 23.5 mmol) was dissolved in a solution of dioxane hydrochloride (40 ml, 4 M). The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, dichloromethane (40 ml) was added, stirred and slurried for 10 min, filtered, and the filtrate was washed with dichloromethane to obtain C100-c (5.8 g). LCMS (ESI) m/z: 233.0 [M+H] + .
(3)将C100-c(5.8g，21.6mmol)和C101-d(6.9g，32.4mmol)溶解在乙腈(80mL)中，然后加入三乙胺(5.5g，54mmol)。混合液在氮气保护下85℃搅拌过夜。反应结束后，将反应液浓缩。所得残余物用硅胶柱层析纯化，用(PE:EA＝85:15)洗脱得C100-d(3.3g)。LCMS(ESI)m/z:297.1[M+H]+.(3) C100-c (5.8 g, 21.6 mmol) and C101-d (6.9 g, 32.4 mmol) were dissolved in acetonitrile (80 mL), and triethylamine (5.5 g, 54 mmol) was then added. The mixture was stirred at 85°C overnight under nitrogen protection. After the reaction was completed, the reaction solution was concentrated. The residue was purified by silica gel column chromatography and eluted with (PE:EA=85:15) to obtain C100-d (3.3 g). LCMS (ESI) m/z: 297.1 [M+H] + .
(4)将C100-d(3.2g，10.8mmol)加溶于二氯甲烷/甲醇(10：1，30ml)溶液中，再滴入水合肼(1.1mL)。混合液在室温下搅拌2h。反应结束后，过滤得到滤液，加入氨水(20ml)，减压浓缩，再加入盐酸/二氧六环溶液(10ml)，搅拌5min，减压浓缩后，再加入二氯甲烷(30ml)，搅拌10min，过滤得到C100-e(512mg)。LCMS(ESI)m/z:167.1[M+H]+.(4) C100-d (3.2 g, 10.8 mmol) was dissolved in a dichloromethane/methanol (10:1, 30 ml) solution, and hydrazine hydrate (1.1 mL) was added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the filtrate was filtered, ammonia water (20 ml) was added, and the mixture was concentrated under reduced pressure. Then, hydrochloric acid/dioxane solution (10 ml) was added, and the mixture was stirred for 5 min. After concentration under reduced pressure, dichloromethane (30 ml) was added, and the mixture was stirred for 10 min. C100-e (512 mg) was obtained by filtration. LCMS (ESI) m/z: 167.1 [M+H] + .
(5)将C100-e(50mg，0.25mmol)和C077-b(85mg，0.30mmol)溶解在DMF(2mL)中，再加入一水合对甲苯磺酸(8mg，0.05mmol)，反应液在90℃下搅拌2h。反应结束后用高效液相制备分析纯化得化合物C100(14.28mg)。LCMS(ESI)m/z:435.2[M+H]+.(5) C100-e (50 mg, 0.25 mmol) and C077-b (85 mg, 0.30 mmol) were dissolved in DMF (2 mL), and p-toluenesulfonic acid monohydrate (8 mg, 0.05 mmol) was added. The reaction solution was stirred at 90°C for 2 h. After the reaction, the compound C100 (14.28 mg) was obtained by HPLC preparative analysis and purification. LCMS (ESI) m/z: 435.2 [M+H] + .
实施例101：
Embodiment 101:
合成路线
synthetic route
(1)在氮气保护下，将C101-a(10.0g，57.7mmol，1eq)，化合物3b(10.4g，63.5mmol，1.1eq)和三苯基膦(7.5g，63.5mmol，1.1eq)溶解在四氢呋喃(160mL)中，在0℃下将溶于四氢呋喃(40mL)的DBAD(14.6g，63.5mmol，1.1eq)滴加入体系中，滴加完毕后将体系移至室温搅拌16h。反应结束后加水(100mL)淬灭反应，再加入二氯甲烷(200ml x 3)萃取，合并有机相，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝80:20)洗脱得C101-b(4g)。LCMS(ESI)m/z:262.9[M-55]+ (1) Under nitrogen protection, C101-a (10.0 g, 57.7 mmol, 1 eq), compound 3b (10.4 g, 63.5 mmol, 1.1 eq) and triphenylphosphine (7.5 g, 63.5 mmol, 1.1 eq) were dissolved in tetrahydrofuran (160 mL), and DBAD (14.6 g, 63.5 mmol, 1.1 eq) dissolved in tetrahydrofuran (40 mL) was added dropwise to the system at 0°C. After the addition was complete, the system was moved to room temperature and stirred for 16 h. After the reaction was completed, water (100 mL) was added to quench the reaction, and then dichloromethane (200 ml x 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=80:20) to obtain C101-b (4 g). LCMS (ESI) m/z: 262.9 [M-55] +
(2)将C101-b(4g，12.6mmol)溶解在盐酸四二氧六环(40mL，4M)溶液中。反应液在室温下搅拌1小时。反应完成后,将反应液减压浓缩，加入二氯甲烷(30ml)，搅拌打浆10min,过滤，滤液用二氯甲烷淋洗，得C101-c(2g)。LCMS(ESI)m/z:219.1[M+H]+.(2) C101-b (4 g, 12.6 mmol) was dissolved in a solution of tetradioxane hydrochloride (40 mL, 4 M). The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, dichloromethane (30 ml) was added, stirred and slurried for 10 min, filtered, and the filtrate was rinsed with dichloromethane to obtain C101-c (2 g). LCMS (ESI) m/z: 219.1 [M+H] + .
(3)将C101-c(2g，7.9mmol)和C101-d(6.9g，11.8mmol)溶解在乙腈(40mL)中，然后加入三乙胺(2.0g，54mmol)。混合液在氮气保护下85℃搅拌过夜。反应结束后，将反应液浓缩。所得残余物用硅胶柱层析纯化，用(PE:EA＝5:1)洗脱得C101-e(360mg)。1H NMR(400MHz,CDCl3)δ7.86-7.84(m,2H),7.78-7.76(m,2H),5.92-5.62(m,1H)4.91-4.85(m,1H),3.80-3.76(m,2H),3.55–3.51(m,2H),2.94-2.86(m,2H).(3) C101-c (2 g, 7.9 mmol) and C101-d (6.9 g, 11.8 mmol) were dissolved in acetonitrile (40 mL), and triethylamine (2.0 g, 54 mmol) was then added. The mixture was stirred at 85°C overnight under nitrogen protection. After the reaction was completed, the reaction solution was concentrated. The residue was purified by silica gel column chromatography and eluted with (PE:EA=5:1) to obtain C101-e (360 mg). 1 H NMR (400 MHz, CDCl 3 ) δ 7.86-7.84 (m, 2H), 7.78-7.76 (m, 2H), 5.92-5.62 (m, 1H) 4.91-4.85 (m, 1H), 3.80-3.76 (m, 2H), 3.55–3.51 (m, 2H), 2.94-2.86 (m, 2H).
(4)将C101-e(3.2g，1.27mmol)加溶于二氯甲烷/甲醇(10：1，30ml)溶液中，再滴入水合肼(1.1mL)。混合液在室温下搅拌2h。反应结束后，过滤得到滤液，减压浓缩后，再加入盐酸/二氧六环溶液(10ml，4M)，搅拌5min，随后旋干溶液，再加入二氯甲烷(30ml)，搅拌10min，过滤得到C101-f(512mg)。1H NMR(400MHz,DMSO_d6)δ6.07–5.77(m,3H),4.22-4.16(m,1H),3.48-3.44(m,2H),3.08-3.04(m,2H),2.84-2.75(m,2H).(4) C101-e (3.2 g, 1.27 mmol) was dissolved in a dichloromethane/methanol (10:1, 30 ml) solution, and hydrazine hydrate (1.1 mL) was added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the filtrate was filtered and concentrated under reduced pressure. Then, hydrochloric acid/dioxane solution (10 ml, 4 M) was added and stirred for 5 min. The solution was then spin-dried and dichloromethane (30 ml) was added. The mixture was stirred for 10 min and filtered to obtain C101-f (512 mg). 1 H NMR (400 MHz, DMSO_d6) δ 6.07–5.77 (m, 3H), 4.22-4.16 (m, 1H), 3.48-3.44 (m, 2H), 3.08-3.04 (m, 2H), 2.84-2.75 (m, 2H).
(5)将C101-f(20mg，0.11mmol)和C077-b(36mg，0.13mmol)溶解在DMF(1mL)中，再加入一水合对甲苯磺酸(4mg，0.02mmol)，反应液在90℃下搅拌2h。反应结束后，反应液直接用高效液相制备分析纯化得化合物C101(13.35mg)。LCMS(ESI)m/z:421.2[M+H]+.(5) C101-f (20 mg, 0.11 mmol) and C077-b (36 mg, 0.13 mmol) were dissolved in DMF (1 mL), and p-toluenesulfonic acid monohydrate (4 mg, 0.02 mmol) was added. The reaction solution was stirred at 90°C for 2 h. After the reaction was completed, the reaction solution was directly purified by high performance liquid chromatography to obtain compound C101 (13.35 mg). LCMS (ESI) m/z: 421.2 [M+H] + .
实施例102：
Embodiment 102:
合成路线
synthetic route
(1)在500ml茄形瓶中加入C102-a(2.9g,12.5mmol)、HATU(5.7g,15mmol)、二甲基羟胺盐酸盐(1.39g,15mmol)，接着加入超干二氯甲烷(125ml)溶解上述混合物，在室温下搅拌反应5分钟后，加入三乙胺(10.4ml,75mmol),反应体系在室温下反应15小时。向反应体系中加入水，用二氯甲烷萃取水相三次至TLC监测水相中无产品残留，使用饱和氯化钠洗涤有机相两次，无水硫酸钠干燥，减压浓缩，粗产品用硅胶柱层析纯化(PE:EA＝2:1),得到C102-b(3.2g)。(1) C102-a (2.9 g, 12.5 mmol), HATU (5.7 g, 15 mmol), and dimethylhydroxylamine hydrochloride (1.39 g, 15 mmol) were added to a 500 ml eggplant-shaped bottle, and then ultra-dry dichloromethane (125 ml) was added to dissolve the above mixture. After stirring at room temperature for 5 minutes, triethylamine (10.4 ml, 75 mmol) was added, and the reaction system was reacted at room temperature for 15 hours. Water was added to the reaction system, and the aqueous phase was extracted with dichloromethane three times until no product remained in the aqueous phase by TLC monitoring. The organic phase was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA=2:1) to obtain C102-b (3.2 g).
(2)在100ml三颈瓶中加入C102-b(825.3mg,3mmol)，加入超干四氢呋喃(20ml)溶解，将上述反应装置置于0℃搅拌10分钟，并在0℃下加入甲基溴化镁(2.2ml,3M in THF),搅拌反应15分钟后，将反应置于室温下搅拌反应2小时。将反应置于0℃，加入饱和氯化铵溶液淬灭反应，加入乙酸乙酯萃取三次(20ml)至TLC监测水相无产品剩余，接着使用饱和氯化钠洗涤有机相两次，使用无水硫酸钠干燥，减压浓缩，粗产品使用硅胶柱层析纯化(PE:EA＝5:1),得到C102-c。1H NMR(400MHz,CDCl3)δ7.94(d,J＝7.6Hz,1H),7.52(d,J＝7.6Hz,1H),4.09(s,3H),2.67(s,3H).(2) C102-b (825.3 mg, 3 mmol) was added to a 100 ml three-necked flask, and ultra-dry tetrahydrofuran (20 ml) was added to dissolve. The above reaction apparatus was placed at 0°C and stirred for 10 minutes, and methylmagnesium bromide (2.2 ml, 3M in THF) was added at 0°C. After stirring for 15 minutes, the reaction was placed at room temperature and stirred for 2 hours. The reaction was placed at 0°C, saturated ammonium chloride solution was added to quench the reaction, and ethyl acetate (20 ml) was added to extract three times until no product remained in the aqueous phase by TLC monitoring, and then the organic phase was washed twice with saturated sodium chloride, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA=5:1) to obtain C102-c. 1 H NMR (400 MHz, CDCl 3 ) δ7.94 (d, J=7.6 Hz, 1H), 7.52 (d, J=7.6 Hz, 1H), 4.09 (s, 3H), 2.67 (s, 3H).
(3)在40ml玻璃瓶中加入C102-c(256mg,1.113mmol)，int2(272mg,1.335mmol)，Pd2dba3(115mg,0.1113mmol),tBubrettphos(107.9mg,0.2226mmol),磷酸钾(708.8mg,3.339mmol),超干叔丁醇(8ml),置换氮气三次后，在100℃反应1h.将反应液转移到茄形瓶中，加入硅胶扮样，使用柱层析纯化(PE:EA＝16:9),得到C102-d(45mg)。LCMS(ESI)m/z:316.1[M+H]+.(3) C102-c (256 mg, 1.113 mmol), int2 (272 mg, 1.335 mmol), Pd 2 dba 3 (115 mg, 0.1113 mmol), tBubrettphos (107.9 mg, 0.2226 mmol), potassium phosphate (708.8 mg, 3.339 mmol), and ultra-dry tert-butyl alcohol (8 ml) were added to a 40 ml glass bottle. After replacing nitrogen three times, the reaction was carried out at 100°C for 1 h. The reaction solution was transferred to an eggplant-shaped bottle, and silica gel was added to purify the mixture. C102-d (45 mg) was obtained. LCMS (ESI) m/z: 316.1 [M+H] + .
(4)在50ml茄形瓶中加入C102-d(96mg，0.304mmol)，用30ml超干二氯甲烷溶解，将反应装置置于0℃下搅拌15分钟，并在0℃下加入三溴化硼(5.5ml，2M in DCM),搅拌反应15分钟后，然后将反应装置置于室温下搅拌反应6小时，在0℃下将反应液滴入饱和碳酸氢钠中，使用二氯甲烷萃取三次至TLC监测反应中无产品残留，使用无水硫酸钠干燥，减压浓缩，粗产品通过高效液相制备纯化得到C102-e(15mg)。LCMS(ESI)m/z:301.9[M+H]+.(4) C102-d (96 mg, 0.304 mmol) was added to a 50 ml eggplant-shaped bottle, dissolved in 30 ml of ultra-dry dichloromethane, and the reaction apparatus was placed at 0°C and stirred for 15 minutes. Boron tribromide (5.5 ml, 2 M in DCM) was added at 0°C, and the reaction was stirred for 15 minutes. Then the reaction apparatus was placed at room temperature and stirred for 6 hours. The reaction solution was dropped into saturated sodium bicarbonate at 0°C, and extracted with dichloromethane three times until no product remained in the reaction as monitored by TLC. The product was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography to obtain C102-e (15 mg). LCMS (ESI) m/z: 301.9 [M+H] + .
(5)在10ml玻璃瓶中加入C102-e(15mg,0.0497mmol)，一水合对甲苯磺酸(12mg,0.063mmol)，以及int6(12mg,0.075mmol),使用超干N,N-二甲基甲酰胺(0.8ml)溶解，在60℃搅拌反应4小时,LCMS监测反应发现仍然有原料剩余，继续加入化合物7(12mg,0.075mmol)，在60℃搅拌反应2h。反应液通过高效液相制备得到C102(11.89mg，产率：59％)。LCMS(ESI)m/z:407.2[M+H]+.(5) C102-e (15 mg, 0.0497 mmol), p-toluenesulfonic acid monohydrate (12 mg, 0.063 mmol), and int6 (12 mg, 0.075 mmol) were added to a 10 ml glass bottle, and dissolved in ultra-dry N,N-dimethylformamide (0.8 ml). The mixture was stirred at 60°C for 4 hours. LCMS monitoring revealed that there was still some raw material left. Compound 7 (12 mg, 0.075 mmol) was added and stirred at 60°C for 2 hours. The reaction solution was prepared by high performance liquid chromatography to obtain C102 (11.89 mg, yield: 59%). LCMS (ESI) m/z: 407.2 [M+H] + .
实施例103：
Embodiment 103:
合成路线
synthetic route
(1)将int39(100mg，crude)、38d(56mg，0.36mmol)和DIEA(93mg，0.72mmol)溶解在二甲基亚砜(2mL)中。混合液在氮气保护下90℃搅拌4小时。反应结束后，反应液用二氯甲烷和水萃取，萃取结束后，合并有机相，减压浓缩所得残余物为C103-a(80mg，粗品)。 (1) Int39 (100 mg, crude), 38d (56 mg, 0.36 mmol) and DIEA (93 mg, 0.72 mmol) were dissolved in dimethyl sulfoxide (2 mL). The mixture was stirred at 90 °C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was extracted with dichloromethane and water. After the extraction was completed, the organic phases were combined and concentrated under reduced pressure to obtain the residue C103-a (80 mg, crude).
(2)将C103-a(40mg，crude)、int28(32mg，0.16mmol)和一水合对甲苯磺酸(2mg，0.013mmol)溶解在超干DMF(1mL)中。混合液在氮气保护下40℃搅拌4小时。反应结束后，反应液减压浓缩，并用二氯甲烷和水萃取，萃取结束后，合并有机相，减压浓缩所得残余物经制备分析纯化得化合物C103(6.39mg，收率：58.9％)。LCMS(ESI)m/z:459.3[M+H]+.(2) C103-a (40 mg, crude), int28 (32 mg, 0.16 mmol) and p-toluenesulfonic acid monohydrate (2 mg, 0.013 mmol) were dissolved in ultra-dry DMF (1 mL). The mixture was stirred at 40°C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and extracted with dichloromethane and water. After the extraction was completed, the organic phases were combined and concentrated under reduced pressure. The residue was purified by preparative analysis to obtain compound C103 (6.39 mg, yield: 58.9%). LCMS (ESI) m/z: 459.3 [M+H] + .
实施例104：
Embodiment 104:
合成路线
synthetic route
(1)将int35(200mg，1.101mmol)和int2(220mg,1.322mmol)溶解在二甲基亚砜(2mL)中，添加N,N-二异丙基乙胺(0.3ml,1.652mmol)。置换氮气后将混合物在20℃下搅拌反应2h。反应结束后加水淬灭析出沉淀，过滤后取滤饼，得粗样C104-a(400mg)，直接用于下一步反应。(1) Int35 (200 mg, 1.101 mmol) and int2 (220 mg, 1.322 mmol) were dissolved in dimethyl sulfoxide (2 mL), and N,N-diisopropylethylamine (0.3 ml, 1.652 mmol) was added. After nitrogen was replaced, the mixture was stirred at 20 °C for 2 h. After the reaction was completed, water was added to quench the precipitate, and the filter cake was filtered to obtain a crude sample C104-a (400 mg), which was directly used in the next step.
(2)将粗品C104-a(200mg，1.283mmol)、int20(140mg，1.540mmol)溶解在N,N-二甲基甲酰胺(2mL)中，添加一水合对甲苯磺酸(25mg,0.257mmol)。置换氮气后将混合物在60℃下搅拌反应4h。反应结束后过滤反应液，取滤液反相制备分析纯化得化合物C104(21.04mg，3.81％)。LCMS(ESI)m/z:431.1[M+H]+.(2) Dissolve the crude product C104-a (200 mg, 1.283 mmol) and int20 (140 mg, 1.540 mmol) in N,N-dimethylformamide (2 mL), and add p-toluenesulfonic acid monohydrate (25 mg, 0.257 mmol). After replacing the nitrogen, the mixture was stirred at 60°C for 4 h. After the reaction, the reaction solution was filtered, and the filtrate was purified by reverse phase preparation analysis to obtain compound C104 (21.04 mg, 3.81%). LCMS (ESI) m/z: 431.1 [M+H] + .
实施例105：
Embodiment 105:
合成路线
synthetic route
(1)依次将int40(100mg，0.552mmol)，int35(132mg，0.663mmol)以及DIEA(213mg,1.656mmol)溶解在DMSO(2mL)中。氮气保护下混合物于室温下搅拌2h。反应结束后，反应液加水析出固体，过滤的粗品C105-a(130mg)，所得残余物可直接用于下一步。LCMS(ESI)m/z:346.0[M+H]+.(1) Int40 (100 mg, 0.552 mmol), int35 (132 mg, 0.663 mmol) and DIEA (213 mg, 1.656 mmol) were dissolved in DMSO (2 mL) in sequence. The mixture was stirred at room temperature for 2 h under nitrogen protection. After the reaction was completed, water was added to the reaction solution to precipitate solids, and the crude product C105-a (130 mg) was filtered. The residue was directly used in the next step. LCMS (ESI) m/z: 346.0 [M+H] + .
(2)将C105-a(130mg，0.376mmol)、int7(84.5mg，0.452mmol)和一水合对甲苯磺酸(14mg，0.075mmol)溶解在DMF(2mL)中。反应液在60℃下反应4小时。反应结束后，反应液直接用高效液相制备分析纯化得化合物C105(5.90mg，收率：3.28％)。LCMS(ESI)m/z:479.0[M+H]+.(2) C105-a (130 mg, 0.376 mmol), int7 (84.5 mg, 0.452 mmol) and p-toluenesulfonic acid monohydrate (14 mg, 0.075 mmol) were dissolved in DMF (2 mL). The reaction solution was reacted at 60°C for 4 hours. After the reaction, the reaction solution was directly purified by high performance liquid chromatography to obtain compound C105 (5.90 mg, yield: 3.28%). LCMS (ESI) m/z: 479.0 [M+H] + .
实施例106：
Embodiment 106:
合成路线
synthetic route
(1)将int37(200mg,0.72mmol)、int20(118mg，0.86mmol，)和对甲苯磺酸水合物(27mg，0.14mmol)溶解在DMF(2mL)中，在60℃下搅拌4h。反应结束后，过滤反应液，用DMF洗涤，合并有机相所得残余物用高效液相制备分析纯化得C106(7.53mg)。LCMS(ESI)m/z:398.2[M+H]+.(1) Int37 (200 mg, 0.72 mmol), int20 (118 mg, 0.86 mmol) and p-toluenesulfonic acid hydrate (27 mg, 0.14 mmol) were dissolved in DMF (2 mL) and stirred at 60°C for 4 h. After the reaction was completed, the reaction solution was filtered and washed with DMF. The organic phases were combined and the residue was purified by high performance liquid chromatography to obtain C106 (7.53 mg). LCMS (ESI) m/z: 398.2 [M+H] + .
实施例107：
Embodiment 107:
合成路线
synthetic route
(1)将C107-a(1.8g，11.1mmol，1eq)和DPPA(6.1g，22.2mmol，2.0eq)溶解在四氢呋喃(40mL)中，在N2保护下，体系移至0℃中，将三乙胺(3.4g，33.3mmol，3.0eq)滴加入体系中，滴加完毕后将体系移至室温搅拌16h。反应结束后，将反应液减压浓缩除去大部分四氢呋喃，再加入叔丁醇(20ml)，减压浓缩除去大部分叔丁醇(不要浓缩干)得混合物C107-b(4g)。(1) C107-a (1.8 g, 11.1 mmol, 1 eq) and DPPA (6.1 g, 22.2 mmol, 2.0 eq) were dissolved in tetrahydrofuran (40 mL). Under N2 protection, the system was moved to 0°C, triethylamine (3.4 g, 33.3 mmol, 3.0 eq) was added dropwise to the system, and after the addition was complete, the system was moved to room temperature and stirred for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove most of the tetrahydrofuran, and tert-butyl alcohol (20 ml) was added. The mixture was concentrated under reduced pressure to remove most of the tert-butyl alcohol (do not concentrate to dryness) to obtain a mixture C107-b (4 g).
(2)将C107-b(4g，11.1mmol)溶解叔丁醇(40ml)溶液中。在氮气保护下80℃搅拌16h。反应完成后将反应液浓缩。所得残余物用硅胶柱层析纯化，用(PE:EA＝90:10)洗脱得C107-c(810mg)。LCMS(ESI)m/z:234.1[M+H]+.(2) C107-b (4 g, 11.1 mmol) was dissolved in tert-butyl alcohol (40 ml) solution. The mixture was stirred at 80°C for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated. The obtained residue was purified by silica gel column chromatography and eluted with (PE:EA=90:10) to obtain C107-c (810 mg). LCMS (ESI) m/z: 234.1 [M+H] + .
(3)将C107-c(750mg，3.2mmol)溶解在盐酸二氧六环(40mL,4M)溶液中。反应液在室温下搅拌1小时。反应完成后，将反应液减压浓缩，加入二氯甲烷(30mL)，搅拌打浆10min,过滤，滤液用二氯甲烷淋洗，得C107-d(500mg)。LCMS(ESI)m/z:134.2[M+H]+.(3) C107-c (750 mg, 3.2 mmol) was dissolved in a solution of dioxane hydrochloride (40 mL, 4 M). The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, dichloromethane (30 mL) was added, stirred and slurried for 10 min, filtered, and the filtrate was rinsed with dichloromethane to obtain C107-d (500 mg). LCMS (ESI) m/z: 134.2 [M+H] + .
(4)将C107-d(400mg，2.4mmol)，1-(5-氯吡嗪-2-基)乙烷-1-酮(443mg，2.8mmol)和TsOH(83mg，0.48mmol)溶于DMF(4ml)溶液中。混合液在90℃下搅拌16h。反应结束后，加入水 析出固体，过滤得到混合物C107-e(50mg)。LCMS(ESI)m/z:254.1[M+H]+.(4) C107-d (400 mg, 2.4 mmol), 1-(5-chloropyrazin-2-yl)ethane-1-one (443 mg, 2.8 mmol) and TsOH (83 mg, 0.48 mmol) were dissolved in DMF (4 ml) solution. The mixture was stirred at 90°C for 16 h. After the reaction was completed, water was added. The precipitated solid was filtered to obtain a mixture C107-e (50 mg). LCMS (ESI) m/z: 254.1 [M+H] + .
(5)将C107-e(50mg，0.20mmol)和int28(48mg，0.24mmol)溶解在N,N-二甲基甲酰胺(1mL)中，再加入一水合对甲苯磺酸(7mg，0.04mmol)，反应液在90℃下搅拌2h。反应结束后，反应液经高效液相制备分析纯化得化合物C107(0.9mg)。LCMS(ESI)m/z:401.2[M+H]+.(5) C107-e (50 mg, 0.20 mmol) and int28 (48 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (1 mL), and p-toluenesulfonic acid monohydrate (7 mg, 0.04 mmol) was added, and the reaction solution was stirred at 90°C for 2 h. After the reaction was completed, the reaction solution was purified by high performance liquid chromatography preparative analysis to obtain compound C107 (0.9 mg). LCMS (ESI) m/z: 401.2 [M+H] + .
实施例108：
Embodiment 108:
合成路线
synthetic route
(1)将C108-a(4g，26.996mmol,1.0eq)溶于浓硫酸(56ml)中，降温至0℃后滴加浓硝酸(1.2ml)。反应液在0℃下搅拌2小时。反应结束后，将反应液滴加入冰水后，在冰浴下逐步滴加饱和碳酸氢钠水溶液(200ml)，调节PH至8有固体析出，过滤，得C108-b(3.4g)。LCMS(ESI)m/z:192.1[M+H]- (1) C108-a (4 g, 26.996 mmol, 1.0 eq) was dissolved in concentrated sulfuric acid (56 ml), cooled to 0°C and concentrated nitric acid (1.2 ml) was added dropwise. The reaction solution was stirred at 0°C for 2 hours. After the reaction was completed, ice water was added dropwise to the reaction solution, and saturated sodium bicarbonate aqueous solution (200 ml) was gradually added dropwise under an ice bath. The pH was adjusted to 8. Solids precipitated and filtered to obtain C108-b (3.4 g). LCMS (ESI) m/z: 192.1 [M+H] -
(2)将C108-b(1g，5.177mmol，1.0eq)溶解在甲醇(10mL)中，然后在常温下加入二碳酸二叔丁酯(1.13g，5.177mmol,1.0eq)和钯碳(100mg)。反应液在氢气保护下常温搅拌过夜。反应完成后过滤，滤液用柱层析纯化，用(石油醚:乙酸乙酯＝4:1)洗脱得C108-c(800mg)。LCMS(ESI)m/z:286.2[M+H]+.(2) C108-b (1 g, 5.177 mmol, 1.0 eq) was dissolved in methanol (10 mL), and then di-tert-butyl dicarbonate (1.13 g, 5.177 mmol, 1.0 eq) and palladium carbon (100 mg) were added at room temperature. The reaction solution was stirred overnight at room temperature under hydrogen protection. After the reaction was completed, the filtrate was filtered and purified by column chromatography, and C108-c (800 mg) was obtained by elution with (petroleum ether: ethyl acetate = 4:1). LCMS (ESI) m/z: 286.2 [M+H] + .
(3)在C108-c(800mg，3.030mmol,1.0eq)中加入盐酸二氧六环溶液(5ml)常温下搅拌过夜。反应结束后，将反应液减压浓缩得C108-d(700mg)。LCMS(ESI)m/z:164.2[M+H]+.(3) Add dioxane hydrochloride solution (5 ml) to C108-c (800 mg, 3.030 mmol, 1.0 eq) and stir overnight at room temperature. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain C108-d (700 mg). LCMS (ESI) m/z: 164.2 [M+H] + .
(4)将C108-d(200mg，1.224mmol,1.1eq)，1-(5-氯吡嗪-2-基)乙烷-1-酮(174mg，1.112mmol,1.0eq)和N,N-二异丙基乙胺(286mg，2.224mmol,2.0eq)溶解在二甲基亚砜(5.0mL)中，在90℃下搅拌4h。反应结束后将反应液降温至常温，加水稀释，有固体析出。过滤混合物，固体即为C108-e粗品(160mg)。LCMS(ESI)m/z:284.1[M+H]+.(4) C108-d (200 mg, 1.224 mmol, 1.1 eq), 1-(5-chloropyrazin-2-yl)ethane-1-one (174 mg, 1.112 mmol, 1.0 eq) and N,N-diisopropylethylamine (286 mg, 2.224 mmol, 2.0 eq) were dissolved in dimethyl sulfoxide (5.0 mL) and stirred at 90°C for 4 h. After the reaction was completed, the reaction solution was cooled to room temperature and diluted with water, and solid precipitated. The mixture was filtered, and the solid was the crude product C108-e (160 mg). LCMS (ESI) m/z: 284.1 [M+H] + .
(5)将C108-e(160mg，0.564mmol，纯度：40％)，int20(85mg，0.621mmol，1.1eq)和一水合对甲苯磺酸水合物(19mg，0.113mmol，0.2eq)溶解在N,N-二甲基甲酰胺(4.0mL)中，在70℃下搅拌4h。反应结束后，加水淬灭反应，后加入乙酸乙酯萃取两次，合并有机相，减压浓缩所得残余物经高效液相制备分析纯化得C108(6.96mg)。LCMS(ESI)m/z:403.2[M+H]+.(5) C108-e (160 mg, 0.564 mmol, purity: 40%), int20 (85 mg, 0.621 mmol, 1.1 eq) and p-toluenesulfonic acid monohydrate (19 mg, 0.113 mmol, 0.2 eq) were dissolved in N,N-dimethylformamide (4.0 mL) and stirred at 70°C for 4 h. After the reaction was completed, water was added to quench the reaction, and then ethyl acetate was added to extract twice. The organic phases were combined and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography preparative analysis to obtain C108 (6.96 mg). LCMS (ESI) m/z: 403.2 [M+H] + .
实施例109：
Embodiment 109:
合成路线
synthetic route
(1)将37d(400mg,2.52mmol)溶解在1,4-二氧六环(4mL)中，加入C109-a(422mg,2.3mmol)和DIEA(892mg,6.9mmol)。在60℃下搅拌2h。反应结束后，过滤反应液，用1,4-二氧六环洗涤，合并有机相所得残余物经高效液相制备分析纯化得C109-b(40mg)。LCMS(ESI)m/z:279.0[M+H]+，1H NMR(400MHz,DMSO_d6)δ11.88(s,1H),9.91(s,1H),8.93(s,2H),8.44(s,1H),8.22(s,1H),8.00(d,J＝8.4Hz,1H),7.72(d,J＝8.4Hz,1H),2.50(s,3H).(1) 37d (400 mg, 2.52 mmol) was dissolved in 1,4-dioxane (4 mL), and C109-a (422 mg, 2.3 mmol) and DIEA (892 mg, 6.9 mmol) were added. The mixture was stirred at 60°C for 2 h. After the reaction was completed, the reaction solution was filtered and washed with 1,4-dioxane. The organic phases were combined and the residue was purified by HPLC to obtain C109-b (40 mg). LCMS (ESI) m/z: 279.0 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 9.91 (s, 1H), 8.93 (s, 2H), 8.44 (s, 1H), 8.22 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 2.50 (s, 3H).
(2)将粗品C109-b(40mg,0.14mmol)、int7(28mg，0.17mmol，)和一水合对甲苯磺酸水合物(2mg，0.01mmol)溶解在DMF(1mL)中，在60℃下搅拌4h。反应结束后，过滤反应液，用DMF洗涤，合并有机相所得残余物经高效液相制备分析纯化得C109(2.08mg)。LCMS(ESI)m/z:412.2[M+H]+.(2) The crude product C109-b (40 mg, 0.14 mmol), int7 (28 mg, 0.17 mmol) and p-toluenesulfonic acid monohydrate (2 mg, 0.01 mmol) were dissolved in DMF (1 mL) and stirred at 60°C for 4 h. After the reaction was completed, the reaction solution was filtered and washed with DMF. The organic phases were combined and the residue was purified by high performance liquid chromatography preparative analysis to obtain C109 (2.08 mg). LCMS (ESI) m/z: 412.2 [M+H] + .
实施例110：
Embodiment 110:
合成路线
synthetic route
(1)将C110-a(50mg，0.27mmol)和38c(63mg，0.32mmol)溶解在超干二甲基亚砜(1mL)中，然后加入DIEA(0.1mL，0.54mmol)。混合液在氮气保护下60℃搅拌4小时。反应结束后，反应液加水析出大量固体，过滤、减压浓缩，所得残余物为C110-b(50mg,收率：66.85％)。LCMS(ESI)m/z:278.1[M+H]+.(1) C110-a (50 mg, 0.27 mmol) and 38c (63 mg, 0.32 mmol) were dissolved in ultra-dry dimethyl sulfoxide (1 mL), and then DIEA (0.1 mL, 0.54 mmol) was added. The mixture was stirred at 60 °C for 4 hours under nitrogen protection. After the reaction was completed, water was added to the reaction solution to precipitate a large amount of solid, which was filtered and concentrated under reduced pressure to obtain C110-b (50 mg, yield: 66.85%). LCMS (ESI) m/z: 278.1 [M+H] + .
(2)将C110-b(50mg，0.18mmol)、int7(41mg，0.22mmol)和一水合对甲苯磺酸(3mg，0.018mmol)溶解在无水乙腈(2mL)中。混合液在氮气保护下70℃搅拌4小时。反应结束后，减压浓缩，所得残余物经高效液相制备分析纯化得化合物C110(5.79mg，收率：7.8％)。LCMS(ESI)m/z:411.2[M+H]+.(2) C110-b (50 mg, 0.18 mmol), int7 (41 mg, 0.22 mmol) and p-toluenesulfonic acid monohydrate (3 mg, 0.018 mmol) were dissolved in anhydrous acetonitrile (2 mL). The mixture was stirred at 70°C for 4 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography preparative analysis to obtain compound C110 (5.79 mg, yield: 7.8%). LCMS (ESI) m/z: 411.2 [M+H] + .
实施例111和实施例113：
Example 111 and Example 113:
合成路线
synthetic route
(1)将int30(100mg，0.51mmol)和化合物37d(119mg，0.61mmol)溶解在无水二甲基亚砜(2mL)中，然后加入DIEA(0.2mL，1.02mmol)。混合液在氮气保护下40℃搅拌4小时。反应结束后，反应液加水析出大量固体，过滤、减压浓缩，所得残余物为C111-a(110mg，收率：54.1％)。1H NMR(400MHz,DMSO)δ11.91(s,1H),9.58(s,1H),8.94(s,1H),8.56(s,1H),8.41(s,1H),8.05(d,J＝8.4Hz,1H),7.77(d,J＝9.6Hz,2H),2.61(s,3H).(1) Int30 (100 mg, 0.51 mmol) and compound 37d (119 mg, 0.61 mmol) were dissolved in anhydrous dimethyl sulfoxide (2 mL), and then DIEA (0.2 mL, 1.02 mmol) was added. The mixture was stirred at 40°C for 4 hours under nitrogen protection. After the reaction was completed, water was added to the reaction solution to precipitate a large amount of solid, which was filtered and concentrated under reduced pressure to obtain C111-a (110 mg, yield: 54.1%). 1 H NMR (400 MHz, DMSO) δ11.91 (s, 1H), 9.58 (s, 1H), 8.94 (s, 1H), 8.56 (s, 1H), 8.41 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 9.6 Hz, 2H), 2.61 (s, 3H).
(2)将C111-a(110mg，0.33mmol)、int7(74mg，0.40mmol)和一水合对甲苯磺酸(6mg，0.033mmol)溶解在超干DMF(5mL)中。混合液在氮气保护下40℃搅拌16小时。反应结束后，反应液过滤后用高效液相制备分析纯化得化合物C111(18.64mg)LCMS(ESI):m/z＝451.3[M+1]+和C113(4.02mg)LCMS(ESI):m/z＝451.3[M+1]+。(2) C111-a (110 mg, 0.33 mmol), int7 (74 mg, 0.40 mmol) and p-toluenesulfonic acid monohydrate (6 mg, 0.033 mmol) were dissolved in ultra-dry DMF (5 mL). The mixture was stirred at 40° C. for 16 hours under nitrogen protection. After the reaction, the reaction solution was filtered and purified by high performance liquid chromatography preparative analysis to obtain compounds C111 (18.64 mg) LCMS (ESI): m/z=451.3[M+1] + and C113 (4.02 mg) LCMS (ESI): m/z=451.3[M+1] + .
实施例114：
Embodiment 114:
合成路线
synthetic route
(1)向盛有粗品C097-h(293mg,1.55mmol)的50mL单口瓶中加入化合物C114-a(216mg，1.55mmol)、无水二甲基亚砜(6.0mL)和N,N-二异丙基乙胺(0.77mL，4.65mmol)，氮气置换三次，油浴90℃搅拌2小时。反应结束后冷却至室温，将反应液滴入水(50mL)中，乙酸乙酯(40mL)萃取3次，合并有机相，食盐水(30mL)洗涤2次，无水硫酸钠干燥并过滤，减压浓缩。即得粗品C114-b(391mg)。LCMS(ESI)m/z:308.9[M+H]+.(1) Add compound C114-a (216 mg, 1.55 mmol), anhydrous dimethyl sulfoxide (6.0 mL) and N,N-diisopropylethylamine (0.77 mL, 4.65 mmol) to a 50 mL single-mouth bottle containing crude product C097-h (293 mg, 1.55 mmol), replace with nitrogen three times, and stir in an oil bath at 90°C for 2 hours. After the reaction is completed, cool to room temperature, drop the reaction solution into water (50 mL), extract with ethyl acetate (40 mL) three times, combine the organic phases, wash twice with brine (30 mL), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product C114-b (391 mg) is obtained. LCMS (ESI) m/z: 308.9 [M+H] + .
(2)向盛有int7的10mL单口瓶中加入C114-b(20mg，0.065mmol)、无水溶剂乙腈(0.3mL)和一水合对甲苯磺酸(2mg，0.007mmol)，氮气置换三次，油浴60℃搅拌2小时。反应结束后冷却至室温，减压浓缩干后，所得残余物经高效液相制备分析纯化得化合物C114(10.46mg)。LCMS(ESI)m/z:441.3[M+H]+.(2) Add C114-b (20 mg, 0.065 mmol), anhydrous solvent acetonitrile (0.3 mL) and p-toluenesulfonic acid monohydrate (2 mg, 0.007 mmol) to a 10 mL single-mouth bottle containing int7, replace with nitrogen three times, and stir in an oil bath at 60°C for 2 hours. After the reaction is completed, cool to room temperature, concentrate to dryness under reduced pressure, and the obtained residue is purified by high-performance liquid chromatography preparative analysis to obtain compound C114 (10.46 mg). LCMS (ESI) m/z: 441.3 [M+H] + .
实施例115：
Embodiment 115:
合成路线
synthetic route
(1)将中间体37d(200mg,1.26mmol)溶解在乙腈(2mL)中，加入C115-a(216mg,1.39mmol)和对甲苯磺酸水合物(24mg,0.12mmol)。在90℃下搅拌2h。反应结束后，过滤反应液，干燥固体得C115-b(100mg，收率：28.6％)。LCMS(ESI)m/z:278.1[M+H]+.(1) Dissolve intermediate 37d (200 mg, 1.26 mmol) in acetonitrile (2 mL), add C115-a (216 mg, 1.39 mmol) and p-toluenesulfonic acid hydrate (24 mg, 0.12 mmol). Stir at 90°C for 2 h. After the reaction, filter the reaction solution and dry the solid to obtain C115-b (100 mg, yield: 28.6%). LCMS (ESI) m/z: 278.1 [M+H] + .
(2)将粗品C115-b(100mg,0.36mmol)，化合物7(66mg，0.43mmol，)和一水合对甲苯磺酸水合物(7.6mg，0.04mmol)溶解在乙腈(1mL)中，在60℃下搅拌4h。反应结束后，过滤反应液，用乙腈洗涤，合并有机相所得残余物经高效液相制备分析纯化得C115(3.86mg)。LCMS(ESI)m/z:411.2[M+H]+.(2) The crude product C115-b (100 mg, 0.36 mmol), compound 7 (66 mg, 0.43 mmol) and p-toluenesulfonic acid monohydrate (7.6 mg, 0.04 mmol) were dissolved in acetonitrile (1 mL) and stirred at 60°C for 4 h. After the reaction was completed, the reaction solution was filtered and washed with acetonitrile. The organic phases were combined and the residue was purified by high performance liquid chromatography preparative analysis to obtain C115 (3.86 mg). LCMS (ESI) m/z: 411.2 [M+H] + .
实施例116：
Embodiment 116:
合成路线
synthetic route
(1)将C116-a(3.8g，24.9mmol，1eq)置于单口瓶中，在0℃搅拌下滴加发烟硝酸(25ml)，滴加完毕后，保持0℃搅拌1h。反应结束后，加入冷水(50ml)淬灭反应，过滤得到C116-b(2.1g，收率：43％)，无需纯化直接用于下一步。LCMS(ESI)m/z:198.0[M+H]+.(1) C116-a (3.8 g, 24.9 mmol, 1 eq) was placed in a single-mouth bottle, and fuming nitric acid (25 ml) was added dropwise under stirring at 0°C. After the addition was completed, the mixture was stirred at 0°C for 1 h. After the reaction was completed, cold water (50 ml) was added to quench the reaction, and C116-b (2.1 g, yield: 43%) was obtained by filtration and used directly in the next step without purification. LCMS (ESI) m/z: 198.0 [M+H] + .
(2)将C116-b(1.0g，5.1mmol)和氯化亚锡二水合物(8.1g，35.7mmol)加入瓶中，再加入溴化氢水溶液(50ml,33％wt)。在氮气保护下室温搅拌16h。反应完成后，将反应液过滤，滤饼加入二氯甲烷(40mL)室温搅拌10min，过滤悬浊液，所得固体为粗品C116-c(680mg)。LCMS(ESI)m/z:168.1[M+H]+.(2) Add C116-b (1.0 g, 5.1 mmol) and stannous chloride dihydrate (8.1 g, 35.7 mmol) into a bottle, and then add aqueous hydrogen bromide solution (50 ml, 33% wt). Stir at room temperature for 16 h under nitrogen protection. After the reaction is completed, filter the reaction solution, add dichloromethane (40 mL) to the filter cake and stir at room temperature for 10 min, filter the suspension, and the obtained solid is the crude product C116-c (680 mg). LCMS (ESI) m/z: 168.1 [M+H] + .
(3)将C116-c(680mg，2.7mmol)，1-(6-氯吡啶-3-基)乙烷-1-酮(511mg，3.2mmol)和DIEA(698mg，5.4mmol)溶于DMF(4ml)溶液中。混合液在90℃下搅拌2h。反应结束后，加入水析出固体，过滤得到混合物C116-d(250mg)。LCMS(ESI)m/z:287.1[M+H]+.(3) C116-c (680 mg, 2.7 mmol), 1-(6-chloropyridin-3-yl)ethane-1-one (511 mg, 3.2 mmol) and DIEA (698 mg, 5.4 mmol) were dissolved in DMF (4 ml) solution. The mixture was stirred at 90°C for 2 h. After the reaction was completed, water was added to precipitate solids, which were filtered to obtain a mixture C116-d (250 mg). LCMS (ESI) m/z: 287.1 [M+H] + .
(4)将混合物C116-d(250mg，0.87mmol)和int7(48mg，1.05mmol)溶解在N,N-二甲基甲酰胺(2mL)中，再加入一水合对甲苯磺酸(30mg，0.17mmol)，反应液在60℃下搅拌2h。反应结束后，反应液直接用高效液相制备分析纯化得化合物C116(23.77mg)。LCMS(ESI)m/z:420.2[M+H]+.(4) The mixture C116-d (250 mg, 0.87 mmol) and int7 (48 mg, 1.05 mmol) were dissolved in N,N-dimethylformamide (2 mL), and p-toluenesulfonic acid monohydrate (30 mg, 0.17 mmol) was added, and the reaction solution was stirred at 60°C for 2 h. After the reaction was completed, the reaction solution was directly purified by high performance liquid chromatography to obtain compound C116 (23.77 mg). LCMS (ESI) m/z: 420.2 [M+H] + .
实施例117：
Embodiment 117:
合成路线
synthetic route
(1)将C108-d(400mg，2.454mmol)和C117-b(284mg,2.045mmol)溶解在N,N-二甲基甲酰胺(10mL)中，添加一水合对甲苯磺酸(78mg,0.409mmol)。置换氮气后将混合物在100℃下搅拌反应4h。反应结束后过滤反应液，取滤液经制备分析纯化得C117-c(55mg，7.95％)。LCMS(ESI)m/z:283.1[M+H]+.(1) C108-d (400 mg, 2.454 mmol) and C117-b (284 mg, 2.045 mmol) were dissolved in N,N-dimethylformamide (10 mL), and p-toluenesulfonic acid monohydrate (78 mg, 0.409 mmol) was added. After nitrogen was replaced, the mixture was stirred at 100°C for 4 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was purified by preparative analysis to obtain C117-c (55 mg, 7.95%). LCMS (ESI) m/z: 283.1 [M+H] + .
(2)将C117-c(55mg，0.195mmol)和int7(33mg，0.234mmol)溶解在N,N-二甲基甲酰胺(2mL)中，添加一水合对甲苯磺酸(5mg,0.039mmol)。置换氮气后将混合物在70℃下搅拌反应4h。反应结束后过滤反应液，滤液用高效液相制备分析纯化得化合物C117(2.80mg，3.46％)。LCMS(ESI)m/z:416.2[M+H]+.(2) C117-c (55 mg, 0.195 mmol) and int7 (33 mg, 0.234 mmol) were dissolved in N,N-dimethylformamide (2 mL), and p-toluenesulfonic acid monohydrate (5 mg, 0.039 mmol) was added. After nitrogen was replaced, the mixture was stirred at 70°C for 4 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography preparative analysis to obtain compound C117 (2.80 mg, 3.46%). LCMS (ESI) m/z: 416.2 [M+H] + .
实施例118：
Embodiment 118:
合成路线
synthetic route
(1)将int45(130mg，0.742mmol)、38d(105mg，0.674mmol)和DIEA(174mg，1.348mmol)溶解在二甲基亚砜(5mL)中。混合液在氮气保护下90℃搅拌4小时。反应结束后，反应液加水稀释(20mL)，用二氯甲烷萃取三次(15mL x 3)，合并有机相减压浓缩所得残余物为C118-a(260mg)。LCMS(ESI)m/z:296.1[M+H]+.(1) Int45 (130 mg, 0.742 mmol), 38d (105 mg, 0.674 mmol) and DIEA (174 mg, 1.348 mmol) were dissolved in dimethyl sulfoxide (5 mL). The mixture was stirred at 90 °C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water (20 mL), extracted with dichloromethane three times (15 mL x 3), and the organic phases were combined and concentrated under reduced pressure to obtain C118-a (260 mg). LCMS (ESI) m/z: 296.1 [M+H] + .
(2)将C118-a(260mg，crude)、int20(133mg，0.968mmol)和对甲苯磺酸(30mg，0.176mmol)溶解在N,N-二甲基甲酰胺(6mL)中。混合液在氮气保护下60℃搅拌3小时。反应结束后，反应液减压浓缩所得残余用物高效液相制备分析纯化得化合物C118(34.76mg)。LCMS(ESI)m/z:415.2[M+H]+.(2) C118-a (260 mg, crude), int20 (133 mg, 0.968 mmol) and p-toluenesulfonic acid (30 mg, 0.176 mmol) were dissolved in N,N-dimethylformamide (6 mL). The mixture was stirred at 60°C for 3 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and the obtained residue was purified by high performance liquid chromatography to obtain compound C118 (34.76 mg). LCMS (ESI) m/z: 415.2 [M+H] + .
实施例119：
Embodiment 119:
合成路线
synthetic route
(1)将C119-a(2g，10.5，1eq)，C119-b(7.6g，21mol，2eq)和四(三苯基膦)钯(1.2g，1.05mmol，0.1eq)溶解在无水甲苯中，在在氮气保护下110℃下搅拌16h，反应结束后得C119-c，加入2M HCl(20mL)淬灭反应并在室温下搅拌2h，加入水和二氯甲烷(50mL x 3)萃取，合并有机相干燥过滤，减压浓缩后经硅胶柱层析纯化(石油醚：乙酸乙酯＝90：10)得到C119-d(1g，收率：62％)。LCMS(ESI)m/z:154.0[M+H]+.(1) C119-a (2 g, 10.5, 1 eq), C119-b (7.6 g, 21 mol, 2 eq) and tetrakis(triphenylphosphine)palladium (1.2 g, 1.05 mmol, 0.1 eq) were dissolved in anhydrous toluene and stirred at 110°C for 16 h under nitrogen protection. After the reaction, C119-c was obtained. 2M HCl (20 mL) was added to quench the reaction and stirred at room temperature for 2 h. Water and dichloromethane (50 mL x 3) were added for extraction. The organic phases were combined, dried and filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 90: 10) to obtain C119-d (1 g, yield: 62%). LCMS (ESI) m/z: 154.0 [M+H] + .
(2)将C119-d(200mg，1.3mmol)，37d(305mg，1.6mmol)和TsOH(224mg，1.3mmol)溶于ACN(2ml)溶液中。混合液在90℃下搅拌20h。反应结束后，加入水析出固体，过滤得到混合物C119-e(112mg)。LCMS(ESI)m/z:292.1[M+H]+.(2) C119-d (200 mg, 1.3 mmol), 37d (305 mg, 1.6 mmol) and TsOH (224 mg, 1.3 mmol) were dissolved in ACN (2 ml) solution. The mixture was stirred at 90°C for 20 h. After the reaction was completed, water was added to precipitate the solid, which was filtered to obtain a mixture C119-e (112 mg). LCMS (ESI) m/z: 292.1 [M+H] + .
将混合物C119-e(100mg，0.34mmol)，int7(77mg，0.41mmol)和一水合对甲苯磺酸(71mg，0.34mmol)溶解在N,N-二甲基甲酰胺(2mL)中，反应液在90℃下搅拌2h。反应结束后用高效液相制备分析纯化得化合物C119(20.82mg)。LCMS(ESI)m/z:425.3[M+H]+.The mixture C119-e (100 mg, 0.34 mmol), int7 (77 mg, 0.41 mmol) and p-toluenesulfonic acid monohydrate (71 mg, 0.34 mmol) were dissolved in N,N-dimethylformamide (2 mL), and the reaction solution was stirred at 90°C for 2 h. After the reaction, the compound C119 (20.82 mg) was obtained by HPLC preparative analysis and purification. LCMS (ESI) m/z: 425.3 [M+H] + .
实施例120：
Embodiment 120:
合成路线
synthetic route
(1)依次将int41(140mg，0.826mmol)，37d(193mg，0.994mmol)以及一水合对甲苯磺酸(157mg,0.826mmol)溶解在乙腈(4mL)中。氮气保护下混合物于90℃油浴中搅拌4h。反应结束后，将反应液冷却至室温，反应液加水析出粗品C120-a(200mg)。所得残余物可直接用于下一步。LCMS(ESI)m/z:308.0[M+H]+.(1) Int41 (140 mg, 0.826 mmol), 37d (193 mg, 0.994 mmol) and p-toluenesulfonic acid monohydrate (157 mg, 0.826 mmol) were dissolved in acetonitrile (4 mL) in sequence. The mixture was stirred in an oil bath at 90 °C for 4 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, and water was added to the reaction solution to precipitate the crude product C120-a (200 mg). The obtained residue was directly used in the next step. LCMS (ESI) m/z: 308.0 [M+H] + .
(2)将C120-a(180mg，0.586mmol)、int7(131mg，0.707mmol)和一水合对甲苯磺酸(22mg，0.117mmol)溶解在N,N-二甲基甲酰胺(3mL)中。反应液在60℃下反应4小时。反应结束后将反应液反相制备分析纯化得化合物C120(21.41mg)。LCMS(ESI)m/z:441.3[M+H]+.(2) C120-a (180 mg, 0.586 mmol), int7 (131 mg, 0.707 mmol) and p-toluenesulfonic acid monohydrate (22 mg, 0.117 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was reacted at 60°C for 4 hours. After the reaction was completed, the reaction solution was purified by reverse phase preparative analysis to obtain compound C120 (21.41 mg). LCMS (ESI) m/z: 441.3 [M+H] + .
实施例121：
Embodiment 121:
合成路线
synthetic route
(1)将C121-a(1g，4.85mmol)溶解在无水甲苯(15mL)中，加入催化剂四(三苯基膦)钯(560mg，0.484mmol)和C121-b(2.2g，6.09mmol)，氮气保护下油浴加热至110℃搅拌反应16小时。反应完全后(TLC显示无原料)，所得反应液即为粗品C121-c溶液直接用于下一步骤。(1) C121-a (1 g, 4.85 mmol) was dissolved in anhydrous toluene (15 mL), and catalyst tetrakis(triphenylphosphine)palladium (560 mg, 0.484 mmol) and C121-b (2.2 g, 6.09 mmol) were added. The mixture was heated to 110° C. in an oil bath under nitrogen protection and stirred for 16 hours. After the reaction was complete (TLC showed no starting material), the resulting reaction solution was the crude C121-c solution, which was directly used in the next step.
(2)向盛有C121-c的混合溶液的反应瓶中加入盐酸水溶液(4mol/L，10mL，40mmol)，室温快速搅拌2小时。反应完成后冷却至室温，分出有机相，水相用二氯甲烷(50mL)萃取一次。合并有机相，无水硫酸钠干燥，过滤后减压浓缩滤液，所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝9:1)洗脱得C121-d(200mg)。LCMS(ESI)m/z:170.1[M+H]+.(2) Add hydrochloric acid aqueous solution (4 mol/L, 10 mL, 40 mmol) to the reaction bottle containing the mixed solution of C121-c and stir rapidly at room temperature for 2 hours. After the reaction is completed, cool to room temperature, separate the organic phase, and extract the aqueous phase once with dichloromethane (50 mL). Combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography, eluting with (petroleum ether: ethyl acetate = 9:1) to obtain C121-d (200 mg). LCMS (ESI) m/z: 170.1 [M + H] + .
(3)依次将C121-d(150mg，0.887mmol)，int2(215mg，1.065mmol)以及N,N-二异丙基乙胺(343mg,2.66mmol)溶解在二甲基亚砜(4mL)中。氮气保护下混合物于90℃油浴中搅拌4h。反应结束后，将反应液冷却至室温，反应液加水析出粗品C121-e(150mg)，可直接用于下一步。(3) C121-d (150 mg, 0.887 mmol), int2 (215 mg, 1.065 mmol) and N,N-diisopropylethylamine (343 mg, 2.66 mmol) were dissolved in dimethyl sulfoxide (4 mL) in sequence. The mixture was stirred in an oil bath at 90 °C for 4 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, and water was added to the reaction solution to precipitate the crude product C121-e (150 mg), which was directly used in the next step.
(4)将C121-e(150mg，0.476mmol)、int7(107mg，0.571mmol)和一水合对甲苯磺酸(18mg，0.095mmol)溶解在N,N-二甲基甲酰胺(3mL)中。反应液在60℃下反应4小时。反应结束后，将反应液反相制备分析纯化得化合物C121(26.67mg，12.4％)。LCMS(ESI)m/z:449.2[M+H]+.(4) C121-e (150 mg, 0.476 mmol), int7 (107 mg, 0.571 mmol) and p-toluenesulfonic acid monohydrate (18 mg, 0.095 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was reacted at 60°C for 4 hours. After the reaction was completed, the reaction solution was purified by reverse phase preparative analysis to obtain compound C121 (26.67 mg, 12.4%). LCMS (ESI) m/z: 449.2 [M+H] + .
实施例122：
Embodiment 122:
合成路线
synthetic route
(1)于25mL单口反应瓶中将原料C122-a(200mg，1.31mmol)和原料38c(506mg，2.61mmol)溶解在无水N,N-二甲基甲酰胺(6mL)中，加入一水合对甲苯磺酸(249mg，1.31mmol)。氮气保护下油浴加热至60℃搅拌反应2小时。反应完全后，将反应液滴入水(25mL)中，并用乙酸乙酯(15mL)萃取3次，经检测，产物在水相中。油泵减压浓缩水相，得到粗品C122-b(470mg)。LCMS(ESI)m/z:291.0[M+H]+.(1) In a 25 mL single-mouth reaction bottle, the raw material C122-a (200 mg, 1.31 mmol) and the raw material 38c (506 mg, 2.61 mmol) were dissolved in anhydrous N,N-dimethylformamide (6 mL), and p-toluenesulfonic acid monohydrate (249 mg, 1.31 mmol) was added. The oil bath was heated to 60 ° C under nitrogen protection and stirred for 2 hours. After the reaction was complete, the reaction solution was dropped into water (25 mL) and extracted with ethyl acetate (15 mL) three times. After testing, the product was in the aqueous phase. The aqueous phase was concentrated under reduced pressure by an oil pump to obtain a crude product C122-b (470 mg). LCMS (ESI) m/z: 291.0 [M+H] + .
(2)向盛有粗品C122-b(470mg，1.31mmol)的25mL单口瓶中加入int7(360mg，1.96mmol)、一水合对甲苯磺酸(62mg，0.33mmol)和无水乙腈(9mL)。氮气保护下油浴60℃搅拌2小时。反应完成后冷却至室温，滤出不溶物，所得不溶物再用高效液相制备得最终化合物C122(18.81mg)。LCMS(ESI)m/z:424.2[M+H]+.(2) Add int7 (360 mg, 1.96 mmol), p-toluenesulfonic acid monohydrate (62 mg, 0.33 mmol) and anhydrous acetonitrile (9 mL) to a 25 mL single-mouth bottle containing crude C122-b (470 mg, 1.31 mmol). Stir in an oil bath at 60 °C for 2 hours under nitrogen protection. After the reaction is completed, cool to room temperature, filter out the insoluble matter, and use high performance liquid chromatography to prepare the final compound C122 (18.81 mg). LCMS (ESI) m/z: 424.2 [M+H] + .
实施例123：
Embodiment 123:
合成路线
synthetic route
(1)将C123-a(195mg，1.156mmol)、37d(200mg，1.272mmol)和一水合对甲苯磺酸(238mg,1.387mmol)溶解在乙腈(5mL)中，混合液在氮气保护下90℃搅拌4小时。反应结束后，反应液加水析出大量固体，过滤、洗涤，滤液减压浓缩，所得残余物为C123-b(345mg)。LCMS(ESI)m/z:307.1[M+H]+.(1) C123-a (195 mg, 1.156 mmol), 37d (200 mg, 1.272 mmol) and p-toluenesulfonic acid monohydrate (238 mg, 1.387 mmol) were dissolved in acetonitrile (5 mL), and the mixture was stirred at 90°C for 4 hours under nitrogen protection. After the reaction was completed, water was added to the reaction solution to precipitate a large amount of solid, which was filtered and washed, and the filtrate was concentrated under reduced pressure to obtain C123-b (345 mg) as the residue. LCMS (ESI) m/z: 307.1 [M+H] + .
(2)将C123-b(345mg，1.126mmol)、int7(232mg，1.238mmol)和一水合对甲苯磺酸(38mg，0.225mmol)溶解在无水N,N-二甲基甲酰胺(5mL)中。混合液在氮气保护下60℃搅拌4小时。反应结束后，反应液加水析出大量固体，过滤，滤饼用硅胶板分离纯化(DCM:MeOH＝20:1)得化合物C123(26.87mg)。LCMS(ESI)m/z:307.1[M+H]+.(2) C123-b (345 mg, 1.126 mmol), int7 (232 mg, 1.238 mmol) and p-toluenesulfonic acid monohydrate (38 mg, 0.225 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL). The mixture was stirred at 60°C for 4 hours under nitrogen protection. After the reaction was completed, water was added to the reaction solution to precipitate a large amount of solid, which was filtered and the filter cake was separated and purified using a silica gel plate (DCM:MeOH=20:1) to obtain compound C123 (26.87 mg). LCMS (ESI) m/z: 307.1 [M+H] + .
实施例124：
Embodiment 124:
合成路线
synthetic route
(1)在30ml玻璃瓶中加入C124-a(108mg,0.32mmol)和int7(71.9mg,0.38mmol)，一水合对甲苯磺酸(18.3mg,0.096mmol)，使用无水N,N-二甲基甲酰胺(3ml)溶解上述反应物，将反应装置置于60℃油浴锅中搅拌反应1.5小时.然后反应体系通过反相柱层析制备分离两次，得到C124(4.83mg)。LCMS(ESI)m/z:435.2[M+H]+.(1) C124-a (108 mg, 0.32 mmol) and int7 (71.9 mg, 0.38 mmol) and p-toluenesulfonic acid monohydrate (18.3 mg, 0.096 mmol) were added to a 30 ml glass bottle, and the above reactants were dissolved in anhydrous N,N-dimethylformamide (3 ml). The reaction device was placed in a 60°C oil bath and stirred for 1.5 hours. The reaction system was then separated twice by reverse phase column chromatography to obtain C124 (4.83 mg). LCMS (ESI) m/z: 435.2 [M+H] + .
实施例125：
Embodiment 125:
合成路线
synthetic route
(1)将C124-a(80mg,0.16mmol)，中间体C011-11g(32mg，0.19mmol，)和对甲苯磺酸水合物(2mg，0.02mmol)溶解在DMF(1mL)中，在60℃下搅拌4h。反应结束后，过滤反应液，用DMF洗涤，合并有机相所得残余物经高效液相制备分析纯化得C125(24.12mg)。LCMS(ESI)m/z:449.2[M+H]+.(1) C124-a (80 mg, 0.16 mmol), intermediate C011-11g (32 mg, 0.19 mmol) and p-toluenesulfonic acid hydrate (2 mg, 0.02 mmol) were dissolved in DMF (1 mL) and stirred at 60°C for 4 h. After the reaction was completed, the reaction solution was filtered and washed with DMF. The organic phases were combined and the residue was purified by HPLC preparative analysis to obtain C125 (24.12 mg). LCMS (ESI) m/z: 449.2 [M+H] + .
实施例126：
Embodiment 126:
合成路线
synthetic route
(1)先将int43(100mg,0.485mmol)，int2(22mg,0.582mmol)溶于DMSO(2ml)，然后加入DIEA(0.3ml,0.97mmol),将反应液氮气保护，加热至60℃，反应4h。反应结束，将反应加入水，过滤所得粗品C126-a(150mg)可直接用于下一步。LCMS(ESI)m/z:337.0[M+H]+.(1) First, int43 (100 mg, 0.485 mmol) and int2 (22 mg, 0.582 mmol) were dissolved in DMSO (2 ml), and then DIEA (0.3 ml, 0.97 mmol) was added. The reaction liquid was protected by nitrogen and heated to 60 °C for 4 h. After the reaction was completed, water was added to the reaction mixture, and the crude product C126-a (150 mg) obtained by filtration was directly used in the next step. LCMS (ESI) m/z: 337.0 [M+H] + .
(2)将粗品C126-a(150mg，0.446mmol)、int7(150mg，0.967mmol)溶于DMF(5ml)中，然后将一水合对甲苯磺酸(2mg,0.0446mmol)加入反应液中,升温60℃，反应4h。反应完成后过滤，滤液经高效液相制备分析纯化得化合物C126(14.52mg，收率：6.9％)。LCMS(ESI)m/z:470.2[M+H]+.(2) The crude product C126-a (150 mg, 0.446 mmol) and int7 (150 mg, 0.967 mmol) were dissolved in DMF (5 ml), and then p-toluenesulfonic acid monohydrate (2 mg, 0.0446 mmol) was added to the reaction solution, the temperature was raised to 60°C, and the reaction was carried out for 4 hours. After the reaction was completed, the filtrate was filtered and purified by high performance liquid chromatography preparative analysis to obtain compound C126 (14.52 mg, yield: 6.9%). LCMS (ESI) m/z: 470.2 [M+H] + .
实施例127：
Embodiment 127:
合成路线
synthetic route
(1)在100ml茄形瓶中加入int2(1.5g,7.38mmol)，用无水二甲亚砜(30ml)溶解上述物质，接着向反应体系中二异丙基乙胺(3.7ml,22.14mmol),室温下搅拌反应15分钟后，加入化合物C127-a(2.0g,8.11mmol),室温下搅拌反应2.5小时。向反应体系中加入45ml水，过滤，每次使用45ml水洗涤滤饼，共洗涤三次，将滤饼转移至100ml茄形瓶中，每次使用40ml超干四氢呋喃共沸除水，前后共四次，得到C127-b(2.6g)。1H NMR(400MHz,DMSO_d6)δ11.33(s,1H),9.42(s,1H),7.70(t,J＝2.4Hz,2H),7.43(d,J＝8.8Hz,1H),7.14(dd,J＝8.8,2.0Hz,1H),2.89(q,J＝7.6Hz,2H),1.27(t,J＝7.6Hz,3H).(1) Add int2 (1.5 g, 7.38 mmol) to a 100 ml eggplant-shaped bottle, dissolve the above substances with anhydrous dimethyl sulfoxide (30 ml), then add diisopropylethylamine (3.7 ml, 22.14 mmol) to the reaction system, stir and react at room temperature for 15 minutes, then add compound C127-a (2.0 g, 8.11 mmol), stir and react at room temperature for 2.5 hours. Add 45 ml of water to the reaction system, filter, wash the filter cake with 45 ml of water each time, wash three times in total, transfer the filter cake to a 100 ml eggplant-shaped bottle, use 40 ml of ultra-dry tetrahydrofuran each time to azeotropically remove water, a total of four times, to obtain C127-b (2.6 g). 1 H NMR (400 MHz, DMSO_d6) δ 11.33 (s, 1H), 9.42 (s, 1H), 7.70 (t, J = 2.4 Hz, 2H), 7.43 (d, J = 8.8 Hz, 1H), 7.14 (dd, J = 8.8, 2.0 Hz, 1H), 2.89 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H).
(2)在100ml三颈瓶中加入C127-b(376.6mg,1mmol)，Pd(dppf)Cl2.DCM(82mg,0.1mmol),将反应物溶解在无水四氢呋喃(40ml),紧接着加入硼氢化钠(64mg,0.17mmol),N,N-四甲基乙二胺(240mg,2.06mmol),加完上述物料，抽换氮气三次后，在室温下反应8h。合并小试C127-b((37.7mg),其余物料当量比不变，40℃下反应3小时)一起处理，向反应体系中加入50ml H2O，用乙酸乙酯萃取(50mL x 2)，有机相用50ml饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，所得混合物用硅胶吸附，使用柱层析(PE:EA＝32:68)得到C127-c(246mg)。1H NMR(400MHz,DMSO_d6)δ11.24(s,1H),9.00(s,1H),8.41(s,1H),7.71(d,J＝2.4Hz,1H),7.61(d,J＝1.6Hz,1H),7.41(d,J＝8.8Hz,1H),7.11(dd,J＝8.8,2.0Hz,1H),2.94(q,J＝7.2Hz,2H),1.29(t,J＝7.2Hz,3H)(2) C127-b (376.6 mg, 1 mmol) and Pd(dppf)Cl 2 .DCM (82 mg, 0.1 mmol) were added to a 100 ml three-necked flask, and the reactants were dissolved in anhydrous tetrahydrofuran (40 ml), followed by sodium borohydride (64 mg, 0.17 mmol) and N,N-tetramethylethylenediamine (240 mg, 2.06 mmol). After the addition of the above materials, the nitrogen was replaced three times and the reaction was carried out at room temperature for 8 h. The small test C127-b (37.7 mg, the equivalent ratio of the other materials remained unchanged, and the reaction was carried out at 40°C for 3 hours) was combined and treated together. 50 ml of H 2 O was added to the reaction system, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was washed once with 50 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and the resulting mixture was adsorbed on silica gel. C127-c (246 mg) was obtained by column chromatography (PE:EA=32:68). 1 H NMR (400 MHz, DMSO_d6) δ 11.24 (s, 1H), 9.00 (s, 1H), 8.41 (s, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.61 (d, J = 1.6 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.11 (dd, J = 8.8, 2.0 Hz, 1H), 2.94 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H)
(3)在25ml三颈瓶中加入C127-c(89.3mg,0.3mmol)，加入无水四氢呋喃(5ml)溶解上述反应物，氮气置换三次，在0℃下滴加甲基溴化镁(3M in THF,1ml)并在该温度下搅拌6分钟后，升温到50℃继续反应17.5小时。反应液降温到0℃，用2M HCl(11ml)淬灭反应,并在50℃下继续反应1小时，反应液用乙酸乙酯萃取(25mL x 2)，有机相用25ml饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩。粗品通过制备板分离(DSM/MeOH:20/1)得到C127-d(31mg)。LCMS(ESI)m/z:315.0[M+H]+.(3) C127-c (89.3 mg, 0.3 mmol) was added to a 25 ml three-necked flask, and anhydrous tetrahydrofuran (5 ml) was added to dissolve the above reactants. The nitrogen was replaced three times, and methylmagnesium bromide (3M in THF, 1 ml) was added dropwise at 0°C and stirred at this temperature for 6 minutes, and then the temperature was raised to 50°C and the reaction was continued for 17.5 hours. The reaction solution was cooled to 0°C, quenched with 2M HCl (11 ml), and the reaction was continued at 50°C for 1 hour. The reaction solution was extracted with ethyl acetate (25 mL x 2), and the organic phase was washed once with 25 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative plate (DSM/MeOH: 20/1) to obtain C127-d (31 mg). LCMS (ESI) m/z: 315.0 [M+H] + .
(4)在8ml玻璃瓶中加入C127-d(232mg,0.737mmol)，化合物6(276.5mg,1.474mmol)，一水合对甲苯磺酸(14mg,0.074mmol),使用无水N,N-二甲基甲酰胺(5ml)溶解上述反应物,反应液在60℃下反应2.5小时.反应液直接通过反相制备分离得到C127(215.38mg)。LCMS(ESI)m/z:448.2[M+H]+.(4) C127-d (232 mg, 0.737 mmol), compound 6 (276.5 mg, 1.474 mmol), p-toluenesulfonic acid monohydrate (14 mg, 0.074 mmol) were added to an 8 ml glass bottle, and anhydrous N,N-dimethylformamide (5 ml) was used to dissolve the above reactants. The reaction solution was reacted at 60°C for 2.5 hours. The reaction solution was directly separated by reverse phase preparation to obtain C127 (215.38 mg). LCMS (ESI) m/z: 448.2 [M+H] + .
实施例128：
Embodiment 128:
合成路线
synthetic route
(1)将int42(200mg，1.086mmol)、int2(362mg，2.173mmol)溶解在二甲基亚砜(2mL)中，加入N,N-二异丙基乙胺(0.358ml，2.173mmol)，反应液在60℃下搅拌4h。反应结束后，向反应液中加入水(10ml)，再加入乙酸乙酯(10ml x 3)进行萃取，所得有机相用饱和的食盐水进行洗涤，再加入无水硫酸钠进行干燥，过滤，有机相减压浓缩，所得粗品C128-a(210mg)。LCMS(ESI)m/z:315.0[M+H]+.(1) Int42 (200 mg, 1.086 mmol) and int2 (362 mg, 2.173 mmol) were dissolved in dimethyl sulfoxide (2 mL), and N,N-diisopropylethylamine (0.358 ml, 2.173 mmol) was added. The reaction solution was stirred at 60°C for 4 h. After the reaction was completed, water (10 ml) was added to the reaction solution, and then ethyl acetate (10 ml x 3) was added for extraction. The obtained organic phase was washed with saturated brine, and then anhydrous sodium sulfate was added for drying, filtered, and the organic phase was concentrated under reduced pressure to obtain a crude product C128-a (210 mg). LCMS (ESI) m/z: 315.0 [M+H] + .
(2)将C128-a(200mg，0.636mmol)、int7(122mg，1.273mmol)和一水合对甲苯磺酸水合物(25mg，0.0636mmol)溶解在DMF(3.0mL)中，反应液在60℃下搅拌1h。反应结束后，将反应液过滤，滤饼用DMF洗涤，合并有机相，减压浓缩。所得残余物用高效液相制备分析纯化得C128(8.01mg)。LCMS(ESI)m/z:448.2[M+H]+.(2) C128-a (200 mg, 0.636 mmol), int7 (122 mg, 1.273 mmol) and p-toluenesulfonic acid monohydrate (25 mg, 0.0636 mmol) were dissolved in DMF (3.0 mL), and the reaction solution was stirred at 60°C for 1 h. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with DMF, the organic phases were combined, and concentrated under reduced pressure. The obtained residue was purified by high performance liquid chromatography preparative analysis to obtain C128 (8.01 mg). LCMS (ESI) m/z: 448.2 [M+H] + .
实施例129：
Embodiment 129:
合成路线
synthetic route
将C093-e(100mg，0.33mmol)，int2(64mg，0.40mmol)和对甲苯磺酸(11mg，0.07mmol)溶解在N,N-二甲基甲酰胺(1mL)中，反应液在60℃下搅拌2h。反应结束后，将反应液经高效液相制备分析纯化得化合物C129(46.08mg)。LCMS(ESI)m/z:406.2[M+H]+.C093-e (100 mg, 0.33 mmol), int2 (64 mg, 0.40 mmol) and p-toluenesulfonic acid (11 mg, 0.07 mmol) were dissolved in N,N-dimethylformamide (1 mL), and the reaction solution was stirred at 60°C for 2 h. After the reaction, the reaction solution was purified by high performance liquid chromatography preparative analysis to obtain compound C129 (46.08 mg). LCMS (ESI) m/z: 406.2 [M+H] + .
实施例131：
Embodiment 131:
合成路线
synthetic route
(1)将12e(725mg,3.94mmol)溶解在DMSO(7mL)中，加入C093-d(560mg,3.28mmol)和DIEA(2.1g,16.4mmol)。在40℃下搅拌16h。反应结束后，冷却至室温，加水析出，过滤反应液，所得固体用乙酸乙酯溶解，合并有机相，所得残余物用硅胶柱层析纯化，用(乙酸乙酯:石油醚＝0％～33％)洗脱得C131-b(200mg)。LCMS(ESI)m/z:319.1[M+H]+，1H NMR(400MHz,DMSO_d6)δ11.23(s,1H),8.81(s,1H),8.50(s,1H),7.82(dd,J＝11.6,6.8Hz,2H),7.40(d,J＝10.4Hz,1H),2.62(s,3H),2.51(s,3H).(1) 12e (725 mg, 3.94 mmol) was dissolved in DMSO (7 mL), and C093-d (560 mg, 3.28 mmol) and DIEA (2.1 g, 16.4 mmol) were added. The mixture was stirred at 40°C for 16 h. After the reaction was completed, the mixture was cooled to room temperature, and water was added to precipitate. The reaction solution was filtered, and the obtained solid was dissolved in ethyl acetate. The organic phases were combined, and the obtained residue was purified by silica gel column chromatography, and C131-b (200 mg) was obtained by eluting with (ethyl acetate: petroleum ether = 0% to 33%). LCMS (ESI) m/z: 319.1 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.81 (s, 1H), 8.50 (s, 1H), 7.82 (dd, J=11.6, 6.8 Hz, 2H), 7.40 (d, J=10.4 Hz, 1H), 2.62 (s, 3H), 2.51 (s, 3H).
(2)将粗品C131-b(200mg,0.63mmol)，int7(113mg，0.75mmol，)和一水合对甲苯磺酸水合物(23mg，0.13mmol)溶解在DMF(2mL)中，在60℃下搅拌4h。反应结束后，过滤反应液，用DMF洗涤，合并有机相所得残余物经高效液相制备分析纯化得C131(110.94mg)。LCMS(ESI)m/z:452.2[M+H]+.(2) The crude product C131-b (200 mg, 0.63 mmol), int7 (113 mg, 0.75 mmol) and p-toluenesulfonic acid monohydrate (23 mg, 0.13 mmol) were dissolved in DMF (2 mL) and stirred at 60°C for 4 h. After the reaction was completed, the reaction solution was filtered and washed with DMF. The organic phases were combined and the residue was purified by high performance liquid chromatography preparative analysis to obtain C131 (110.94 mg). LCMS (ESI) m/z: 452.2 [M+H] + .
实施例132：
Embodiment 132:
合成路线
synthetic route
(1)将int2(597mg，2.94mmol)和C093-d(500mg，2.94mmol)溶解在二甲基亚砜(15mL)中，添加N,N-二异丙基乙胺(1.45ml，8.82mmol)。将混合物在90℃下搅拌2小时。反应结束后加水淬灭，乙酸乙酯萃取，有机相加饱和盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩后，残留物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝1:1)洗脱得C132-a(300mg)。LCMS(ESI)m/z:301.1[M+H]+，1H NMR(400MHz,DMSO_d6)δ11.26(s,1H),8.82(s,1H),8.49(s,1H),7.79(d,J＝2.5Hz,1H),7.67(d,J＝2.0Hz,1H),7.41(d,J＝8.6Hz,1H),7.11(dd,J＝8.4,2.0Hz,1H),2.63(s,3H),2.51(s,3H).(1) Int2 (597 mg, 2.94 mmol) and C093-d (500 mg, 2.94 mmol) were dissolved in dimethyl sulfoxide (15 mL), and N,N-diisopropylethylamine (1.45 ml, 8.82 mmol) was added. The mixture was stirred at 90°C for 2 hours. After the reaction was completed, water was added to quench, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 1:1) to obtain C132-a (300 mg). LCMS (ESI) m/z: 301.1 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 8.82 (s, 1H), 8.49 (s, 1H), 7.79 (d, J = 2.5 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.11 (dd, J = 8.4, 2.0 Hz, 1H), 2.63 (s, 3H), 2.51 (s, 3H).
(2)将C132-a(100mg，0.334mmol)、C132-b(65mg，0.277mmol)和一水合对甲苯磺酸(10mg，0.056mmol)溶解在N，N-二甲基甲酰胺(2mL)中。反应液在60℃下反应2小时。反应结束后，反应液经高效液相制备分析纯化得化合物C132(2.74mg)。LCMS(ESI)m/z:481.3[M+H]+.(2) C132-a (100 mg, 0.334 mmol), C132-b (65 mg, 0.277 mmol) and p-toluenesulfonic acid monohydrate (10 mg, 0.056 mmol) were dissolved in N,N-dimethylformamide (2 mL). The reaction solution was reacted at 60°C for 2 hours. After the reaction was completed, the reaction solution was purified by high performance liquid chromatography preparative analysis to obtain compound C132 (2.74 mg). LCMS (ESI) m/z: 481.3 [M+H] + .
实施例135：
Embodiment 135:
合成路线
synthetic route
(1)将C135-a(10g，64.9mmol)和硫化钠(5.06g，64.9mmol)溶解在二甲基亚砜(100mL)中，氮气保护下油浴加热至70℃搅拌反应16小时。反应完全后(TLC显示无原料)，将反应体系冷却至0℃，并滴加50mL氨水和50mL15％次氯酸钠水溶液。滴加完毕后，加入水(100mL)和乙酸乙酯(200mL)萃取一次。有机相用无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化，用(乙酸乙酯：石油醚＝0-10％)洗脱得C135-b(5g)。LCMS(ESI)m/z:185.0[M+H]+.(1) C135-a (10 g, 64.9 mmol) and sodium sulfide (5.06 g, 64.9 mmol) were dissolved in dimethyl sulfoxide (100 mL), heated to 70 ° C in an oil bath under nitrogen protection, and stirred for 16 hours. After the reaction was complete (TLC showed no starting material), the reaction system was cooled to 0 ° C, and 50 mL of ammonia water and 50 mL of 15% sodium hypochlorite aqueous solution were added dropwise. After the addition was complete, water (100 mL) and ethyl acetate (200 mL) were added and extracted once. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (ethyl acetate: petroleum ether = 0-10%) to obtain C135-b (5 g). LCMS (ESI) m/z: 185.0 [M+H] + .
(2)将C135-b(1.0g，5.435mmol)，C135-c(1.5g，10.87mmol),醋酸钯(121mg，0.543mmol)，Xantphos(627mg，0.1087mmol)和碳酸铯(3.5g，10.87mmol)溶解在甲苯(20mL)中，在100℃下搅拌3h。反应结束后，加入水(10mL)和乙酸乙酯(20mL)萃取一次。合并有机相，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，用(乙酸乙酯：石油醚＝0-20％)洗脱得C135-d(800mg)。LCMS(ESI)m/z:288.0[M+H]+.(2) C135-b (1.0 g, 5.435 mmol), C135-c (1.5 g, 10.87 mmol), palladium acetate (121 mg, 0.543 mmol), Xantphos (627 mg, 0.1087 mmol) and cesium carbonate (3.5 g, 10.87 mmol) were dissolved in toluene (20 mL) and stirred at 100° C. for 3 h. After the reaction was completed, water (10 mL) and ethyl acetate (20 mL) were added and extracted once. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (ethyl acetate: petroleum ether = 0-20%) to obtain C135-d (800 mg). LCMS (ESI) m/z: 288.0 [M+H] + .
(3)将C135-d(800mg,2.787mmol)溶于THF(10.0ml)，将反应液用氮气保护并降温至0℃，然后加入MeMgBr(1.92ml,5.769mmol)，反应液缓慢升至45℃反应16h。反应结束后，向反应液中加入水(20ml)，再加入乙酸乙酯(10ml X 3)进行萃取，所得有机相用饱和的食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗产品用硅胶柱层析纯化(乙酸乙酯：石油醚＝0-20％)得到产物C135-e(400mg)。LCMS(ESI)m/z:305.0[M+H]+.(3) C135-d (800 mg, 2.787 mmol) was dissolved in THF (10.0 ml), the reaction solution was protected with nitrogen and cooled to 0°C, then MeMgBr (1.92 ml, 5.769 mmol) was added, and the reaction solution was slowly heated to 45°C for 16 h. After the reaction was completed, water (20 ml) was added to the reaction solution, and then ethyl acetate (10 ml x 3) was added for extraction. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-20%) to obtain the product C135-e (400 mg). LCMS (ESI) m/z: 305.0 [M+H] + .
(4)将C135-e(400mg，1.315mmol)，int6(418mg，2.631mmol)和一水合对甲苯磺酸水合物(25mg，0.131mmol)溶解在DMF(4.0mL)中，反应液在90℃下搅拌4h。反应结束后，将反应液过滤，滤饼用DMF洗涤，合并有机相，减压浓缩。所得残余物用高效液相制备分析纯化得C135(20.81mg)。LCMS(ESI)m/z:410.1[M+H]+.(4) C135-e (400 mg, 1.315 mmol), int6 (418 mg, 2.631 mmol) and p-toluenesulfonic acid monohydrate (25 mg, 0.131 mmol) were dissolved in DMF (4.0 mL), and the reaction solution was stirred at 90°C for 4 h. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with DMF, the organic phases were combined and concentrated under reduced pressure. The obtained residue was purified by high performance liquid chromatography preparative analysis to obtain C135 (20.81 mg). LCMS (ESI) m/z: 410.1 [M+H] + .
实施例136：
Embodiment 136:
合成路线
synthetic route
(1)将C136-a(10g，64.9mmol)和硫化钠(5.06g，64.9mmol)溶解在二甲基亚砜(100mL)中，氮气保护下油浴加热至70℃搅拌反应16小时。反应完全后(TLC显示无原料)，将反应体系 冷却至0℃，并滴加50mL氨水和50mL15％次氯酸钠水溶液。滴加完毕后，加入水(100mL)和乙酸乙酯(200mL)萃取一次。合并有机相，无水硫酸钠干燥，有机相过滤后减压浓缩滤液，所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝9:1)洗脱得C136-b(5g)。LCMS(ESI)m/z:185.0[M+H]+.(1) C136-a (10 g, 64.9 mmol) and sodium sulfide (5.06 g, 64.9 mmol) were dissolved in dimethyl sulfoxide (100 mL), and the mixture was heated to 70° C. in an oil bath under nitrogen protection and stirred for 16 hours. After the reaction was complete (TLC showed no starting material), the reaction system was Cool to 0°C, and dropwise add 50 mL of ammonia water and 50 mL of 15% sodium hypochlorite aqueous solution. After the addition is complete, add water (100 mL) and ethyl acetate (200 mL) and extract once. Combine the organic phases, dry over anhydrous sodium sulfate, filter the organic phase, and concentrate the filtrate under reduced pressure. The resulting residue is purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 9:1) to obtain C136-b (5 g). LCMS (ESI) m/z: 185.0 [M + H] + .
(2)将C136-b(460mg，2.50mmol)，C136-c(500mg，2.50mmol),醋酸钯(56mg，0.25mmol)，Xantphos(290mg，0.5mmol)和碳酸铯(1.6g，5.0mmol)溶解在甲苯(20mL)中，在100℃下搅拌3h。反应结束后，加入水(10mL)和乙酸乙酯(20mL)萃取一次。合并有机相，无水硫酸钠干燥，有机相过滤后减压浓缩，所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝4:1)洗脱得C136-d(80mg)。LCMS(ESI)m/z:304.0[M+H]+.(2) C136-b (460 mg, 2.50 mmol), C136-c (500 mg, 2.50 mmol), palladium acetate (56 mg, 0.25 mmol), Xantphos (290 mg, 0.5 mmol) and cesium carbonate (1.6 g, 5.0 mmol) were dissolved in toluene (20 mL) and stirred at 100° C. for 3 h. After the reaction was completed, water (10 mL) and ethyl acetate (20 mL) were added and extracted once. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 4:1) to obtain C136-d (80 mg). LCMS (ESI) m/z: 304.0 [M+H] + .
(3)将C136-d(80mg，0.264mmol)，int6(42mg，0.264mmol)和一水合对甲苯磺酸(10mg，0.053mmol)溶解在N,N-二甲基甲酰胺(1mL)中。反应液在60℃下反应4小时。反应结束后将反应液反相制备分析纯化得化合物C136(30.89mg)。LCMS(ESI)m/z:409.2[M+H]+.(3) C136-d (80 mg, 0.264 mmol), int6 (42 mg, 0.264 mmol) and p-toluenesulfonic acid monohydrate (10 mg, 0.053 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction solution was reacted at 60°C for 4 hours. After the reaction was completed, the reaction solution was purified by reverse phase preparative analysis to obtain compound C136 (30.89 mg). LCMS (ESI) m/z: 409.2 [M+H] + .
实施例137：
Embodiment 137:
合成路线
synthetic route
(1)于100mL单口反应瓶中将C136-b(1.00g，5.42mmol)溶解在二氯乙烷(40mL)中，加入间氯过氧苯甲酸(4.2g，20.58mmol)，氮气保护下油浴加热至40℃搅拌反应16小时。反应完全后，向反应液中加入二氯甲烷(60mL)搅拌30分钟，过滤收集滤饼真空干燥即得C137-b(700mg)。LCMS(ESI)m/z:216.9[M+H]+.(1) Dissolve C136-b (1.00 g, 5.42 mmol) in dichloroethane (40 mL) in a 100 mL single-mouth reaction bottle, add m-chloroperbenzoic acid (4.2 g, 20.58 mmol), heat to 40 ° C in an oil bath under nitrogen protection, and stir for 16 hours. After the reaction is complete, add dichloromethane (60 mL) to the reaction solution and stir for 30 minutes. Filter and collect the filter cake and vacuum dry to obtain C137-b (700 mg). LCMS (ESI) m/z: 216.9 [M+H] + .
(2)向20mL封管中依次加入C137-b(200mg，0.923mmol)、C137-c(144mg，0.923mmol)、醋酸钯(21mg，0.092mmol)、配体Xant-Phos(107mg，0.185mmol)、碳酸铯(602mg，1.846mmol)和无水甲苯(6mL)。氮气保护下油浴加热至100℃，搅拌3小时。反应完成后冷却至室温，过滤后将滤饼倒入二氯甲烷(50mL)中打浆10分钟；再次过滤后，将滤饼倒入二氯甲烷(50mL)中打浆10分钟。收集所有二氯甲烷相(不要甲苯相)，减压浓缩即得粗品C137-d(240mg)。LCMS(ESI)m/z:335.8[M+H]+.(2) C137-b (200 mg, 0.923 mmol), C137-c (144 mg, 0.923 mmol), palladium acetate (21 mg, 0.092 mmol), ligand Xant-Phos (107 mg, 0.185 mmol), cesium carbonate (602 mg, 1.846 mmol) and anhydrous toluene (6 mL) were added to a 20 mL sealed tube. The mixture was heated to 100 °C in an oil bath under nitrogen protection and stirred for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filter cake was poured into dichloromethane (50 mL) and slurried for 10 minutes; after filtering again, the filter cake was poured into dichloromethane (50 mL) and slurried for 10 minutes. All dichloromethane phases (excluding toluene phase) were collected and concentrated under reduced pressure to obtain crude product C137-d (240 mg). LCMS (ESI) m/z: 335.8 [M+H] + .
(3)向20mL封管中依次加入C137-d(220mg，0.655mmol)、int7(148mg，0.786mmol)、一水合对甲苯磺酸(25mg，0.131mmol)和无水乙腈(4mL)，氮气保护下油浴加热至60℃搅拌2小时。反应完成后，向反应液中加入N,N-二甲基甲酰胺(2mL)，溶清后再加入一滴氨水，过滤除去不溶物后用高效液相制备分析纯化得化合物C137(26.45mg)。LCMS(ESI)m/z:469.2[M+H]+.(3) C137-d (220 mg, 0.655 mmol), int7 (148 mg, 0.786 mmol), p-toluenesulfonic acid monohydrate (25 mg, 0.131 mmol) and anhydrous acetonitrile (4 mL) were added to a 20 mL sealed tube in sequence, and the mixture was heated to 60°C in an oil bath under nitrogen protection and stirred for 2 hours. After the reaction was completed, N,N-dimethylformamide (2 mL) was added to the reaction solution, and a drop of ammonia water was added after the solution was dissolved. The insoluble matter was removed by filtration and purified by high performance liquid chromatography to obtain compound C137 (26.45 mg). LCMS (ESI) m/z: 469.2 [M+H] + .
实施例138：
Embodiment 138:
合成路线
synthetic route
(1)将1-(6-氯吡啶-3-基)乙烷-1-酮(1.0g，6.427mmol)溶解在醋酸(10mL)中，加入int2(1.3g，7.713mmol)，氮气保护下在90℃恒温搅拌16h。反应结束后，直接旋干溶剂，然后加石油醚打浆搅拌30min，过滤取滤饼，得到粗产物C138-a(2.4g)。LCMS(ESI)m/z:286.0[M+H]+.(1) 1-(6-chloropyridin-3-yl)ethane-1-one (1.0 g, 6.427 mmol) was dissolved in acetic acid (10 mL), int2 (1.3 g, 7.713 mmol) was added, and the mixture was stirred at 90°C for 16 h under nitrogen protection. After the reaction, the solvent was directly dried, and then petroleum ether was added to stir for 30 min, and the filter cake was filtered to obtain a crude product C138-a (2.4 g). LCMS (ESI) m/z: 286.0 [M+H] + .
(2)将C138-a(1.0g，纯度：30％，1.052mmol)和int7(236mg，1.263mmol)溶解在乙腈(10ml)中，加入一水合对甲苯磺酸(40mg，0.210mmol)后在氮气保护下，60℃恒温搅拌4h。反应结束后，用柱层析纯化，用(二氯甲烷:甲醇＝10:1)洗脱得C138-b(160mg)。LCMS(ESI)m/z:419.2[M+H]+.(2) C138-a (1.0 g, purity: 30%, 1.052 mmol) and int7 (236 mg, 1.263 mmol) were dissolved in acetonitrile (10 ml), p-toluenesulfonic acid monohydrate (40 mg, 0.210 mmol) was added, and the mixture was stirred at 60°C for 4 h under nitrogen protection. After the reaction was completed, column chromatography was used for purification, and C138-b (160 mg) was obtained by elution with (dichloromethane: methanol = 10:1). LCMS (ESI) m/z: 419.2 [M+H] + .
(3)将C138-b(140mg，0.334mmol)溶解在二氯甲烷(1mL)中，加入三乙胺(0.1ml，0.668mmol)，在氮气保护下冰水浴中搅拌10min。然后在0℃下缓慢加入丙烯酰氯(24mg，0.267mmol)，在冰水浴中反应2h。反应结束后浓缩反应液，反相制备分析纯化得化合物C138(2.25mg)。LCMS(ESI)m/z:473.3[M+H]+。(3) C138-b (140 mg, 0.334 mmol) was dissolved in dichloromethane (1 mL), triethylamine (0.1 ml, 0.668 mmol) was added, and the mixture was stirred in an ice-water bath under nitrogen protection for 10 min. Acryloyl chloride (24 mg, 0.267 mmol) was then slowly added at 0°C, and the mixture was reacted in an ice-water bath for 2 h. After the reaction, the reaction solution was concentrated and purified by reverse phase preparative analysis to obtain compound C138 (2.25 mg). LCMS (ESI) m/z: 473.3 [M+H] + .
各实施例的1H NMR和MS数据如下表所示：The 1 H NMR and MS data of each example are shown in the following table:
表1:1H NMR和MS数据












Table 1: 1 H NMR and MS data












实施例139：
Embodiment 139:
合成路线
synthetic route
(1)将浓硫酸(10.8ml)溶解在水(61ml)中，搅拌5分钟混合均匀后，在室温下加入化合物C139-a(1.0g，6.66mmol)，加入亚硝酸钠(645.7mg,9.36mmol)(溶解在8ml水中，逐滴加入)，继续搅拌反应1小时。反应结束后，加入磷酸二氢钠(1.09g,9.08mmol)和氢氧化钠(2.74g,68.5mmol)(溶解在15ml水中，逐滴加入)，滴加完毕后，过滤，洗涤，干燥后得到化合物C139-b(1.248g)。1H NMR(400MHz,DMSO_d6)δ8.04(s,1H).LCMS(ESI)m/z:210.9[M+2+H]+。(1) Dissolve concentrated sulfuric acid (10.8 ml) in water (61 ml), stir for 5 minutes to mix well, add compound C139-a (1.0 g, 6.66 mmol) at room temperature, add sodium nitrite (645.7 mg, 9.36 mmol) (dissolved in 8 ml water, added dropwise), and continue stirring to react for 1 hour. After the reaction is completed, add sodium dihydrogen phosphate (1.09 g, 9.08 mmol) and sodium hydroxide (2.74 g, 68.5 mmol) (dissolved in 15 ml water, added dropwise), after the addition is complete, filter, wash, and dry to obtain compound C139-b (1.248 g). 1 H NMR (400 MHz, DMSO_d6) δ8.04 (s, 1H). LCMS (ESI) m/z: 210.9 [M+2+H] + .
(2)将C139-b(1.25g，5.96mmol)溶解在超干N,N-二甲基甲酰胺(15mL)中，在室温下加入碳酸钾(1.73g,12.5mmol)，反应液在室温下搅拌反应，在室温下逐滴加入碘甲烷(930.6mg,6.56mmol)，反应液在室温下继续搅拌反应2h,反应结束后，向反应体系中加入水(30mL)，混合液用乙酸乙酯(55mL x 3)萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，合并有机相减压浓缩，所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝6:1)洗脱得C139-c(728mg)。1H NMR(400MHz,CDCl3)δ7.36(s,1H),3.79(s,3H)。(2) C139-b (1.25 g, 5.96 mmol) was dissolved in ultra-dry N,N-dimethylformamide (15 mL), potassium carbonate (1.73 g, 12.5 mmol) was added at room temperature, the reaction solution was stirred at room temperature, iodomethane (930.6 mg, 6.56 mmol) was added dropwise at room temperature, the reaction solution was stirred at room temperature for 2 h, after the reaction was completed, water (30 mL) was added to the reaction system, the mixed solution was extracted with ethyl acetate (55 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the organic phases were combined and concentrated under reduced pressure, the residue was purified by column chromatography, and C139-c (728 mg) was obtained by eluting with (petroleum ether: ethyl acetate = 6:1). 1 H NMR (400 MHz, CDCl 3 ) δ7.36 (s, 1H), 3.79 (s, 3H).
(3)将C139-c(250mg，1.12mmol)、三丁基(1-乙氧基乙烯基)锡(525.5mg,1.45mmol)和四(三苯基膦)钯(129.4mg，0.11mmol)溶解在超干甲苯(15mL)中。氮气保护下反应液于100℃油浴中搅拌3h，补加三丁基(1-乙氧基乙烯基)锡(525.5mg,1.45mmol)和四(三苯基膦)钯(129.4mg，0.11mmol)，在100℃油浴中继续搅拌反应4h。反应结束后，减压除去甲苯，残 余物溶于乙酸乙酯(75mL),向反应液中加入饱和氟化钾溶液(65mL),混合液在室温下搅拌45分钟，过滤，分液，水相用乙酸乙酯(50mL x 2)萃取，有机相用食盐水洗涤，无水硫酸钠干燥，过滤，合并有机相减压浓缩，所得残余物用TLC制备板纯化(石油醚:乙酸乙酯＝5:1)，得到C139-d(115mg)。1H NMR(400MHz,CDCl3)δ7.17(s,1H),4.54(d,J＝4.0Hz,2H),3.91(q,J＝6.8Hz,2H),3.53(s,3H),1.39(t,J＝6.8Hz,3H).(3) C139-c (250 mg, 1.12 mmol), tributyl (1-ethoxyvinyl) tin (525.5 mg, 1.45 mmol) and tetrakis (triphenylphosphine) palladium (129.4 mg, 0.11 mmol) were dissolved in ultra-dry toluene (15 mL). The reaction solution was stirred in an oil bath at 100°C for 3 h under nitrogen protection, and tributyl (1-ethoxyvinyl) tin (525.5 mg, 1.45 mmol) and tetrakis (triphenylphosphine) palladium (129.4 mg, 0.11 mmol) were added, and the reaction was continued in an oil bath at 100°C with stirring for 4 h. After the reaction was completed, the toluene was removed under reduced pressure, and the residual The residue was dissolved in ethyl acetate (75 mL), saturated potassium fluoride solution (65 mL) was added to the reaction solution, the mixture was stirred at room temperature for 45 minutes, filtered, separated, the aqueous phase was extracted with ethyl acetate (50 mL x 2), the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, the organic phases were combined and concentrated under reduced pressure, and the residue was purified by TLC preparation plate (petroleum ether: ethyl acetate = 5: 1) to obtain C139-d (115 mg). 1 H NMR (400 MHz, CDCl3) δ7.17 (s, 1H), 4.54 (d, J = 4.0 Hz, 2H), 3.91 (q, J = 6.8 Hz, 2H), 3.53 (s, 3H), 1.39 (t, J = 6.8 Hz, 3H).
(4)将C139-d(93.7mg，0.44mmol)、int2(110.2mg,0.54mmol)和对甲苯磺酸(41.5mg，0.22mmol)溶解在超干N,N-二甲基甲酰胺(6mL)中。反应液于90℃油浴中搅拌1h，反应结束后，向反应体系中加入水(15mL)，混合液在用乙酸乙酯(25mL x 3)萃取，有机相用食盐水洗涤，无水硫酸钠干燥，过滤，合并有机相减压浓缩，使用TLC制备板(石油醚:乙酸乙酯＝3:1)纯化，得到C139-e(85mg)。LCMS(ESI)m/z:317.0[M+H]+。(4) C139-d (93.7 mg, 0.44 mmol), int2 (110.2 mg, 0.54 mmol) and p-toluenesulfonic acid (41.5 mg, 0.22 mmol) were dissolved in ultra-dry N,N-dimethylformamide (6 mL). The reaction solution was stirred in an oil bath at 90°C for 1 h. After the reaction was completed, water (15 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. Purification was performed using a TLC preparation plate (petroleum ether: ethyl acetate = 3:1) to obtain C139-e (85 mg). LCMS (ESI) m/z: 317.0 [M+H] + .
(5)将C139-e(84mg，0.27mmol)、int7(99.5mg,0.53mmol)和一水合对甲苯磺酸(5.0mg，0.03mmol)溶解在超干N,N-二甲基甲酰胺(3mL)中。反应液于60℃油浴中搅拌18h，反应结束后，过滤反应液，滤液用高效液相制备分析纯化得化合物C139(1.53mg)。1H NMR(400MHz,DMSO_d6)δ11.10(s,1H),9.21(s,1H),7.93(dd,J＝20.4,2.4Hz,2H),7.37(d,J＝8.8Hz,1H),7.10(dd,J＝8.6,2.0Hz,1H),6.97(s,1H),4.35(s,1H),3.47(s,3H),2.15(s,3H),2.04-1.85(m,8H)，LCMS(ESI)m/z:450.2[M+H]+。(5) C139-e (84 mg, 0.27 mmol), int7 (99.5 mg, 0.53 mmol) and p-toluenesulfonic acid monohydrate (5.0 mg, 0.03 mmol) were dissolved in ultra-dry N,N-dimethylformamide (3 mL). The reaction solution was stirred in an oil bath at 60°C for 18 h. After the reaction was completed, the reaction solution was filtered and the filtrate was purified by high performance liquid chromatography to obtain compound C139 (1.53 mg). 1 H NMR (400 MHz, DMSO_d6) δ 11.10 (s, 1H), 9.21 (s, 1H), 7.93 (dd, J = 20.4, 2.4 Hz, 2H), 7.37 (d, J = 8.8 Hz, 1H), 7.10 (dd, J = 8.6, 2.0 Hz, 1H), 6.97 (s, 1H), 4.35 (s, 1H), 3.47 (s, 3H), 2.15 (s, 3H), 2.04-1.85 (m, 8H), LCMS (ESI) m/z: 450.2 [M+H] + .
实施例140：
Embodiment 140:
合成路线
synthetic route
(1)将C140-a(5g，40.6mmol)加到二氯甲烷和N,N-二甲基甲酰胺50mL/5mL)混合溶剂中，将混合物降温至0℃,分批加入NBS(7.6g，43.0mmol)。反应液恢复至室温，氮气保护下搅拌2h。反应结束后用，加入水(100mL)和乙酸乙酯(100mL x 2)萃取，合并有机相,用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得粗品C140-b(7.2g)。LCMS(ESI)m/z:202.0[M+H]+。(1) C140-a (5 g, 40.6 mmol) was added to a mixed solvent of dichloromethane and N,N-dimethylformamide (50 mL/5 mL), the mixture was cooled to 0°C, and NBS (7.6 g, 43.0 mmol) was added in batches. The reaction solution was returned to room temperature and stirred for 2 h under nitrogen protection. After the reaction was completed, water (100 mL) and ethyl acetate (100 mL x 2) were added for extraction, the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product C140-b (7.2 g). LCMS (ESI) m/z: 202.0 [M+H] + .
(2)将C140-b(4.3g，21.39mmol)溶解在N,N-二甲基甲酰胺(40mL)中，然后将四(三苯基膦)钯(2.4g，2.1mmol)和氰化锌(7.4g,63.8mmol)加入到溶液中。混合液在氮气保护、100℃下搅拌16h。反应结束后加入水(100mL)稀释，用乙酸乙酯(100mL x 2)萃取，合并有机相。有机相用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，洗脱(乙酸乙酯：石油醚＝0～50％)，得C140-c(2.2g)。LCMS(ESI)m/z:149.1[M+H]+。(2) C140-b (4.3 g, 21.39 mmol) was dissolved in N,N-dimethylformamide (40 mL), and then tetrakis(triphenylphosphine)palladium (2.4 g, 2.1 mmol) and zinc cyanide (7.4 g, 63.8 mmol) were added to the solution. The mixture was stirred at 100°C for 16 h under nitrogen protection. After the reaction was completed, water (100 mL) was added for dilution, and the mixture was extracted with ethyl acetate (100 mL x 2), and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted (ethyl acetate: petroleum ether = 0-50%), and C140-c (2.2 g) was obtained. LCMS (ESI) m/z: 149.1 [M+H] + .
(3)将C140-c(2.8g，18.9mmol)溶解在超干乙腈(30mL)中，然后将氯化铜(3g，22.7mmol)、氯化亚铜(374mg，3.8mmol)加入到溶液中。将反应液降温到0℃，滴加亚硝酸异戊脂(2.7g，22.7mmol)。混合液在65℃、氮气保护下搅拌16h。反应结束后，将反应液过滤，滤液加水稀释(50mL)，用乙酸乙酯(30mL x 2)萃取，合并有机相。有机相用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化，洗脱(乙酸乙酯：石油醚＝0～5％)，得C140-d(1g)。1H NMR(400MHz,DMSO_d6)δ2.64(s,3H),2.59(s,3H).(3) C140-c (2.8 g, 18.9 mmol) was dissolved in ultra-dry acetonitrile (30 mL), and then cupric chloride (3 g, 22.7 mmol) and cuprous chloride (374 mg, 3.8 mmol) were added to the solution. The reaction solution was cooled to 0°C, and isoamyl nitrite (2.7 g, 22.7 mmol) was added dropwise. The mixture was stirred at 65°C under nitrogen protection for 16 h. After the reaction was completed, the reaction solution was filtered, the filtrate was diluted with water (50 mL), extracted with ethyl acetate (30 mL x 2), and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted (ethyl acetate: petroleum ether = 0-5%) to obtain C140-d (1 g). 1 H NMR (400 MHz, DMSO_d6) δ2.64 (s, 3H), 2.59 (s, 3H).
(4)将C140-d(1g，5.99mmol)溶解在超干二甲亚砜(10mL)中，然后将int2(1.3g，6.59mmol)、DIEA(1.9g，14.98mmol)加入到溶液中。反应液在室温、氮气保护下搅拌2h。反应结 束后加水析出固体，过滤，滤饼干燥后得粗品C140-e(2.2g)。LCMS(ESI)m/z:298.0[M+H]+。(4) C140-d (1 g, 5.99 mmol) was dissolved in ultra-dry dimethyl sulfoxide (10 mL), and then int2 (1.3 g, 6.59 mmol) and DIEA (1.9 g, 14.98 mmol) were added to the solution. The reaction solution was stirred at room temperature under nitrogen protection for 2 h. After drying, water was added to precipitate the solid, which was filtered and dried to obtain crude product C140-e (2.2 g). LCMS (ESI) m/z: 298.0 [M+H] + .
(5)在氮气保护下，将C140-e(2g)溶解在无水四氢呋喃(20mL)中，在0℃下，滴加甲基溴化镁(28mL，3mmol/mL)。滴加完成后，将反应液移至50℃油浴中继续反应4h。反应完毕后，将反应液用冰水浴降温，并缓慢滴加饱和NH4Cl溶液(放热且有大量气泡)淬灭，加水(20mL)稀释，混合物用二氯甲烷萃取(20mL x 3)，合并有机相，减压浓缩，所得残余物用硅胶柱层析纯化，洗脱(乙酸乙酯：石油醚＝0～20％)，得C140-f(1.2g)。LCMS(ESI)m/z:315.1[M+H]+。(5) Under nitrogen protection, C140-e (2 g) was dissolved in anhydrous tetrahydrofuran (20 mL), and methylmagnesium bromide (28 mL, 3 mmol/mL) was added dropwise at 0°C. After the addition was completed, the reaction solution was moved to a 50°C oil bath and continued to react for 4 h. After the reaction was completed, the reaction solution was cooled with an ice-water bath, and saturated NH 4 Cl solution (exothermic and with a large number of bubbles) was slowly added dropwise to quench, and water (20 mL) was added to dilute, and the mixture was extracted with dichloromethane (20 mL x 3), the organic phases were combined, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted (ethyl acetate: petroleum ether = 0-20%), to obtain C140-f (1.2 g). LCMS (ESI) m/z: 315.1 [M+H] + .
(6)将C140-f(200mg，0.64mmol)、int7(106mg，0.7mmol)和一水合对甲苯磺酸水合物(24mg，0.13mmol)溶解在DMF(2mL)中，混合物在60℃下搅拌4h。反应结束后，将反应液过滤，滤液用制备型高效液相纯化，得C140(25.14mg)。LCMS(ESI)m/z:448.2[M+H]+；1H NMR(400MHz,DMSO_d6)δ11.01(s,1H),8.21(s,1H),7.91(d,J＝2.4Hz,1H),7.81(s,1H),7.38(d,J＝8.4Hz,1H),7.10(dd,J＝8.8,2.0Hz,1H),4.31(s,1H),2.55(s,3H),2.47(s,3H),2.21(s,3H),2.09–1.88(m,8H).(6) C140-f (200 mg, 0.64 mmol), int7 (106 mg, 0.7 mmol) and p-toluenesulfonic acid monohydrate (24 mg, 0.13 mmol) were dissolved in DMF (2 mL), and the mixture was stirred at 60° C. for 4 h. After the reaction was completed, the reaction solution was filtered and the filtrate was purified by preparative high performance liquid chromatography to obtain C140 (25.14 mg). LCMS (ESI) m/z: 448.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.21 (s, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.81 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.10 (dd, J = 8.8, 2.0 Hz, 1H), 4.31 (s, 1H), 2.55 (s, 3H), 2.47 (s, 3H), 2.21 (s, 3H), 2.09–1.88 (m, 8H).
实施例141：
Example 141:
合成路线
synthetic route
(1)将化合物C141-a(10.0g，45.04mmol)、[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)二氯甲烷络合物(1.95g,2.38mmol)、碳酸钾(12.5g,90.08mmol)和2,4,6-三甲基-1,3,5,2,4,6-三甲氧基三硼烷溶解在超干1,4-二氧六环(300.0mL)中，然后氮气置换三次，将反应体系置于110℃油浴搅拌反应17小时，反应结束后，减压浓缩除去溶剂，残余物用大量硅胶吸附，用柱层析纯化(二氯甲烷:甲醇＝100:0～98:2)洗脱得C141-b(2.74g)。LCMS(ESI)m/z:202.0[M+H]+。(1) Compound C141-a (10.0 g, 45.04 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1.95 g, 2.38 mmol), potassium carbonate (12.5 g, 90.08 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trimethoxytriborane were dissolved in ultra-dry 1,4-dioxane (300.0 mL), and then replaced with nitrogen three times. The reaction system was placed in an oil bath at 110° C. and stirred for 17 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the residue was adsorbed with a large amount of silica gel and purified by column chromatography (dichloromethane:methanol=100:0-98:2) to obtain C141-b (2.74 g). LCMS (ESI) m/z: 202.0 [M+H] + .
(2)将C141-b(2.74g，13.59mmol)、亚硝酸异戊酯(2.39g,20.39mmol)和溴化亚铜(5.85g，40.77mmol)溶解在超干乙腈(36ml)中，氮气置换三次后，将反应体系置于60℃油浴搅拌反应2小时。反应结束后，减压浓缩除去溶剂，残余物硅胶柱层析纯化(石油醚:乙酸乙酯＝100:0～97:3)洗脱得C141-c(1.4g)。1H NMR(400MHz,DMSO_d6)δ3.93(s,3H),2.63(s,3H).(2) C141-b (2.74 g, 13.59 mmol), isoamyl nitrite (2.39 g, 20.39 mmol) and cuprous bromide (5.85 g, 40.77 mmol) were dissolved in ultra-dry acetonitrile (36 ml). After nitrogen replacement three times, the reaction system was placed in a 60°C oil bath and stirred for 2 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:0 to 97:3) to obtain C141-c (1.4 g). 1 H NMR (400 MHz, DMSO_d6) δ 3.93 (s, 3H), 2.63 (s, 3H).
(3)将C141-c(300mg，1.13mmol)溶解在超干四氢呋喃(6ml)中。氮气置换三次后，将反应体系的温度降低到-30℃，在该温度下逐滴滴加二异丁基氢化铝(4.5ml,6.78mmol)。加完后，将反应装置置于室温下搅拌反应2小时，反应结束后，在-10℃下加入十水合硫酸钠(4.1g,12.7mmol)，搅拌反应25分钟后，过滤，滤饼使用乙酸乙酯(200ml)润洗，滤液减压浓缩，残余物用硅胶柱层析纯化，(石油醚:乙酸乙酯＝100:0～85:15)洗脱得C141-d(147mg)。1H NMR(400MHz,DMSO_d6)δ5.57(t,J＝6.0Hz,1H),4.59(d,J＝6.0Hz,2H),2.57(s,3H).(3) C141-c (300 mg, 1.13 mmol) was dissolved in ultra-dry tetrahydrofuran (6 ml). After nitrogen replacement three times, the temperature of the reaction system was lowered to -30°C, and diisobutylaluminum hydride (4.5 ml, 6.78 mmol) was added dropwise at this temperature. After the addition, the reaction apparatus was placed at room temperature and stirred for 2 hours. After the reaction was completed, sodium sulfate decahydrate (4.1 g, 12.7 mmol) was added at -10°C, stirred for 25 minutes, and filtered. The filter cake was rinsed with ethyl acetate (200 ml), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:0 to 85:15) to obtain C141-d (147 mg). 1 H NMR (400 MHz, DMSO_d6) δ 5.57 (t, J = 6.0 Hz, 1H), 4.59 (d, J = 6.0 Hz, 2H), 2.57 (s, 3H).
(4)将C141-d(310mg，1.31mmol)、三丁基(1-乙氧基乙烯基)锡(565.6mg,1.57mmol)和四(三苯基膦)钯(150.8mg,0.13mmol)溶解在超干甲苯(4ml)中。氮气置换三次后，将反应体系置于80℃油浴搅拌反应16小时，直接用于下一步。(4) C141-d (310 mg, 1.31 mmol), tributyl(1-ethoxyvinyl)tin (565.6 mg, 1.57 mmol) and tetrakis(triphenylphosphine)palladium (150.8 mg, 0.13 mmol) were dissolved in ultra-dry toluene (4 ml). After nitrogen substitution three times, the reaction system was placed in an 80°C oil bath and stirred for 16 hours, and then used directly in the next step.
(5)待上步的反应体系冷却到室温后，向反应体系中加入盐酸(4M in H2O,6ml)，室温下搅拌反应2小时，反应结束后，将上述反应液用乙酸乙酯(45ml)转移到盛有饱和氟化钾溶液(30ml)的250ml三角烧瓶中，在室温下搅拌反应50分钟后，水相用乙酸乙酯萃取(30ml x 3)，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，残余物用硅胶板纯化(石油醚:乙酸乙酯＝7:1)，得到C141-f(233mg,粗产品，含有锡试剂)。1H NMR(400MHz,CD3OD_d4)δ4.91(s,2H),2.70(s,3H),2.66(s,3H).(5) After the reaction system in the previous step was cooled to room temperature, hydrochloric acid (4M in H 2 O, 6ml) was added to the reaction system, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was transferred to a 250ml conical flask containing a saturated potassium fluoride solution (30ml) with ethyl acetate (45ml). After stirring at room temperature for 50 minutes, the aqueous phase was extracted with ethyl acetate (30ml x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel plate (petroleum ether: ethyl acetate = 7:1) to obtain C141-f (233mg, crude product, containing tin reagent). 1 H NMR (400MHz, CD 3 OD_d4) δ4.91 (s, 2H), 2.70 (s, 3H), 2.66 (s, 3H).
(6)将C141-f(60mg，0.3mmol)和咪唑(101.8mg,1.5mmol)溶解在超干二氯甲烷(1.5mL)中,室温下搅拌反应10分钟后，加入叔丁基二甲基氯硅烷(135.6mg,0.9mmol),室温下反应16 小时，反应结束后，直接通过制备板纯化(石油醚:乙酸乙酯＝10:1)，得C141-g(73mg)。1H NMR(400MHz,CD3OD_d4)δ4.93(s,2H),2.58(s,3H),2.53(s,3H),0.81(s,9H),0.00(s,6H).(6) C141-f (60 mg, 0.3 mmol) and imidazole (101.8 mg, 1.5 mmol) were dissolved in ultra-dry dichloromethane (1.5 mL). After stirring at room temperature for 10 minutes, tert-butyldimethylsilyl chloride (135.6 mg, 0.9 mmol) was added and the mixture was reacted at room temperature for 16 minutes. After the reaction was completed, the product was directly purified by preparative plate (petroleum ether:ethyl acetate=10:1) to obtain C141-g (73 mg). 1 H NMR (400 MHz, CD 3 OD_d4) δ4.93 (s, 2H), 2.58 (s, 3H), 2.53 (s, 3H), 0.81 (s, 9H), 0.00 (s, 6H).
(7)将C141-g(23mg，0.073mmol)、int2(118.6mg,0.584mmol),和N,N-二异丙基乙胺(176mg,1.36mmol)溶解在二甲亚砜(2.0ml)中,并在反应中加入两滴水,将反应体系置于90℃油浴搅拌反应2.5小时，反应结束后向反应体系中加入水(5ml)，过滤，滤饼用水(2ml)洗涤，抽干后，将滤饼溶解，使用制备板纯化(石油醚:乙酸乙酯＝4:1)得化合物C141-h(3.5mg)。LCMS(ESI)m/z:445.2[M+H]+。(7) C141-g (23 mg, 0.073 mmol), int2 (118.6 mg, 0.584 mmol), and N,N-diisopropylethylamine (176 mg, 1.36 mmol) were dissolved in dimethyl sulfoxide (2.0 ml), and two drops of water were added to the reaction. The reaction system was placed in a 90°C oil bath and stirred for 2.5 hours. After the reaction, water (5 ml) was added to the reaction system, filtered, and the filter cake was washed with water (2 ml). After drying, the filter cake was dissolved and purified using a preparative plate (petroleum ether: ethyl acetate = 4:1) to obtain compound C141-h (3.5 mg). LCMS (ESI) m/z: 445.2 [M+H] + .
(8)将C141-h(23.4mg，0.053mmol)、int7(19.8mg,0.106mmol)和一水合对甲苯磺酸(3mg,0.3mmol)溶解在超干N,N-二甲基甲酰胺(1.0ml)中，将反应体系置于60℃油浴搅拌反应1.5小时，反应结束后，合并7.3mg小试产品，通过高效液相制备分离得到C141(9.01mg)。1H NMR(400MHz,CD3OD_d4)δ7.69(s,1H),7.52(d,J＝2.0Hz,1H),7.34(d,J＝8.8Hz,1H),7.09(dd,J＝8.8,2.0Hz,1H),4.63(s,2H),4.37-4.31(m,1H),2.60(s,3H),2.31(s,3H),2.07–1.90(m,8H).LCMS(ESI)m/z:464.1[M+H]+。(8) C141-h (23.4 mg, 0.053 mmol), int7 (19.8 mg, 0.106 mmol) and p-toluenesulfonic acid monohydrate (3 mg, 0.3 mmol) were dissolved in ultra-dry N,N-dimethylformamide (1.0 ml). The reaction system was placed in a 60°C oil bath and stirred for 1.5 hours. After the reaction, 7.3 mg of the small test products were combined and separated by HPLC to obtain C141 (9.01 mg). 1 H NMR (400 MHz, CD 3 OD_d4) δ7.69 (s, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.09 (dd, J=8.8, 2.0 Hz, 1H), 4.63 (s, 2H), 4.37-4.31 (m, 1H), 2.60 (s, 3H), 2.31 (s, 3H), 2.07-1.90 (m, 8H). LCMS (ESI) m/z: 464.1 [M+H] + .
实施例142：
Embodiment 142:
合成路线
synthetic route
将C093-e(200mg，0.665mmol，1eq)、int3(91mg，0.798mmol，1.2eq)和对甲苯磺酸水合物(22mg，0.133mmol，0.2eq)溶解在DMF(4mL)中，在60℃下搅拌2h。TLC监测反应，将反应液用高效液相制备分析纯化得C142(43.88mg)。1H NMR(400MHz,DMSO_d6)δ11.10(s,1H),8.38(s,1H),8.31(s,1H),7.77(d,J＝2.4Hz,1H),7.68(d,J＝2.0Hz,1H),7.39(d,J＝8.8Hz,1H),7.10(dd,J＝8.8,2.0Hz,1H),4.77(q,J＝9.2Hz,2H),2.59(s,3H),2.25(s,3H).LCMS(ESI)m/z:398.2[M+H]+。C093-e (200 mg, 0.665 mmol, 1 eq), int3 (91 mg, 0.798 mmol, 1.2 eq) and p-toluenesulfonic acid hydrate (22 mg, 0.133 mmol, 0.2 eq) were dissolved in DMF (4 mL) and stirred at 60° C. for 2 h. The reaction was monitored by TLC, and the reaction solution was purified by HPLC preparative analysis to obtain C142 (43.88 mg). 1 H NMR (400 MHz, DMSO_d6) δ 11.10 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.10 (dd, J = 8.8, 2.0 Hz, 1H), 4.77 (q, J = 9.2 Hz, 2H), 2.59 (s, 3H), 2.25 (s, 3H). LCMS (ESI) m/z: 398.2 [M+H] + .
实施例143：
Embodiment 143:
合成路线
synthetic route
(1)将硝酸钾(0.72g，7.1mmol)中加入浓硫酸(12mL)并室温搅拌1分钟，然后将反应瓶置于冰水浴中，待内温降至0～3℃后加入C143-a(1g，5.1mmol)。冰水浴中继续搅拌30分钟。反应完成后，向反应液中加入冰水(约50mL)，过滤并减压干燥滤饼，即得粗品C143-b(2.2g)可直接用于下一步。1H NMR(400MHz,DMSO_d6)δ13.00(s,1H),8.87(d,J＝4.0Hz,1H),7.97(d,J＝ 8.8Hz,1H),7.54(d,J＝8.4Hz,1H).(1) Add concentrated sulfuric acid (12 mL) to potassium nitrate (0.72 g, 7.1 mmol) and stir at room temperature for 1 minute. Then place the reaction bottle in an ice-water bath. After the internal temperature drops to 0-3°C, add C143-a (1 g, 5.1 mmol). Continue stirring in the ice-water bath for 30 minutes. After the reaction is completed, add ice water (about 50 mL) to the reaction solution, filter and dry the filter cake under reduced pressure to obtain a crude product C143-b (2.2 g) which can be used directly in the next step. 1 H NMR (400 MHz, DMSO_d6) δ13.00 (s, 1H), 8.87 (d, J = 4.0 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H).
(2)将粗品C143-b(2.1g，5.0mmol)倒入装有甲醇(42mL)与饱和氯化铵水溶液(21mL)混合溶剂的反应瓶中，室温搅拌下，加入锌粉(3.3g，50mmol)，继续室温搅拌10分钟。向反应瓶中加入二碳酸二叔丁酯(2.2g，10mmol)，室温搅拌后，加入乙醇(100mL)稀释反应液，硅藻土过滤，将滤液减压浓缩。向残余物中加入乙酸乙酯(70mL)和碳酸氢钠水溶液(50mL)，震荡后分出乙酸乙酯相，无水硫酸钠干燥有机相，过滤后将滤液减压浓缩至干。所得粗品经硅胶柱层析纯化，用(乙酸乙酯/石油醚＝0％～20％)洗脱得C143-c(680mg)。1H NMR(400MHz,DMSO_d6)δ11.30(s,1H),8.73(s,1H),7.71(d,J＝8.4Hz,2H),7.24(d,J＝8.4Hz,1H),1.37(s,9H).(2) The crude product C143-b (2.1 g, 5.0 mmol) was poured into a reaction flask containing a mixed solvent of methanol (42 mL) and saturated aqueous ammonium chloride solution (21 mL). Zinc powder (3.3 g, 50 mmol) was added under stirring at room temperature, and stirring was continued at room temperature for 10 minutes. Di-tert-butyl dicarbonate (2.2 g, 10 mmol) was added to the reaction flask, and after stirring at room temperature, ethanol (100 mL) was added to dilute the reaction solution, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. Ethyl acetate (70 mL) and sodium bicarbonate aqueous solution (50 mL) were added to the residue, and the ethyl acetate phase was separated after shaking. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography, and C143-c (680 mg) was obtained by eluting with (ethyl acetate/petroleum ether = 0% to 20%). 1 H NMR (400 MHz, DMSO_d6) δ 11.30 (s, 1H), 8.73 (s, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 1H), 1.37 (s, 9H).
(3)向盛有C143-c(600mg，1.92mmol)的反应瓶中依次加入催化剂RuPhosPd-G3(161mg，0.19mmol)、碳酸铯(1.25g，3.84mmol)、超干溶剂甲苯(9mL)和2,4,6-三甲基-1,3,5,2,4,6-三甲氧基三硼烷(0.9mL，2.88mmol)，氮气置换三次后，油浴加热至80℃搅拌2小时。反应完成后冷却至室温，用二氯甲烷(50mL)稀释反应液，过滤除去不溶物，将滤液减压浓缩至干。所得残余物用硅胶柱层析纯化，用(乙酸乙酯/石油醚＝0％～50％)洗脱得C143-d(340mg)。1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.35(s,1H),7.61–7.51(m,2H),6.99–6.94(m,1H),2.50(s,3H),1.45(s,9H).(3) Catalyst RuPhosPd-G3 (161 mg, 0.19 mmol), cesium carbonate (1.25 g, 3.84 mmol), ultra-dry solvent toluene (9 mL) and 2,4,6-trimethyl-1,3,5,2,4,6-trimethoxytriborane (0.9 mL, 2.88 mmol) were added to the reaction bottle containing C143-c (600 mg, 1.92 mmol) in sequence. After nitrogen replacement three times, the oil bath was heated to 80 ° C and stirred for 2 hours. After the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with dichloromethane (50 mL), the insoluble matter was filtered out, and the filtrate was concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography and eluted with (ethyl acetate/petroleum ether = 0% to 50%) to obtain C143-d (340 mg). 1 H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.35 (s, 1H), 7.61–7.51 (m, 2H), 6.99–6.94 (m, 1H), 2.50 (s, 3H), 1.45 (s, 9H).
(4)向装有C143-d(320mg,1.29mmol)的单口瓶中加入盐酸二氧六环溶液(6mL)，室温搅拌2小时。反应完成后，减压浓缩干即得C143-e(246mg)。1H NMR(400MHz,DMSO_d6)δ12.71(s,1H),8.40(d,J＝8.4Hz,1H),8.10(s,1H),7.50(d,J＝8.4Hz,1H),2.79(s,3H).(4) Add dioxane hydrochloride solution (6 mL) to a single-necked bottle containing C143-d (320 mg, 1.29 mmol) and stir at room temperature for 2 hours. After the reaction is completed, concentrate under reduced pressure to dryness to obtain C143-e (246 mg). 1 H NMR (400 MHz, DMSO_d6) δ12.71 (s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.10 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 2.79 (s, 3H).
(5)将C143-e(138mg,0.75mmol)、C093-d(129mg，0.75mmol)和一水合对甲苯磺酸(143mg，0.75mmol)溶解在超干溶剂N,N-二甲基甲酰胺(2.5mL)中，反应液在90℃下搅拌16小时。反应完成后，此反应液可直接用于下一步。LCMS(ESI)m/z:282.2[M+H]+。(5) C143-e (138 mg, 0.75 mmol), C093-d (129 mg, 0.75 mmol) and p-toluenesulfonic acid monohydrate (143 mg, 0.75 mmol) were dissolved in an ultra-dry solvent N,N-dimethylformamide (2.5 mL), and the reaction solution was stirred at 90° C. for 16 hours. After the reaction was completed, the reaction solution was directly used in the next step. LCMS (ESI) m/z: 282.2 [M+H] + .
(6)向冷却至室温后的上一步反应液中加入int7(282mg，1.50mmol)，混合物在60℃下搅拌2小时。反应完成后，将反应液经高效液相分析纯化得C143(12.15mg)。1H NMR(400MHz,CD3OD)δ8.46(s,1H),8.27(s,1H),7.73(d,J＝8.4Hz,1H),7.10(d,J＝8.4Hz,1H),4.38(s,1H),2.67(s,3H),2.65(s,3H),2.28(s,3H),2.06–1.89(m,8H).LCMS(ESI)m/z:415.2[M+H]+。(6) Int7 (282 mg, 1.50 mmol) was added to the reaction solution cooled to room temperature, and the mixture was stirred at 60°C for 2 hours. After the reaction was completed, the reaction solution was purified by HPLC to obtain C143 (12.15 mg). 1 H NMR (400 MHz, CD 3 OD) δ8.46 (s, 1H), 8.27 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 4.38 (s, 1H), 2.67 (s, 3H), 2.65 (s, 3H), 2.28 (s, 3H), 2.06–1.89 (m, 8H). LCMS (ESI) m/z: 415.2 [M+H] + .
实施例144：
Embodiment 144:
合成路线
synthetic route
(1)将C144-a(4.5g，37.465mmol)溶解在二氯乙烷(500mL)中，分批加入间氯过氧苯甲酸(12.284g,71.184mmol，85％纯度)。混合液在氮气保护、85℃下搅拌4个小时。点板显示反应结束后，趁热过滤反应液。合并滤液后减压浓缩，所得残余物加入乙醇(200ml)，加热至溶解，然后冷却至室温，过滤混合物，合并滤饼，得C144-b(2g)。1H NMR(400MHz,DMSO_d6)δ8.48(d,J＝3.2Hz,1H),7.99(s,2H),7.86(d,J＝2.8Hz,1H).(1) C144-a (4.5 g, 37.465 mmol) was dissolved in dichloroethane (500 mL), and m-chloroperbenzoic acid (12.284 g, 71.184 mmol, 85% purity) was added in batches. The mixture was stirred at 85°C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was filtered while hot. The filtrates were combined and concentrated under reduced pressure. Ethanol (200 ml) was added to the residue, heated until dissolved, and then cooled to room temperature. The mixture was filtered and the filter cakes were combined to obtain C144-b (2 g). 1 H NMR (400 MHz, DMSO_d6) δ8.48 (d, J = 3.2 Hz, 1H), 7.99 (s, 2H), 7.86 (d, J = 2.8 Hz, 1H).
(2)将C144-b(1g，7.346mmol)溶解在N,N-二甲基甲酰胺(10mL)中，降温至0℃后向溶液中滴加三氯氧磷(1.6g,11.02mmol)，滴加过程中混合液温度不超过5℃。滴加完成后，将混合液在氮气保护、80℃下搅拌1小时。反应结束后，将反应液滴入冰水中，搅拌过夜。混合液用乙酸乙酯萃取三次(50mL x 3)，合并有机相，减压浓缩，所得残余物用硅胶柱分离纯化(0％-10％乙酸乙酯/石油醚)，得C144-c(500mg)。LCMS(ESI)m/z:155.0[M+H]+。(2) C144-b (1 g, 7.346 mmol) was dissolved in N,N-dimethylformamide (10 mL), and phosphorus oxychloride (1.6 g, 11.02 mmol) was added dropwise to the solution after cooling to 0°C. The temperature of the mixed solution did not exceed 5°C during the addition. After the addition was completed, the mixed solution was stirred at 80°C for 1 hour under nitrogen protection. After the reaction was completed, the reaction solution was dropped into ice water and stirred overnight. The mixed solution was extracted three times with ethyl acetate (50 mL x 3), the organic phases were combined, and concentrated under reduced pressure. The residue was separated and purified by silica gel column (0%-10% ethyl acetate/petroleum ether) to obtain C144-c (500 mg). LCMS (ESI) m/z: 155.0 [M+H] + .
(3)将C144-c(500mg，3.234mmol)、C144-d(445mg,3.545mmol)、四(三苯基膦)钯(186 mg,0.161mmol)和碳酸钾(875mg,6.331mmol)加入二氧六环(20mL)中，混合液在氮气保护下于95℃搅拌16小时。LCMS显示反应结束，将反应液减压浓缩后，加水稀释，用乙酸乙酯萃取三次(20mL x 3)，合并有机相,减压浓缩,所得残余物用硅胶柱分离纯化(0％-30％乙酸乙酯/石油醚)，得C144-e(300mg)。LCMS(ESI)m/z:135.1[M+H]+。(3) C144-c (500 mg, 3.234 mmol), C144-d (445 mg, 3.545 mmol), tetrakis(triphenylphosphine)palladium (186 mg, 0.161mmol) and potassium carbonate (875mg, 6.331mmol) were added to dioxane (20mL), and the mixture was stirred at 95°C for 16 hours under nitrogen protection. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate three times (20mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was separated and purified by silica gel column (0%-30% ethyl acetate/petroleum ether) to obtain C144-e (300mg). LCMS (ESI) m/z: 135.1 [M+H] + .
(4)将C144-e(122mg，0.909mmol)溶解在N,N-二甲基甲酰胺(4mL)中，降温至0℃。将NBS(663mg，3.727mmol)溶解在N,N-二甲基甲酰胺(5mL)中，然后滴加到反应液中，滴加过程中混合溶液温度不超过5℃。滴加结束后，将混合液在氮气保护下常温搅拌。反应结束后向混合溶液中加入饱和氯化铵水溶液(10mL)淬灭反应，并加水稀释，用乙酸乙酯萃取三次(50mL x 3)，合并有机相，减压浓缩，所得残余物用硅胶板纯化(石油醚：乙酸乙酯＝5：1)，得C144-f(100mg)。LCMS(ESI)m/z:215.0[M+H]+。(4) C144-e (122 mg, 0.909 mmol) was dissolved in N,N-dimethylformamide (4 mL) and cooled to 0°C. NBS (663 mg, 3.727 mmol) was dissolved in N,N-dimethylformamide (5 mL) and then added dropwise to the reaction solution. The temperature of the mixed solution did not exceed 5°C during the addition. After the addition was completed, the mixed solution was stirred at room temperature under nitrogen protection. After the reaction was completed, a saturated aqueous solution of ammonium chloride (10 mL) was added to the mixed solution to quench the reaction, and the mixture was diluted with water and extracted with ethyl acetate three times (50 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel plate (petroleum ether: ethyl acetate = 5:1) to obtain C144-f (100 mg). LCMS (ESI) m/z: 215.0 [M+H] + .
(5)将C144-f(120mg，0.563mmol)、C144-g(244mg,0.675mmol)和四(三苯基膦)钯(64mg,0.056mmol)溶解在超干甲苯(5mL)中，混合液在氮气保护下于110℃搅拌16个小时。点板检测反应结束后，向混合溶液中加入2M盐酸水溶液(4ml),在60℃下搅拌2个小时。反应结束后，缓慢滴加饱和碳酸氢钠水溶液调节pH至中性。混合溶液加水稀释，用乙酸乙酯萃取三次(40mL x 3)，合并有机相，减压浓缩，所得残余物用硅胶板纯化(石油醚：乙酸乙酯＝4：1)，得到C144-h(240mg)。LCMS(ESI)m/z:177.0[M+H]+。(5) C144-f (120 mg, 0.563 mmol), C144-g (244 mg, 0.675 mmol) and tetrakis(triphenylphosphine)palladium (64 mg, 0.056 mmol) were dissolved in ultra-dry toluene (5 mL), and the mixture was stirred at 110°C for 16 hours under nitrogen protection. After the reaction was completed by spot plate detection, 2M hydrochloric acid aqueous solution (4 ml) was added to the mixed solution and stirred at 60°C for 2 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution was slowly added dropwise to adjust the pH to neutral. The mixed solution was diluted with water and extracted with ethyl acetate three times (40 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel plate (petroleum ether: ethyl acetate = 4:1) to obtain C144-h (240 mg). LCMS (ESI) m/z: 177.0 [M+H] + .
(6)将C144-h(240mg，纯度60％)、氯化铜(220mg,1.636mmol)和亚硝酸叔丁酯(191mg,1.636mmol)溶解在乙腈(10mL)中，混合液在氮气保护下于65℃搅拌16个小时。点板检测反应结束后，向混合溶液中加水，淬灭反应，用乙酸乙酯萃取三次(40mL x 3)，合并有机相，减压浓缩，所得残余物用硅胶板纯化(石油醚：乙酸乙酯＝4：1)，得到C144-i(80mg)。1H NMR(400MHz,DMSO_d6)δ2.78(s,3H),2.62(s,3H).(6) C144-h (240 mg, purity 60%), cupric chloride (220 mg, 1.636 mmol) and tert-butyl nitrite (191 mg, 1.636 mmol) were dissolved in acetonitrile (10 mL), and the mixture was stirred at 65 ° C for 16 hours under nitrogen protection. After the reaction was completed, water was added to the mixed solution to quench the reaction, and it was extracted with ethyl acetate three times (40 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel plate (petroleum ether: ethyl acetate = 4:1) to obtain C144-i (80 mg). 1 H NMR (400 MHz, DMSO_d6) δ2.78 (s, 3H), 2.62 (s, 3H).
(7)将C144-i(80mg，0.408mmol)、int2(81mg,0.49mmol)和N-乙基二异丙胺(63mg,0.49mmol)溶解在二甲基亚砜(2mL)中。混合液在氮气保护下于20℃搅拌2个小时。反应结束后向混合溶液中加水淬灭反应，用乙酸乙酯萃取三次(15mL x 3)，合并有机相，减压浓缩，所得残余物用硅胶板纯化(二氯甲烷：甲醇＝10：1)，得到C144-j(100mg)。LCMS(ESI)m/z:326.0[M+H]+。(7) C144-i (80 mg, 0.408 mmol), int2 (81 mg, 0.49 mmol) and N-ethyldiisopropylamine (63 mg, 0.49 mmol) were dissolved in dimethyl sulfoxide (2 mL). The mixture was stirred at 20 °C for 2 hours under nitrogen protection. After the reaction was completed, water was added to the mixed solution to quench the reaction, and the mixture was extracted with ethyl acetate three times (15 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel plate (dichloromethane: methanol = 10: 1) to obtain C144-j (100 mg). LCMS (ESI) m/z: 326.0 [M+H] + .
(8)将C144-j(100mg，0.306mmol)、int7(51mg,0.337mmol)和一水合对甲苯磺酸(10mg,0.061mmol)溶解在N,N-二甲基甲酰胺(2mL)中。混合液在氮气保护下于70℃搅拌4个小时。反应结束后过滤反应液，滤液用制备型高效液相纯化，得化合物C144(5.06mg)。LCMS(ESI)m/z:459.2[M+H]+，1H NMR(400MHz,DMSO_d6)δ11.24(s,1H),9.47(s,1H),7.65(s,1H),7.56(s,1H),7.41(d,J＝8.8Hz,1H),7.11(d,J＝8.8Hz,1H),4.33-4.37(m,1H),2.55(s,3H),2.19(s,3H),2.03–1.88(m,8H).(8) C144-j (100 mg, 0.306 mmol), int7 (51 mg, 0.337 mmol) and p-toluenesulfonic acid monohydrate (10 mg, 0.061 mmol) were dissolved in N,N-dimethylformamide (2 mL). The mixture was stirred at 70 °C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was filtered and the filtrate was purified by preparative high performance liquid chromatography to obtain compound C144 (5.06 mg). LCMS (ESI) m/z: 459.2 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 9.47 (s, 1H), 7.65 (s, 1H), 7.56 (s, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 4.33-4.37 (m, 1H), 2.55 (s, 3H), 2.19 (s, 3H), 2.03–1.88 (m, 8H).
实施例146：
Embodiment 146:
合成路线
synthetic route
(1)将C146-a(5g，24.1mmol，1eq)、甲硫醇钠(2.03g，29mmol，1.2eq)溶解在甲醇(60mL)中。反应体系用氮气置换三次，并在65℃下搅拌3h。反应结束后，将反应液浓缩，并加入水(300mL)，用乙酸乙酯(300mL x 2)萃取，有机相用饱和的食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸馏，所得粗产品经过硅胶柱层析(石油醚:乙酸乙酯＝0-10％)纯化得C146-b(3g)。LCMS(ESI) m/z:221.9[M+H]+。(1) C146-a (5 g, 24.1 mmol, 1 eq) and sodium thiomethoxide (2.03 g, 29 mmol, 1.2 eq) were dissolved in methanol (60 mL). The reaction system was replaced with nitrogen three times and stirred at 65° C. for 3 h. After the reaction, the reaction solution was concentrated, and water (300 mL) was added, and extracted with ethyl acetate (300 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0-10%) to obtain C146-b (3 g). LCMS (ESI) m/z: 221.9 [M+H] + .
(2)将C146-b(2.5g，11.41mmol，1eq)溶解在二氯甲烷(70mL)中，在0℃下分批加入间氯过氧苯甲酸(4.92g，28.5mmol，2.5eq)。之后将反应体系温度升至室温反应，将反应液在室温下减压浓缩，所得粗产品经过硅胶柱层析(石油醚:乙酸乙酯＝0～20％)纯化得化合物得到C146-c(1.2g)LCMS(ESI)m/z:251.9[M+H]+。(2) C146-b (2.5 g, 11.41 mmol, 1 eq) was dissolved in dichloromethane (70 mL), and m-chloroperbenzoic acid (4.92 g, 28.5 mmol, 2.5 eq) was added in batches at 0°C. The reaction system was then heated to room temperature for reaction, and the reaction solution was concentrated under reduced pressure at room temperature. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0-20%) to obtain compound C146-c (1.2 g) LCMS (ESI) m/z: 251.9 [M+H] + .
(3)将C146-c(1g，3.98mmol,1eq)溶解在甲苯(15mL)中，加入四(三苯基膦)钯(460mg，0.4mmol，0.1eq)和三丁基(1-乙氧基乙烯基)锡(1.73g，4.78mmol，1.2eq)，氮气保护下，油浴加热至80℃，搅拌反应16小时。反应完全后，所得反应液即为粗品C146-d溶液直接用于下一步骤。(3) C146-c (1 g, 3.98 mmol, 1 eq) was dissolved in toluene (15 mL), and tetrakis(triphenylphosphine)palladium (460 mg, 0.4 mmol, 0.1 eq) and tributyl(1-ethoxyvinyl)tin (1.73 g, 4.78 mmol, 1.2 eq) were added. Under nitrogen protection, the oil bath was heated to 80°C and stirred for 16 hours. After the reaction was complete, the resulting reaction solution was the crude C146-d solution, which was directly used in the next step.
(4)向盛有C146-d的混合溶液的反应瓶中加入盐酸水溶液(4mol/L，15mL，60mmol)，反应液在60℃下搅拌2小时。反应完成后冷却至室温，分出有机相，水相用二氯甲烷(100mL)萃取一次。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物用硅胶柱层析纯化，经(石油醚:乙酸乙酯＝0-15％)洗脱得C146-e(300mg)。LCMS(ESI)m/z:216.0[M+H]+。(4) Aqueous hydrochloric acid solution (4 mol/L, 15 mL, 60 mmol) was added to the reaction flask containing the mixed solution of C146-d, and the reaction solution was stirred 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 once with dichloromethane (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 0-15%) to obtain C146-e (300 mg). LCMS (ESI) m/z: 216.0 [M+H] + .
(5)将C146-e(300mg，1.39mmol，1eq)、亚硝酸叔丁酯(172mg，0.167mmol，1.2eq)、氯化铜(220mg，0.167mmol，1.2eq)溶解在乙腈(7mL)中。置换氮气，在65℃下搅拌16h。反应结束后，浓缩反应液，向反应液加入水(30mL)，用乙酸乙酯萃取。有机相用饱和的食盐水洗涤，再加入无水硫酸钠干燥，过滤，有机相减压蒸馏，所得残余物经过硅胶柱层析(石油醚:乙酸乙酯＝0～25％)纯化得C146-f(100mg)。1H NMR(400MHz,DMSO_d6)δ9.19(s,1H),3.60(s,3H),2.67(s,3H).(5) C146-e (300 mg, 1.39 mmol, 1 eq), tert-butyl nitrite (172 mg, 0.167 mmol, 1.2 eq), and cupric chloride (220 mg, 0.167 mmol, 1.2 eq) were dissolved in acetonitrile (7 mL). The nitrogen atmosphere was replaced and the mixture was stirred at 65°C for 16 h. After the reaction was completed, the reaction solution was concentrated, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was distilled under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0-25%) to obtain C146-f (100 mg). 1 H NMR (400 MHz, DMSO_d 6 )δ9.19 (s, 1H), 3.60 (s, 3H), 2.67 (s, 3H).
(6)依次将C146-f(100mg，0.425mmol，1.0eq)、int2(105mg，0.515mmol，1.2eq)以及N,N-二异丙基乙胺(110mg,0.85mmol，2.0eq)溶解在二甲基亚砜(3mL)中。氮气保护下混合物于60℃油浴中搅拌2h。反应结束后，将反应液冷却至室温，反应液加水析出粗品C146-g(120mg)，直接用于下一步。LCMS(ESI)m/z:365.1[M+H]+。(6) C146-f (100 mg, 0.425 mmol, 1.0 eq), int2 (105 mg, 0.515 mmol, 1.2 eq) and N,N-diisopropylethylamine (110 mg, 0.85 mmol, 2.0 eq) were dissolved in dimethyl sulfoxide (3 mL) in sequence. The mixture was stirred in a 60 °C oil bath under nitrogen protection for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, and water was added to the reaction solution to precipitate the crude product C146-g (120 mg), which was directly used in the next step. LCMS (ESI) m/z: 365.1 [M+H] + .
(7)将C146-g(120mg，0.33mmol，1eq)、int7(72mg，0.396mmol，1.2eq)和一水合对甲苯磺酸(14mg，0.08mmol，0.2eq)溶解在N,N-二甲基甲酰胺(2mL)中。反应液在60℃下反应2小时，反应结束后，反应液直接用高效液相制备纯化得化合物C146(64.50mg)。1H NMR(400MHz,DMSO_d6)δ11.27(s,1H),9.11(s,1H),8.87(s,1H),7.81(d,J＝2.4Hz,1H),7.44(d,J＝8.8Hz,1H),7.37(s,1H),7.15(dd,J＝8.4,2.0Hz,1H),4.40(s,1H),3.51(s,3H),2.24(s,3H),2.04-1.89(m,8H).LCMS(ESI)m/z:498.2[M+H]+。(7) C146-g (120 mg, 0.33 mmol, 1 eq), int7 (72 mg, 0.396 mmol, 1.2 eq) and p-toluenesulfonic acid monohydrate (14 mg, 0.08 mmol, 0.2 eq) were dissolved in N,N-dimethylformamide (2 mL). The reaction solution was reacted at 60° C. for 2 hours. After the reaction was completed, the reaction solution was directly purified by high performance liquid chromatography to obtain compound C146 (64.50 mg). 1 H NMR (400 MHz, DMSO_d6) δ 11.27 (s, 1H), 9.11 (s, 1H), 8.87 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.37 (s, 1H), 7.15 (dd, J = 8.4, 2.0 Hz, 1H), 4.40 (s, 1H), 3.51 (s, 3H), 2.24 (s, 3H), 2.04-1.89 (m, 8H). LCMS (ESI) m/z: 498.2 [M+H] + .
实施例147：
Embodiment 147:
合成路线
synthetic route
(1)将C147-a(1g，3.225mmol，1eq)、甲磺酸钠(430mg，4.2mmol，1.3eq)、碘化亚铜(380mg，0.65mmol，0.2eq)、L-脯氨酸(150mg，1.3mmol，0.4eq)溶解在二甲基亚砜(20mL)中。反应体系用氮气置换三次，然后在120℃下搅拌3h。反应结束后，将反应液降温至室温，加入 水(100mL)，搅拌5分钟。再用乙酸乙酯萃取，有机相用饱和的食盐水洗涤，无水硫酸钠干燥，过滤。有机相减压蒸馏，所得粗产品经过硅胶柱层析(石油醚:乙酸乙酯＝0～10％)纯化得C147-b(300mg)。LCMS(ESI)m/z:255.0[M-55]+。(1) C147-a (1 g, 3.225 mmol, 1 eq), sodium methanesulfonate (430 mg, 4.2 mmol, 1.3 eq), cuprous iodide (380 mg, 0.65 mmol, 0.2 eq), and L-proline (150 mg, 1.3 mmol, 0.4 eq) were dissolved in dimethyl sulfoxide (20 mL). The reaction system was replaced with nitrogen three times and then stirred at 120°C for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature and added Water (100 mL), stirred for 5 minutes. Extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The organic phase was distilled under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0-10%) to obtain C147-b (300 mg). LCMS (ESI) m/z: 255.0 [M-55] + .
(2)将C147-b(300mg，0.967mmol，1eq)溶解在盐酸二氧六环(3mL)中，在室温下搅拌1h。反应结束后，将反应液减压浓缩，得到C147-c(200mg)用于下一步反应。LCMS(ESI)m/z:211.1[M+H]+。(2) C147-b (300 mg, 0.967 mmol, 1 eq) was dissolved in dioxane hydrochloride (3 mL) and stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain C147-c (200 mg) for the next reaction. LCMS (ESI) m/z: 211.1 [M+H] + .
(3)依次将C147-c(200mg，0.81mmol，1.2eq)、C093-d(115mg，0.675mmol，1.0eq)以及N,N-二异丙基乙胺(175mg,1.35mmol，2.0eq)溶解在二甲基亚砜(2mL)中。氮气保护下，混合物于90℃油浴中搅拌1h。反应结束后，将反应液冷却至室温，向反应液加入水(20mL)，再加入乙酸乙酯(20mL x 2)萃取，分液。有机相用饱和的食盐水洗涤，无水硫酸钠进行干燥，过滤。有机相减压蒸馏，所得粗产品经过硅胶柱层析(石油醚:乙酸乙酯＝0-30％)纯化得化合物得到C147-d(30mg)。LCMS(ESI)m/z:345.1[M+H]+。(3) C147-c (200 mg, 0.81 mmol, 1.2 eq), C093-d (115 mg, 0.675 mmol, 1.0 eq) and N,N-diisopropylethylamine (175 mg, 1.35 mmol, 2.0 eq) were dissolved in dimethyl sulfoxide (2 mL) in sequence. Under nitrogen protection, the mixture was stirred in an oil bath at 90°C for 1 h. After the reaction was completed, the reaction solution was cooled to room temperature, water (20 mL) was added to the reaction solution, and then ethyl acetate (20 mL x 2) was added for extraction and separation. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The organic phase was distilled under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0-30%) to obtain the compound C147-d (30 mg). LCMS (ESI) m/z: 345.1 [M+H] + .
(4)将C147-d(30mg，0.087mmol，1eq)、int7(20mg，0.104mmol，1.2eq)和一水合对甲苯磺酸(4mg，0.0208mmol，0.2eq)溶解在N,N-二甲基甲酰胺(1mL)中。反应液在60℃下反应4小时。反应结束后，反应液用高效液相制备纯化得化合物C147(6.80mg)。LCMS(ESI)m/z:478.3[M+H]+，1H NMR(400MHz,DMSO_d6)δ11.47(s,1H),8.55(s,1H),8.38(s,1H),8.35(s,1H),7.95(d,J＝2.4Hz,1H),7.64–7.57(m,2H),4.35(s,1H),3.15(s,3H),2.62(s,3H),2.22(s,3H),2.03–1.85(m,8H).(4) C147-d (30 mg, 0.087 mmol, 1 eq), int7 (20 mg, 0.104 mmol, 1.2 eq) and p-toluenesulfonic acid monohydrate (4 mg, 0.0208 mmol, 0.2 eq) were dissolved in N,N-dimethylformamide (1 mL). The reaction solution was reacted at 60° C. for 4 hours. After the reaction was completed, the reaction solution was purified by high performance liquid chromatography to obtain compound C147 (6.80 mg). LCMS (ESI) m/z: 478.3 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.55 (s, 1H), 8.38 (s, 1H), 8.35 (s, 1H), 7.95 (d, J=2.4 Hz, 1H), 7.64–7.57 (m, 2H), 4.35 (s, 1H), 3.15 (s, 3H), 2.62 (s, 3H), 2.22 (s, 3H), 2.03–1.85 (m, 8H).
实施例148：
Embodiment 148:
合成路线
synthetic route
(1)将C148-a(5.0g，23.44mmol)、3b(4.21g，25.78mmol)和三苯基膦(18.0g，25.78mmol)溶解在超干四氢呋喃(150mL)中，氮气保护下搅拌，在0℃滴加DBAD(5.94g，25.78mmol)。反应液在搅拌下自然升温至室温下搅拌16小时。反应液减压浓缩所得残余物用硅胶柱层析纯化，用(PE:EA＝4:1)洗脱得C148-b(6.5g)。1H NMR(400MHz,DMSO_d6)δ7.87(s,4H),4.66–4.63(m,1H),3.85–3.80(m,4H),2.50-2.48(m,2H),2.38–2.31(m,2H),1.36(s,9H).(1) C148-a (5.0 g, 23.44 mmol), 3b (4.21 g, 25.78 mmol) and triphenylphosphine (18.0 g, 25.78 mmol) were dissolved in ultra-dry tetrahydrofuran (150 mL), stirred under nitrogen protection, and DBAD (5.94 g, 25.78 mmol) was added dropwise at 0°C. The reaction solution was naturally heated to room temperature under stirring and stirred for 16 hours. The reaction solution was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain C148-b (6.5 g). 1 H NMR (400 MHz, DMSO_d6) δ7.87 (s, 4H), 4.66–4.63 (m, 1H), 3.85–3.80 (m, 4H), 2.50-2.48 (m, 2H), 2.38–2.31 (m, 2H), 1.36 (s, 9H).
(2)将C148-b(1g，2.79mmol)溶解在二氯甲烷/甲醇(10:1)(11mL)中，然后滴加水合肼(0.28g，5.56mmol，68％)。反应液在室温搅拌2小时。反应完成后，将反应液过滤，先用二氯甲烷(10mL)洗涤滤饼，再用氨水洗涤滤饼，分离有机相减压浓缩，得C148-c(610mg)。1H NMR(400MHz,DMSO-d6)δ5.80(s,2H),3.97–3.94(m,1H),3.79–3.76(m,4H),2.34–2.29(m,2H),2.07–2.02(m,2H),1.36(s,9H).(2) C148-b (1 g, 2.79 mmol) was dissolved in dichloromethane/methanol (10:1) (11 mL), and then hydrazine hydrate (0.28 g, 5.56 mmol, 68%) was added dropwise. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with dichloromethane (10 mL) first, and then with ammonia water, the organic phase was separated and concentrated under reduced pressure to obtain C148-c (610 mg). 1 H NMR (400 MHz, DMSO-d6) δ5.80 (s, 2H), 3.97–3.94 (m, 1H), 3.79–3.76 (m, 4H), 2.34–2.29 (m, 2H), 2.07–2.02 (m, 2H), 1.36 (s, 9H).
(3)将C148-c(0.2g，0.69mmol)、C093-e(0.25g，0.83mmol)、一水合对甲苯磺酸(0.03g,0.14mmol)溶解在超干乙腈(5mL)中，氮气保护下60℃搅拌2小时。反应结束后，反应液减压浓缩所得残余物用硅胶柱层析纯化，用(PE:EA＝4:1)洗脱得C148-d(290mg)。LCMS(ESI)m/z:511.1[M+H]+。(3) C148-c (0.2 g, 0.69 mmol), C093-e (0.25 g, 0.83 mmol), p-toluenesulfonic acid monohydrate (0.03 g, 0.14 mmol) were dissolved in ultra-dry acetonitrile (5 mL) and stirred at 60°C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain C148-d (290 mg). LCMS (ESI) m/z: 511.1 [M+H] + .
(4)将C148-d(290mg，0.57mmol)溶解在二氯甲烷(2.5mL)中，加入三氟乙酸(0.5mL)。反应液在室温下搅拌1小时。反应结束后，将反应液减压浓缩所得C148-e(280mg)。LCMS(ESI)m/z:411.2[M+H]+。(4) C148-d (290 mg, 0.57 mmol) was dissolved in dichloromethane (2.5 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain C148-e (280 mg). LCMS (ESI) m/z: 411.2 [M+H] + .
(5)将C148-e(100mg，0.24mmol)溶解在超干乙腈(1.5mL)中，然后加入TEA(49mg， 0.48mmol)，再加入3a(57mg，0.24mmol)。室温下搅拌1小时。反应结束后，反应液减压浓缩所得残余用高效液相制备分析纯化得化合物C148(14.84mg)。LCMS(ESI)m/z:493.2[M+H]+，1H NMR(400MHz,CD3CN)δ9.27(s,1H),8.37(s,1H),7.71(d,J＝2.4Hz,1H),7.60(s,1H),7.43(d,J＝8.8Hz,1H),7.17(dd,J＝8.4,2.0Hz,1H),6.96(s,1H),4.70–4.63(m,1H),3.40–3.70(m,4H),3.05(q,J＝9.2Hz,2H),2.58(s,3H),2.55–2.49(m,2H),2.31–2.26(m,2H),2.24(s,3H).(5) C148-e (100 mg, 0.24 mmol) was dissolved in ultra-dry acetonitrile (1.5 mL), and then TEA (49 mg, 0.48 mmol), and then 3a (57 mg, 0.24 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and the residue was purified by high performance liquid chromatography to obtain compound C148 (14.84 mg). LCMS (ESI) m/z: 493.2 [M+H] + , 1 H NMR (400 MHz, CD 3 CN) δ 9.27 (s, 1H), 8.37 (s, 1H), 7.71 (d, J=2.4 Hz, 1H), 7.60 (s, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.17 (dd, J=8.4, 2.0 Hz, 1H), 6.96 (s, 1H), 4.70–4.63 (m, 1H), 3.40–3.70 (m, 4H), 3.05 (q, J=9.2 Hz, 2H), 2.58 (s, 3H), 2.55–2.49 (m, 2H), 2.31–2.26 (m, 2H), 2.24 (s, 3H).
实施例151：
Embodiment 151:
合成路线
synthetic route
(1)将C151-a(1.5g，17.83mmol)溶解在超干二氯甲烷(15.0mL)中，然后加入三乙胺(2.97ml，21.4mmol)，室温下搅拌反应15分钟后，加入苯甲酰氯(2.5ml,21.4mmol)。室温下搅拌反应18小时后停止反应。反应结束后，加入水洗涤有机相，使用无水硫酸钠干燥有机相，过滤，所得有机相减压浓缩，所得残余物用柱层析纯化(石油醚:乙酸乙酯＝100:0到97:3)洗脱得到C151-b(2.13g)。1H NMR(400MHz,CDCl3)δ8.08–7.98(m,2H),7.54(t,J＝7.2Hz,1H),7.42(t,J＝7.6Hz,2H),5.80–5.72(m,2H),5.64-5.60(m,1H),2.86(dd,J＝16.4,7.2Hz,2H),2.55(dd,J＝16.4,2.4Hz,2H).(1) C151-a (1.5 g, 17.83 mmol) was dissolved in ultra-dry dichloromethane (15.0 mL), and then triethylamine (2.97 ml, 21.4 mmol) was added. After stirring at room temperature for 15 minutes, benzoyl chloride (2.5 ml, 21.4 mmol) was added. After stirring at room temperature for 18 hours, the reaction was stopped. After the reaction was completed, water was added to wash the organic phase, and the organic phase was dried over anhydrous sodium sulfate and filtered. The obtained organic phase was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0 to 97:3) to obtain C151-b (2.13 g). 1 H NMR (400 MHz, CDCl 3 ) δ 8.08–7.98 (m, 2H), 7.54 (t, J=7.2 Hz, 1H), 7.42 (t, J=7.6 Hz, 2H), 5.80–5.72 (m, 2H), 5.64-5.60 (m, 1H), 2.86 (dd, J=16.4, 7.2 Hz, 2H), 2.55 (dd, J=16.4, 2.4 Hz, 2H).
(2)在25ml三口烧瓶中加入C151-b(2.25g，11.95mmol)和氟化钠(15mg,0.36mmol)，氮气置换三次后，在100℃下滴加三甲基硅烷基2-(氟磺酰基)二氟乙酸酯(5.9ml,30mmol)，反应液在100℃下反应17小时。反应结束后，使用二氯甲烷(60ml)稀释反应液，用水(30ml)洗涤有机相，接着使用饱和碳酸氢钠溶液(30ml)洗涤有机相，然后用饱和食盐水(30ml)洗涤有机相，有机相用无水硫酸钠干燥，过滤，所得有机相减压浓缩，所得残余物用硅胶柱层析纯化，(石油醚:乙酸乙酯＝100:0到95:5)洗脱得到C151-c(344mg)。1H NMR(400MHz,CDCl3)δ8.05–7.98(m,2H),7.55(t,J＝7.2Hz,1H),7.45–7.41(m,2H),5.59–5.53(m,1H),2.71–2.56(m,2H),2.07–2.02(m,4H).(2) C151-b (2.25 g, 11.95 mmol) and sodium fluoride (15 mg, 0.36 mmol) were added to a 25 ml three-necked flask. After nitrogen replacement three times, trimethylsilyl 2-(fluorosulfonyl) difluoroacetate (5.9 ml, 30 mmol) was added dropwise at 100°C. The reaction solution was reacted at 100°C for 17 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane (60 ml), and the organic phase was washed with water (30 ml), followed by a saturated sodium bicarbonate solution (30 ml), and then with a saturated saline solution (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and the obtained organic phase was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:0 to 95:5) to obtain C151-c (344 mg). 1 H NMR (400 MHz, CDCl 3 ) δ 8.05–7.98 (m, 2H), 7.55 (t, J=7.2 Hz, 1H), 7.45–7.41 (m, 2H), 5.59–5.53 (m, 1H), 2.71–2.56 (m, 2H), 2.07–2.02 (m, 4H).
(3)将C151-c(344mg，1.39mmol)溶解在甲醇(3ml)中。加入氢氧化钾水溶液(85.3mg in3ml H2O)，室温下搅拌反应16小时。反应结束后，使用二氯甲烷(10mlx3)萃取反应液，合并有机相，使用无水硫酸钠干燥，过滤，减压浓缩得到C151-d(214mg)。1H NMR(400MHz,CDCl3)δ4.52–4.45(m,1H),2.47–2.43(m,2H),1.99–1.91(m,2H),1.84–1.80(m,2H).(3) C151-c (344 mg, 1.39 mmol) was dissolved in methanol (3 ml). Aqueous potassium hydroxide solution (85.3 mg in 3 ml H 2 O) was added and the mixture was stirred at room temperature for 16 hours. After the reaction, the reaction solution was extracted with dichloromethane (10 ml x 3), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain C151-d (214 mg). 1 H NMR (400 MHz, CDCl 3 ) δ 4.52–4.45 (m, 1H), 2.47–2.43 (m, 2H), 1.99–1.91 (m, 2H), 1.84–1.80 (m, 2H).
(4)将C151-d(210mg，1.57mmol)和N-羟基邻苯二甲酰亚胺(333mg,2.04mmol)溶解在超干四氢呋喃(5.0mL)中，氮气置换三次,然后,在0℃下加入三苯基膦(535mg，2.04mmol)，搅拌反应17分钟后，滴加偶氮二甲酸二叔丁酯(470mg，2.04mmol)(溶解在4mL超干四氢呋喃中)，滴加完毕后，反应液在室温下搅拌16小时。反应结束后，直接加入硅胶吸附反应物，减压浓缩，所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝100:0到85:15)洗脱得C151-e(150mg)。1H NMR(400MHz,CDCl3)δ7.87–7.82(m,2H),7.79–7.74(m,2H),4.85–4.76(m,1H),2.46–2.38(m,2H),2.30–2.25(m,2H),2.22–2.15(m,2H).(4) C151-d (210 mg, 1.57 mmol) and N-hydroxyphthalimide (333 mg, 2.04 mmol) were dissolved in ultra-dry tetrahydrofuran (5.0 mL), and the atmosphere was replaced with nitrogen three times. Then, triphenylphosphine (535 mg, 2.04 mmol) was added at 0°C, and the mixture was stirred for 17 minutes. Then, di-tert-butyl azodicarboxylate (470 mg, 2.04 mmol) (dissolved in 4 mL ultra-dry tetrahydrofuran) was added dropwise. After the addition was complete, the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, silica gel was directly added to absorb the reactants, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography and eluted with (petroleum ether: ethyl acetate = 100:0 to 85:15) to obtain C151-e (150 mg). 1 H NMR (400 MHz, CDCl 3 ) δ 7.87–7.82 (m, 2H), 7.79–7.74 (m, 2H), 4.85–4.76 (m, 1H), 2.46–2.38 (m, 2H), 2.30–2.25 (m, 2H), 2.22–2.15 (m, 2H).
(5)将C151-e(150mg，0.54mmol)溶解在二氯甲烷(5ml)和甲醇(0.5ml)的混合溶剂中，在室温下滴加水合肼(32.3mg,0.64mmol)，反应液在室温下反应2小时。反应结束后，反应液用氨水(5N，10ml)洗涤，水相用二氯甲烷(10mlx3)萃取，减压浓缩后，将残余物溶解在二氯甲烷(20ml)和水(20ml)中，加入浓盐酸(10ml),分液后，水相用二氯甲烷(15mL x 3)洗涤，水相冷冻干燥得到C151-f(66mg)。1H NMR(400MHz,DMSO_d6)δ10.85(s,2H),4.62–4.51(m,1H),2.31–2.05(m,6H). (5) C151-e (150 mg, 0.54 mmol) was dissolved in a mixed solvent of dichloromethane (5 ml) and methanol (0.5 ml), and hydrazine hydrate (32.3 mg, 0.64 mmol) was added dropwise at room temperature. The reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was washed with ammonia water (5N, 10 ml), and the aqueous phase was extracted with dichloromethane (10 ml x 3). After reduced pressure concentration, the residue was dissolved in dichloromethane (20 ml) and water (20 ml), and concentrated hydrochloric acid (10 ml) was added. After separation, the aqueous phase was washed with dichloromethane (15 mL x 3), and the aqueous phase was freeze-dried to obtain C151-f (66 mg). 1 H NMR (400 MHz, DMSO_d6) δ10.85 (s, 2H), 4.62–4.51 (m, 1H), 2.31–2.05 (m, 6H).
(6)将C151-f(61.2mg，0.33mmol)、C093-e(66.2mg,0.22mmol)和一水合对甲苯磺酸(5mg，0.027mmol)溶解在超干N,N-二甲基甲酰胺(0.8ml)中。反应液于60℃油浴中搅拌96分钟。反应结束后，过滤反应液，通过高效液相制备分离(甲酸酸法分离)C151(27.15mg)。1H NMR(400MHz,DMSO_d6)δ11.08(s,1H),8.33(s,1H),8.30(s,1H),7.77(d,J＝2.4Hz,1H),7.68(d,J＝2.0Hz,1H),7.38(d,J＝8.4Hz,1H),7.09(dd,J＝8.4,2.0Hz,1H),4.75–4.56(m,1H),2.58(s,3H),2.28–2.10(m,9H)，LCMS(ESI)m/z:432.2[M+H]+。(6) C151-f (61.2 mg, 0.33 mmol), C093-e (66.2 mg, 0.22 mmol) and p-toluenesulfonic acid monohydrate (5 mg, 0.027 mmol) were dissolved in ultra-dry N,N-dimethylformamide (0.8 ml). The reaction solution was stirred in an oil bath at 60°C for 96 minutes. After the reaction was completed, the reaction solution was filtered and C151 (27.15 mg) was separated by HPLC (formic acid separation). 1 H NMR (400 MHz, DMSO_d6) δ 11.08 (s, 1H), 8.33 (s, 1H), 8.30 (s, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.09 (dd, J = 8.4, 2.0 Hz, 1H), 4.75–4.56 (m, 1H), 2.58 (s, 3H), 2.28–2.10 (m, 9H), LCMS (ESI) m/z: 432.2 [M+H] + .
实施例152：
Embodiment 152:
合成路线
synthetic route
(1)将C152-a(2.0g，10.22mmol)、DPPA(5.6g，20.44mmol)和TEA(3.0g，30.66mmol)溶解在超干四氢呋喃(60mL)中。反应液在常温下搅拌16小时。反应结束后，向反应液中加入无水甲醇，搅拌30分钟，抽滤，干燥得C152-b(1.6g)。1H NMR(400MHz,DMSO_d6)δ12.31(s,1H),8.24(s,1H),8.03(d,J＝8.4Hz,1H),7.57(d,J＝1.6Hz,1H),7.28(dd,J＝8.4,2.0Hz,1H).(1) C152-a (2.0 g, 10.22 mmol), DPPA (5.6 g, 20.44 mmol) and TEA (3.0 g, 30.66 mmol) were dissolved in ultra-dry tetrahydrofuran (60 mL). The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, anhydrous methanol was added to the reaction solution, stirred for 30 minutes, filtered and dried to obtain C152-b (1.6 g). 1 H NMR (400 MHz, DMSO_d6) δ12.31 (s, 1H), 8.24 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.28 (dd, J = 8.4, 2.0 Hz, 1H).
(2)将C152-b(1.4g，6.36mmol)溶解在叔丁醇(50mL)中，然后在氮气保护下80℃搅拌16小时。反应完成后，将反应液减压浓缩，所得残余物用硅胶柱层析纯化，得到C152-c(1.2g)。LCMS(ESI)m/z:267.2[M+H]+。(2) C152-b (1.4 g, 6.36 mmol) was dissolved in tert-butyl alcohol (50 mL), and then stirred at 80° C. for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain C152-c (1.2 g). LCMS (ESI) m/z: 267.2 [M+H] + .
(3)将C152-c(1.2g，4.51mmol)溶解在盐酸二氧六环(10mL)中，室温搅拌2小时。反应结束后，将反应液减压浓缩，得C152-d(900mg)。LCMS(ESI)m/z:167.1[M+H]+。(3) C152-c (1.2 g, 4.51 mmol) was dissolved in dioxane hydrochloride (10 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain C152-d (900 mg). LCMS (ESI) m/z: 167.1 [M+H] + .
(4)将C152-d(200mg，1.18mmol)和C093-d(360mg，1.77mmol)溶解在DMSO(5mL)中，然后加入DIEA(380mg，2.95mmol)。混合液在氮气保护下90℃搅拌2小时。反应结束后，反应液加水稀释(20mL)，用乙酸乙酯萃取三次(20mL x 3)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物用硅胶柱层析纯化，用(PE:EA＝4:1)洗脱得C152-e(90mg)。LCMS(ESI)m/z:301.1[M+H]+。(4) C152-d (200 mg, 1.18 mmol) and C093-d (360 mg, 1.77 mmol) were dissolved in DMSO (5 mL), and DIEA (380 mg, 2.95 mmol) was added. The mixture was stirred at 90 °C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate three times (20 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain C152-e (90 mg). LCMS (ESI) m/z: 301.1 [M+H] + .
(5)将C152-e(90mg，0.30mmol)溶解在超干DMF(2mL)中，然后加入int7(50mg，0.33mmol)和一水合对甲苯磺酸(11mg，0.06)。混合液在氮气保护下60℃搅拌2小时。反应结束后，反应液减压浓缩所得残余用物高效液相制备分析纯化得化合物C152(24.32mg)。LCMS(ESI)m/z:434.2[M+H]+，1H NMR(400MHz,DMSO_d6)δ11.01(s,1H),8.33(d,J＝4.0Hz,2H),7.70(d,J＝2.4Hz,1H),7.58(d,J＝8.4Hz,1H),7.41(d,J＝2.0Hz,1H),7.00(dd,J＝8.4,2.0Hz,1H),4.33(s,1H),2.58(s,3H),2.21(s,3H),2.07–1.88(m,8H).(5) C152-e (90 mg, 0.30 mmol) was dissolved in ultra-dry DMF (2 mL), and then int7 (50 mg, 0.33 mmol) and p-toluenesulfonic acid monohydrate (11 mg, 0.06) were added. The mixture was stirred at 60°C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and the obtained residue was purified by HPLC to obtain compound C152 (24.32 mg). LCMS (ESI) m/z: 434.2 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.33 (d, J = 4.0 Hz, 2H), 7.70 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.00 (dd, J = 8.4, 2.0 Hz, 1H), 4.33 (s, 1H), 2.58 (s, 3H), 2.21 (s, 3H), 2.07–1.88 (m, 8H).
实施例153：
Embodiment 153:
合成路线
synthetic route
(1)将C153-a(7.5g，40.67mmol)溶解在超干四氢呋喃(100.0mL)中，氮气置换三次，在-65℃下加入甲基溴化镁(1mol/L，44.8ml),在12分钟内加完(内部温度在-65℃到-48℃之间)，加完甲基溴化镁10分钟后保证反应温度-65℃到-63℃之间反应5小时，反应结束后，将反应液在三分钟内加到冰水(250ml)中，并用乙酸乙酯(250ml)转移剩余的反应物到上述冰水中，搅拌反应1小时后，分液，水相用乙酸乙酯(120mL x 2)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，合并有机相减压浓缩，所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝92:8)洗脱得C153-b(4.8g)。1H NMR(400MHz,CDCl3)δ2.70(s,3H).(1) C153-a (7.5 g, 40.67 mmol) was dissolved in ultra-dry tetrahydrofuran (100.0 mL), and the atmosphere was replaced with nitrogen three times. Methylmagnesium bromide (1 mol/L, 44.8 ml) was added at -65°C within 12 minutes (internal temperature was between -65°C and -48°C). Ten minutes after the addition of methylmagnesium bromide, the reaction temperature was maintained between -65°C and -63°C and the reaction was continued for 5 hours. After the reaction was completed, the reaction solution was added to ice water (250 ml) within three minutes, and the remaining reactant was transferred to the above ice water with ethyl acetate (250 ml). After stirring for 1 hour, the liquids were separated, the aqueous phase was extracted with ethyl acetate (120 mL x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (petroleum ether:ethyl acetate = 92:8) to obtain C153-b (4.8 g). 1 H NMR (400 MHz, CDCl 3 )δ2.70 (s, 3H).
(2)将C153-b(2.5g，15.24mmol)C153-c(6.06g,16.77mmol)和四(三苯基膦钯)溶解在超干甲苯(30mL)中，氮气置换三次后，在80℃下反应2小时。反应结束后,将反应液加入后饱和氟化钾(200ml)和乙酸乙酯(200mL)的混合溶剂中，搅拌反应17小时后，过滤，分液，水相用乙酸乙酯(65mL x 3)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，合并有机相减压浓缩，所得残余物用柱层析纯化，用(石油醚:乙酸乙酯＝96:4)洗脱得C153-d(580mg)。1H NMR(400MHz,DMSO_d6)δ4.78(dd,J＝20.4,2.8Hz,2H),4.00(q,J＝6.8Hz,2H),2.58(s,3H),1.34(t,J＝6.8Hz,3H).(2) C153-b (2.5 g, 15.24 mmol) C153-c (6.06 g, 16.77 mmol) and tetrakis(triphenylphosphine palladium) were dissolved in ultra-dry toluene (30 mL), replaced with nitrogen three times, and reacted at 80°C for 2 hours. After the reaction, the reaction solution was added to a mixed solvent of saturated potassium fluoride (200 ml) and ethyl acetate (200 mL), stirred for 17 hours, filtered, separated, the aqueous phase was extracted with ethyl acetate (65 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the combined organic phases were concentrated under reduced pressure, and the residue was purified by column chromatography, eluted with (petroleum ether: ethyl acetate = 96:4) to obtain C153-d (580 mg). 1 H NMR (400 MHz, DMSO_d6) δ 4.78 (dd, J = 20.4, 2.8 Hz, 2H), 4.00 (q, J = 6.8 Hz, 2H), 2.58 (s, 3H), 1.34 (t, J = 6.8 Hz, 3H).
(3)将C153-d(150mg，0.75mmol)、int2(152.6mg,0.75mmol)和一水合对甲苯磺酸(8.6mg，0.045mmol)溶解在超干N,N-二甲基甲酰胺(5.0mL)中。在90℃油浴中搅拌1小时，得到C153-e，直接用于下一步。LCMS(ESI)m/z:302.0[M+H]+。(3) C153-d (150 mg, 0.75 mmol), int2 (152.6 mg, 0.75 mmol) and p-toluenesulfonic acid monohydrate (8.6 mg, 0.045 mmol) were dissolved in ultra-dry N,N-dimethylformamide (5.0 mL). The mixture was stirred in an oil bath at 90°C for 1 hour to obtain C153-e, which was used directly in the next step. LCMS (ESI) m/z: 302.0 [M+H] + .
(4)在上述反应体系中加入C153-e(281mg，1.5mmol)和对甲苯磺酸(8.6mg,0.045mmol),将反应体系置于60℃油浴搅拌反应16小时，反应结束后，加入水(25mL)淬灭反应，过滤，所得的固体用TLC分离(石油醚:乙酸乙酯＝3：1),所得到粗产品(77mg)，再通过高效液相制备分离(甲酸酸法分离)，得到C153(7.6mg)。LCMS(ESI)m/z:435.2[M+H]+，1H NMR(400MHz,DMSO_d6)δ11.10(s,1H),10.14(s,1H),8.00(d,J＝2.0Hz,1H),7.92(s,1H),7.38(d,J＝8.8Hz,1H),7.10(dd,J＝8.8,2.0Hz,1H),4.45–4.34(m,1H),2.60(s,3H),2.33(s,3H),2.06–1.87(m,8H).(4) C153-e (281 mg, 1.5 mmol) and p-toluenesulfonic acid (8.6 mg, 0.045 mmol) were added to the above reaction system, and the reaction system was placed in a 60°C oil bath with stirring for 16 hours. After the reaction was completed, water (25 mL) was added to quench the reaction and filtered. The obtained solid was separated by TLC (petroleum ether: ethyl acetate = 3:1). The obtained crude product (77 mg) was then separated by HPLC (formic acid separation) to obtain C153 (7.6 mg). LCMS (ESI) m/z: 435.2 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 10.14 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.92 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.10 (dd, J = 8.8, 2.0 Hz, 1H), 4.45-4.34 (m, 1H), 2.60 (s, 3H), 2.33 (s, 3H), 2.06-1.87 (m, 8H).
实施例154：
Embodiment 154:
合成路线
synthetic route
(1)将C153-b(2.5g，15.24mmol)、C153-c(6.06g,16.77mmol)和四(三苯基膦钯)溶解在超干甲苯(30ml)中，氮气置换三次后，在80℃下反应2小时。反应结束后,将反应液加入后饱和氟化钾(200ml)和乙酸乙酯(200ml)的混合溶剂中，搅拌反应17小时后，过滤，分液，水相用乙酸乙酯(65mL x 3)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，合并有 机相减压浓缩，所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝96:4)洗脱得C154-b(740mg)。1H NMR(400MHz,DMSO_d6)δ5.60(d,J＝2.0Hz,1H),4.85(d,J＝2.4Hz,1H),3.99(q,J＝7.2Hz,2H),2.61(s,3H),1.37(t,J＝7.2Hz,3H).(1) C153-b (2.5 g, 15.24 mmol), C153-c (6.06 g, 16.77 mmol) and tetrakis(triphenylphosphine palladium) were dissolved in ultra-dry toluene (30 ml), replaced with nitrogen three times, and reacted at 80°C for 2 hours. After the reaction, the reaction solution was added to a mixed solvent of saturated potassium fluoride (200 ml) and ethyl acetate (200 ml), stirred for 17 hours, filtered, separated, the aqueous phase was extracted with ethyl acetate (65 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phases were combined. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with (petroleum ether:ethyl acetate=96:4) to obtain C154-b (740 mg). 1 H NMR (400 MHz, DMSO_d6) δ5.60 (d, J=2.0 Hz, 1H), 4.85 (d, J=2.4 Hz, 1H), 3.99 (q, J=7.2 Hz, 2H), 2.61 (s, 3H), 1.37 (t, J=7.2 Hz, 3H).
(2)将C154-b(725mg，3.63mmol)、int2(737.5mg,3.63mmol)和二异丙基乙胺(1.8mL，10.9mmol)溶解在二甲亚砜(6mL)中。在90℃油浴中搅拌2.5小时。反应结束后，加入水(40mL)淬灭反应，过滤，所得固体用二氯甲烷溶解后，减压浓缩，所得残余物用硅胶柱层析纯化，用(石油醚:乙酸乙酯＝96:4)洗脱得化合物4(740mg，收率：24.3％)，黄色油状液体。继续用(石油醚:乙酸乙酯＝62:38到55:45)洗脱得粗产物C154-c(158mg)。LCMS(ESI)m/z:330.2[M+H]+。(2) C154-b (725 mg, 3.63 mmol), int2 (737.5 mg, 3.63 mmol) and diisopropylethylamine (1.8 mL, 10.9 mmol) were dissolved in dimethyl sulfoxide (6 mL). The mixture was stirred in a 90°C oil bath for 2.5 hours. After the reaction was completed, water (40 mL) was added to quench the reaction, and the solid was filtered. The solid was dissolved in dichloromethane and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 96:4) to obtain compound 4 (740 mg, yield: 24.3%), a yellow oily liquid. The crude product C154-c (158 mg) was obtained by further elution with (petroleum ether: ethyl acetate = 62:38 to 55:45). LCMS (ESI) m/z: 330.2 [M+H] + .
(3)将C154-c(158mg，0.48mmol)溶解在四氢呋喃(10ml)中，加入盐酸(4M in H2O,6.0mL),室温下搅拌反应2小时。反应结束后，用二氯甲烷(50mL x 3)萃取,合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，所得残余物不纯化，直接投下一步，所得粗产品C154-d(89mg)。LCMS(ESI)m/z:302.1[M+H]+。(3) C154-c (158 mg, 0.48 mmol) was dissolved in tetrahydrofuran (10 ml), and hydrochloric acid (4M in H 2 O, 6.0 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, it was extracted with dichloromethane (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was not purified and directly used in the next step to obtain a crude product C154-d (89 mg). LCMS (ESI) m/z: 302.1 [M+H] + .
将C154-d(89mg，0.295mmol)、化合物8(110.4mg,0.59mmol)和一水合对甲苯磺酸(5.8mg,0.03mmol)溶解在超干N,N-二甲基甲酰胺(3.0mL)中,将反应体系置于60℃油浴搅拌反应1.5小时，反应结束后，通过高效液相制备分离(甲酸酸法分离)，得到C154(8.57mg)。LCMS(ESI)m/z:435.2[M+H]+，1H NMR(400MHz,DMSO_d6)δ11.20(s,1H),8.67(s,1H),7.88(d,J＝2.4Hz,1H),7.78(d,J＝2.0Hz,1H),7.41(d,J＝8.8Hz,1H),7.12(dd,J＝8.8,2.0Hz,1H),4.46–4.39(m,1H),2.63(s,3H),2.29(s,3H),2.05–1.84(m,8H).C154-d (89 mg, 0.295 mmol), compound 8 (110.4 mg, 0.59 mmol) and p-toluenesulfonic acid monohydrate (5.8 mg, 0.03 mmol) were dissolved in ultra-dry N,N-dimethylformamide (3.0 mL). The reaction system was placed in a 60°C oil bath and stirred for 1.5 hours. After the reaction was completed, C154 (8.57 mg) was obtained by high performance liquid chromatography preparative separation (formic acid separation). LCMS (ESI) m/z: 435.2 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.67 (s, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.12 (dd, J = 8.8, 2.0 Hz, 1H), 4.46-4.39 (m, 1H), 2.63 (s, 3H), 2.29 (s, 3H), 2.05-1.84 (m, 8H).
实施例155：
Embodiment 155:
合成路线
synthetic route
(1)将C155-a(1g，4.820mmol)、三丁基(1-乙氧基乙烯)锡(2.1g,5.784mmol)和四(三苯基膦)钯(556mg,0.482mmol)溶解在无水甲苯(15ml)中。混合液在氮气保护下于100℃搅拌16小时。点板检测反应结束后，混合液用水淬灭，乙酸乙酯萃取三次(50mL x 3)，合并有机相，减压浓缩，所得残余物用硅胶柱分析纯化(0％-25％乙酸乙酯/石油醚中)，得C155-c(600mg)。LCMS(ESI)m/z:200.6[M+H]+。(1) C155-a (1 g, 4.820 mmol), tributyl (1-ethoxyethylene) tin (2.1 g, 5.784 mmol) and tetrakis (triphenylphosphine) palladium (556 mg, 0.482 mmol) were dissolved in anhydrous toluene (15 ml). The mixture was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed by spot plate detection, the mixture was quenched with water and extracted with ethyl acetate three times (50 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column analysis (0%-25% ethyl acetate/petroleum ether) to obtain C155-c (600 mg). LCMS (ESI) m/z: 200.6 [M+H] + .
(2)将C155-c(600mg，3.00mmol)溶解在1M盐酸(10mL)中，将混合液在氮气保护下于60℃搅拌2小时。反应结束后，混合液减压浓缩，所得残余物加入饱和氟化钾水溶液(10ml)，搅拌1个小时后，加水稀释，滴加饱和碳酸氢钠溶液调节pH至中性，乙酸乙酯萃取三次(30mL x 3).合并有机相，减压浓缩，所得残余物即为C155-d(400mg)。LCMS(ESI)m/z:170.9[M+H]+。(2) C155-c (600 mg, 3.00 mmol) was dissolved in 1 M hydrochloric acid (10 mL), and the mixture was stirred at 60 ° C for 2 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was added with saturated potassium fluoride aqueous solution (10 ml), stirred for 1 hour, diluted with water, and saturated sodium bicarbonate solution was added dropwise to adjust the pH to neutral. The mixture was extracted with ethyl acetate three times (30 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was C155-d (400 mg). LCMS (ESI) m/z: 170.9 [M+H] + .
(3)将C155-d(150mg，0.879mmol)、int2(161mg,0.967mmol)溶解在醋酸(4mL)中，将混合液在氮气保护下于100℃搅拌2个小时。反应结束后，将反应液减压浓缩得C155-e(350mg)。LCMS(ESI)m/z:301.0[M+H]+。(3) C155-d (150 mg, 0.879 mmol) and int2 (161 mg, 0.967 mmol) were dissolved in acetic acid (4 mL), and the mixture was stirred at 100 °C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain C155-e (350 mg). LCMS (ESI) m/z: 301.0 [M+H] + .
(4)将C155-e(350mg，30％purity)、int7(166mg,1.097mmol)和一水合对甲苯磺酸(34mg,0.199mmol)溶解在N,N-二甲基甲酰胺(5mL)中。混合液在氮气保护下于70℃搅拌2个小时。反应结束后，将反应液过滤，滤液用制备型高效液相纯化，得化合物C155(5.04mg)。LCMS(ESI)m/z:434.2[M+H]+，1H NMR(400MHz,DMSO_d6)δ11.09(s,1H),8.12(s,1H),7.87(d,J＝2.0Hz,1H),7.69(d,J＝4.4Hz,2H),7.40(d,J＝8.4Hz,1H),7.10(d,J＝8.4Hz,1H),4.44–4.34(m,1H),2.38(s,3H),2.30(s,3H),2.07–1.88(m,8H).(4) C155-e (350 mg, 30% purity), int7 (166 mg, 1.097 mmol) and p-toluenesulfonic acid monohydrate (34 mg, 0.199 mmol) were dissolved in N,N-dimethylformamide (5 mL). The mixture was stirred at 70°C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was filtered and the filtrate was purified by preparative high performance liquid chromatography to obtain compound C155 (5.04 mg). LCMS (ESI) m/z: 434.2 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.12 (s, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 4.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 4.44-4.34 (m, 1H), 2.38 (s, 3H), 2.30 (s, 3H), 2.07-1.88 (m, 8H).
实施例157：
Embodiment 157:
合成路线
synthetic route
(1)将C157-a(20g，93.35mmol)和N,N-二异丙基乙胺(18g,140.03mmol)溶解在二氯乙烷(300mL)中，向混合溶液中滴加碘甲烷(15.9g,112.02mmol)。混合液在氮气保护下常温搅拌过夜。点板检测反应结束后，直接加入硅胶拌样，用硅胶柱分离纯化(0％-30％乙酸乙酯/石油醚)，得C157-b(11.2g)。1H NMR(400MHz,DMSO_d6)δ8.41(s,1H),4.22(q,J＝7.2Hz,2H),3.43(s,3H),2.61(s,3H),1.27(t,J＝7.2Hz,3H).(1) Dissolve C157-a (20 g, 93.35 mmol) and N,N-diisopropylethylamine (18 g, 140.03 mmol) in dichloroethane (300 mL), and add iodomethane (15.9 g, 112.02 mmol) dropwise to the mixed solution. Stir the mixed solution overnight at room temperature under nitrogen protection. After the reaction is completed, add silica gel directly to mix the sample, and separate and purify it with a silica gel column (0%-30% ethyl acetate/petroleum ether) to obtain C157-b (11.2 g). 1 H NMR (400 MHz, DMSO_d6) δ8.41 (s, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.43 (s, 3H), 2.61 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H).
(2)将C157-b(5g，21.90mmol)和int2(18g,109.52mmol)溶解在超干N,N-二甲基甲酰胺(30mL)中，向混合溶液中加入N,N-二异丙基乙胺(18ml,109.52mmol)，将混合液在氮气保护下于120℃搅拌2小时。反应结束后，混合液用水淬灭，乙酸乙酯萃取三次(50mL x 3)，合并有机相，减压浓缩，所得残余物用硅胶柱分离纯化(0％-5％甲醇/二氯甲烷)，得C157-c(500mg)。LCMS(ESI)m/z:347.1[M+H]+。(2) C157-b (5 g, 21.90 mmol) and int2 (18 g, 109.52 mmol) were dissolved in ultra-dry N,N-dimethylformamide (30 mL), N,N-diisopropylethylamine (18 ml, 109.52 mmol) was added to the mixed solution, and the mixed solution was stirred at 120°C for 2 hours under nitrogen protection. After the reaction was completed, the mixed solution was quenched with water, extracted with ethyl acetate three times (50 mL x 3), the organic phases were combined, concentrated under reduced pressure, and the residue was separated and purified by silica gel column (0%-5% methanol/dichloromethane) to obtain C157-c (500 mg). LCMS (ESI) m/z: 347.1 [M+H] + .
(3)将C157-c(500mg，1.442mmol)溶解在盐酸二氧六环(5mL)和水(0.5mL)中，混合液在70℃下搅拌3个小时。LCMS显示反应结束后，将反应液减压浓缩得C157-d(410mg)。LCMS(ESI)m/z:317.0[M-H]-。(3) C157-c (500 mg, 1.442 mmol) was dissolved in dioxane hydrochloride (5 mL) and water (0.5 mL), and the mixture was stirred at 70°C for 3 hours. After LCMS showed that the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain C157-d (410 mg). LCMS (ESI) m/z: 317.0 [MH] - .
(4)将C157-d(100mg，0.313mmol)、C157-e(61mg,0.627mmol)和HATU(178mg,0.471mmol)溶解在N,N-二甲基甲酰胺(4mL)中，加入三乙胺(111mg,1.098mmol)。将混合液在氮气保护下常温搅拌1个小时。反应结束后向混合溶液中加水稀释，用乙酸乙酯萃取三次(15mL x 3)，合并有机相，减压浓缩，所得残余物用硅胶板纯化(0-6％甲醇/二氯甲烷)，得C157-f(30mg)。LCMS(ESI)m/z:362.1[M+H]+ (4) C157-d (100 mg, 0.313 mmol), C157-e (61 mg, 0.627 mmol) and HATU (178 mg, 0.471 mmol) were dissolved in N,N-dimethylformamide (4 mL), and triethylamine (111 mg, 1.098 mmol) was added. The mixture was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was completed, water was added to dilute the mixed solution, and it was extracted with ethyl acetate three times (15 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel plate (0-6% methanol/dichloromethane) to obtain C157-f (30 mg). LCMS (ESI) m/z: 362.1 [M+H] +
(5)将C157-f(240mg，0.663mmol)溶解在四氢呋喃(5mL)中，降温至0℃，向混合液中滴加甲基溴化镁(0.3ml,3mol/L)，在氮气保护下常温搅拌1个小时。反应结束后，缓慢滴加饱和氯化铵水溶液淬灭反应，然后加水稀释，用乙酸乙酯萃取两次(30mL x 2)。合并有机相,减压浓缩，所得残余物用硅胶板纯化(二氯甲烷：甲醇＝15：1)，得到C157-g(160mg)。LCMS(ESI)m/z:317.0[M+H]+。(5) C157-f (240 mg, 0.663 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0°C, methylmagnesium bromide (0.3 ml, 3 mol/L) was added dropwise to the mixture, and stirred at room temperature for 1 hour under nitrogen protection. After the reaction was completed, saturated aqueous ammonium chloride solution was slowly added dropwise to quench the reaction, then diluted with water, and extracted twice with ethyl acetate (30 mL x 2). The organic phases were combined and concentrated under reduced pressure. The residue was purified on a silica gel plate (dichloromethane: methanol = 15: 1) to obtain C157-g (160 mg). LCMS (ESI) m/z: 317.0 [M+H] + .
(6)将C157-g(160mg，0.504mmol)、int7(83mg,0.555mmol)和一水合对甲苯磺酸(17mg,0.100mmol)溶解在乙腈(4mL)中。混合液在氮气保护下于60℃搅拌4个小时。反应结束后，过滤反应液，滤液相用制备型高效液相纯化，得化合物C157(7.42mg)。LCMS(ESI)m/z:450.2[M+H]+，1H NMR(400MHz,DMSO_d6)δ11.22(s,1H),8.82(s,1H),7.63(s,1H),7.55(s,1H),7.51(s,1H),7.40(s,1H),7.10(s,1H),4.23(s,1H),3.53(s,3H),2.08(s,3H),1.92–1.83(m,8H).(6) C157-g (160 mg, 0.504 mmol), int7 (83 mg, 0.555 mmol) and p-toluenesulfonic acid monohydrate (17 mg, 0.100 mmol) were dissolved in acetonitrile (4 mL). The mixture was stirred at 60 °C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was filtered and the filtrate was purified by preparative high performance liquid chromatography to obtain compound C157 (7.42 mg). LCMS (ESI) m/z: 450.2 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 8.82 (s, 1H), 7.63 (s, 1H), 7.55 (s, 1H), 7.51 (s, 1H), 7.40 (s, 1H), 7.10 (s, 1H), 4.23 (s, 1H), 3.53 (s, 3H), 2.08 (s, 3H), 1.92–1.83 (m, 8H).
实施例158：
Embodiment 158:
合成路线
synthetic route
(1)将158-a(10g，45.2mmol)、158-b(13.6g，108mmol)溶解在四氢呋喃(200mL)中，室温搅拌下添加氢氧化钾(5g，90.4mmol)，将混合物在室温下搅拌16h。反应结束后将反应液浓缩，加入乙酸乙酯(300mL)和水(300mL)，分液，水相用乙酸乙酯(150mL)萃取一次，合并有机相。有机相用饱和食盐水洗三次，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化，洗脱(石油醚:乙酸乙酯＝0-30％)，得158-c(7g)。LCMS(ESI)m/z:235.1[M+H]+。(1) 158-a (10 g, 45.2 mmol) and 158-b (13.6 g, 108 mmol) were dissolved in tetrahydrofuran (200 mL), potassium hydroxide (5 g, 90.4 mmol) was added under stirring at room temperature, and the mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated, ethyl acetate (300 mL) and water (300 mL) were added, and the liquid was separated. The aqueous phase was extracted once with ethyl acetate (150 mL), and the organic phases were combined. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether: ethyl acetate = 0-30%), and 158-c (7 g) was obtained. LCMS (ESI) m/z: 235.1 [M+H] + .
(2)于500mL单口反应瓶中将原料158-c(5g，21.3mmol)溶解在甲苯(100mL)中，加入催化剂四(三苯基膦)钯(2.5g，2.13mmol)和158-d(9.25g，25.6mmol)，氮气保护下油浴加热至80℃，搅拌反应16小时。反应完全后，反应液158-e可直接投入下一步骤。(2) In a 500 mL single-mouth reaction bottle, the raw material 158-c (5 g, 21.3 mmol) was dissolved in toluene (100 mL), and the catalyst tetrakis(triphenylphosphine)palladium (2.5 g, 2.13 mmol) and 158-d (9.25 g, 25.6 mmol) were added. The mixture was heated to 80° C. in an oil bath under nitrogen protection, and stirred for 16 hours. After the reaction was complete, the reaction solution 158-e could be directly used in the next step.
(3)向盛有粗品158-e的甲苯溶液的单口瓶中加入盐酸水溶液(4mol/L，100mL，400mmol)，室温搅拌2小时。反应完成后冷却至室温，乙酸乙酯(100mL)萃取两次，无水硫酸钠干燥有机相，过滤后减压浓缩滤液，所得残余物用硅胶柱层析纯化，洗脱(石油醚:乙酸乙酯＝0-20％)，得158-f(1.1g)。LCMS(ESI)m/z:199.0[M+H]+。(3) Aqueous hydrochloric acid solution (4 mol/L, 100 mL, 400 mmol) was added to a single-mouth bottle containing a toluene solution of the crude product 158-e, and stirred at room temperature for 2 hours. After the reaction was completed, it was cooled to room temperature, extracted twice with ethyl acetate (100 mL), and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted (petroleum ether: ethyl acetate = 0-20%), and 158-f (1.1 g) was obtained. LCMS (ESI) m/z: 199.0 [M+H] + .
(4)将158-f(500mg，2.52mmol)、int2(2.56g，12.61mmol)、N,N-二异丙基乙胺(2.1mL，12.61mmol)以及超干N,N-二甲基甲酰胺(10mL)依次倒入100mL单口瓶中。氮气置换三次后，在氮气保护下混合物于120℃油浴中搅拌2小时。反应结束后，将反应液冷却至室温。用50mL水稀释反应液，然后用乙酸乙酯(30mL)萃取此水相三次。合并后的有机相用饱和食盐水(30mL)洗涤三次，用适量无水硫酸钠处理有机相，并过滤。将滤液减压浓缩干，所得残余物用硅胶柱层析纯化，洗脱(乙酸乙酯:石油醚＝0～1:1)，得粗品158-g(0.4g)。LCMS(ESI)m/z:317.0[M+H]+，1H NMR(400MHz,DMSO_d6)δ11.27(s,1H),9.35(s,1H),8.24(s,1H),7.56(s,1H),7.53(d,J＝2.4Hz,1H),7.40(d,J＝8.8Hz,1H),7.10(dd,J＝8.4,1.6Hz,1H),3.53(s,3H),2.46(s,3H).(4) 158-f (500 mg, 2.52 mmol), int2 (2.56 g, 12.61 mmol), N,N-diisopropylethylamine (2.1 mL, 12.61 mmol) and ultra-dry N,N-dimethylformamide (10 mL) were poured into a 100 mL single-mouth bottle in sequence. After nitrogen replacement three times, the mixture was stirred in an oil bath at 120°C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature. The reaction solution was diluted with 50 mL of water, and then the aqueous phase was extracted three times with ethyl acetate (30 mL). The combined organic phase was washed three times with saturated brine (30 mL), treated with an appropriate amount of anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography, eluting (ethyl acetate: petroleum ether = 0-1:1) to obtain a crude product 158-g (0.4 g). LCMS (ESI) m/z: 317.0 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 9.35 (s, 1H), 8.24 (s, 1H), 7.56 (s, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.10 (dd, J = 8.4, 1.6 Hz, 1H), 3.53 (s, 3H), 2.46 (s, 3H).
(5)将158-g(80mg，0.253mmol)、int7(57mg，0.303mmol)和一水合对甲苯磺酸(10mg，0.051mmol)溶解在超干乙腈(1mL)中。反应液在60℃下搅拌反应2小时。反应结束后，将反应液溶于超干N,N-二甲基甲酰胺(1.5mL)中，通过制备分析纯化得化合物158(38.62mg)。LCMS(ESI)m/z:450.2[M+H]+，1H NMR(400MHz,CD3OD)δ7.66(s,1H),7.43(d,J＝2.0Hz,1H),7.39(s,1H),7.36(d,J＝8.8Hz,1H),7.11(dd,J＝8.4,2.0Hz,1H),4.28–4.27(m,1H),3.62(s,3H),2.16(s,3H),2.16–1.86(m,8H).(5) 158-g (80 mg, 0.253 mmol), int7 (57 mg, 0.303 mmol) and p-toluenesulfonic acid monohydrate (10 mg, 0.051 mmol) were dissolved in ultra-dry acetonitrile (1 mL). The reaction solution was stirred at 60° C. for 2 hours. After the reaction was completed, the reaction solution was dissolved in ultra-dry N,N-dimethylformamide (1.5 mL) and purified by preparative analysis to obtain compound 158 (38.62 mg). LCMS (ESI) m/z: 450.2 [M+H] + , 1 H NMR (400 MHz, CD 3 OD) δ 7.66 (s, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.39 (s, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.11 (dd, J=8.4, 2.0 Hz, 1H), 4.28-4.27 (m, 1H), 3.62 (s, 3H), 2.16 (s, 3H), 2.16-1.86 (m, 8H).
实施例159：
Embodiment 159:
合成路线
synthetic route
(1)将C159-a(7.8g，50.93mmol)溶解在超干N,N-二甲基甲酰胺(78mL)中，在0℃下搅拌5分钟后，在约10分钟内逐滴加入N-溴代丁二酰亚胺(8.89g,49.94mmol)(溶解在42mL超干N,N-二甲基甲酰胺中)，然后在0℃搅拌反应2小时。反应结束后，向反应体系中加入水(200mL),乙酸乙酯萃取(150mL x 4)，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，残余物用硅胶柱分离纯化，洗脱(0–25％乙酸乙酯/石油醚)，得C159-b(6.9g)。LCMS(ESI)m/z:234.0[M+H]+。(1) C159-a (7.8 g, 50.93 mmol) was dissolved in ultra-dry N,N-dimethylformamide (78 mL), stirred at 0°C for 5 minutes, and then N-bromosuccinimide (8.89 g, 49.94 mmol) (dissolved in 42 mL ultra-dry N,N-dimethylformamide) was added dropwise over about 10 minutes, and then stirred at 0°C for 2 hours. After the reaction, water (200 mL) was added to the reaction system, and ethyl acetate was extracted (150 mL x 4). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column elution (0–25% ethyl acetate/petroleum ether) to obtain C159-b (6.9 g). LCMS (ESI) m/z: 234.0 [M+H] + .
(2)将C159-b(6.9g，29.74mmol)溶解在超干四氢呋喃(280ml)中，氮气置换后，将反应体系置于-35℃的乙醇干冰浴中搅拌，并于-35℃下在约10分钟内逐滴加入二异丁基氢化铝(89.2ml，1M在己烷中)，滴加过程中始终控温在0℃以下。加完后，自然升温到室温下搅拌反应。将反应液逐滴加入到盐酸(80ml,1M水溶液)中，室温下搅拌反应。反应结束后，用二氯甲烷与甲醇(二氯甲烷：甲醇＝10:1)的混合溶液萃取水相(150mL x 12)，合并有机相，并用无水硫酸钠干燥，过滤，减压浓缩，得粗产品C159-c(6.2g)。1H NMR(400MHz,DMSO_d6)δ7.58(s,1H),6.63(s,2H),5.11(s,1H),4.40(s,2H).(2) C159-b (6.9 g, 29.74 mmol) was dissolved in ultra-dry tetrahydrofuran (280 ml). After nitrogen replacement, the reaction system was placed in an ethanol dry ice bath at -35°C and stirred. Diisobutylaluminum hydride (89.2 ml, 1 M in hexane) was added dropwise at -35°C for about 10 minutes. The temperature was always controlled below 0°C during the addition. After the addition was completed, the temperature was naturally raised to room temperature and stirred for reaction. The reaction solution was added dropwise to hydrochloric acid (80 ml, 1 M aqueous solution) and stirred for reaction at room temperature. After the reaction was completed, the aqueous phase was extracted with a mixed solution of dichloromethane and methanol (dichloromethane: methanol = 10:1) (150 mL x 12), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product C159-c (6.2 g). 1 H NMR (400 MHz, DMSO_d6) δ7.58 (s, 1H), 6.63 (s, 2H), 5.11 (s, 1H), 4.40 (s, 2H).
(3)将C159-c(6.2g，10.63mmol)、叔丁基二苯基氯硅烷(12.93g，47.05mmol)和咪唑(6.4g，94.1mmol)溶解在超干二氯甲烷(80ml)中,室温下搅拌反应。反应结束后，反应液直接用大量硅胶吸附，并用硅胶柱分离纯化(0–60％乙酸乙酯/石油醚)，得C159-d(10.8g)。LCMS(ESI)m/z:444.1[M+H]+。(3) C159-c (6.2 g, 10.63 mmol), tert-butyldiphenylsilyl chloride (12.93 g, 47.05 mmol) and imidazole (6.4 g, 94.1 mmol) were dissolved in ultra-dry dichloromethane (80 ml) and stirred at room temperature. After the reaction, the reaction solution was directly adsorbed with a large amount of silica gel and separated and purified by a silica gel column (0–60% ethyl acetate/petroleum ether) to obtain C159-d (10.8 g). LCMS (ESI) m/z: 444.1 [M+H] + .
(4)将C159-d(5g，11.3mmol)、C159-e(4.9g,13.56mmol)和四(三苯基膦)钯(1.31g,1.13mmol)溶解在超干甲苯(50ml)中。氮气置换三次后，将反应体系置于100℃油浴中搅拌反应。反应结束后，将反应液倒入饱和氟化钾和乙酸乙酯的混合溶剂中，室温下搅拌反应，过滤，分液，水相用乙酸乙酯萃取，使用饱和食盐水洗涤，并用无水硫酸钠干燥，过滤，减压浓缩。残余物用硅胶吸附，并用硅胶柱层析纯化(0-25％乙酸乙酯/石油醚)，得粗产品C159-f(4.5g)。LCMS(ESI)m/z:434.2[M+H]+。(4) C159-d (5 g, 11.3 mmol), C159-e (4.9 g, 13.56 mmol) and tetrakis(triphenylphosphine)palladium (1.31 g, 1.13 mmol) were dissolved in ultra-dry toluene (50 ml). After nitrogen replacement three times, the reaction system was placed in an oil bath at 100°C and stirred for reaction. After the reaction was completed, the reaction solution was poured into a mixed solvent of saturated potassium fluoride and ethyl acetate, stirred for reaction at room temperature, filtered, separated, the aqueous phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was adsorbed on silica gel and purified by silica gel column chromatography (0-25% ethyl acetate/petroleum ether) to obtain a crude product C159-f (4.5 g). LCMS (ESI) m/z: 434.2 [M+H] + .
(5)将C159-f(4.5g，10.38mmol)溶解在四氢呋喃(40mL)中，加入盐酸(13mL，4M水溶液),室温下搅拌反应。反应结束后，用二氯甲烷与甲醇(二氯甲烷：甲醇＝10:1)的混合溶液萃取水相(160mL x 5)。合并有机相，并用无水硫酸钠干燥，过滤，减压浓缩，残余物用硅胶柱分离纯化(0–25％乙酸乙酯/石油醚)，得粗产品C159-g(2.29g)。LCMS(ESI)m/z:406.2[M+H]+。(5) C159-f (4.5 g, 10.38 mmol) was dissolved in tetrahydrofuran (40 mL), and hydrochloric acid (13 mL, 4 M aqueous solution) was added, and the reaction was stirred at room temperature. After the reaction was completed, the aqueous phase was extracted with a mixed solution of dichloromethane and methanol (dichloromethane: methanol = 10:1) (160 mL x 5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column (0-25% ethyl acetate/petroleum ether) to obtain the crude product C159-g (2.29 g). LCMS (ESI) m/z: 406.2 [M+H] + .
(6)将C159-g(2.279g，5.6mmol)溶解在超干乙腈(27mL)中,于0℃下搅拌并在该温度下在约10分钟内逐滴加入N-溴代丁二酰亚胺(8.89g,49.94mmol)。反应结束后，向反应体系中加入水，用乙酸乙酯萃取(120mL x 3)。合并有机相，并用无水硫酸钠干燥，过滤，减压浓缩，残余物用硅胶吸附，并用硅胶柱分离纯化(0–20％乙酸乙酯/石油醚)，得C159-h(1.86g)。LCMS (ESI)m/z:486.0[M+H]+。(6) C159-g (2.279 g, 5.6 mmol) was dissolved in ultra-dry acetonitrile (27 mL), stirred at 0°C and N-bromosuccinimide (8.89 g, 49.94 mmol) was added dropwise at this temperature over about 10 minutes. After the reaction was completed, water was added to the reaction system and extracted with ethyl acetate (120 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was adsorbed on silica gel and separated and purified using a silica gel column (0–20% ethyl acetate/petroleum ether) to obtain C159-h (1.86 g). LCMS (ESI) m/z: 486.0 [M+H] + .
(7)将化合物将C159-h(1.864g，3.85mmol)、三(二亚苄基丙酮)二钯(529mg,0.58mmol)、氰化锌(678mg,5.77mmol)和1,1'-双(二苯基膦)二茂铁(2.13g,3.85mmol)溶解在超干N,N-二甲基甲酰胺(19.0mL)中,反应体系用氮气置换三次后，在120℃油浴下反应。反应结束后，反应液使用硅藻土过滤，滤饼用乙酸乙酯冲洗。向所得的滤液中加入水，用乙酸乙酯(80mL x 4)萃取。合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，残余物用硅胶柱分离纯化(100％二氯甲烷)得C159-i(880mg)。1H NMR(400MHz,DMSO_d6),8.06(s,2H),7.62(dd,J＝7.6,1.2Hz,4H),7.49–7.37(m,6H),5.02(s,2H),2.38(s,3H),1.01(s,9H).(7) Compound C159-h (1.864 g, 3.85 mmol), tris(dibenzylideneacetone)dipalladium (529 mg, 0.58 mmol), zinc cyanide (678 mg, 5.77 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (2.13 g, 3.85 mmol) were dissolved in ultra-dry N,N-dimethylformamide (19.0 mL). The reaction system was replaced with nitrogen three times and reacted in an oil bath at 120°C. After the reaction was completed, the reaction solution was filtered using diatomaceous earth and the filter cake was rinsed with ethyl acetate. Water was added to the obtained filtrate and extracted with ethyl acetate (80 mL x 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified using a silica gel column (100% dichloromethane) to obtain C159-i (880 mg). 1 H NMR (400 MHz, DMSO_d6), 8.06 (s, 2H), 7.62 (dd, J=7.6, 1.2 Hz, 4H), 7.49–7.37 (m, 6H), 5.02 (s, 2H), 2.38 (s, 3H), 1.01 (s, 9H).
(8)将C159-i(876mg,2.03mmol)、氯化铜(1.09g,8.14mmol)、氯化亚铜(729mg,8.14mmol)和亚硝酸异戊酯(477mg,4.07mmol)溶解在超干乙腈(22mL)中,氮气置换三次后，将反应体系置于65℃油浴中搅拌反应。反应结束后，反应液直接用大量硅胶吸附，并用硅胶柱分离纯化(0-15％乙酸乙酯石油醚)，得到粗产品C159-j(888.3mg)。1H NMR(400MHz,DMSO_d6)δ7.65–7.64(m,4H),7.50–7.37(m,6H),5.19(s,2H),2.53(s,3H),1.06(s,9H).(8) C159-i (876 mg, 2.03 mmol), cupric chloride (1.09 g, 8.14 mmol), cuprous chloride (729 mg, 8.14 mmol) and isoamyl nitrite (477 mg, 4.07 mmol) were dissolved in ultra-dry acetonitrile (22 mL). After nitrogen replacement three times, the reaction system was placed in a 65°C oil bath and stirred for reaction. After the reaction was completed, the reaction solution was directly adsorbed with a large amount of silica gel and separated and purified by a silica gel column (0-15% ethyl acetate petroleum ether) to obtain a crude product C159-j (888.3 mg). 1 H NMR (400 MHz, DMSO_d6) δ7.65–7.64 (m, 4H), 7.50–7.37 (m, 6H), 5.19 (s, 2H), 2.53 (s, 3H), 1.06 (s, 9H).
(9)将C159-j(880.3mg，1.956mmol)、int2(421.1mg,2.074mmol)和三乙胺(0.86ml,6.22mmol)溶解在超干二甲亚砜(7.0mL)中,室温下搅拌反应。反应结束后，向反应体系中加入水，并用乙酸乙酯(50mL x 5)萃取。合并有机相，并用无水硫酸钠干燥，过滤，减压浓缩，残余物用硅胶吸附，并用硅胶柱分离纯化(0–25％乙酸乙酯石油醚)，得C159-k(696.2mg)。LCMS(ESI)m/z:580.3[M+H]+。(9) C159-j (880.3 mg, 1.956 mmol), int2 (421.1 mg, 2.074 mmol) and triethylamine (0.86 ml, 6.22 mmol) were dissolved in ultra-dry dimethyl sulfoxide (7.0 mL) and stirred at room temperature. After the reaction was completed, water was added to the reaction system and extracted with ethyl acetate (50 mL x 5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was adsorbed on silica gel and separated and purified on a silica gel column (0–25% ethyl acetate petroleum ether) to obtain C159-k (696.2 mg). LCMS (ESI) m/z: 580.3 [M+H] + .
(10)将C159-k(200mg，0.345mmol)、int7(129mg,0.69mmol)和一水合对甲苯磺酸(1.13mg,0.07mmol)溶解在超干N,N-二甲基甲酰胺(4.0ml)中，将反应体系于60℃油浴中搅拌反应。反应结束后，反应液直接加入硅胶吸附，使用硅胶柱分离纯化(0-10％甲醇/二氯己烷)，所得含N,N-二甲基甲酰胺的粗产品通过制备型高效液相分离(甲酸酸法分离)，得到C159(41.62mg)。LCMS(ESI)m/z:475.3[M+H]+；1H NMR(400MHz,DMSO_d6)δ11.27(s,1H),9.70(s,1H),7.95(d,J＝2.4Hz,1H),7.71(d,J＝1.6Hz,1H),7.40(d,J＝8.8Hz,1H),7.12(dd,J＝8.8,2.0Hz,1H),4.83(t,J＝5.6Hz,1H),4.72(d,J＝5.2Hz,2H),4.41–4.28(m,1H),2.21(s,3H),2.07–1.84(m,8H).(10) C159-k (200 mg, 0.345 mmol), int7 (129 mg, 0.69 mmol) and p-toluenesulfonic acid monohydrate (1.13 mg, 0.07 mmol) were dissolved in ultra-dry N,N-dimethylformamide (4.0 ml), and the reaction system was stirred in an oil bath at 60°C. After the reaction was completed, the reaction solution was directly added to silica gel for adsorption, and was separated and purified using a silica gel column (0-10% methanol/dichlorohexane). The crude product containing N,N-dimethylformamide was separated by preparative high performance liquid separation (formic acid separation) to obtain C159 (41.62 mg). LCMS (ESI) m/z: 475.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 9.70 (s, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.12 (dd, J = 8.8, 2.0 Hz, 1H), 4.83 (t, J = 5.6 Hz, 1H), 4.72 (d, J = 5.2 Hz, 2H), 4.41-4.28 (m, 1H), 2.21 (s, 3H), 2.07-1.84 (m, 8H).
实施例160：
Embodiment 160:
合成路线
synthetic route
(1)将C160-a(11g，50mmol)溶于超干四氢呋喃(75mL)中，在氮气保护下将反应瓶置 于冰水浴中。向搅拌下的反应瓶中缓慢滴加四氢铝锂的正己烷溶液(1M，75mL，75mmol)并保持反应液内温不超过5℃。滴加完毕后，冰水浴下继续搅拌90分钟。反应结束后，依次向反应液中滴加水(5.4mL)、氢氧化钠饱和水溶液(5.4mL)和水(10.8mL)。然后滤去不溶物，并向滤液中加入适量无水硫酸钠，再次过滤。将干燥后的滤液减压浓缩，所得残余物用硅胶柱层析纯化(石油醚:乙酸乙酯＝0-75％)，洗脱得C160-b(6.3g，60％)。LCMS(ESI)m/z:203.1[M+H]+。1H NMR(400MHz,DMSO_d6)δ7.51(d,J＝8.8Hz,1H),6.33(d,J＝8.8Hz,1H),6.20(s,2H),4.84(t,J＝5.6Hz,1H),4.38(d,J＝5.2Hz,2H).(1) Dissolve C160-a (11 g, 50 mmol) in ultra-dry tetrahydrofuran (75 mL) and place the reaction flask in a nitrogen atmosphere. In an ice-water bath. Slowly drop a n-hexane solution of lithium aluminum tetrahydride (1M, 75mL, 75mmol) into the stirred reaction flask and keep the temperature of the reaction solution not exceeding 5°C. After the addition is complete, continue stirring for 90 minutes in an ice-water bath. After the reaction is completed, water (5.4mL), a saturated aqueous solution of sodium hydroxide (5.4mL) and water (10.8mL) are added dropwise to the reaction solution in sequence. Then filter out the insoluble matter, add an appropriate amount of anhydrous sodium sulfate to the filtrate, and filter again. The dried filtrate is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0-75%) to obtain C160-b (6.3g, 60%). LCMS (ESI) m/z: 203.1 [M + H] + . 1 H NMR (400 MHz, DMSO_d6) δ7.51 (d, J=8.8 Hz, 1H), 6.33 (d, J=8.8 Hz, 1H), 6.20 (s, 2H), 4.84 (t, J=5.6 Hz, 1H), 4.38 (d, J=5.2 Hz, 2H).
(2)类似与实施例159步骤(3)-(10)所述的方法，由C160-b合成化合物C160。LCMS(ESI)m/z:474.2[M+H]+。1H NMR(400MHz,DMSO_d6)δ11.19(s,1H),9.21(s,1H),8.10(s,1H),7.79(d,J＝2.0Hz,1H),7.56(s,1H),7.39(d,J＝8.4Hz,1H),7.10(dd,J＝8.6,2.0Hz,1H),4.71(t,J＝5.2Hz,1H),4.55(d,J＝5.6Hz,2H),4.30(s,1H),2.17(s,3H),2.02–1.85(m,8H).(2) Compound C160 was synthesized from C160-b in a similar manner to that described in steps (3) to (10) of Example 159. LCMS (ESI) m/z: 474.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.21 (s, 1H), 8.10 (s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.56 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.10 (dd, J = 8.6, 2.0 Hz, 1H), 4.71 (t, J = 5.2 Hz, 1H), 4.55 (d, J = 5.6 Hz, 2H), 4.30 (s, 1H), 2.17 (s, 3H), 2.02–1.85 (m, 8H).
实施例161：
Example 161:
合成路线
synthetic route
(1)将C141-c(2.0g，7.53mmol)、C161-a(2.9g,7.99mmol)和四(三苯基膦钯)(870mg,0.75mmol)溶解在超干甲苯(12.0ml)中，然后氮气置换三次，将反应体系温度置于100℃下搅拌反应16小时，反应结束后不处理直接用于下一步反应。(1) C141-c (2.0 g, 7.53 mmol), C161-a (2.9 g, 7.99 mmol) and tetrakis(triphenylphosphine palladium) (870 mg, 0.75 mmol) were dissolved in ultra-dry toluene (12.0 ml), and then replaced with nitrogen three times. The reaction system was stirred at 100°C for 16 hours. After the reaction was completed, it was directly used for the next step without treatment.
(2)向上一步得到的反应液中加入盐酸(4M in H2O,18ml)，室温下搅拌反应2小时。反应结束后，反应液用乙酸乙酯(60mL x 3)萃取，合并有机相，向有机相中加入饱和氟化钾溶液(120mL),室温下搅拌反应3小时后，分液，水相用乙酸乙酯(80mL x 2)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化，洗脱(石油醚:乙酸乙酯＝95:5)，得C161-c(1.13g，两步收率：65.6％)。LCMS(ESI)m/z:229.0[M+H]+。(2) Add hydrochloric acid (4M in H 2 O, 18 ml) to the reaction solution obtained in the previous step, and stir at room temperature for 2 hours. After the reaction is completed, the reaction solution is extracted with ethyl acetate (60 mL x 3), the organic phases are combined, and a saturated potassium fluoride solution (120 mL) is added to the organic phase. After stirring at room temperature for 3 hours, the liquids are separated, the aqueous phase is extracted with ethyl acetate (80 mL x 2), the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluted (petroleum ether: ethyl acetate = 95:5), and C161-c (1.13 g, two-step yield: 65.6%) is obtained. LCMS (ESI) m/z: 229.0 [M+H] + .
(3)将C161-c(228mg，1mmol)、int2(223mg,1.1mmol)和三乙胺(334mg，3.3mmol)溶解在超干二甲亚砜(1.5mL)中。在室温下搅拌反应1小时。反应结束后，向反应体系中加入水(12mL)，过滤，滤饼用水(4mL)洗涤，收集滤饼，减压浓缩除去残留的少量水，得C161-d(322mg)。LCMS(ESI)m/z:359.1[M+H]+，1H NMR(400MHz,DMSO_d6)δ11.21(s,1H),9.10(s,1H),7.73(dd,J＝5.2,2.0Hz,2H),7.41(d,J＝8.8Hz,1H),7.12(dd,J＝8.8,2.0Hz,1H),3.77(s,3H),2.66(s,3H),2.52(s,3H).(3) C161-c (228 mg, 1 mmol), int2 (223 mg, 1.1 mmol) and triethylamine (334 mg, 3.3 mmol) were dissolved in ultra-dry dimethyl sulfoxide (1.5 mL). The reaction was stirred at room temperature for 1 hour. After the reaction was completed, water (12 mL) was added to the reaction system, filtered, and the filter cake was washed with water (4 mL). The filter cake was collected and concentrated under reduced pressure to remove a small amount of residual water to obtain C161-d (322 mg). LCMS (ESI) m/z: 359.1 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 9.10 (s, 1H), 7.73 (dd, J=5.2, 2.0 Hz, 2H), 7.41 (d, J=8.8 Hz, 1H), 7.12 (dd, J=8.8, 2.0 Hz, 1H), 3.77 (s, 3H), 2.66 (s, 3H), 2.52 (s, 3H).
(4)将C161-d(194mg，0.54mmol)和一水合氢氧化锂(113.4mg,2.70mmol)溶解在四氢呋喃(5.5mL)和水(1.1mL)中，在室温下搅拌反应13分钟。反应结束后，向反应体系中加入盐酸(4M in H2O,15mL),接着使用二氯甲烷/甲醇(10/1)(55mL x 6)萃取，合并有机相，用无水硫酸钠干燥有机相，过滤，减压浓缩后得到粗产品C161-e(186.3mg)。LCMS(ESI)m/z:345.1[M+H]+。(4) C161-d (194 mg, 0.54 mmol) and lithium hydroxide monohydrate (113.4 mg, 2.70 mmol) were dissolved in tetrahydrofuran (5.5 mL) and water (1.1 mL), and the mixture was stirred at room temperature for 13 minutes. After the reaction, hydrochloric acid (4 M in H 2 O, 15 mL) was added to the reaction system, followed by extraction with dichloromethane/methanol (10/1) (55 mL x 6), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product C161-e (186.3 mg). LCMS (ESI) m/z: 345.1 [M+H] + .
(5)将C161-e(186.3mg，0.54mmol)(假定步骤6等当量反应)和O-(7-氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(HATU,246.6mg,0.65mmol)、氯化铵(101.2mg,1.89mmol)溶解在超干N,N-二甲基甲酰胺(11mL)中，室温下搅拌反应5分钟后，向反应体系中加入三乙胺(0.53ml,3.78mmol)，室温下反应34分钟。反应结束后，向反应体系中加入水(110mL),水相用乙酸乙酯(90 mL x 4)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤，减压浓缩后得到粗产品用制备板纯化(二氯甲烷：甲醇＝7：1)，得到粗产品C161-f(46mg)。LCMS(ESI)m/z:326.1[M+H]+，1H NMR(400MHz,DMSO_d6)δ11.12(s,1H),8.95(s,1H),8.35(s,1H),7.92(d,J＝2.4Hz,1H),7.76(d,J＝2.0Hz,1H),7.41(d,J＝8.8Hz,1H),7.11(dd,J＝8.8,2.0Hz,1H),6.04(s,1H),2.69(s,3H),1.59(s,3H).(5) C161-e (186.3 mg, 0.54 mmol) (assuming equivalent reaction in step 6), O-(7-nitrobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU, 246.6 mg, 0.65 mmol), and ammonium chloride (101.2 mg, 1.89 mmol) were dissolved in ultra-dry N,N-dimethylformamide (11 mL). After stirring at room temperature for 5 minutes, triethylamine (0.53 ml, 3.78 mmol) was added to the reaction system and reacted at room temperature for 34 minutes. After the reaction was completed, water (110 mL) was added to the reaction system, and the aqueous phase was washed with ethyl acetate (90 mL x 4) extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a crude product, which was purified by preparative plate (dichloromethane: methanol = 7: 1) to obtain a crude product C161-f (46 mg). LCMS (ESI) m/z: 326.1 [M+H] + , 1 H NMR (400MHz, DMSO_d6) δ 11.12 (s, 1H), 8.95 (s, 1H), 8.35 (s, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.11 (dd, J = 8.8, 2.0 Hz, 1H), 6.04 (s, 1H), 2.69 (s, 3H), 1.59 (s, 3H).
(6)将C161-f(46mg，0.13mmol)、int7(51mg,0.27mmol)和一水合对甲苯磺酸(8.1mg,0.043mmol)溶解在超干N,N-二甲基甲酰胺(1.4mL)中,将反应体系置于60℃油浴搅拌反应2小时，反应结束后，反应液通过高效液相制备分离(甲酸酸法分离)，得到C161,(9.85mg，三步收率：3.8％)。LCMS(ESI)m/z:477.2[M+H]+，1H NMR(400MHz,DMSO_d6)δ11.09(s,1H),8.45(s,1H),7.95(d,J＝2.4Hz,1H),7.84(d,J＝2.0Hz,1H),7.52(s,1H),7.38(d,J＝8.4Hz,2H),7.10(dd,J＝8.4,2.0Hz,1H),4.25–4.18(m,1H),2.62(s,3H),2.15(s,3H),2.05–1.78(m,8H).(6) C161-f (46 mg, 0.13 mmol), int7 (51 mg, 0.27 mmol) and p-toluenesulfonic acid monohydrate (8.1 mg, 0.043 mmol) were dissolved in ultra-dry N,N-dimethylformamide (1.4 mL), and the reaction system was placed in a 60°C oil bath with stirring for 2 hours. After the reaction, the reaction solution was separated by high performance liquid chromatography (formic acid separation) to obtain C161 (9.85 mg, three-step yield: 3.8%). LCMS (ESI) m/z: 477.2 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.45 (s, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.52 (s, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.10 (dd, J = 8.4, 2.0 Hz, 1H), 4.25-4.18 (m, 1H), 2.62 (s, 3H), 2.15 (s, 3H), 2.05-1.78 (m, 8H).
实施例162：
Embodiment 162:
合成路线
synthetic route
步骤1：step 1:
将化合物C162-1(8.0g，66.61mmol)溶解在超干四氢呋喃(320ml)中，氮气置换三次后，在-50℃下经11分钟加入甲基溴化镁(178ml,3M于2-甲基四氢呋喃中)，始终控温在-50℃到-30℃之间，然后将反应装置在-50℃到-25℃之间搅拌反应130分钟。反应结束后，在低温下，将反应液缓慢倒入到盐酸(350ml,2M水溶液)，并用二氯甲烷(120ml)转移剩余的反应液，加完后，室温下搅拌反应3.5小时，然后加入碳酸钾调节pH＝5，使用硅藻土过滤，用二氯甲烷/甲醇＝10:1(200mL x 15)萃取。合并有机相，用无水硫酸钠干燥有机相，过滤，减压浓缩以除去溶剂，残余物用硅胶柱层析纯化(0-20％甲醇/二氯甲烷)，得粗产品化合物C162-2(8.3g)，为黄色固体。Compound C162-1 (8.0 g, 66.61 mmol) was dissolved in ultra-dry tetrahydrofuran (320 ml), and after nitrogen replacement three times, methylmagnesium bromide (178 ml, 3M in 2-methyltetrahydrofuran) was added at -50°C for 11 minutes, and the temperature was always controlled between -50°C and -30°C, and then the reaction apparatus was stirred and reacted at -50°C to -25°C for 130 minutes. After the reaction was completed, the reaction solution was slowly poured into hydrochloric acid (350 ml, 2M aqueous solution) at low temperature, and the remaining reaction solution was transferred with dichloromethane (120 ml). After the addition was completed, the reaction was stirred at room temperature for 3.5 hours, and then potassium carbonate was added to adjust the pH to 5, filtered using diatomaceous earth, and extracted with dichloromethane/methanol = 10:1 (200 mL x 15). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (0-20% methanol/dichloromethane) to give the crude product compound C162-2 (8.3 g) as a yellow solid.
1H NMR(400MHz,DMSO_d6)δ8.50(d,J＝1.2Hz,1H),7.92(d,J＝1.2Hz,1H),7.43(s,2H),2.46(s,3H). 1 H NMR (400 MHz, DMSO_d6) δ 8.50 (d, J = 1.2 Hz, 1H), 7.92 (d, J = 1.2 Hz, 1H), 7.43 (s, 2H), 2.46 (s, 3H).
步骤2:Step 2:
将化合物C162-2(7.3g，53.23mmol)溶解在超干N,N-二甲基甲酰胺(73mL)中，在0℃下加入N-溴代丁二酰亚胺(10.42g,58.55mmol)(溶解在45ml超干N,N-二甲基甲酰胺中，7分钟内加完)，然后将反应装置置于室温下反应2小时。(合并来自小试反应的1.0g(7.29mmol)一起处理)。反应结束后，向反应体系中加入水(100mL)，用乙酸乙酯(150mL x 4)萃取水相，合并有机相，并用无水硫酸钠干燥，过滤，减压浓缩以除去溶剂，所得残余物用硅胶吸附，经柱层析纯化(0-20％乙酸乙酯/石油醚)，得到3.9g粗产品。用石油醚/乙酸乙酯(2/1，120mL)打浆，过滤，干燥,得到粗产品化合物C162-3(3.4g,两步收率：23.7％),为黄色固体。Compound C162-2 (7.3 g, 53.23 mmol) was dissolved in ultra-dry N,N-dimethylformamide (73 mL), N-bromosuccinimide (10.42 g, 58.55 mmol) (dissolved in 45 ml ultra-dry N,N-dimethylformamide, added within 7 minutes) was added at 0°C, and then the reaction apparatus was placed at room temperature for 2 hours. (1.0 g (7.29 mmol) from the pilot reaction was combined and processed together). After the reaction was completed, water (100 mL) was added to the reaction system, and the aqueous phase was extracted with ethyl acetate (150 mL x 4). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was adsorbed on silica gel and purified by column chromatography (0-20% ethyl acetate/petroleum ether) to obtain 3.9 g of crude product. The mixture was slurried with petroleum ether/ethyl acetate (2/1, 120 mL), filtered, and dried to obtain the crude product compound C162-3 (3.4 g, two-step yield: 23.7%) as a yellow solid.
LCMS(ESI)m/z:217.9[M+H]+。LCMS (ESI) m/z: 217.9 [M+H] + .
步骤3:Step 3:
将化合物C162-3(1.0g，4.63mmol)、化合物C162-4(1.2g,13.89mmol)、1,1’-双(二苯基膦) 二茂铁二氯化钯(678mg,0.93mmol)和碳酸钾(3.84g,27.78mmol)溶解在1,4-二氧六环(21mL)和水(6mL)中，氮气置换三次后，将反应体系置于90℃油浴中搅拌反应18小时。反应结束后，反应液直接用硅藻土过滤，用乙酸乙酯(350mL)冲洗滤饼，加入水(100mL),萃取分液后，接着将水相用乙酸乙酯(80mL x 3)萃取，合并有机相，用饱和食盐水洗涤，并用无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶吸附，并用硅胶柱层析纯化(0-48％乙酸乙酯/石油醚)，洗脱得化合物C162-5(385.5mg,收率：46.8％)，为黄色固体。Compound C162-3 (1.0 g, 4.63 mmol), compound C162-4 (1.2 g, 13.89 mmol), 1,1'-bis(diphenylphosphine) Ferrocene palladium dichloride (678 mg, 0.93 mmol) and potassium carbonate (3.84 g, 27.78 mmol) were dissolved in 1,4-dioxane (21 mL) and water (6 mL). After nitrogen replacement three times, the reaction system was placed in a 90°C oil bath and stirred for 18 hours. After the reaction was completed, the reaction solution was directly filtered with diatomaceous earth, the filter cake was rinsed with ethyl acetate (350 mL), water (100 mL) was added, and after extraction and separation, the aqueous phase was then extracted with ethyl acetate (80 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was adsorbed with silica gel and purified by silica gel column chromatography (0-48% ethyl acetate/petroleum ether) to obtain compound C162-5 (385.5 mg, yield: 46.8%) as a yellow solid.
LCMS(ESI)m/z:178.1[M+H]+。LCMS (ESI) m/z: 178.1 [M+H] + .
1H NMR(400MHz,DMSO_d6)δ8.31(s,1H),7.31(s,2H),2.41(s,3H),2.21–2.13(m,1H),0.96(s,2H),0.95(s,2H). 1 H NMR (400 MHz, DMSO_d6) δ8.31 (s, 1H), 7.31 (s, 2H), 2.41 (s, 3H), 2.21–2.13 (m, 1H), 0.96 (s, 2H), 0.95 (s, 2H).
步骤4:Step 4:
将化合物C162-5(385.5mg,2.18mmol)、氯化铜(1.17g,8.7mmol)、氯化亚铜(861.3mg,8.7mmol)和亚硝酸异戊酯(1.53g,13.05mmol)溶解在超干乙腈(9ml)中,置换氮气三次后，将反应体系置于65℃油浴中搅拌反应17小时。反应结束后，反应液直接用大量硅胶吸附，并用硅胶柱层析纯化(0-8％乙酸乙酯/石油醚)，得到化合物C162-6(244mg,收率：57％)，为黄色固体。Compound C162-5 (385.5 mg, 2.18 mmol), cupric chloride (1.17 g, 8.7 mmol), cuprous chloride (861.3 mg, 8.7 mmol) and isoamyl nitrite (1.53 g, 13.05 mmol) were dissolved in ultra-dry acetonitrile (9 ml), and after replacing nitrogen three times, the reaction system was placed in a 65°C oil bath and stirred for 17 hours. After the reaction was completed, the reaction solution was directly adsorbed with a large amount of silica gel and purified by silica gel column chromatography (0-8% ethyl acetate/petroleum ether) to obtain compound C162-6 (244 mg, yield: 57%) as a yellow solid.
LCMS(ESI)m/z:197.1[M+H]+。LCMS (ESI) m/z: 197.1 [M+H] + .
步骤5:Step 5:
将化合物C162-6(148mg,0.75mmol)、化合物C162-7(229mg,1.13mmol)、磷酸钾(798mg,3.76mmol)和甲烷磺酸(2-二叔丁基膦基-2’,4’,6’-三异丙基-1,1’-联苯基)(2’-氨基-1,1’-联苯-2-基)钯(120mg,0.15mmol)溶解在1,4-二氧六环(5.6mL)和水(0.1mL)中，氮气置换三次后，将反应体系置于100℃油浴中搅拌反应2小时。反应结束后，反应液直接用硅藻土过滤，用乙酸乙酯(300mL)冲洗滤饼，减压浓缩以除去溶剂，所得残余物用制备板(石油醚/乙酸乙酯＝2/1)分离纯化，得到粗产品化合物C162-8(70mg)，为黑色固体。Compound C162-6 (148 mg, 0.75 mmol), compound C162-7 (229 mg, 1.13 mmol), potassium phosphate (798 mg, 3.76 mmol) and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (120 mg, 0.15 mmol) were dissolved in 1,4-dioxane (5.6 mL) and water (0.1 mL). After nitrogen replacement three times, the reaction system was placed in a 100°C oil bath and stirred for 2 hours. After the reaction was completed, the reaction solution was directly filtered with diatomaceous earth, the filter cake was rinsed with ethyl acetate (300 mL), and the solvent was removed by concentration under reduced pressure. The residue was separated and purified by a preparation plate (petroleum ether/ethyl acetate = 2/1) to obtain a crude product compound C162-8 (70 mg) as a black solid.
LCMS(ESI)m/z:327.1[M+H]+。LCMS (ESI) m/z: 327.1 [M+H] + .
步骤6:Step 6:
将化合物C162-8(70mg，0.21mmol)、化合物C162-9(80.1mg,0.43mmol)和一水合对甲苯磺酸(6.1mg,0.032mmol)溶解在超干N,N-二甲基甲酰胺(1.5mL)中,将反应体系置于60℃油浴中搅拌反应2小时，反应结束后，反应液通过高效液相制备分离(甲酸酸法分离)，得到C162(38.36mg,两步收率：6.3％)，为黄色固体。Compound C162-8 (70 mg, 0.21 mmol), compound C162-9 (80.1 mg, 0.43 mmol) and p-toluenesulfonic acid monohydrate (6.1 mg, 0.032 mmol) were dissolved in ultra-dry N,N-dimethylformamide (1.5 mL), and the reaction system was placed in a 60°C oil bath and stirred for 2 hours. After the reaction, the reaction solution was separated by high performance liquid phase preparation (formic acid separation) to obtain C162 (38.36 mg, two-step yield: 6.3%) as a yellow solid.
LCMS(ESI)m/z:460.2[M+H]+。LCMS (ESI) m/z: 460.2 [M+H] + .
1H NMR(400MHz,DMSO_d6)δ11.08(s,1H),8.61(s,1H),8.28(s,1H),7.79(d,J＝2.4Hz,1H),7.70(d,J＝2.0Hz,1H),7.39(d,J＝8.4Hz,1H),7.10(dd,J＝8.8,2.0Hz,1H),4.35–4.29(m,1H),2.62–2.55(m,1H),2.17(s,3H),2.04–1.81(m,8H),1.08–1.00(m,4H). 1 H NMR (400 MHz, DMSO_d6) δ 11.08 (s, 1H), 8.61 (s, 1H), 8.28 (s, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.10 (dd, J = 8.8, 2.0 Hz, 1H), 4.35–4.29 (m, 1H), 2.62–2.55 (m, 1H), 2.17 (s, 3H), 2.04–1.81 (m, 8H), 1.08–1.00 (m, 4H).
实施例163
Embodiment 163
合成路线：
synthetic route:
步骤1：step 1:
将化合物C163-1(678mg，3.14mmol)、Pd(PPh3)Cl2(221mg，0.31mmol)和碘化亚铜(60mg，0.31mmol)依次加入100mL单口反应瓶中，再加入超干四氢呋喃(12mL)和三乙胺(1.3mL，9.41mmol)，氮气置换并保护下室温搅拌，然后加入化合物C163-2(0.62mL，4.39mmol)。反应体系在室温下搅拌过夜。反应结束后，加水(40mL)稀释，并用乙酸乙酯(30mL*3)萃取三次。合并有机相，并用无水硫酸钠干燥，然后过滤。将滤液减压浓缩至干。所得残余物用硅胶柱层析纯化(乙酸乙酯:石油醚＝0-40％)，得化合物C163-3(330mg，收率：45％)，为黄色固体。Compound C163-1 (678 mg, 3.14 mmol), Pd(PPh 3 )Cl 2 (221 mg, 0.31 mmol) and cuprous iodide (60 mg, 0.31 mmol) were added to a 100 mL single-mouth reaction bottle in sequence, and then ultra-dry tetrahydrofuran (12 mL) and triethylamine (1.3 mL, 9.41 mmol) were added. The mixture was replaced with nitrogen and stirred at room temperature under protection, and then compound C163-2 (0.62 mL, 4.39 mmol) was added. The reaction system was stirred at room temperature overnight. After the reaction was completed, water (40 mL) was added to dilute the mixture, and the mixture was extracted three times with ethyl acetate (30 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-40%) to obtain compound C163-3 (330 mg, yield: 45%) as a yellow solid.
LCMS(ESI)m/z:234.2[M+H]+。LCMS (ESI) m/z: 234.2 [M+H] + .
1H NMR(400MHz,DMSO_d6)δ8.52(s,1H),7.68–7.26(m,2H),2.45(s,3H),0.29(s,9H). 1 H NMR (400 MHz, DMSO_d6) δ8.52 (s, 1H), 7.68–7.26 (m, 2H), 2.45 (s, 3H), 0.29 (s, 9H).
步骤2：Step 2:
将化合物C163-3(330mg，1.41mmol)、氯化铜(761mg，5.66mmol)和氯化亚铜(561mg，5.66mmol)依次加入100mL单口反应瓶中，再加入超干乙腈(14mL)和亚硝酸异戊酯(663mg，5.66mmol)，氮气保护下在油浴中于65℃搅拌4小时。反应结束后，反应液直接用硅胶柱层析纯化(0-15％乙酸乙酯/石油醚)，得化合物C163-4(230mg，收率：64％)，黄色固体。Compound C163-3 (330 mg, 1.41 mmol), cupric chloride (761 mg, 5.66 mmol) and cuprous chloride (561 mg, 5.66 mmol) were added to a 100 mL single-mouth reaction bottle in sequence, and then ultra-dry acetonitrile (14 mL) and isoamyl nitrite (663 mg, 5.66 mmol) were added, and stirred at 65 ° C in an oil bath under nitrogen protection for 4 hours. After the reaction was completed, the reaction solution was directly purified by silica gel column chromatography (0-15% ethyl acetate/petroleum ether) to obtain compound C163-4 (230 mg, yield: 64%) as a yellow solid.
LCMS(ESI)m/z:253.2[M+H]+。LCMS (ESI) m/z: 253.2 [M+H] + .
1H NMR(400MHz,CDCl3)δ8.80(s,1H),2.64(s,3H),0.27(s,9H). 1 H NMR (400 MHz, CDCl 3 )δ8.80(s,1H),2.64(s,3H),0.27(s,9H).
步骤3：Step 3:
将化合物C163-4(200mg，0.79mmol)和化合物C163-5(160mg，0.79mmol)溶解在二甲基亚砜(4.2mL)中，加入N,N-二异丙基乙胺(0.4mL，2.37mmol)，将混合物在氮气保护下室温搅拌过夜。反应结束后，加水(40mL)稀释，并用乙酸乙酯(30mL*3)萃取三次。合并有机相，并用无水硫酸钠干燥，然后过滤。将滤液减压浓缩至干，即得粗品化合物C163-6(250mg)。Compound C163-4 (200 mg, 0.79 mmol) and compound C163-5 (160 mg, 0.79 mmol) were dissolved in dimethyl sulfoxide (4.2 mL), N, N-diisopropylethylamine (0.4 mL, 2.37 mmol) was added, and the mixture was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, water (40 mL) was added to dilute, and ethyl acetate (30 mL*3) was used for extraction three times. The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated to dryness under reduced pressure to obtain a crude compound C163-6 (250 mg).
LCMS(ESI)m/z:311.1[M+H]+。LCMS (ESI) m/z: 311.1 [M+H] + .
步骤4:Step 4:
将化合物C163-6(250mg，0.79mmol)、化合物C163-7(178mg，0.95mmol)和一水合对甲苯磺酸(30mg，0.16mmol)溶解在超干溶剂N,N-二甲基甲酰胺(4.4mL)中。反应液在油浴中于60℃下搅拌2小时。反应结束后，反应液用高效液相制备纯化，然后再用制备板(石油醚/乙酸乙酯：10/1)纯化，得化合物C163(26.75mg，收率：10.6％)，为黄色固体。Compound C163-6 (250 mg, 0.79 mmol), compound C163-7 (178 mg, 0.95 mmol) and p-toluenesulfonic acid monohydrate (30 mg, 0.16 mmol) were dissolved in an ultra-dry solvent N,N-dimethylformamide (4.4 mL). The reaction solution was stirred at 60°C in an oil bath for 2 hours. After the reaction was completed, the reaction solution was purified by high-performance liquid chromatography and then purified by a preparative plate (petroleum ether/ethyl acetate: 10/1) to obtain compound C163 (26.75 mg, yield: 10.6%) as a yellow solid.
LCMS(ESI)m/z:444.2[M+H]+。LCMS (ESI) m/z: 444.2 [M+H] + .
1H NMR(400MHz,CD3OD)δ8.51(s,1H),7.60(s,1H),7.38(d,J＝2.0Hz,1H),7.35(d,J＝8.8Hz,1H),7.10(dd,J＝8.8,2.0Hz,1H),4.36(s,1H),4.27(s,1H),2.25(s,3H),2.06–1.88(m,8H). 1 H NMR (400 MHz, CD 3 OD) δ8.51 (s, 1H), 7.60 (s, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.10 (dd, J = 8.8, 2.0 Hz, 1H), 4.36 (s, 1H), 4.27 (s, 1H), 2.25 (s, 3H), 2.06–1.88 (m, 8H).
生物测试Biological Testing
实验例1：体外细胞活实验Experimental Example 1: In vitro cell viability experiment
A.主要材料 A.Main Materials
细胞系：Cell lines:
THP1细胞系(来自ATCC，批号TIB-202)THP1 cell line (from ATCC, lot number TIB-202)
试剂： Reagents:
1.DPBS(Invitrogen，14190-144)；2.FBS(GIBCO，10099-141)；3.DMSO(Sigma，D8418-1L)；4.PMA(MCE，HY-18739)；5.RPMI培养基1640(Invitrogen，A10491-01)；6.Pen/Strep青链霉素混合液(GIBCO，15140-122)；7.IFNb ELISA试剂盒(R&D，DY814-05)。1. DPBS (Invitrogen, 14190-144); 2. FBS (GIBCO, 10099-141); 3. DMSO (Sigma, D8418-1L); 4. PMA (MCE, HY-18739); 5. RPMI medium 1640 (Invitrogen, A10491-01); 6. Pen/Strep penicillin-streptomycin mixture (GIBCO, 15140-122); 7. IFNb ELISA kit (R&D, DY814-05).
耗材：Consumables:
1.T75培养瓶(Corning，430641)；2.96孔板(Corning，3599)；3.移液管(5ml,10ml,25ml,50ml)(Thermo Scientific，159625159633)；4.移液枪枪头(10μl,200μl,1ml)(Axygen，T-300-R-S/T-200-Y-R-S/T-1000-B-R-S)。1. T75 culture flask (Corning, 430641); 2. 96-well plate (Corning, 3599); 3. Pipette (5ml, 10ml, 25ml, 50ml) (Thermo Scientific, 159625159633); 4. Pipette tip (10μl, 200μl, 1ml) (Axygen, T-300-R-S/T-200-Y-R-S/T-1000-B-R-S).
仪器：instrument:
1.生物安全操作柜(Thermo Scientific，1300Series A2)；2.离心机(Eppendorf，5702)；3.二氧化碳培养箱(Thermo Scientific，371)；4.细胞计数器(Invitrogen，C10281)；5.移液器控制器(BIOHIT，Easypet)；6.倒置显微镜(Olympus，CKX41)；7.移液器(BIOHIT，Proline Plus)；8.涡流混合器(IKA，MS3basic)；9.EnVision酶标仪(Perkin Elmer，2014)。1. Biosafety cabinet (Thermo Scientific, 1300 Series A2); 2. Centrifuge (Eppendorf, 5702); 3. Carbon dioxide incubator (Thermo Scientific, 371); 4. Cell counter (Invitrogen, C10281); 5. Pipette controller (BIOHIT, Easypet); 6. Inverted microscope (Olympus, CKX41); 7. Pipette (BIOHIT, Proline Plus); 8. Vortex mixer (IKA, MS3basic); 9. EnVision microplate reader (Perkin Elmer, 2014).
B.方法(THP1细胞中的人IFN-β检测)B. Methods (Human IFN-β Detection in THP1 Cells)
a)THP1细胞系a) THP1 cell line
RPMI培养基1640,10％FBS,1％PS中悬浮培养106个细胞/mL，37℃&5％CO2培养箱。10 6 cells/mL were suspended and cultured in RPMI medium 1640, 10% FBS, 1% PS in a 37°C & 5% CO 2 incubator.
移种100μL/孔至96孔板中，其包含50ng/mL PMA，置于37℃&5％CO2培养箱。Transfer 100 μL/well to a 96-well plate containing 50 ng/mL PMA and place in a 37°C & 5% CO2 incubator.
b)IFN-β检测b) IFN-β detection
1.用DPBS洗涤培养的THP1细胞，加入100μL无FBS的RPMI培养基1640；1. Wash the cultured THP1 cells with DPBS and add 100 μL of RPMI medium 1640 without FBS;
2.加入25μL化合物(终DMSO含量为0.1％)并置于37℃、5％CO2培养箱中培养；2. Add 25 μL of compound (final DMSO content is 0.1%) and culture in a 37°C, 5% CO 2 incubator;
3.用Lip3000转染1μg/mL dsDNA并置于37℃、5％CO2培养箱中培养；3. Transfect 1 μg/mL dsDNA with Lip3000 and culture in a 37°C, 5% CO 2 incubator;
4.离心，将上清液转移至96孔板中；4. Centrifuge and transfer the supernatant to a 96-well plate;
5.使用IFN-βELISA试剂盒监测IFN-β水平。5. Monitor IFN-β levels using IFN-β ELISA kit.
c)IFN-βELISA试剂盒c) IFN-β ELISA kit
1.在不含载体蛋白的PBS中将Capture抗体稀释至工作浓度。在96孔板中每孔加入100μL稀释的Capture抗体。将96孔板密封后在室温下过夜培养。1. Dilute the Capture antibody to a working concentration in PBS without carrier protein. Add 100 μL of the diluted Capture antibody to each well of a 96-well plate. Seal the 96-well plate and incubate overnight at room temperature.
2.抽吸出每个孔中的培养液并用缓冲洗涤液洗涤，重复两次或共洗涤三次。使用喷瓶向每个孔填充洗涤缓冲液(400μL)进行洗涤。2. Aspirate the culture medium in each well and wash with buffered wash solution, repeat twice or three times in total. Use a squirt bottle to fill each well with wash buffer (400 μL) for washing.
3.加入300μL稀释剂试剂来封闭培养板，置于室温培养1～2小时。3. Add 300 μL of diluent reagent to seal the culture plate and incubate at room temperature for 1 to 2 hours.
4.重复步骤2中的抽吸/洗涤两次。4. Repeat the aspiration/washing in step 2 twice.
5.向稀释剂试剂中加入100μL样品(Supes)或标准品，用胶条覆盖并在室温下培养2小时。5. Add 100 μL of sample (Supes) or standard to the diluent reagent, cover with a strip and incubate at room temperature for 2 hours.
6.重复步骤2中的抽吸/洗涤两次。6. Repeat the aspiration/washing in step 2 twice.
7.向每孔中加入100μL检测抗体，稀释于稀释剂试剂中。7. Add 100 μL of detection antibody diluted in diluent reagent to each well.
8.用新的胶条覆盖并在室温下培养2小时。8. Cover with a new strip and incubate at room temperature for 2 hours.
9.重复步骤2中的抽吸/洗涤两次。9. Repeat the aspiration/washing in step 2 twice.
10.向每孔中加入100μL Streptavidin-HRP工作稀释液。用新的胶条覆盖并在室温下培养2小时(避光)。10. Add 100 μL of Streptavidin-HRP working dilution to each well. Cover with a new strip and incubate at room temperature for 2 hours (protect from light).
11.向每孔中加入50μL终止液。11. Add 50 μL of stop solution to each well.
12.在EnVision酶标仪上读取化学发光信号OD450。12. Read the chemiluminescent signal OD450 on the EnVision microplate reader.
C.实验结果 C. Experimental Results
表2.体外活性测试结果

Table 2. In vitro activity test results

结论：本发明化合物对STING有强的抑制活性。Conclusion: The compounds of the present invention have strong inhibitory activity on STING.
实验例2：在(人/小鼠)肝微粒体中的代谢稳定性Experimental Example 2: Metabolic stability in (human/mouse) liver microsomes
A.实验设计：A. Experimental Design:
测定浓度：1μM；对照化合物：睾酮；培养条件：于37℃下培养0、5、15、30、45分钟；测定方法：LC-MS/MS；计算方法：T1/2＝0.693/K(K是ln[浓度]相对于温育时间图的速率常数)，Clint＝(0.693/T1/2)×(1/(微粒体蛋白浓度(0.5mg/mL)))×比例因子。下表为微粒体中内在清除预测的比例因子。
Assay concentration: 1 μM; control compound: testosterone; incubation conditions: incubated at 37°C for 0, 5, 15, 30, 45 minutes; assay method: LC-MS/MS; calculation method: T 1/2 = 0.693/K (K is the rate constant of the ln[concentration] versus incubation time graph), Cl int = (0.693/T 1/2 )×(1/(microsomal protein concentration (0.5 mg/mL)))×proportional factor. The following table shows the proportional factors for the prediction of intrinsic clearance in microsomes.
B.实验方法：B. Experimental Methods:
1.预热0.1M K-buffer，5nM MgCl2，pH＝7.4；2.测试化合物和参比化合物的实验溶液，500μM添加溶液：将5μL10mM储备溶液加入95μL ACN中；1.5μM微粒体中的掺加溶液(0.75mg/mL)：将1.5μL的500μM的添加溶液和18.75μL的20Mg/mL肝微粒体加入到479.75μL的K/Mg缓冲液中；3.3×NADPH的原液(6mM，5mg/mL)是将NADPH溶解于缓冲液中；4.将30μL含有0.75mg/mL微粒体溶液的1.5μM的添加溶液分配到指定用于不同时间点(0，5，15，30，45分钟)的测定板上；5.在0分钟时，将150μL含IS的ACN加入平板的孔中，然后加入15μL NADPH储备溶液(6mM，步骤3)；6.将所有其它板在37℃下预孵育5分钟；7.向板中加入15μL NADPH储备溶液以开始反应和计时；8.在5分钟、15分钟、30分钟和45分钟时，分别向相应板的孔中加入150μL含有IS的 ACN以终止反应；9.淬灭后，在振动器上将板摇动10分钟(600rpm/分钟)，然后在6000rpm下离心15分钟；10.将80μL上清液从每个孔转移到含有140μL水的96孔样品板中，用于LC/MS分析。1. Preheat 0.1M K-buffer, 5nM MgCl 2 , pH=7.4; 2. Experimental solution of test compound and reference compound, 500μM Addition solution: add 5μL 10mM stock solution to 95μL ACN; 1.5 μM spike solution in microsomes (0.75 mg/mL): 1.5 μL of 500 μM spike solution and 18.75 μL of 20 Mg/mL liver microsomes were added to 479.75 μL of K/Mg buffer; 3.3× NADPH stock solution (6 mM, 5 mg/mL) was NADPH dissolved in buffer; 4. 30 μL of 1.5 μM spike solution containing 0.75 mg/mL microsomal solution was distributed to the assay plates designated for different time points (0, 5, 15, 30, 45 minutes); 5. At 0 minutes, 150 μL of ACN containing IS was added to the wells of the plate, followed by 15 μL of NADPH stock solution (6 mM, step 3); 6. All other plates were pre-incubated at 37°C for 5 minutes; 7. 15 μL of NADPH stock solution to start the reaction and timing; 8. At 5 minutes, 15 minutes, 30 minutes and 45 minutes, add 150 μL of IS to the wells of the corresponding plate. ACN to terminate the reaction; 9. After quenching, shake the plate on a shaker for 10 minutes (600 rpm/min), then centrifuge at 6000 rpm for 15 minutes; 10. Transfer 80 μL of supernatant from each well to a 96-well sample plate containing 140 μL of water for LC/MS analysis.
分析方法：Analytical method:
检测方法：LC-MS/MS-11(8050)，内标：甲苯磺丁脲，MS条件为睾酮和待测化合物正离子ESI；甲苯磺丁脲负离子ESI；流动相：流动相A为0.1％FA于水中，流动相B为0.1％FA于ACN中；柱及规格：ACQUITY UPLC HSS T3 1.8um 2.1*50mm。Detection method: LC-MS/MS-11 (8050), internal standard: tolbutamide, MS conditions are testosterone and the test compound positive ion ESI; tolbutamide negative ion ESI; mobile phase: mobile phase A is 0.1% FA in water, mobile phase B is 0.1% FA in ACN; column and specifications: ACQUITY UPLC HSS T3 1.8um 2.1*50mm.
LC条件：
LC conditions:
C.实验结果：
C. Experimental results:
D.实验结论：本发明化合物表现出良好的肝微粒体稳定性。D. Experimental conclusion: The compounds of the present invention exhibit good liver microsome stability.
实验例3：小鼠药代动力学实验Experimental Example 3: Pharmacokinetic Experiment in Mice
A.实验目的：评估化合物在小鼠体内的药代动力学特征A. Experimental purpose: To evaluate the pharmacokinetic characteristics of the compound in mice
B.实验方法：雄性C57BL/6N小鼠，体重18-22g，试验前禁食过夜。待测化合物溶解在溶媒中。IV组按2mg/kg静脉注射(n＝3)给药，PO组按10mg/kg经口管饲法(n＝3)给药。在给药后15分钟、30分钟和1、2、4、6、8及24小时通过眼眶静脉丛取血，每个时间点约0.08mL，置于含EDTA-2K抗凝剂的1.5mL离心管中，血样在2小时内经离心处理(3200g，10分钟，4℃)获得血浆样品。血浆样品在处理前冻存于-70℃至-80℃超低温冰箱中。样品处理前将血浆样品从冰箱取出，室温解冻后，分别20μL血浆样品加入到96孔板中，然后加入120μL含内标的乙腈沉淀蛋白，涡旋混合后，于4℃、4950g离心15分钟，取上清与0.1％甲酸水等体积混匀进行LC-MS/MS分析。B. Experimental methods: Male C57BL/6N mice, weighing 18-22 g, fasted overnight before the experiment. The test compound was dissolved in the solvent. The IV group was administered intravenously at 2 mg/kg (n=3), and the PO group was administered by oral gavage at 10 mg/kg (n=3). Blood was collected from the orbital venous plexus at 15 minutes, 30 minutes and 1, 2, 4, 6, 8 and 24 hours after administration. About 0.08 mL at each time point was placed in a 1.5 mL centrifuge tube containing EDTA-2K anticoagulant. The blood sample was centrifuged within 2 hours (3200g, 10 minutes, 4°C) to obtain plasma samples. The plasma samples were frozen in an ultra-low temperature freezer at -70°C to -80°C before processing. Before sample processing, the plasma samples were taken out of the refrigerator and thawed at room temperature. 20 μL of plasma samples were added to a 96-well plate, and then 120 μL of acetonitrile containing internal standard was added to precipitate the protein. After vortex mixing, the plates were centrifuged at 4°C and 4950 g for 15 min. The supernatant was mixed with an equal volume of 0.1% formic acid water for LC-MS/MS analysis.
C.实验结果
C. Experimental Results
D.实验结论：本发明化合物显示出较好的药代动力学性质。D. Experimental conclusion: The compounds of the present invention show good pharmacokinetic properties.
本文中使用实施例对本发明的原理及实施方式进行了阐述，以上实施例只是用于帮助理解本发明而不是对其进行限制。应当指出，对于本领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的范围。 The principles and implementation methods of the present invention are described herein using examples, and the above examples are only used to help understand the present invention rather than to limit it. It should be noted that for those of ordinary skill in the art, several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of the claims of the present invention.

Claims (38)

  1. 下式I-A的化合物：
    The compound of formula IA:
    或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof,
    其中：in:
    L0选自-NH-、-NH-C(O)-NH-、-NH-S(O)-和-NH-S(O)2-；L 0 is selected from -NH-, -NH-C(O)-NH-, -NH-S(O)- and -NH-S(O) 2 -;
    LC为 L C is
    L1选自C、S和S(O)；L is selected from C, S and S(O);
    L2选自单键、-CH2-、-O-、-S(O)0-2-和-NH-，其中所述-CH2-和-NH-任选地被Ra取代1～3次；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 ;
    环A选自C3～10饱和或部分不饱和的单环或双环环烃基、3～10元饱和或部分不饱和的单环或双环杂环基、C6-10芳基和5～10元单环或双环杂芳基；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;
    环B选自C3～6饱和或部分不饱和的单环环烃基、3～6元饱和或部分不饱和的单环杂环基、苯基和5或6元杂芳基；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选自CRaRb、N Ra、O、S和S(O)2；X is selected from CR a R b , NR a , O, S and S(O) 2 ;
    Q选自CRa和N；Q is selected from CR a and N;
    R1选自H、N(Rb)2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、C3～6环烷基、3～6元杂环烷基、C6-10芳基、5～10元杂芳基、-O-C3～6环烷基、-O-3～6元杂环烷基、-O-C6-10芳基、-O-5～10元杂芳基、-C(O)-O-C1～6烷基、-C(O)-NRaRb、-NRb-C(O)-C1～6烷基、-S(O)-C1～6烷基、-S(O)2-C1～6烷基、-S(O)-O-C1～6烷基、-S(O)-NRaRb、-S(O)2-O-C1～6烷基和-S(O)2-NRaRb，其中所述C1～6烷基、C1～6烷氧基、C3～6环烷基、3～6元杂环烷基、C6-10芳基和5～10元杂芳基任选地被Ra取代1～3次； R1 is selected from 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) 2 -OC1~6 alkyl and -S(O) 2-NRaRb, wherein the 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 , 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted 1-3 times by Ra ;
    R2选自H、N(Rb)2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、氧代基、-C(O)-NRaRb、-NRb-C(O)-C1～6烷基、-C1～3烷基-NH(C1～3烷基)、-C1～3烷基-N(C1～3烷基)2、-S(O)-C1～6烷基、-S(O)2-C1～6烷基、-S(O)-O-C1～6烷基、-S(O)-NRaRb、-S(O)2-O-C1～6烷基、-S(O)2-NRaRb、C3～10饱和或部分不饱和的环烃基、5～10元饱和或部分不饱和的杂环基、C6-10芳基和5～10元芳杂基，其中所述烷基、烷氧基、环烃基、杂环基、芳基和芳杂基任选地被Ra取代1～3次； 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 alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaromatic groups are optionally substituted 1 to 3 times by Ra ;
    R3选自H、C1～6烷基、C3～6环烷基、3～6元杂环烷基、-C1～6亚烷基-O-C1～6烷基、-C1～6亚烷基-NH-C1～6烷基、-C1～6亚烷基-N(C1～6烷基)2、-C1～6亚烷基-C3～6环烷基、-C1～6亚烷基-3～6元杂环烷基、-C1～6亚烷基-C6-10芳基和-C1～6亚烷基-5或6元杂芳基，其中所述烷基、亚烷基、环烷基、杂环烷基、芳基和杂芳基任选地被Ra取代1～3次，并且 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
    其中R3任选地与环A的环原子连接以形成C3～7饱和或部分不饱和的单环环烃基、3～7元饱和或部分不饱和的单环杂环基、苯基、或者5或6元杂芳基，其中所述环烃基、杂环基、芳基和杂芳基任选地被Ra取代1～3次；wherein 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选自H、CN、OH、NH2、卤素、C1～6烷基、-C1～6亚烷基-O-C1～6烷基、-C1～6亚烷基-NH-C1～6烷基、C3～10环烷基、C7～12螺环烷基、C7-10桥环烷基、3～10元杂环烷基、5-12元螺杂环烷基、6至9元桥杂环烷基、C6～10芳基、5～10元杂芳基、-C1～6亚烷基-C3～7环烷基、-C1～6亚烷基-3～7元杂环烷基、-C1～6亚烷基-C6～10芳基、-C1～6亚烷基-5～10元杂芳基、-C1～6亚烷基-C(O)-C3～7环烷基、-C1～6亚烷基-C(O)-3～7元杂环烷基、-C1～6亚烷基-C(O)-C6～10芳基和-C1～6亚烷基-C(O)-5～10元杂芳基，其中所述烷基、亚烷基、环烷基、螺环烷基、桥环烷基、杂环烷基、螺杂环烷基、桥杂环烷基、芳基和杂芳基在每次出现时任选地被Rb取代1～3次； 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-5~10 membered heteroaryl, -C1 ~6 alkylene-C(O)-C3 ~7 cycloalkyl, -C 1-6 alkylene-C(O)-3-7 membered heterocycloalkyl, -C 1-6 alkylene-C(O)-C 6-10 aryl and -C 1-6 alkylene-C(O)-5-10 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, spirocycloalkyl, bridged cycloalkyl, heterocycloalkyl, spiroheterocycloalkyl, bridged heterocycloalkyl, aryl and heteroaryl are optionally substituted 1-3 times by R b at each occurrence;
    p选自1、2和3； p is selected from 1, 2 and 3;
    q选自0、1、2和3；q is selected from 0, 1, 2 and 3;
    Ra独立地选自H、卤素、NH2、OH、CN、C1～6烷基、-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和-S(O)2-NHRc，其中所述C1～6烷基任选被卤素取代1～3次；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;
    Rb独立地选自H、卤素、NH2、OH、CN、C1-6烷基和C1-6烷氧基，其中所述C1～6烷基和C1～6烷氧基任选被卤素取代1～3次；以及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
    Rc独立地选自任选地被NH2、OH、CN和1～3个卤素取代的C1-6烷基、C2-6烯基和C2-6炔基。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.
  2. 根据权利要求1所述的化合物，其中：The compound according to claim 1, wherein:
    R1选自H、N(Rb)2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、C3～6环烷基、3～6元杂环烷基、C6-10芳基、5～10元杂芳基、-O-C3～6环烷基、-O-3～6元杂环烷基、-O-C6-10芳基、-O-5～10元杂芳基、-C(O)-O-C1～6烷基、-C(O)-NRaRb、-NRb-C(O)-C1～6烷基和-S(O)2-C1～6烷基，其中所述C1～6烷基、C1～6烷氧基、C3～6环烷基、3～6元杂环烷基、C6-10芳基和5～10元杂芳基任选地被Ra取代1～3次；和/或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 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
    R2选自H、N(Rb)2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、氧代基、-C(O)-NRaRb、-NRb-C(O)-C1～6烷基、C1～3烷基-NH(C1～3烷基)、-C1～3烷基-N(C1～3烷基)2、-S(O)2-C1～6烷基、C3～10饱和或部分不饱和的环烃基、5～10元饱和或部分不饱和的杂环基、C6-10芳基和5～10元芳杂基，其中所述烷基、烷氧基、环烃基、杂环基、芳基和芳杂基任选地被Ra取代1～3次；和/或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 ; and/or
    R4选自H、CN、OH、NH2、卤素、C1～6烷基、-C1～6亚烷基-O-C1～6烷基、-C1～6亚烷基-NH-C1～6烷基、C3～10环烷基、3～7元杂环烷基、7-11元螺杂环烷基、C6～10芳基、5～10元杂芳基、-C1～6亚烷基-C3～7环烷基、-C1～6亚烷基-3～7元杂环烷基、-C1～6亚烷基-C6～10芳基、-C1～6亚烷基-5～10元杂芳基、-C1～6亚烷基-C(O)-C3～7环烷基、-C1～6亚烷基-C(O)-3～7元杂环烷基、-C1～6亚烷基-C(O)-C6～10芳基和-C1～6亚烷基-C(O)-5～10元杂芳基，其中所述烷基、亚烷基、环烷基、杂环烷基、螺杂环烷基、芳基和杂芳基在每次出现时任选地被Rb取代1～3次。 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, -C1 ~6 alkylene-C(O)-3~7 membered heterocycloalkyl, -C1 ~6 alkylene-C(O)-C6 ~10 aryl and -C1~6 1-6 alkylene-C(O)-5-10 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, spiroheterocycloalkyl, aryl and heteroaryl are optionally substituted 1-3 times by R b at each occurrence.
  3. 根据权利要求1或2所述的化合物，其中：The compound according to claim 1 or 2, wherein:
    R1选自H、N(Rb)2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、C3～6环烷基、3～6元杂环烷基、C6-10芳基、5～10元杂芳基、-O-C3～6环烷基、-O-3～6元杂环烷基、-O-C6-10芳基、-O-5～10元杂芳基、-C(O)-O-C1～6烷基、-C(O)-NRaRb和-NRb-C(O)-C1～6烷基，其中所述C1～6烷基、C1～6烷氧基、C3～6环烷基、3～6元杂环烷基、C6-10芳基和5～10元杂芳基任选地被Ra取代1～3次；和/或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
    R2选自H、N(Rb)2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、氧代基、-C(O)-NRaRb、-NRb-C(O)-C1～6烷基、C3～10饱和或部分不饱和的环烃基、5～10元饱和或部分不饱和的杂环基、C6-10芳基和5～10元芳杂基，其中所述烷基、烷氧基、环烃基、杂环基、芳基和芳杂基任选地被Ra取代1～3次；和/或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选自H、CN、OH、NH2、卤素、C1～6烷基、-C1～6亚烷基-O-C1～6烷基、-C1～6亚烷基-NH-C1～6烷基、C3～7环烷基、3～7元杂环烷基、C6～10芳基、5～10元杂芳基、-C1～6亚烷基-C3～7环烷基、-C1～6亚烷基-3～7元杂环烷基、-C1～6亚烷基-C6～10芳基、-C1～6亚烷基-5～10元杂芳基、-C1～6亚烷基-C(O)-C3～7环烷基、-C1～6亚烷基-C(O)-3～7元杂环烷基、-C1～6亚烷基-C(O)-C6～10芳基和-C1～6亚烷基-C(O)-5～10元杂芳基，其中所述烷基、亚烷基、环烷基、杂环烷基、芳基和杂芳基在每次出现时任选地被Rb取代1～3次。 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 heterocycloalkyl, -C1 ~6 alkylene-C(O)-C6 ~10 aryl and -C1~6 1-6 alkylene-C(O)-5-10 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted 1-3 times by R b at each occurrence.
  4. 根据权利要求1至3中任一项所述的化合物，其中L0为-NH-。The compound according to any one of claims 1 to 3, wherein L 0 is -NH-.
  5. 根据权利要求1至4中任一项所述的化合物，其中所述化合物具有式I-B或式I-C所示的结构：
    The compound according to any one of claims 1 to 4, wherein the compound has a structure shown in Formula IB or Formula IC:
  6. 根据权利要求1至5中任一项所述的化合物，其中： The compound according to any one of claims 1 to 5, wherein:
    环B选自C6饱和或部分不饱和的单环环烃基、6元饱和或部分不饱和的单环杂环基、苯基和6元杂芳基。Ring B is selected from a C 6 saturated or partially unsaturated monocyclic cycloalkyl group, a 6-membered saturated or partially unsaturated monocyclic heterocyclic group, a phenyl group and a 6-membered heteroaryl group.
  7. 根据权利要求1至6中任一项所述的化合物，其中所述部分为所述化合物具有式I-D或I-E所示的结构：
    The compound according to any one of claims 1 to 6, wherein the Part of The compound has a structure shown in Formula ID or IE:
    其中：in:
    表示单键或双键，条件是相邻的两个不同时为双键； represents a single bond or a double bond, provided that two adjacent Not a double bond at the same time;
    Y1、Y2和Y3各自独立地选自CH2、CH、NH、N、O和S，其中所述CH2、CH和NH在化合价允许的条件下任选地被R1取代1或2次；以及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选自CH2、CH、NH和N，其中所述CH2、CH和NH在化合价允许的条件下任选地被R1取代1或2次。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.
  8. 根据权利要求1至7中任一项所述的化合物，其中所述化合物具有式I-F或I-G所示的结构：
    The compound according to any one of claims 1 to 7, wherein the compound has a structure shown in formula IF or IG:
    其中Y1、Y2、Y3和Z各自为CH；或者Y1、Y2、Y3和Z中的一个N，其余均为CH。wherein 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.
  9. 根据权利要求8所述的化合物，其中所述部分选自：
    The compound according to claim 8, wherein the Some selected from:
  10. 根据权利要求1至9中任一项所述的化合物，其中：The compound according to any one of claims 1 to 9, wherein:
    X选自NRa、O、S和S(O)2，X is selected from NR a , O, S and S(O) 2 ,
    Ra选自H、C1～6烷基、-C(O)-Rc、-S(O)-Rc和-S(O)2-Rc，其中所述C1～6烷基任选被卤素取代1～3次，并且 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
    Rc选自任选地被NH2、OH、CN和1～3个卤素取代的C1-6烷基、C2-6烯基和C2-6炔基；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;
    优选地，X选自NRa、O、S和S(O)2，Preferably, X is selected from NR a , O, S and S(O) 2 ,
    Ra选自H、C1～3烷基、-C(O)-Rc、-S(O)-Rc和-S(O)2-Rc，其中所述C1～3烷基任选被F、Cl、Br或I取代1～3次，并且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
    Rc选自任选地被NH2、OH、CN和1～3个卤素取代的C1-3烷基、C2-3烯基和C2-3炔基；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;
    更优选地，X选自NRa、O、S和S(O)2，More preferably, X is selected from NR a , O, S and S(O) 2 ,
    Ra选自H、C1～3烷基和-C(O)-Rc，并且R a is selected from H, C 1-3 alkyl and -C(O)-R c , and
    Rc选自C1-3烷基、C2-3烯基和C2-3炔基；R c is selected from C 1-3 alkyl, C 2-3 alkenyl and C 2-3 alkynyl;
    更优选地，X选自NH、N(C(O)-CH＝CH2)、S和S(O)2。More preferably, X is selected from NH, N(C(O)-CH=CH 2 ), S and S(O) 2 .
  11. 根据权利要求1至10中任一项所述的化合物，其中：The compound according to any one of claims 1 to 10, wherein:
    Q选自CRa和N，并且Ra选自H、卤素、NH2、OH、CN和C1～6烷基，其中所述C1～6烷基任选被卤素取代1～3次；Q is selected from CR a and N, and R a is selected from H, halogen, NH 2 , OH, CN and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted 1 to 3 times by halogen;
    优选地，Q选自CRa和N，并且Ra选自H和C1～3烷基，其中所述C1～3烷基任选被卤素取代1～3次；Preferably, Q is selected from CR a and N, and R a is selected from H and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted 1 to 3 times by halogen;
    更优选地，Q选自CH和N。More preferably, Q is selected from CH and N.
  12. 根据权利要求1至11中任一项所述的化合物，其中：The compound according to any one of claims 1 to 11, wherein:
    R1选自H、N(Rb)2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、C3～6环烷基、3～6元杂环烷基、C6-10芳基、5～10元杂芳基、-O-C3～6环烷基、-O-3～6元杂环烷基、-O-C6-10芳基、-O-5～10元杂芳基、-C(O)-O-C1～6烷基、-C(O)-NRaRb和-S(O)2-C1～6烷基，其中所述C1～6烷基、C1～6烷氧基、C3～6环烷基、3～6元杂环烷基、C6-10芳基和5～10元杂芳基任选地被Ra取代1～3次，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 ,
    优选地，R1选自H、N(Rb)2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、C3～6环烷基、3～6元杂环烷基、C6-10芳基、5～10元杂芳基、-O-C3～6环烷基、-O-3～6元杂环烷基、-O-C6-10芳基、-O-5～10元杂芳基、-C(O)-O-C1～6烷基、-C(O)-NRaRb和-S(O)2-C1～6烷基，其中所述C1～6烷基、C1～6烷氧基、C3～6环烷基、3～6元杂环烷基、C6-10芳基和5～10元杂芳基任选地被Ra取代1～3次，Preferably, 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 ,
    更优选地，R1选自H、N(Rb)2、CN、OH、卤素、C1～3烷基、C1～3烷氧基、C3～6环烷基、3～6元杂环烷基、苯基、5或6元杂芳基、-O-C3～6环烷基、-O-3～6元杂环烷基、-O-苯基、-O-5或6元杂芳基、-C(O)-O-C1～3烷基和-C(O)-NRaRb，其中所述C1～3烷基、C1～3烷氧基、C3～6环烷基、3～6元杂环烷基、苯基和5～6元杂芳基任选地被Ra取代1～3次，More preferably, 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 ,
    其中Ra和Rb独立地选自H和C1～6烷基，其中所述C1～6烷基任选被卤素取代1～3次；wherein 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;
    更优选地，R1选自H、N(Rb)2、CN、OH、F、Cl、Br、C1～3烷基、C1～3卤代烷基、C1～3烷氧基、C3～6环烷基、3～6元杂环烷基、苯基、5或6元杂芳基、-O-C3～6环烷基、-O-3～6元杂环烷基、-O-苯基、-O-5或6元杂芳基、-C(O)-O-C1～3烷基和-C(O)-NRaRb，其中所述C3～6环烷基、3～6元杂环烷基、苯基和5～6元杂芳基任选地被Ra取代1～3次，More preferably, 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 ,
    其中Ra和Rb独立地选自H和C1～3烷基，优选H、甲基和乙基；wherein Ra and Rb are independently selected from H and C1-3 alkyl, preferably H, methyl and ethyl;
    更优选地，R1选自H、NH2、-NH(C1～3烷基)、-N(C1～3烷基)2、CN、OH、F、Cl、Br、C1～3烷基、C1～3卤代烷基、C1～3烷氧基、3～6元杂环烷基、5或6元杂芳基、-O-C3～6环烷基、-O-苯基、-C(O)-O-C1～3 烷基、-C(O)-NH2、-C(O)-NH(C1～3烷基)、-C(O)-N(C1～3烷基)2，其中所述C3～6环烷基、3～6元杂环烷基、苯基和5～6元杂芳基任选地被Ra取代1～3次；More preferably, R1 is selected from H, NH2 , -NH( C1-3 alkyl), -N( C1-3 alkyl) 2 , CN, OH, F, Cl, Br, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, 3-6 membered heterocycloalkyl, 5 or 6 membered heteroaryl, -OC3-6 cycloalkyl, -O-phenyl, -C(O) -OC1-3 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 ;
    更优选地，R1选自NH2、CN、OH、F、Cl、Br、CH3、CH2CH3、CH(CH3)CH3、CF3、甲氧基、-C(O)OCH3、-C(O)-N(CH3)2、-S(O)2-CH3、环丙基、环丙基氧基、苯氧基和 More preferably, 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
    更优选地，R1选自NH2、CN、OH、F、Cl、Br、CH3、CH2CH3、CH(CH3)CH3、CF3、甲氧基、-C(O)OCH3、-C(O)-N(CH3)2、环丙基、环丙基氧基、苯氧基和 More preferably, 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
    更优选地，R1选自CN、OH、F、Cl、CF3、甲氧基、-C(O)OCH3、-C(O)-N(CH3)2、环丙基氧基、苯氧基和 More preferably, 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
  13. 根据权利要求8至12中任一项所述的化合物，其中所述部分选自：
    The compound according to any one of claims 8 to 12, wherein the Some selected from:
    优选自 Selected from
    其中Ra如权利要求1、优选如权利要求10中所定义。wherein Ra is as defined in claim 1, preferably in claim 10.
  14. 根据权利要求13所述的化合物，其中所述化合物具有式I-H至I-O所示的结构：
    The compound according to claim 13, wherein the compound has a structure shown in Formula IH to IO:
    其中Ra如权利要求1、优选如权利要求8中所定义。 wherein Ra is as defined in claim 1, preferably in claim 8.
  15. 根据权利要求13所述的化合物，其中所述部分选自：
    The compound according to claim 13, wherein the Some selected from:
  16. 根据权利要求1至15中任一项所述的化合物，其中：The compound according to any one of claims 1 to 15, wherein:
    所述环A选自C3～6饱和或部分不饱和的单环环烃基、C8～10饱和或部分不饱和的双环环烃基、3～6元饱和或部分不饱和的单环杂环基、8～10元饱和或部分不饱和的双环杂环基、C6-10芳基、5或6元杂芳基和8～10元双环杂芳基；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 heterocyclic group, an 8-10 membered saturated or partially unsaturated bicyclic heterocyclic group, a C 6-10 aryl group, a 5- or 6-membered heteroaryl group, and an 8-10 membered bicyclic heteroaryl group;
    优选地，所述环A选自C3～6环烷基、3～6元杂环烷基、3～6元单环杂环烯基、8～10元双环杂环烯基、苯基、具有1、2、3或4个氮杂原子和0或1个氧或硫杂原子的5或6元杂芳基(例如吡啶、咪唑、哒嗪、噁唑、异噁唑、噻唑、嘧啶、吡嗪)和具有1、2、3、4、5或6个氮杂原子和0或1个氧或硫杂原子的8～10元双环杂芳基(例如喹啉、异喹啉、苯并咪唑、咪唑并吡啶和萘啶)。Preferably, 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 (e.g. pyridine, imidazole, pyridazine, oxazole, isoxazole, thiazole, pyrimidine, pyrazine) and 8-10 membered bicyclic heteroaryl having 1, 2, 3, 4, 5 or 6 nitrogen heteroatoms and 0 or 1 oxygen or sulfur heteroatoms (e.g. quinoline, isoquinoline, benzimidazole, imidazopyridine and naphthyridine).
  17. 根据权利要求16所述的化合物，其中所述环A选自：
    以及    The compound according to claim 16, wherein the ring A is selected from:
    as well as
    以下结构(1)-(18)：
    The following structures (1)-(18):
    优选 Best
    其中：in:
    以所示的字母“a”和“b”标识的键之一与L0连接，另一个与L1连接；One of the bonds identified with the letters "a" and "b" shown is connected to L 0 , and the other is connected to L 1 ;
    Xa和Xg各自独立地选自CH2、O、S和NH； Xa and Xg are each independently selected from CH2 , O, S and NH;
    Xb、Xc、Xd、Xe、Xf和Xh分别独立地选自CH和N；并且 Xb , Xc, Xd , Xe , Xf and Xh are each independently selected from CH and N; and
    在所述结构(1)和(2)中，Xa、Xb、Xc和Xd中至少一个是可以取代的。In the structures (1) and (2), at least one of Xa , Xb , Xc and Xd may be substituted.
  18. 根据权利要求17所述的化合物，其中所述环A选自：

    The compound according to claim 17, wherein the ring A is selected from:

    优选自： Selected from:
  19. 根据权利要求17或18所述的化合物，其中所示的以字母“a”标识的键与L0连接，并且所示的以字母“b”标识的键与L1连接。The compound according to claim 17 or 18, wherein the bond shown identified by the letter "a" is connected to L0 , and the bond shown identified by the letter "b" is connected to L1 .
  20. 根据权利要求1至19中任一项所述的化合物，其中：The compound according to any one of claims 1 to 19, wherein:
    R2选自H、N(Rb)2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、氧代基、-C(O)-NRaRb、-NRb-C(O)-C1～6烷基、C1～3烷基-NH(C1～3烷基)、-C1～3烷基-N(C1～3烷基)2、-S(O)2-C1～6烷基、C3～6饱和或部分不饱和的环烃基、5～6元饱和或部分不饱和的杂环基、苯基和5～6元芳杂基， 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) 2 - C1-6 alkyl, C3-6 saturated or partially unsaturated cyclic hydrocarbon group, 5-6 membered saturated or partially unsaturated heterocyclic group, phenyl and 5-6 membered aromatic hetero group,
    优选地选自H、N(Rb)2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、氧代基、-C(O)-NRaRb、-NRb-C(O)-C1～6烷基、C3～6饱和或部分不饱和的环烃基、5～6元饱和或部分不饱和的杂环基、苯基和5～6元芳杂基，其中所述烷基、烷氧基、环烃基、杂环基、苯基和芳杂基任选地被Ra取代1～3次，Preferably, 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 ,
    其中Ra选自H、卤素、NH2、OH、CN和C1～6烷基；并且wherein Ra is selected from H, halogen, NH2 , OH, CN and C1-6 alkyl; and
    其中Rb选自H和C1～6烷基，其中所述C1～6烷基任选被卤素取代1～3次；wherein 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;
    优选地，R2选自H、NH2、NH(C1～3烷基)、N(C1～3烷基)2、CN、OH、卤素、C1～3烷基、C1～3烷氧基、氧代基、-C(O)-NRaRb、-NRb-C(O)-C1～3烷基、C3～6环烷基和具有1、2或3个氮杂原子和0或1个氧或硫杂原子的5～6元芳杂基，其中所述烷基和芳杂基任选地被Ra取代1～3次，Preferably, 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, C 3-6 cycloalkyl, and 5-6 membered aromatic hetero groups 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 ,
    其中Ra选自H、F、Cl、NH2、OH、CN和C1～3烷基；并且wherein Ra is selected from H, F, Cl, NH2 , OH, CN and C1-3 alkyl; and
    其中Rb选自H和C1～3烷基，其中所述C1～3烷基任选被F或Cl取代1～3次；wherein 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;
    更优选地，R2选自H、NH2、NH(C1～3烷基)、N(C1～3烷基)2、CN、OH、F、Cl、Br、任选地被1、2或3个独立地选自F、Cl和OH的取代基取代的C1～3烷基、C1～3烷氧基、氧代基、-C(O)-NH2、-C(O)-NH(C1～3烷基)、-C(O)-N(C1～3烷基)2、环丙基、环丁基、环戊基、环己基和任选地被1个选自C1～3烷基的取代基取代的吡咯、吡唑基或三唑基；More preferably, 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 with 1, 2 or 3 substituents independently selected from F, Cl and OH, C 1-3 alkoxy, oxo, -C(O)-NH 2 , -C(O)-NH(C 1-3 alkyl), -C(O)-N(C 1-3 alkyl) 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and pyrrole, pyrazolyl or triazolyl optionally substituted with 1 substituent selected from C 1-3 alkyl;
    更优选地，R2选自H、NH2、-NHCH3、-N(CH3)2、CN、OH、F、Cl、甲基、乙基、-CH2F、-CHF2、-CH2CH2F、-CH2-OH、甲氧基、氧代基、环丙基、-CH2-NH(CH3)、-CH2-N(CH3)2、-S(O)2-CH3、-C(O)-NH2、-C(O)-NHCH3、-C(O)-N(CH3)2和 More preferably, R2 is selected from H, NH2 , -NHCH3 , -N( CH3 ) 2 , CN, OH, F, Cl, methyl , ethyl, -CH2F , -CHF2 , -CH2CH2F, -CH2 - OH, methoxy, oxo, cyclopropyl, -CH2 -NH( CH3 ), -CH2 - N(CH3) 2 , -S(O) 2 - CH3, -C(O) -NH2 , -C(O) -NHCH3 , -C(O)-N( CH3 ) 2 , and
  21. 根据权利要求1至20中任一项所述的化合物，其中：The compound according to any one of claims 1 to 20, wherein:
    p为1或2；和/或p is 1 or 2; and/or
    q为0、1或2。q is 0, 1, or 2.
  22. 根据权利要求1至21中任一项所述的化合物，其中L1选自C和S(O)。The compound according to any one of claims 1 to 21, wherein L 1 is selected from C and S(O).
  23. 根据权利要求1至22中任一项所述的化合物，其中：The compound according to any one of claims 1 to 22, wherein:
    R3选自H、C1～6烷基、C3～6环烷基、3～6元杂环烷基、-C1～3亚烷基-O-C1～6烷基、-C1～3亚烷基-NH-C1～6烷基、-C1～3亚烷基-N(C1～6烷基)2、-C1～3亚烷基-C3～6环烷基、-C1～3亚烷基-3～6元杂环烷基、-C1～3亚烷基-苯基和-C1～3亚烷基-5或6元杂芳基，其中所述烷基、亚烷基、环烷基、杂环烷基、芳基和杂芳基任选地被Ra取代1～3次， 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 ,
    优选地，R3选自H、C1～6烷基、C3～6环烷基、3～6元杂环烷基、-C1～3亚烷基-O-C1～6烷基、-C1～3亚烷基-NH-C1～6烷基、-C1～3亚烷基-N(C1～3烷基)2、-C1～3亚烷基-C3～6环烷基和-C1～3亚烷基-3～6元杂环烷基，其中所述烷基、亚烷基、环烷基和杂环烷基任选地被Ra取代1～3次，Preferably, 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 ,
    其中Ra选自卤素、NH2、OH和CN和C1～6烷基；wherein Ra is selected from halogen, NH2 , OH, CN and C1-6 alkyl;
    更优选地，R3选自H、C1～6烷基、C3～6环烷基、3～6元杂环烷基、-CH2-O-C1～6烷基、-CH2-NH-C1～6烷基、-CH2-C3～6环烷基和-CH2-3～6元杂环烷基，其中所述烷基、环烷基和杂环烷基任选地被Ra取代1～3次，More preferably, 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 ,
    其中Ra选自F、Cl、NH2、OH和CN，优选F；wherein Ra is selected from F, Cl, NH2 , OH and CN, preferably F;
    更优选地，R3选自H、CH3、-CH2CH3、-CH(CH3)CH3、-CH2CH2CH3、-CH2CH2CH2CH3、 -CH2OCH3、-CH2NHCH3、 More preferably, 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 ,
  24. 根据权利要求1至22中任一项所述的化合物，其中：The compound according to any one of claims 1 to 22, wherein:
    R3与在L1邻位的环A的环原子连接以形成C3～7饱和或部分不饱和的单环环烃基、3～7元饱和或部分不饱和的单环杂环基、苯基、或者5或6元杂芳基，其中所述环烃基、杂环基、芳基和杂芳基任选地被Ra取代1～3次， R3 is connected to the ring atom of ring A at the ortho position of L1 to form a C3-7 saturated or partially unsaturated monocyclic cycloalkyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic group, a phenyl group, or a 5- or 6-membered heteroaryl group, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl group are optionally substituted 1 to 3 times by Ra ,
    优选地，R3与在L1邻位的环A的环原子连接以形成C5～6饱和或部分不饱和的单环环烃基、或者5或6元饱和或部分不饱和的单环杂环基，其中所述环烃基和杂环基任选地被Ra取代1～3次，Preferably, R3 is connected to the ring atom of ring A in the ortho position of L1 to form a C5-6 saturated or partially unsaturated monocyclic cycloalkyl group, or a 5- or 6-membered saturated or partially unsaturated monocyclic heterocyclic group, wherein the cycloalkyl group and the heterocyclic group are optionally substituted 1 to 3 times by Ra ,
    更优选地，R3与在L1邻位的环A的环原子连接以形成选自以下的环结构，其任选地被Ra取代1～3次：
    More preferably, 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 :
    其中：in:
    表示单键或双键， represents a single bond or a double bond,
    以所示的字母“c”和“d”标识的环原子为所述环A的环原子，以所示的字母“e”标识的双键连接至与L1和L2连接的N原子；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 connected to L1 and L2 ;
    更优选地，所述环A、L1和R3一起形成选自以下的结构：
    More preferably, the ring A, L1 and R3 together form a structure selected from the following:
    其中以所示的字母“e”标识的双键连接至与L1和L2连接的N原子，以所示的字母“f”标识的双键连接至与L0。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 .
  25. 根据权利要求1至24中任一项所述的化合物，其中L2选自单键、-CH2-、-O-和S(O)，其中所述-CH2-任选地被Ra取代1～3次。The compound according to any one of claims 1 to 24, wherein 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 .
  26. 根据权利要求1至25中任一项所述的化合物，其中：The compound according to any one of claims 1 to 25, wherein:
    R4选自H、CN、OH、NH2、卤素、C1～6烷基、-C1～3亚烷基-O-C1～6烷基、-C1～3亚烷基-NH-C1～6烷基、C3～10(优选C3～7)环烷基、3～7元杂环烷基、7-11元螺杂环烷基、苯基、5～6元杂芳基、-C1～3亚烷基-C3～7环烷基、-C1～3亚烷基-3～7元杂环烷基、-C1～3亚烷基-苯基、-C1～3亚烷基-5～6元杂芳基、-C1～3亚烷基-C(O)-C3～7环烷基、-C1～3亚烷基-C(O)-3～7元杂环烷基、-C1～3亚烷基-C(O)-苯基和-C1～3亚烷基-C(O)-5～6元杂芳基，其中所述烷基、亚烷基、环烷基、杂环烷基、螺杂环烷基、苯基和杂芳基在每次出现时任选地被Rb取代1～3次， 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 alkylene-C(O)-3~7 membered heterocycloalkyl, -C1 ~3 alkylene-C(O)-phenyl and -C1~3 1-3 alkylene-C(O)-5-6 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, spiroheterocycloalkyl, phenyl and heteroaryl are optionally substituted 1-3 times by R b at each occurrence,
    其中Rb独立地选自F、Cl、Br、NH2、OH、CN、C1-6烷基和C1-6烷氧基，其中所述C1～6烷基和C1～6烷氧基任选被F、Cl或Br取代1～3次；wherein 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;
    优选地，R4选自H、CN、C1～6烷基、C3～7环烷基、3～7元杂环烷基、7-11元螺杂环烷基、苯基、5～6元杂芳基、-C1～3亚烷基-C3～7环烷基、-C1～3亚烷基-3～7元杂环烷基、-C1～3亚烷基-苯基、-C1～3亚烷基-5～6元杂芳基、-C1～3亚烷基-C(O)-C3～7环烷基、-C1～3亚烷基-C(O)-3～7元杂环烷基、-C1～3亚烷基-C(O)-苯基和-C1～3亚烷基-C(O)-5～6元杂芳基，其中所述烷基、亚烷基、环烷基、杂环烷基、螺杂环烷基、苯基和杂芳基任选地被Rb取代1～3次，Preferably, R4 is selected from H, CN, C1 ~6 alkyl, 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 alkylene-C(O)-3~7 membered heterocycloalkyl, -C1 ~3 alkylene-C(O)-phenyl and -C1 ~3 alkylene-C(O)-5~6 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, spiroheterocycloalkyl, phenyl and heteroaryl are optionally substituted 1 to 3 times by Rb ,
    其中Rb独立地选自F、Cl、NH2、OH、CN和C1-3烷基，其中所述C1～3烷基任选被F或Cl取代1～3次；wherein 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;
    更优选地，R4选自H、CN、-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH2CH(CH3)CH2CH3、-CH2CH2CH(CH3)CH3、-CH(CH3)CH3、-C(CH3)3、-CH2CHF2、-CH2CF3、-CH2CH2CF3、-CH(CH3)CF3、-CH2CH2CH2CF3、(包括)、 (包括)。More preferably, 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 ), (include ).
  27. 根据权利要求8至26中任一项所述的化合物，其中：A compound according to any one of claims 8 to 26, wherein:
    所述部分选自 Said Partially selected
    R1选自H、CN、卤素、C1～6卤代烷基、C1～6烷氧基、3～6元杂环烷基、5或6元杂芳基、-C(O)-NH(C1～3烷基)和-C(O)-N(C1～3烷基)2，其中所述3～6元杂环烷基和5～6元杂芳基任选地被Ra取代C1～6烷基次；R 1 is selected from H, CN, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, 3-6 membered heterocycloalkyl, 5- or 6-membered heteroaryl, -C(O)-NH(C 1-3 alkyl) and -C(O)-N(C 1-3 alkyl) 2 , wherein the 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with Ra for a C 1-6 alkyl second;
    p为1或2；p is 1 or 2;
    所述环A选自 The ring A is selected from
    R2选自H、NH2、CN、OH、卤素、C1～6烷基、C1～6烷氧基、氧代基、-C(O)-NRaRb、苯基和5～6元芳杂基，其中所述烷基、烷氧基、苯基和芳杂基任选地被Ra取代1～3次， 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 ,
    其中Ra选自H、卤素、OH和C1～6烷基；并且wherein Ra is selected from H, halogen, OH and C1-6 alkyl; and
    其中Rb选自H和C1～6烷基，其中所述C1～6烷基任选被卤素取代1～3次；wherein 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为0、1或2；q is 0, 1, or 2;
    L1为C；L 1 is C;
    R3选自H、C1～6烷基和C3～6环烷基；R 3 is selected from H, C 1-6 alkyl and C 3-6 cycloalkyl;
    或者，R3与在L1邻位的环A的环原子连接，从而所述环A、L1和R3一起形成 其中以所示的字母“e”标识的双键连接至与L1和L2连接的N原子，以所示的字母“f”标识的双键连接至与作为L0的NH；Alternatively, 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为-O-； L2 is -O-;
    R4选自C1～6卤代烷基、C3～10(优选C3～7)环烷基、3～7元杂环烷基、7-11元螺杂环烷基、-C1～6亚烷基-C3～7环烷基、-C1～6亚烷基-3～7元杂环烷基、-C1～3亚烷基-苯基、-C1～3亚烷基-5～6元杂芳基、-C1～6 亚烷基-C(O)-C3～7环烷基、-C1～6亚烷基-C(O)-3～7元杂环烷基、-C1～6亚烷基-C(O)-苯基和-C1～6亚烷基-C(O)-5～6元杂芳基，其中所述环烷基、杂环烷基、螺杂环烷基、苯基和杂芳基任选地被Rb取代1～3次， R4 is selected from C1-6 haloalkyl, C3-10 (preferably C3-7 ) 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)-C 3-7 cycloalkyl, -C 1-6 alkylene-C(O)-3-7 membered heterocycloalkyl, -C 1-6 alkylene-C(O)-phenyl and -C 1-6 alkylene-C(O)-5-6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, spiroheterocycloalkyl, phenyl and heteroaryl are optionally substituted 1-3 times by R b ,
    其中Rb独立地选自F、Cl、CN和被F或Cl取代1～3次的C1-3烷基。wherein R b is independently selected from F, Cl, CN and C 1-3 alkyl substituted 1 to 3 times by F or Cl.
  28. 根据权利要求27所述的化合物，其中所述部分选自 The compound according to claim 27, wherein the Partially selected
  29. 根据权利要求25或26所述的化合物，其中：The compound according to claim 25 or 26, wherein:
    R1选自H、CN、F、Cl、C1～3卤代烷基、C1～3烷氧基、3～6元杂环烷基、5或6元杂芳基和-C(O)-N(C1～3烷基)2，其中所述3～6元杂环烷基和5～6元杂芳基任选地被C1～3烷基取代1～3次；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;
    优选地，R1选自H、CN、F、Cl、CF3、甲氧基、-C(O)-N(CH3)2、 Preferably, R 1 is selected from H, CN, F, Cl, CF 3 , methoxy, -C(O)-N(CH 3 ) 2 ,
  30. 根据权利要求27至29中任一项所述的化合物，其中所述环A选自 The compound according to any one of claims 27 to 29, wherein the ring A is selected from
  31. 根据权利要求27至30中任一项所述的化合物，其中：A compound according to any one of claims 27 to 30, wherein:
    R2选自H、NH2、CN、OH、F、Cl、C1～3烷氧基、氧代基、-C(O)-NH(C1～3烷基)、-C(O)-N(C1～3烷基)2、任选地被1、2或3个独立地选自F、Cl和OH的取代基取代的C1～3烷基、和任选地被1个选自C1～3烷基的取代基取代的吡咯、吡唑基或三唑基， R2 is selected from H, NH2 , CN, OH, F, Cl, C1-3 alkoxy, oxo, -C(O)-NH( C1-3 alkyl), -C(O)-N( C1-3 alkyl) 2 , C1-3 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl and OH, and pyrrole, pyrazolyl or triazolyl optionally substituted by 1 substituent selected from C1-3 alkyl,
    更优选地，R2选自H、F、CN、OH、NH2、氧代基、甲氧基、甲基、乙基、-CHF2、-CH2CH2F、-CH2-OH、-C(O)-NHCH3、-C(O)-N(CH3)2和 More preferably, R2 is selected from H, F, CN, OH, NH2, oxo , methoxy, methyl, ethyl, -CHF2 , -CH2CH2F, -CH2 - OH , -C(O) -NHCH3 , -C(O)-N( CH3 ) 2 and
  32. 根据权利要求27-31中任一项所述的化合物，其中：The compound according to any one of claims 27 to 31, wherein:
    R3选自H、CH3、-CH2CH3、-CH(CH3)CH3、-CH2CH2CH3和或者 R3 is selected from H, CH3 , -CH2CH3 , -CH( CH3 ) CH3 , -CH2CH2CH3 and or
    R3与在L1邻位的环A的环原子连接，从而所述环A、L1和R3一起形成 R3 is linked to a ring atom of ring A at an ortho position to L1 , so that ring A, L1 and R3 together form
  33. 根据权利要求27至32中任一项所述的化合物，其中：A compound according to any one of claims 27 to 32, wherein:
    R4选自C1～4卤代烷基、C3～7环烷基、3～7元杂环烷基、7-11元螺杂环烷基、-CH2-C3～7环烷基、-CH2-苯基、-CH2-5～6元杂芳基和-CH2-C(O)-3～7元杂环烷基，其中所述环烷基、杂环烷基、螺杂环烷基苯基和杂芳基任选地被Rb取代1～3次， R4 is selected from C1-4 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocycloalkyl, 7-11 membered spiroheterocycloalkyl, -CH2 - C3-7 cycloalkyl, -CH2 -phenyl, -CH2-5-6 membered heteroaryl and -CH2 -C(O)-3-7 membered heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, spiroheterocycloalkylphenyl and heteroaryl are optionally substituted 1-3 times by Rb ,
    其中Rb独立地选自F、Cl、CN和被F或Cl取代1～3次的甲基或乙基；wherein R b is independently selected from F, Cl, CN, and a methyl or ethyl group substituted 1 to 3 times by F or Cl;
    优选地，R4选自-CH2CF3、-CH2CH2CH2CF3、(包括)、 (包括)；Preferably, R 4 is selected from -CH 2 CF 3 , -CH 2 CH 2 CH 2 CF 3 , (include ), (include );
    更优选地，R4选自-CH2CF3、-CH2CH2CH2CF3、(包括)、 (包括)。More preferably, R 4 is selected from -CH 2 CF 3 , -CH 2 CH 2 CH 2 CF 3 , (include ), (include ).
  34. 根据权利要求1所述的化合物，其中所述化合物选自：










    (包括 )、     The compound according to claim 1, wherein the compound is selected from:










    (include ),
  35. 药物组合物，其包含根据权利要求1至34中任一项所述的化合物、或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药，以及药学上可接受的载体。A pharmaceutical composition comprising a compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier.
  36. 权利要求1至34中任一项所述的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药、或者根据权利要求33所述的药物组合物在制备作为STING抑制剂的药物中的用途。Use of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition according to claim 33 in the preparation of a medicament as a STING inhibitor.
  37. 权利要求1至34中任一项所述的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂合物、代谢物、同位素标记的化合物或前药、或者根据权利要求33所述的药物组合物在制备用于预防和/或治疗STING介导的疾病或病症及相关疾病或病症的药物中的用途。Use of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition according to claim 33 in the preparation of a medicament for preventing and/or treating STING-mediated diseases or disorders and related diseases or disorders.
  38. 根据权利要求37所述的用途，其中所述STING介导的疾病或病症选自：The use according to claim 37, wherein the STING-mediated disease or condition is selected from:
    肿瘤和/或癌症，包括黑色素瘤、甲状腺瘤、头颈癌、宫颈癌、乳腺癌、卵巢癌、前列腺癌、睾丸癌、尿路上皮癌、膀胱癌、非小细胞肺癌、小细胞肺癌、结直肠腺瘤、肉瘤、肠道间质瘤、胃癌、食道癌、结肠直肠癌、胰腺癌、小肠癌、肾癌、肝癌、肝细胞癌、胆管细胞癌、间皮瘤、淋巴瘤、 白血病、骨髓异常增生综合症、多发性骨髓瘤、浆细胞瘤、成神经细胞瘤、成视网膜细胞瘤和生殖细胞瘤；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;
    中枢神经系统、周围神经系统和自主神经系统疾病或病症，包括但不限于癫痫样失语、脑脊髓炎、黄斑变性、阿尔珀斯病、胼胝体发育不全、艾卡迪综合征、交替性偏瘫、阿尔茨海默氏病、血管性痴呆、肌萎缩侧索硬化症、蛛网膜囊肿、蛛网膜炎、阿斯伯格综合征、共济失调远程扩张症、注意缺陷多动障碍、自闭症、自主神经功能障碍、肌萎缩、良性颅内高压、宾斯旺格病、脑萎缩、脑巨人症、脑动脉硬化、舞蹈病、慢性炎症性脱髓鞘性多发性神经病、先天性面瘫、皮质基底节变性、颅动脉炎、颅缝早闭、克雅氏病、累积性创伤障碍、库欣综合征、巨细胞包涵体病、糖尿病性神经病变、弥漫性硬化症、肌张力障碍、巨细胞动脉炎、巨细胞包涵体病、面肌痉挛、遗传性痉挛性截瘫、多发性神经炎性遗传病、带状疱疹、亨廷顿病、重症肌无力、髓细胞性弥漫性硬化症、帕金森病、闭锁综合征、腰椎间盘疾病、偏头痛、线粒体肌病、莫比乌斯综合征、单体肌萎缩、运动神经元病、多梗死性痴呆、多发性硬化症、肌阵挛、神经肌强直、面肌萎缩、多灶性白质脑病、硬化性脊髓灰质炎和脊髓损伤；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 cell arteritis, giant cell inclusion disease, hemifacial spasm, hereditary spastic paraplegia, multiple neuritis genetic disease, herpes zoster, Huntington disease, myasthenia gravis, diffuse myeloid sclerosis, Parkinson disease, locked-in syndrome, lumbar disc disease, migraine, mitochondrial myopathy, Möbius syndrome, monosomic muscular dystrophy, motor neuron disease, multi-infarct dementia, multiple sclerosis, myoclonus, neuromyotonia, hemifacial muscular atrophy, multifocal leukoencephalopathy, sclerosing poliomyelitis, and spinal cord injury;
    STING相关病症，包括I型干扰素病、Aicardi-Goutières综合征(AGS)、狼疮和类风湿性关节炎；STING-associated conditions, including type I interferonopathies, Aicardi-Goutières syndrome (AGS), lupus, and rheumatoid arthritis;
    自身免疫性疾病，包括类风湿性关节炎、系统性红斑狼疮、多发性硬化症、克罗恩病(CD)、炎症性肠病(IBD)、溃疡性结肠炎(UC)、自身免疫性结肠炎、医源性自身免疫性结肠炎、溃疡性结肠炎、由一种或多种化学治疗剂诱导的结肠炎、由过继细胞疗法治疗诱导的结肠炎、肠易激综合征、硬皮病、银屑病、皮肤T细胞淋巴瘤、葡萄膜炎和粘膜炎；以及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
    银屑病性关节炎、接触性皮炎、特异性皮炎、白癜风、I型糖尿病、哮喘、肾小球肾炎、牙周疾病、睫状体扁平部炎、移植排异、神经退行性疾病、肥胖症、高血压。 Psoriatic arthritis, contact dermatitis, atopic dermatitis, vitiligo, type 1 diabetes, asthma, glomerulonephritis, periodontal disease, pars planitis, transplant rejection, neurodegenerative diseases, obesity, hypertension.
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