WO2021052499A1 - 稠合吡啶酮类化合物及其制备方法和应用 - Google Patents

稠合吡啶酮类化合物及其制备方法和应用 Download PDF

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Publication number
WO2021052499A1
WO2021052499A1 PCT/CN2020/116510 CN2020116510W WO2021052499A1 WO 2021052499 A1 WO2021052499 A1 WO 2021052499A1 CN 2020116510 W CN2020116510 W CN 2020116510W WO 2021052499 A1 WO2021052499 A1 WO 2021052499A1
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Prior art keywords
compound
alkyl
membered heterocycloalkyl
cycloalkyl
group
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English (en)
French (fr)
Chinese (zh)
Inventor
郭淑春
范珺
刘洋
包方
彭建彪
郭海兵
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Jiangxi Jemincare Group Co Ltd
Shanghai Jemincare Pharmaceuticals Co Ltd
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Jiangxi Jemincare Group Co Ltd
Shanghai Jemincare Pharmaceuticals Co Ltd
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Priority to CN202411842480.6A priority Critical patent/CN119462689A/zh
Priority to CA3155066A priority patent/CA3155066A1/en
Priority to MX2022003401A priority patent/MX2022003401A/es
Priority to JP2022517446A priority patent/JP7642619B2/ja
Priority to CN202411842482.5A priority patent/CN119591618A/zh
Priority to CN202080078771.6A priority patent/CN114728968B/zh
Priority to US17/761,983 priority patent/US20220389029A1/en
Priority to CN202410656034.XA priority patent/CN118619971A/zh
Priority to AU2020350745A priority patent/AU2020350745B2/en
Priority to PH1/2022/550681A priority patent/PH12022550681A1/en
Priority to EP20865331.1A priority patent/EP4043464A4/en
Priority to CN202310905052.2A priority patent/CN116947885B/zh
Application filed by Jiangxi Jemincare Group Co Ltd, Shanghai Jemincare Pharmaceuticals Co Ltd filed Critical Jiangxi Jemincare Group Co Ltd
Priority to KR1020227013103A priority patent/KR20220086573A/ko
Priority to BR112022005193A priority patent/BR112022005193A2/pt
Publication of WO2021052499A1 publication Critical patent/WO2021052499A1/zh
Priority to IL291467A priority patent/IL291467B1/en
Anticipated expiration legal-status Critical
Priority to CONC2022/0004686A priority patent/CO2022004686A2/es
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to a compound represented by formula (I-B), its optical isomers and pharmacologically acceptable salts thereof, and the application of the compound as a KRAS inhibitor.
  • Cancer has been the top ten cause of death in China for 31 consecutive years. Among them, lung cancer is one of the tumors with the highest incidence. Non-small cell lung cancer accounts for more than 80%. At the same time, the incidence of lung cancer is high and there are many types of mutations. In order to enrich the company's R&D pipeline and focus on unmet medical needs, the development of innovative drugs for cancer treatment is very necessary for the company's long-term development, and has important economic and social significance.
  • RAS gene mutations About 30% of cancer patients have RAS gene mutations.
  • scientists have discovered more than 20 years ago that the RAS gene is a key gene for cancers including lung cancer, colorectal cancer and pancreatic cancer.
  • pancreatic cancer In the United States, the three cancers with the highest mortality rates (pancreatic cancer, colorectal cancer, and lung cancer) also happen to be the three cancers with the most common RAS mutations, accounting for 95%, 52%, and 31% of the three cancer patients, respectively.
  • KRAS mutations account for the absolute majority, while NRAS mutations are more common in melanoma and acute myeloid leukemia, and HRAS mutations are more common in bladder cancer and head and neck cancer.
  • KRAS The mutation rate of KRAS gene in Asian population is 10-15%.
  • KRAS is mutated in many cancers and is one of the main oncogenes.
  • KRAS mutant tumor is the most potentially targeted molecular subtype of non-small cell lung cancer (NSCLC), and its mutation rate is about 15%-25% in non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • KRAS mutations mainly occur at codons 12 and 13. The most common codon variation accounts for about 39% of KRAS mutant NSCLCs, which is the KRAS-G12C mutation.
  • KRAS small molecule drugs Including 10 KRAS GTPase inhibitors, 4 KRAS gene inhibitors, 2 KRAS GTPase modulators and 2 KRAS gene modulators; currently one drug of this type is under clinical research.
  • the first KRAS inhibitor Antogen developed by a Taiwanese company has entered the Phase II clinical trial of the US FDA, and AstraZeneca's inhibitor, Smetinib, which targets the MEK downstream pathway of KRAS, is also undergoing phase II clinical trials.
  • KRAS mutation is the most important tumor driver gene.
  • the present invention proposes the compound represented by formula (I-B), its optical isomers and their pharmacologically acceptable salts,
  • R 1 and R 2 are each independently selected from H, halogen and C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted with 1, 2 or 3 R;
  • R 3 is selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 heteroalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkyl, 3-6 Membered heterocycloalkyl-O- and C 3-6 cycloalkyl-O-, the C 1-6 alkyl group, C 1-6 heteroalkyl group, 3-6 membered heterocycloalkyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl-O- or C 3-6 cycloalkyl-O- is optionally substituted with 1, 2 or 3 R;
  • R 4 is each independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Phenyl, 5- to 10-membered heteroaryl, phenyl and 5- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl and 5- to 6-membered heterocycloalkyl, the C 1-6 alkyl group, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5 to 10-membered heteroaryl, phenyl and 5 to 6-membered heterocycloalkyl or 5 to 6
  • the membered heteroaryl and 5- to 6-membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;
  • R 5 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl-C 1-3 alkyl-, 3-8 membered heterocycloalkyl, phenyl, Naphthyl, 5 to 10 membered heteroaryl, phenyl and 5 to 6 membered heterocycloalkyl and 5 to 6 membered heteroaryl and 5 to 6 membered heterocycloalkyl, the C 1-6 alkyl group, C 3-6 cycloalkyl, 5 to 6 membered heterocycloalkyl-C 1-3 alkyl-, 3 to 8 membered heterocycloalkyl, phenyl, naphthyl, 5 to 10 membered heteroaryl, phenyl and 5- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl and 5- to 6-membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;
  • T 1 and T 2 are independently selected from N and -C(R 8 )-;
  • R 8 is selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, said C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;
  • R 9 is selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl and C 1-6 heteroalkyl, the C 1-6 alkyl or C 1-6 heteroalkyl is optionally selected by 1 , 2 or 3 R substitutions;
  • R 10 is selected from H, halogen, CN, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino, the C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylamino is optionally substituted with 1, 2 or 3 R;
  • R is independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 heterocycloalkane, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6 cycloalkyl-O- and 5-6 membered heterocycloalkane Group -O-, the C 1-6 alkyl, C 1-6 heterocycloalkane, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6 cycloalkyl-O- or The 5- to 6-membered heterocycloalkyl-O- is optionally substituted with 1, 2 or 3 R';
  • R' is selected from F, Cl, Br, I, OH, NH 2 and CH 3 ;
  • Ring A is independently selected from C 6-10 aryl, 5 to 10 membered heteroaryl, phenyl and 5 to 6 membered heterocycloalkyl, 5 to 6 membered heteroaryl and 5 to 6 membered heterocycloalkyl;
  • n is selected from 0, 1, 2, 3 or 4;
  • n is selected from 0, 1, 2, 3 or 4;
  • D 1 is selected from O;
  • Y is selected from N, CH or C
  • the present invention also proposes the compound represented by formula (I-A), its optical isomers and pharmacologically acceptable salts thereof,
  • R 1 and R 2 are each independently selected from H, halogen and C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted with 1, 2 or 3 R;
  • R 3 is selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 heteroalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkyl, 3-6 Membered heterocycloalkyl-O- and C 3-6 cycloalkyl-O-, the C 1-6 alkyl group, C 1-6 heteroalkyl group, 3-6 membered heterocycloalkyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl-O- or C 3-6 cycloalkyl-O- is optionally substituted with 1, 2 or 3 R;
  • R 4 is each independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Phenyl, 5- to 10-membered heteroaryl, phenyl and 5- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl and 5- to 6-membered heterocycloalkyl, the C 1-6 alkyl group, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5 to 10-membered heteroaryl, phenyl and 5 to 6-membered heterocycloalkyl or 5 to 6
  • the membered heteroaryl and 5- to 6-membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;
  • R 5 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl-C 1-3 alkyl-, 3-8 membered heterocycloalkyl, phenyl, Naphthyl, 5 to 10 membered heteroaryl, phenyl and 5 to 6 membered heterocycloalkyl and 5 to 6 membered heteroaryl and 5 to 6 membered heterocycloalkyl, the C 1-6 alkyl group, C 3-6 cycloalkyl, 5 to 6 membered heterocycloalkyl-C 1-3 alkyl-, 3 to 8 membered heterocycloalkyl, phenyl, naphthyl, 5 to 10 membered heteroaryl, phenyl and 5- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl and 5- to 6-membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;
  • T 1 and T 2 are independently selected from N and -C(R 8 )-;
  • R 8 is selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, said C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;
  • R is independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 heterocycloalkane, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6 cycloalkyl-O- and 5-6 membered heterocycloalkane Group -O-, the C 1-6 alkyl, C 1-6 heterocycloalkane, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6 cycloalkyl-O- or The 5- to 6-membered heterocycloalkyl-O- is optionally substituted with 1, 2 or 3 R';
  • R' is selected from F, Cl, Br, I, OH, NH 2 and CH 3 ;
  • Ring A is independently selected from C 6-10 aryl, 5 to 10 membered heteroaryl, phenyl and 5 to 6 membered heterocycloalkyl, 5 to 6 membered heteroaryl and 5 to 6 membered heterocycloalkyl;
  • n is selected from 0, 1, 2, 3 or 4;
  • the above-mentioned compound, its optical isomer and its pharmacologically acceptable salt are selected from
  • the above-mentioned R is independently selected from H, halogen, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, C 3- 6 -cycloalkyl-O- and -5 to 6-membered heterocycloalkyl-O-, the C 1-3 alkyl group, C 1-3 alkoxy group, C 1-3 alkylthio group, C 1-3 Alkylamino, C 3-6 cycloalkyl, 5 to 6 membered heterocycloalkyl, C 3-6 cycloalkyl-O- or 5 to 6 membered heterocycloalkyl-O- may be selected by 1, 2 or 3
  • Each R' is substituted, and other variables are as defined in the present invention.
  • the above-mentioned R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, Me, CH 2 CH 3 , Other variables are as defined in the present invention.
  • R 1 and R 2 are independently selected from H, F, Me, CF 3 , Other variables are as defined in the present invention.
  • the above-mentioned R 3 is selected from H, halogen, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkane Thio, 3 to 6 membered heterocycloalkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl-O- and C 3-6 cycloalkyl-O-, the C 1-3 alkane Group, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio, 3-6 membered heterocycloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl -O- or C 3-6 cycloalkyl-O- is optionally substituted with 1, 2 or 3 R, and other variables are as defined in the present invention.
  • R 3 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Other variables are as defined in the present invention.
  • the above-mentioned R 4 is independently selected from H, halogen, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1 -3 Alkylthio, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl , Imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl and indolyl, the C 1-3 alkyl , C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, pyridyl
  • R 4 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl , Imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl , 1H-benzo[d]imidazolyl, benzopyrazolyl, purinyl, quinolinyl, isoquinolinyl, isoquinolin-1(2H)-onyl, isoindolin-1-onyl , Benzo[d]oxazole-2(H)-keto, benzo[d]oxazole-2(H)-keto,
  • the above-mentioned R 5 is selected from H, C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyran Group, piperidinyl, piperazinyl, 5- to 6-membered heterocycloalkyl-C 1-3 alkyl-, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, Thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzo Thienyl, indolyl, benzimidazolyl, benzo
  • R 5 is selected from H, Me, Other variables are as defined in the present invention.
  • R 7 is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Other variables are as defined in the present invention.
  • R 6 is independently selected from H, CN, Me, CF 3 , Other variables are as defined in the present invention.
  • Other variables are as defined in the present invention.
  • the above-mentioned R 8 is selected from H, halogen, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, and C 1-3 alkane.
  • a thio group, the C 1-3 alkyl group, C 1-3 alkoxy group, C 1-3 alkylamino group or C 1-3 alkylthio group is optionally substituted by 1, 2 or 3 R, and other variables are as described herein. Defined by the invention.
  • R 8 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Other variables are as defined in the present invention.
  • the present invention also proposes compounds of the following formula, its optical isomers and their pharmacologically acceptable salts,
  • the present invention also provides a pharmaceutical composition, which contains the aforementioned compound, its optical isomers and pharmacologically acceptable salts, and a Or multiple pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention also proposes that the aforementioned compounds, their optical isomers, and their pharmacologically acceptable salts or the aforementioned pharmaceutical compositions can be used for the prevention and/or treatment of KRAS- The use of G12C-related diseases in medicine.
  • the above-mentioned KRAS-G12C related diseases are selected from non-small cell lung cancer, colon cancer and pancreatic cancer.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from the compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting the neutral form of the compound 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 salt or similar salts.
  • the acid addition salt can be obtained by contacting the neutral form of the compound 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 including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or organic solvent or a mixture of both.
  • a dash (“-") that is not between two letters or symbols indicates the point of attachment of the substituent.
  • C 1-6 alkylcarbonyl- refers to a C 1-6 alkyl group attached to the rest of the molecule through a carbonyl group.
  • the attachment point of the substituent is obvious to those skilled in the art, for example, the halogen substituent, "-" may be omitted.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric or optical isomer forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All 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 each other.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate the double bond or the single bond of the ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the relationship between the molecules is non-mirror mirror image.
  • wedge-shaped solid line keys and wedge-shaped dashed key Represents the absolute configuration of a three-dimensional center.
  • the compound of the present invention may be specific.
  • tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomer also called prototropic tautomer
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers include some recombination of bonding electrons to carry out mutual transformation.
  • keto-enol tautomerization is the tautomerization between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterium can be substituted for hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs can reduce toxic side effects and increase drug stability. , Enhance the efficacy, prolong the biological half-life of drugs and other advantages.
  • the racemic mixture can be used in its own form or resolved into individual isomers for use. Through resolution, a stereochemically pure compound or a mixture enriched in one or more isomers can be obtained. Methods for separating isomers are well known (see Allinger N.L. and Eliel E.L., "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), including physical methods such as chromatography using chiral adsorbents. Individual isomers in chiral form can be prepared from chiral precursors.
  • a chiral acid for example, single enantiomers of 10-camphorsulfonic acid, camphor acid, ⁇ -bromocamphoric acid, tartaric acid, diacetyl tartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.
  • a diastereomeric salt is formed and the mixture is chemically separated to obtain a single isomer.
  • the salt is fractionally crystallized, and then one or two of the resolved bases are freed, and this process is optionally repeated, thereby Obtain one or two isomers that do not substantially contain another isomer, that is, the optical purity by weight is, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% of the desired stereoisomer.
  • the racemate can be covalently attached to a chiral compound (auxiliary) to obtain diastereomers.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • oxygen it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • substituents When the listed substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • linking group L is at this time It can be formed by connecting benzene ring and cyclohexane in the same direction as the reading order from left to right It is also possible to connect the benzene ring and cyclohexane in the opposite direction to the reading order from left to right. Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
  • the number of atoms in a ring is generally defined as the number of ring members.
  • “5-7 membered ring” refers to a “ring” in which 5-7 atoms are arranged around.
  • C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 alkyl examples include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • heteroalkyl by itself or in combination with another term means a stable linear or branched alkyl group or a combination thereof composed of a certain number of carbon atoms and at least one heteroatom or heteroatom group.
  • the heteroatoms are selected from B, O, N, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized.
  • the heteroalkyl group is C 1-6 heteroalkyl; in other embodiments, the heteroalkyl group is C 1-3 heteroalkyl.
  • heteroatom or heteroatom group can be located in any internal position of the heteroalkyl group, including the connection position of the alkyl group to the rest of the molecule, but the terms “alkoxy”, “alkylamino” and “alkylthio” (or thioalkane (Oxy) belongs to the customary expression and refers to those alkyl groups that are connected to the rest of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively.
  • Up to two heteroatoms can
  • C 1-6 alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
  • the C 1-6 alkoxy group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy, etc. .
  • C 1- 6 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n- butoxy, isobutoxy Oxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy and the like.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy) and the like.
  • C 1-6 alkylamino refers to those alkyl groups containing 1 to 6 carbon atoms attached to the rest of the molecule through an amino group.
  • the C 1-6 alkylamino group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkylamino group Wait.
  • C 1-6 alkylamino examples include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 )( CH 2 CH 3 ), -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 , -NHCH 2 CH 2 CH 2 CH 3 and so on.
  • C 1-3 alkylamino refers to those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an amino group.
  • the C 1-3 alkylamino group includes C 1-2 , C 3 and C 2 alkylamino groups and the like.
  • Examples of C 1-3 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 ,- NHCH 2 (CH 3 ) 2 and so on.
  • C 1-6 alkylthio refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through a sulfur atom.
  • the C 1-6 alkylthio group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkane Sulfur-based and so on.
  • Example C 1- 6 alkylthio include, but are not limited to, -SCH 3, -SCH 2 CH 3, -SCH 2 CH 2 CH 3, -SCH 2 (CH 3) 2 and the like.
  • C 1-3 alkylthio refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through a sulfur atom.
  • the C 1-3 alkylthio group includes C 1-3 , C 1-2 and C 3 alkylthio groups and the like. Examples of C 1-3 alkylthio include but are not limited to -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 etc.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, and the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the term "3-8 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 8 ring atoms, with 1, 2, 3 or 4 ring atoms.
  • heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings.
  • a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
  • the 3-8 membered heterocycloalkyl group includes 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4-membered, 5-membered, and 6-membered heterocycloalkyl group.
  • 3-8 membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazolidin
  • 3-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms.
  • heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings.
  • a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
  • the 3-6 membered heterocycloalkyl group includes 4-6 membered, 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl group.
  • Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazo
  • C 6-10 aromatic ring and “C 6-10 aryl” can be used interchangeably in the present invention.
  • C 6-10 aromatic ring or “C 6-10 aryl” means that A cyclic hydrocarbon group with a conjugated ⁇ -electron system composed of 6 to 10 carbon atoms, which can be a monocyclic, fused bicyclic or fused tricyclic system, in which each ring is aromatic. It may be monovalent, divalent or multivalent, and C 6-10 aryl groups include C 6-9 , C 9 , C 10 and C 6 aryl groups and the like. Examples of C 6-10 aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl, 2-naphthyl, etc.).
  • 5-10 membered heteroaryl ring and “5-10 membered heteroaryl group” can be used interchangeably in the present invention.
  • the term “5-10 membered heteroaryl group” means a ring consisting of 5 to 10 rings.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized (ie NO and S(O) p , p is 1 or 2).
  • the 5-10 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-10 membered heteroaryl groups include 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl groups and the like.
  • Examples of the 5-10 membered heteroaryl include but are not limited to pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazoly
  • 5-6 membered heteroaryl ring and “5-6 membered heteroaryl group” can be used interchangeably in the present invention.
  • the term “5-6 membered heteroaryl group” means a ring consisting of 5 to 6 ring atoms. It is composed of a monocyclic group with a conjugated ⁇ -electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may optionally be oxidized (ie NO and S(O) p , p is 1 or 2).
  • the 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,
  • benzo 5- to 6-membered heterocycloalkyl means a bi-cyclic structure formed by the combination of a phenyl group, a heterocyclic ring and a 5- to 6-membered heterocycloalkyl group, and the substituent may be through a benzene ring or The 5- to 6-membered heterocycloalkyl ring is connected to other structures.
  • Examples of the benzo 5- to 6-membered heterocycloalkyl include but are not limited to Wait.
  • 5- to 6-membered heteroaryl and 5- to 6-membered heterocycloalkyl means a diplex formed by the combination of a 5- to 6-membered heteroaryl group and a heterocyclic ring and a 5- to 6-membered heterocycloalkyl group. Ring structure, the substituent can be connected to other structures through a 5- to 6-membered heteroaryl group or a 5- to 6-membered heterocycloalkyl ring. Examples of the benzo 5- to 6-membered heterocycloalkyl include but are not limited to Wait.
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , including any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; similarly, from n to n +m member means that the number of atoms in the ring is from n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered
  • treatment refers to the administration of one or more drug substances, particularly the compound of formula (I) described herein and/or a pharmaceutically acceptable compound thereof, to an individual suffering from a disease or having symptoms of the disease Salt is used to cure, alleviate, alleviate, change, cure, ameliorate, improve or affect the disease or the symptoms of the disease.
  • prevention refers to the administration of one or more drug substances, especially the compound of formula (I) and/or a pharmaceutically acceptable salt thereof as described herein, to an individual with a constitution susceptible to the disease, To prevent individuals from suffering from the disease.
  • the terms “treating”, “contacting” and “reacting” refer to the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and/or desired product. It should be understood that the reaction to produce the indicated and/or desired product may not necessarily come directly from the combination of the two reagents initially added, that is, one or more intermediates may be present in the mixture. The body ultimately leads to the formation of the indicated and/or desired product.
  • the term "effective amount” as used herein refers to an amount generally sufficient to produce a beneficial effect on an individual.
  • Conventional methods such as modeling, dose escalation studies, or clinical trials
  • conventional influencing factors such as the method of administration, the pharmacokinetics of the compound, the severity and course of the disease, the individual's medical history, the individual's health, the individual The degree of response to the drug, etc.
  • 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, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • CDCl 3 stands for deuterated chloroform
  • CD 3 OD stands for deuterated methanol
  • DMSO-d 6 stands for deuterated dimethyl sulfoxide
  • TBS stands for tert-butyldimethylsilyl.
  • Fig. 1 is a graph showing the relationship between the number of days inoculated with NCI-H358 cells and the change in body weight after administration of the compound 29B of the example according to the present invention.
  • Figure 2 is a graph showing the relationship between the number of days of NCI-H358 cell inoculation and tumor volume after administration of Example Compound 29B according to an embodiment of the present invention.
  • the raw material 1-1 (2.00 g, 9.57 mmol) was dissolved in thionyl chloride (10 mL), and the mixture was heated to 80° C. to react for 16 h. The system was concentrated to obtain a crude product. The crude product was dissolved in dioxane (10mL). At 0°C, a mixed solution of dioxane (5mL) and ethanol (5mL) was added dropwise to it. After the addition, the system was in Stir at room temperature (20°C) for 1 h. After dissolving the system with ethyl acetate (20 mL), washing with saturated potassium carbonate solution, standing to separate the layers, the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound 1-2 as a yellow oil.
  • the reaction solution was washed with water (5 mL), extracted with dichloromethane (3 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.
  • the crude product was purified by high-efficiency preparative liquid phase (separation conditions: chromatographic column Welch Ultimate XB-C18 10*250mm, 5 ⁇ m, water phase 0.15TFA, organic phase acetonitrile, gradient 52%-70%, time 12min) to obtain compound 1A and compound 1B.
  • Chromatographic column Waters Xselect CSH C18 3.5 ⁇ m, 100*4.6mm; column temperature: 60°C; mobile phase: water (0.01% trifluoroacetic acid solution)-acetonitrile (0.01% trifluoroacetic acid solution); acetonitrile: 5 %-95% 7min, 95% 8min; flow rate: 1.2mL/min. Retention time 6.175min
  • Chromatographic column Waters Xselect CSH C18 3.5 ⁇ m, 100*4.6mm; column temperature: 60°C; mobile phase: water (0.01% trifluoroacetic acid solution)-acetonitrile (0.01% trifluoroacetic acid solution); acetonitrile: 5 %-95% 7min, 95% 8min; flow rate: 1.2mL/min. Retention time 6.327min.
  • the system was warmed to room temperature, the reaction was quenched with water, extracted with ethyl acetate (10 mL), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.
  • Step 6 Preparation of product 2A and product 2B
  • Chromatographic column Waters Xbridge C18 3.5 ⁇ m, 100*4.6mm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile: 5%-95% 7min, 95% 8min; Flow rate: 1.2 mL/min. Retention time 5.743min.
  • Chromatographic column Waters Xbridge C18 3.5 ⁇ m, 100*4.6mm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile: 5%-95% 7min, 95% 8min; Flow rate: 1.2 mL/min. Retention time 5.879min.
  • the raw material chloral hydrate (19.08g, 115.38mmol, 15.03mL) and sodium sulfate (122.92g, 865.37mmol) were dissolved in water (360mL), the system was heated to 35°C, and the raw material 3-1 (20g, 96.15mmol) in water (120mL), hydrochloric acid (12M, 10.82mL) and hydroxylamine hydrochloride (21.38g, 307.69mmol). After the addition, the system was heated to 90°C for 16h. Gray precipitation appeared in the system. The system was cooled to room temperature and filtered to obtain a filter cake. The filter cake was washed with water and dried in vacuum to obtain compound 3-2, which was used directly in the next reaction without further purification.
  • compound 3-2 35 g, 125.43 mmol was added to concentrated sulfuric acid (368.00 g, 3.75 mol, 200 mL). After the addition, the system was heated to 90°C and stirred for 3h. The system was cooled to room temperature, poured into ice water, a black precipitate separated out, filtered to obtain a filter cake, and the filter cake was dried to obtain crude product A. The filtrate was extracted with ethyl acetate (500 mL x 2), the organic phases were combined, washed with saturated brine (500 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude product B. The crude product A and B were combined to obtain compound 3-3, which was directly used in the next reaction without further purification.
  • the compound 3-5 (2.3g, 8.65mmol), compound 1-13 (2.20g, 12.97mmol), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1 ,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (723mg, 864.53 ⁇ mol), 2-dicyclohexylphosphorus-2',6'-di Isopropoxy-1,1'-biphenyl (403mg, 864.53 ⁇ mol) and potassium carbonate (3.58g, 25.94mmol) were dissolved in a mixed solution of dioxane (25mL) and water (5mL).
  • compound 3-8 (1.26g, 2.83mmol) was dissolved in N,N-dimethylformamide (15mL), and sodium hydride (454mg, 11.35mmol, purity 60%) was added in batches . After the addition, acetyl chloride (888.59mg, 11.32mmol, 807.81 ⁇ L) was added dropwise to it. After the addition, under a nitrogen atmosphere, the system was heated to 100°C for 8 hours.
  • the pH of the system was adjusted to neutral with 1N hydrochloric acid, extracted with ethyl acetate (10 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.
  • the crude product is purified by high-efficiency preparative liquid phase (Separation conditions: Column: Phenomenex Gemini-NX 80*30mm*3 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile%: 41%-51% 9.5min ) To obtain compounds 3A and 3B.
  • Diastereomer compound 3A was purified by SFC (Separation conditions: Column: DAICEL CHIRALCEL OJ-H (250mm*30mm, 5 ⁇ m); mobile phase: [0.1% ammonia solution-ethanol]; ethanol%: 30%-30 %; Flow rate: 60mL/min). After concentration, compound 3A-1 and compound 3A-2 were obtained.
  • Chromatographic column Xbridge C18, 5 ⁇ m, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.02% ammonia solution)-acetonitrile; acetonitrile: 10%-80% 6min, 80% 2min; flow rate: 0.8 mL/min.
  • Chromatographic column Xbridge C18, 5 ⁇ m, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.02% ammonia solution)-acetonitrile; acetonitrile: 10%-80% 6min, 80% 2min; flow rate: 0.8 mL/min.
  • Diastereomer compound 3B was purified by SFC (Separation conditions: Column: DAICEL CHIRALCEL OJ-H (250mm*30mm, 5 ⁇ m); mobile phase: [0.1% ammonia solution-ethanol]; ethanol%: 30%-30 %; Flow rate: 60mL/min). After concentration, compound 3B-1 and compound 3B-2 were obtained.
  • Chromatographic column Xbridge C18, 5 ⁇ m, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.02% ammonia solution)-acetonitrile; acetonitrile: 10%-80% 6min, 80% 2min; flow rate: 0.8 mL/min.
  • Chromatographic column Xbridge C18, 5 ⁇ m, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.02% ammonia solution)-acetonitrile; acetonitrile: 10%-80% 6min, 80% 2min; flow rate: 0.8 mL/min.
  • compound 4-2 (30.8 g, 117.99 mmol) was added to concentrated sulfuric acid (460.00 g, 4.60 mol, 250 mL, purity 98%). After the addition, the system was heated to 90°C and stirred for 3h. The system was cooled to room temperature, poured into ice water, a yellow precipitate separated out, filtered to obtain a filter cake, and the filter cake was dried to obtain a yellow solid 4-3, which was directly used in the next reaction without further purification.
  • the compound 4-6 (6g, 21.24mmol), compound 4-7 (10g, 43.10mmol), three (dibenzylideneacetone) two palladium (840mg, 1.46mmol), 2-dicyclohexylphosphorus-2,4 ,6-Triisopropylbiphenyl (2.03g, 4.25mmol), and potassium carbonate (7.34g, 53.10mmol) were dissolved in a mixed solution of dioxane (100mL) and water (20mL). Under a nitrogen atmosphere, the system was heated to 100°C and stirred for 16 hours. After the system was concentrated, it was separated and extracted with ethyl acetate (50mL x 2) and water (80mL).
  • the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.
  • the pH of the system was adjusted to neutral with 1N hydrochloric acid, extracted with ethyl acetate (10 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.
  • the crude product is purified by high-efficiency preparative liquid phase (Separation conditions: Column: Phenomenex Gemini-NX 80*30mm*3 ⁇ m; Mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; Acetonitrile%: 43%-73% 9.5min ) To obtain compounds 4A and 4B.
  • Chromatographic column YMC-Pack ODS-A 150*4.6mm, 5 ⁇ m; Column temperature: 40°C; Mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% for 10 min, 80% for 5 min; flow rate: 1.5 mL/min.
  • Chromatographic column YMC-Pack ODS-A 150*4.6mm, 5 ⁇ m; Column temperature: 40°C; Mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% for 10 min, 80% for 5 min; flow rate: 1.5 mL/min.
  • the crude product is purified by high-efficiency preparative liquid phase (Separation conditions: chromatographic column Welch Xtimate C18 10*250mm, 5 ⁇ m; column temperature 25°C; mobile phase: water (10mM/L ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile 32%-47% 16min ; Flow rate 8mL/min) to obtain compound 5A and compound 5B.
  • Chromatographic column Waters Xbridge C18 3.5 ⁇ m, 100*4.6mm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile: 5%-95% 7min, 95% 8min; Flow rate: 1.2 mL/min.
  • Chromatographic column Waters Xbridge C18 3.5 ⁇ m, 100*4.6mm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile: 5%-95% 7min, 95% 8min; Flow rate: 1.2 mL/min.
  • the reaction solution was washed with water (5 mL), extracted with dichloromethane (3 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.
  • the crude product is purified by high-efficiency preparative liquid phase (Separation conditions: Column Welch Xtimate C18 10*250mm, 5 ⁇ m; column temperature 25°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile 28%-50% 19min; flow rate 8mL/min) to obtain compound 6A and compound 6B.
  • Chromatographic column Waters Xbridge C18 3.5 ⁇ m, 100*4.6mm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile: 5%-95% 7min, 95% 8min; Flow rate: 1.2 mL/min.
  • Chromatographic column Waters Xbridge C18 3.5 ⁇ m, 100*4.6mm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile: 5%-95% 7min, 95% 8min; Flow rate: 1.2 mL/min.
  • the crude product was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and water (10 mL), lithium hydroxide (40 mg) was added thereto, and after the addition, the system was stirred at room temperature (20° C.) for 30 min.
  • the system was extracted with ethyl acetate (50mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.
  • the crude product was purified by high-performance preparative liquid phase (Separation condition: chromatographic column Phenomenex Gemini-NX 80*30mm*3 ⁇ m, Mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile 51%-81% 9.5min; flow rate 30mL/min) to obtain compound 7.
  • Diastereomer compound 7 was purified by SFC (Separation conditions: Column: DAICEL CHIRALCEL OD (250mm*30mm, 10 ⁇ m); mobile phase: [0.1% ammonia solution-ethanol]; ethanol%: 40%-40%; Flow rate: 70mL/min). After concentration, compound 7A and compound 7B were obtained.
  • chromatographic column Ultimate C18 3.0*50mm, 3 ⁇ m; column temperature: 40°C; mobile phase: water (0.0688% trifluoroacetic acid aqueous solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 6min, 80% for 2min; flow rate: 1.2mL/min.
  • Chromatographic column Chiralcel OD-3 3 ⁇ m, 100*4.6mm; column temperature: 35°C; mobile phase: CO 2 -ethanol (0.05% DEA); ethanol: 5%-40% 4min, 40% 2.5min, 5% 1.5min; Flow rate: 2.8mL/min.
  • chromatographic column Ultimate C18 3.0*50mm, 3 ⁇ m; column temperature: 40°C; mobile phase: water (0.0688% trifluoroacetic acid aqueous solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 6min, 80% for 2min; flow rate: 1.2mL/min.
  • Chromatographic column Chiralcel OD-3 3 ⁇ m, 100*4.6mm; column temperature: 35°C; mobile phase: CO 2 -ethanol (0.05% DEA); ethanol: 5%-40% 4min, 40% 2.5min, 5% 1.5min; Flow rate: 2.8mL/min.
  • the raw material 8-1 (10g, 52.351mmol) was dissolved in thionyl chloride (30mL), and the system was heated to 85°C for 16h. The system was concentrated, and the residue was dissolved in 1,4 dioxane (30 mL). At 0°C, the solution was slowly added to stirring methanol, and the system was heated to 70°C for 2h. The system was concentrated to obtain compound 8-2.
  • compound 8-5 (6.3g, 7.82mmol) was dissolved in N,N-dimethylformamide (30mL), at 0°C, sodium hydride (2.17g , 54.15mmol), after the addition, the system was reacted at 0°C for 30min, and acetyl chloride (3.85mL, 54.15mmol) was added dropwise to it. Water (30 mL) and a saturated aqueous solution of potassium carbonate were sequentially added to the system, and the system was reacted at room temperature (20° C.) for 3 hours.
  • the pH of the system was adjusted to neutral with 1N hydrochloric acid, extracted with ethyl acetate (10 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.
  • the crude product is purified by high-performance preparative liquid phase (Separation conditions: Column: Agilent 10 Prep-C8 250 ⁇ 21.2mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 30%-50 %In 16min; flow rate 30mL/min, compound 8 is obtained.
  • Chromatographic column Waters X-bridge C18, 4.6*100mm, 3.5 ⁇ m; mobile phase: [water (10Mm ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile: 5%-95% 7min; flow rate: 1.2mL/min .
  • the pH of the system was adjusted to neutral with 1N hydrochloric acid, extracted with ethyl acetate (10 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.
  • the crude product is purified by high-performance preparative liquid phase (Separation conditions: Column: Agilent 10 Prep-C8 250 ⁇ 21.2mm; Mobile phase: [Water (0.1% FA)-Acetonitrile]; Acetonitrile%: 30%-50% 9min, flow rate 30mL /min) to obtain compound 9.
  • Chromatographic column Waters XSelect CSH C18, 4.6*100mm, 3.5 ⁇ m; mobile phase: [water (0.01% trifluoroacetic acid)-acetonitrile (0.01% trifluoroacetic acid)]; acetonitrile: 5%-95% 7min; Flow rate: 1.2 mL/min.
  • the crude product is purified by high-performance preparative liquid phase (Separation conditions: Column: Welch Ultimate XB-C18 10 ⁇ 250mm 5 ⁇ m; Mobile phase: [Water (0.1% FA)-Acetonitrile]; Acetonitrile%: 50%-60% 10min, 60% 20min; flow rate 8mL/min). After concentration, compound 10A and compound 10B are obtained.
  • Chromatographic column Waters X-bridge C18, 4.6*100mm, 3.5 ⁇ m; mobile phase: water (10mM ammonium bicarbonate solution)-acetonitrile; acetonitrile: 5%-95% 7min; flow rate: 1.2mL/min.
  • Chromatographic column Waters X-bridge C18, 4.6*100mm, 3.5 ⁇ m; mobile phase: water (10mM ammonium bicarbonate solution)-acetonitrile; acetonitrile: 5%-95% 7min; flow rate: 1.2mL/min.
  • the crude product is purified by high-performance preparative liquid phase (Separation conditions: Column: Welch Ultimate XB-C18 10 ⁇ 250mm 5 ⁇ m; Mobile phase: [Water (0.1% FA)-Acetonitrile]; Acetonitrile%: 50%-60% 10min, 60% 20 min; flow rate 8 mL/min) to obtain compound 11A and compound 11B.
  • Chromatographic column Waters X-bridge C18, 4.6*100mm, 3.5 ⁇ m; mobile phase: [water (10Mm ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile: 5%-95% 7min; flow rate: 1.2mL/min .
  • Chromatographic column Waters X-bridge C18, 4.6*100mm, 3.5 ⁇ m; mobile phase: [water (10Mm ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile: 5%-95% 7min; flow rate: 1.2mL/min .
  • the crude product is purified by high-efficiency preparative liquid phase (Separation conditions: column: Agilent 10 Prep-C8 250 ⁇ 21.2mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 40%-52 %In 12min, 52%-52% 16min; flow rate 30mL/min) to obtain compound 12A and compound 12B.
  • Chromatographic column Waters X-bridge C18, 4.6*100mm, 3.5 ⁇ m; mobile phase: [water (10Mm ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile: 5%-95% 7min; flow rate: 1.2mL/min .
  • Chromatographic column Waters X-bridge C18, 4.6*100mm, 3.5 ⁇ m; mobile phase: [water (10Mm ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile: 5%-95% 7min; flow rate: 1.2mL/min .
  • the crude product is purified by high-efficiency preparative liquid phase (chromatographic column: Agilent 10 Prep-C8 250 ⁇ 21.2mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 25%-40% in 9min , 40%-45% in 12min; flow rate 30mL/min) to obtain compound 13A and compound 13B.
  • chromatographic column Agilent 10 Prep-C8 250 ⁇ 21.2mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 25%-40% in 9min , 40%-45% in 12min; flow rate 30mL/min
  • Chromatographic column Waters X-bridge C18, 4.6*100mm, 3.5 ⁇ m; mobile phase: [water (10Mm ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile: 5%-95% 7min; flow rate: 1.2mL/min .
  • Chromatographic column Waters X-bridge C18, 4.6*100mm, 3.5 ⁇ m; mobile phase: [water (10Mm ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile: 5%-95% 7min; flow rate: 1.2mL/min .
  • the crude product is purified by high-performance preparative liquid phase (separation conditions: chromatographic column: 5 ⁇ m F5 LC Column 150 x 21.2 mm; column temperature: 25° C.; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile: 20%-35% in 10 min; flow rate 30 mL/min) to obtain compound 14.
  • the crude product is purified by high-efficiency preparative liquid phase (separation condition: chromatographic column 5 ⁇ m F5 LC Column 150 x 21.2mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile: 15%-35% in 10min, 35%-35% in 16min; flow rate 30mL/min) to obtain the compound 15.
  • high-efficiency preparative liquid phase separation condition: chromatographic column 5 ⁇ m F5 LC Column 150 x 21.2mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile: 15%-35% in 10min, 35%-35% in 16min; flow rate 30mL/min
  • Chromatographic column Waters Xbridge C18 3.5 ⁇ m, 100*4.6mm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile: 5%-95% 7min, 95% 8min; Flow rate: 1.2 mL/min.
  • reaction solution was diluted with water (10mL), extracted with ethyl acetate (20mL x 2), combined the organic phases, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated by high performance liquid phase separation (Separation conditions: Column: Phenomenex Gemini-NX 80*30mm*3 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 36%-66%, 9.5min). Obtain compound 16A (peak 1) and compound 16B (peak B).
  • Chromatographic column Xbridge Shield RP-18, 5 ⁇ m, 2.1*50mm; column temperature: 50°C; mobile phase: [water (0.02% ammonia solution)-acetonitrile]; acetonitrile: 10%-80% 6min, 80% 2min; Flow rate: 0.8mL/min.
  • Chromatographic column Xbridge Shield RP-18, 5 ⁇ m, 2.1*50mm; column temperature: 50°C; mobile phase: [water (0.02% ammonia solution)-acetonitrile]; acetonitrile: 10%-80% 6min, 80% 2min; Flow rate: 0.8mL/min.
  • the diastereomer compound 16A was purified by SFC (Separation conditions: column: DAICEL CHIRALPAK AD-H (250mm*30mm, 5 ⁇ m); mobile phase: [CO 2 -isopropanol (0.1% ammonia)]; isopropyl Alcohol %: 35%). After concentration, compound 16A-1 and compound 16A-2 were obtained.
  • Chromatographic column Column: Chiralpak AD-3 50 x 4.6mm ID, 3 ⁇ m; column temperature: 35°C; mobile phase: CO 2 -isopropanol (0.05% DEA); isopropanol: 5%-40% 2min, 40% 1.2min, 5% 0.8min; flow rate: 4mL/min.
  • Chromatographic column Column: Chiralpak AD-3 50 x 4.6mm ID, 3 ⁇ m; column temperature: 35°C; mobile phase: CO 2 -isopropanol (0.05% DEA); isopropanol: 5%-40% 2min, 40% 1.2min, 5% 0.8min; flow rate: 4mL/min.
  • the diastereomer compound 16B was purified by SFC (Separation conditions: column: DAICEL CHIRALPAK AD-H (250mm*30mm, 5 ⁇ m); mobile phase: [CO 2 -isopropanol (0.1% ammonia)]; isopropyl Alcohol %: 35%). After concentration, compound 16B-1 and compound 16B-2 were obtained.
  • Chromatographic column Column: Chiralpak AD-3 50 x 4.6mm ID, 3 ⁇ m; column temperature: 35°C; mobile phase: CO 2 -isopropanol (0.05% DEA); isopropanol: 5%-40% 2min, 40% 1.2min, 5% 0.8min; flow rate: 4mL/min.
  • Chromatographic column Column: Chiralpak AD-3 50 x 4.6mm ID, 3 ⁇ m; column temperature: 35°C; mobile phase: CO 2 -isopropanol (0.05% DEA); isopropanol: 5%-40% 2min, 40% 1.2min, 5% 0.8min; flow rate: 4mL/min.
  • Dissolve compound 17-7 (300mg, 1.0mmol), pinacol biborate (500mg, 2.0mmol), potassium acetate (300mg, 3.0mmol) and ditricyclohexylphosphorus palladium dichloride (74mg, 0.1mmol)
  • a mixed solvent of N,N-dimethylacetamide (10mL) and water (1mL) Under a nitrogen atmosphere, the system was heated to 155°C and stirred for 2 hours.
  • the crude product is purified by high-performance preparative liquid phase (Separation conditions: chromatographic column Agilent 10 Prep-C8 250 ⁇ 21.2mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile: 20%-40% in 12min ; Flow rate 30 mL/min) to obtain compound 17.
  • Chromatographic column Waters X-bridge C18, 4.6*100mm, 3.5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile: 5%-95% for 7min; flow rate: 1.2mL/min .
  • compound 4-8 (8.6g, 26.24mmol) was dissolved in acetonitrile (40mL), and cuprous iodide (5.05g, 26.51mmol), potassium iodide (8.84g, 53.27mmol) and Tert-butyl nitrite (5.66g, 54.85mmol, 6.52mL), the reaction was heated to 80°C and stirred for 2h.
  • compound 18-4 500 mg, 1.06 mmol was dissolved in acetic acid (10 mL), concentrated nitric acid (1.23 g, 19.51 mmol, 878.20 ⁇ L) was added, and the reaction was heated to 80° C. and stirred for 2 h.
  • the reaction solution was concentrated under reduced pressure to remove most of the acetic acid, cooled to 0°C, water (50 mL) was added, filtered, and the filter cake was vacuum dried to obtain crude product 18-5, which was directly used in the next reaction without further purification.
  • reaction solution was diluted with water (10mL), extracted with ethyl acetate (10mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by high-performance preparative liquid phase separation and purification (Separation conditions: Column :Phenomenex Gemini-NX 80*30mm*3 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile%: 50%-80%, 9min), get:
  • HPLC analysis conditions Column: Xbridge Shield RP-18, 5 ⁇ m, 2.1*50mm; mobile phase: [water (0.02% ammonia solution v/v)-acetonitrile]; acetonitrile%: 10%-80%, column temperature: 50 °C.
  • Step 17 Isolation of compounds 18A-1 and 18A-2
  • Compound 18A was separated and purified by SFC (Separation conditions: column: REGIS(s,s)WHELK-O1 (250mm*30mm, 5 ⁇ m); mobile phase: [supercritical carbon dioxide-ethanol]; ethanol%: 50%-50%) , Get:
  • HPLC analysis conditions Column: WELCH Ultimate LP-C18 150*4.6mm, 5 ⁇ m; Mobile phase: [water (0.06875% trifluoroacetic acid solution v/v)-acetonitrile (0.0625% trifluoroacetic acid solution v/v)]; Acetonitrile%: 10%-80%, column temperature: 40°C.
  • Step 18 Isolation of compounds 18B-1 and 18B-2
  • Compound 18B was separated and purified by SFC (Separation conditions: column: REGIS(s,s)WHELK-O1 (250mm*30mm, 5 ⁇ m); mobile phase: [supercritical carbon dioxide-ethanol]; ethanol%: 50%-50%) , Get:
  • HPLC analysis conditions Column: WELCH Ultimate LP-C18 150*4.6mm, 5 ⁇ m; Mobile phase: [water (0.06875% trifluoroacetic acid solution v/v)-acetonitrile (0.0625% trifluoroacetic acid solution v/v)]; Acetonitrile%: 10%-80%, column temperature: 40°C.
  • compound 19-1 (9.5g, 57.93mmol), compound 19-2 (29.20g, 173.79mmol), 1,1-bis(diphenylphosphine)ferrocene dichloride Palladium (3.39g, 4.63mmol) and potassium carbonate (24.02g, 173.79mmol) were dissolved in 1,4-dioxane (150mL) and water (30mL). Under nitrogen atmosphere, the system was heated to 100°C and stirred for 12h .

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CN113853373A (zh) * 2019-10-30 2021-12-28 劲方医药科技(上海)有限公司 取代的杂环并环类化合物，其制法与医药上的用途
WO2022037630A1 (zh) * 2020-08-21 2022-02-24 浙江海正药业股份有限公司 四环类衍生物、其制备方法及其医药上的用途
WO2022143995A1 (zh) * 2020-12-31 2022-07-07 正大天晴药业集团股份有限公司 四环类化合物及其医药用途
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WO2022199669A1 (zh) * 2021-03-25 2022-09-29 上海济煜医药科技有限公司 稠合吡啶酮类化合物盐型、晶型及其应用
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