WO2023143424A1 - Dérivé azacyclique et son application médicale - Google Patents

Dérivé azacyclique et son application médicale Download PDF

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Publication number
WO2023143424A1
WO2023143424A1 PCT/CN2023/073285 CN2023073285W WO2023143424A1 WO 2023143424 A1 WO2023143424 A1 WO 2023143424A1 CN 2023073285 W CN2023073285 W CN 2023073285W WO 2023143424 A1 WO2023143424 A1 WO 2023143424A1
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Prior art keywords
alkyl
cyano
substituted
halogen
cycloalkyl
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PCT/CN2023/073285
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English (en)
Chinese (zh)
Inventor
张晨
王健民
黄正刚
钱国飞
余彦
唐平明
李瑶
严庞科
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四川海思科制药有限公司
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Publication of WO2023143424A1 publication Critical patent/WO2023143424A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound described in general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and Its intermediate and preparation method, as well as its application in the preparation of medicines for treating diseases related to USP1 activity or expression.
  • DUBs E3 ubiquitin ligases and deubiquitinating enzymes
  • DUBs can cleave the isopeptide bond between ubiquitin and modified proteins, and are responsible for removing ubiquitin from target proteins and rescuing them from degradation pathways; they are also involved in the editing, maturation and recycling of ubiquitin molecules after degradation. More than 100 deubiquitinating enzymes are currently known, and these proteins are subdivided into six subfamilies.
  • the ubiquitin-specific protease (USP) subfamily is the largest subfamily, with 58 known members.
  • USP is a cysteine protease with a highly conserved catalytic domain
  • USP1 is a member of the USP subfamily of DUBs (Cancers, 2020, 12, 1579; Molecular Cell, 2018, 72, 925–941).
  • Fanconi Anemia (FA) and DNA Translesion Synthesis (TLS) pathways are the first DNA damage tolerance and repair pathways regulated by reversible ubiquitination.
  • USP1 can regulate the deubiquitination of specific proteins in FA and TLS pathways to participate in the regulation of DNA Damage-repair pathway (Nature Chemical Biology, 2014, 10, 298–304).
  • USP1 plays an important role in DNA repair of tumor cells, and it has been reported that loss of USP1 leads to decreased survival and replication fork degradation in BRCA1-deficient cells (Molecular Cell, 2018, 72, 925–941).
  • UAF1 USP1-associated factor 1
  • USP1-associated factor 1 can enhance their deubiquitinase activity by forming a stable USP/UAF1 protein complex; the USP1/UAF1 complex deactivates various substrates.
  • USP1 inhibitors has broad application prospects.
  • the object of the present invention is to provide a compound capable of inhibiting USP1 or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and wherein Intermediates and preparation methods, and applications in the preparation of drugs for treating diseases related to USP1 activity or expression.
  • the present invention provides a compound described in general formula (I) or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein
  • Ring A is selected from
  • Ring A is selected from
  • Ring A is selected from
  • R 1 , R 8 , R 9 are each independently selected from H, F, Cl, Br, I, cyano, methyl or ethyl;
  • R is selected from H
  • R is selected from H
  • R9 is selected from H
  • R 2 is selected from C 6-10 carbocycle or 5 to 10 membered heterocycle, which is optionally substituted by 0 to 4 R 2a ;
  • R is selected from phenyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, Said R 2 is optionally substituted by 0 to 4 R 2a ;
  • R is selected from pyrrolyl, pyrazolyl, imidazolyl, pyrimidinyl,
  • the R 2 is optionally replaced by 0 to 4 selected from H, F, Cl, Br, I, cyano, -SO 2 -methyl, -SO 2 -ethyl, -SO 2 -propyl, -SO 2 -different Propyl, -SO 2 -cyclopropyl, CH 2 F, CHF 2 , CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , methyl, ethyl, propyl, isopropyl, methoxy , Ethoxy, Propoxy, Methylthio, Ethylthio, Propylthio, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Azetidinyl, Azacyclopentyl, Azepine Cyclohexyl, piperazinyl, oxetanyl, oxolyl, oxanyl, morpholinyl, -
  • R is selected from phenyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, the phenyl, pyridine Base, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl are optionally substituted by 0 to 4 R 2a ;
  • R is selected from pyrrolyl, pyrazolyl, imidazolyl, pyrimidinyl, and said pyrrolyl, pyrazolyl, imidazolyl, pyrimidinyl are optionally selected from 0 to 4 selected from H, F , Cl, Br, I, cyano, -SO 2 -methyl, -SO 2 -ethyl, -SO 2 -propyl, -SO 2 -isopropyl, -SO 2 -cyclopropyl, methyl , ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Azetidinyl, Azetidinyl, Azetidinyl, Piperazinyl, Oxetanyl,
  • R is selected from
  • R is selected from
  • R is selected from
  • each R 2a is independently selected from H, F, Cl, Br, I, cyano, or each R 2a is independently selected from one of the following substituted or unsubstituted groups: -SO 2 - Methyl, -SO 2 -ethyl, -SO 2 -propyl, -SO 2 -isopropyl, -SO 2 -cyclopropyl, methyl, ethyl, propyl, isopropyl, methoxy, Ethoxy, Propoxy, Methylthio, Ethylthio, Propylthio, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Azetidinyl, Azacyclopentyl, Azacyclic Hexyl, piperazinyl, oxetanyl, oxolyl, oxanyl, morpholinyl, -O-azetidinyl, -
  • R 3 and R 4 are each independently selected from H, halogen, OH, cyano, C 1-4 alkyl;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, methyl, ethyl;
  • R 3 , R 4 are selected from H
  • Cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octyl, bicyclo[1.1.1]pentyl, cyclopentylcyclo Pentyl, cyclobutylspirocyclohexyl, cyclobutylspirocyclopentyl, azetidinyl, azetidinyl, azetidinyl, azetidinylspirocyclobutyl, azetidinyl Spirocyclopentyl, Azetidinylspirocyclohexyl, Azetidinylspiroazetidinyl, Azetidinylspiroazetidinyl, Azetidinylspiroazetidinyl , Benzene ring, thienyl, furyl
  • Cy is selected from Said Cy is optionally replaced by 0 to 4 selected from H, F, Cl, Br, I, cyano, CH 2 F, CHF 2 , CF 3 , Substituents of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl;
  • Cy is selected from Said Cy is optionally replaced by 0 to 4 selected from H, F, Cl, Br, I, cyano, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, propyl, isopropyl, methyl Oxygen, ethoxy, cyclopropyl substituents are substituted;
  • R 5 is selected from -ZC 3-12 carbocycle or -Z-4 to 12 membered heterocycle, said R 5 is optionally substituted by 0 to 4 R 5a ;
  • R 5 is selected from -ZC 6-12 carbocycle or -Z-5 to 12 membered heterocycle, said R 5 is optionally substituted by 0 to 4 R 5a ;
  • R is selected from phenyl, 5-6 membered heteroaryl, pyrazolo 4-9 membered heterocyclyl, said R being optionally substituted by 0 to 4 R 5a ;
  • R is selected from benzene, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,
  • the R 5 is optionally substituted by 0 to 4 R 5a ;
  • R is selected from pyrrolyl, pyrazolyl, imidazolyl
  • the R 5 is optionally replaced by 0 to 4 members selected from H, F, Cl, Br, I, cyano, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, propyl, isopropyl, - CH 2 CH 2 F, methoxy, ethoxy, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, -CH 2 -ethynyl, -CH(CH 3 )-ethynyl, C(CH 3 ) 2 -ethynyl, replaced by substituents;
  • R is selected from
  • R is selected from
  • R 5 is selected from -ZC 3-10 carbocycle or -Z-4 to 10 membered heterocycle, said R 5 is optionally substituted by 0 to 4 R 5a ;
  • R 5 is selected from -ZC 6-10 carbocycle or -Z-5 to 10 membered heterocycle, said R 5 is optionally substituted by 0 to 4 R 5a ;
  • R is selected from benzene ring , pyrazolyl, pyrrolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, said R is optionally replaced by 0 to 4 R 5a substitutions;
  • R is selected from pyrrolyl, pyrazolyl, and imidazolyl, and said pyrrolyl, pyrazolyl, and imidazolyl are optionally replaced by 0 to 4 selected from H, F, Cl, Br, I, cyano, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl are substituted by substituents;
  • R is selected from
  • the substituent of the cyclic group is substituted, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
  • the substituent of the cyclic group is substituted, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
  • each of R 6 and R 7 is independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, -CH 2 F, isopropyl, -CH 2 -ring Propyl, cyclopropyl;
  • R 6 and R 7 are each independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, cyclopropyl;
  • R 6 , R 7 together with the carbon atom to which they are attached form cyclopropyl
  • the compound represented by general formula (I) is not
  • the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic is represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
  • Ring A is selected from
  • R 2 is selected from C 6-10 carbocycle or 5 to 10 membered heterocycle, said carbocycle or heterocycle is optionally substituted by 0 to 4 R 2a ;
  • R 5 is selected from -ZC 3-12 carbocycle or -Z-4 to 12 membered heterocycle, said R 5 is optionally substituted by 0 to 4 R 5a ;
  • R 5a are each independently selected from H, halogen, OH, cyano, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 alkoxy Base, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 to 8 membered heterocycle, -CONHC 1-6 alkyl, -CONHC 1-6 alkoxy, -CONHC 3-6 cycloalkyl, -CONH3 to 8-membered heterocycle, -NHCO-C 1-6 alkyl, -NHCO-C 1-6 alkoxy, -NHCO-C 3-6 cycloalkyl or -NHCO-3 to 8-membered heterocycle,
  • the heterocycle contains 1 to 4 selected from O , S, N heteroatoms;
  • R 3 and R 4 are each independently selected from H, halogen, OH, cyano, C 1-4 alkyl;
  • R 5 is selected from -ZC 6-12 carbocycle or -Z-5 to 12 membered heterocycle, said R 5 is optionally substituted by 0 to 4 R 5a ;
  • R 6 and R 7 are each independently selected from H, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3 to 6-membered heterocycle, and said alkyl, cycloalkyl, hetero
  • the substituent of the group is substituted, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
  • R 1 , R 8 , R 9 are each independently selected from H, F, Cl, Br, I, cyano, methyl or ethyl;
  • R is selected from phenyl, pyridyl, pyrimidyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, Said R 2 is optionally substituted by 0 to 4 R 2a ;
  • Each R 2a is independently selected from H, F, Cl, Br, I, cyano, or each R 2a is independently selected from one of the following substituted or unsubstituted groups: -SO 2 -methyl, -SO 2 - Ethyl, -SO 2 -propyl , -SO 2 -isopropyl, -SO 2 -cyclopropyl , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy , Methylthio, Ethylthio, Propylthio, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Azetidinyl, Azacyclopentyl, Azacyclohexyl, Piperazinyl, Oxygen Heterobutyl, oxolyl, oxanyl, morpholinyl, -O-azetidinyl, -O
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, methyl, ethyl;
  • Cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.2] octane, bicyclo [1.1.1] pentyl, cyclopentyl and cyclopentyl, cyclobutyl spiro Cyclohexyl, Cyclobutylspirocyclopentyl, Azetidinyl, Azacyclopentyl, Azetidinyl, Azetidinylspirocyclobutyl, Azetidinylspirocyclopentyl, Azetidinyl Cyclobutylspirocyclohexyl, azetidinylspiroazetidinyl, azetidinylspiroazetidinyl, azetidinylspiroazetidinyl, Benzene ring, thienyl, furyl
  • R is selected from benzene ring, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,
  • the R 5 is optionally substituted by 0 to 4 R 5a ;
  • R 5a are each independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, propyl, isopropyl, ethynyl, propynyl, propargyl, methoxy, ethoxy Base, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, the methyl, ethyl, propyl, isopropyl, Ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl
  • R 1 , R 8 , R 9 are selected from H;
  • R is selected from pyrrolyl, pyrazolyl, imidazolyl, pyrimidinyl,
  • the R 2 is optionally replaced by 0 to 4 selected from H, F, Cl, Br, I, cyano, -SO 2 -methyl, -SO 2 -ethyl, -SO 2 -propyl, -SO 2 -isopropyl, -SO 2 -cyclopropyl, CH 2 F, CHF 2 , CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , methyl, ethyl, propyl, isopropyl, methyl Oxy, Ethoxy, Propoxy, Methylthio, Ethylthio, Propylthio, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Azetidinyl, Azetidinyl, Azacyclohexyl, piperazinyl
  • Cy selected from Said Cy is optionally replaced by 0 to 4 selected from H, F, Cl, Br, I, cyano, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, propyl, isopropyl, methyl Oxygen, ethoxy, cyclopropyl substituents are substituted;
  • Cy selected from Said Cy is optionally replaced by 0 to 4 selected from H, F, Cl, Br, I, cyano, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, propyl, isopropyl, methyl Oxygen, ethoxy, cyclopropyl substituents are substituted;
  • R is selected from pyrrolyl, pyrazolyl, imidazolyl,
  • the R 5 is optionally replaced by 0 to 4 members selected from H, F, Cl, Br, I, cyano, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, propyl, isopropyl, - CH 2 CH 2 F, methoxy, ethoxy, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, -CH 2 -ethynyl, -CH(CH 3 )-ethynyl, C(CH 3 ) 2 -ethynyl, replaced by substituents;
  • R2 is selected from
  • R2 is selected from R 5 selected from
  • R 5 is selected from
  • R 6 and R 7 are each independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, -CH 2 F, isopropyl, -CH 2 -cyclopropyl, cyclopropyl;
  • the present invention relates to the following compounds or their stereoisomers, tautomers, deuterated products, solvates, prodrugs, metabolites
  • the present invention relates to a pharmaceutical composition, comprising the compound described in the present invention or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal , and a pharmaceutically acceptable carrier.
  • the present invention relates to a compound of the present invention or its stereoisomers, tautomers, deuteriums, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals used in the preparation of therapeutic Application in medicines for diseases related to USP1 activity or expression level, preferably in the preparation of medicines for tumor diseases.
  • the present invention relates to any of the above-mentioned compounds or their stereoisomers, tautomers, deuteriums, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, or the above-mentioned pharmaceutical composition for use in Application in the preparation of medicines for treating diseases related to USP1 activity or expression level, preferably, the diseases are selected from cancer.
  • the present invention relates to any of the above-mentioned compounds or their stereoisomers, tautomers, deuteriums, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals used in the preparation of therapeutic and inhibition or degradation Application in medicine of USP1-related diseases, preferably, the diseases are selected from tumors.
  • the present invention relates to any of the above-mentioned compounds or their stereoisomers, deuteriums, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, or the above-mentioned pharmaceutical compositions used in the preparation of treatments with USP1 activity or Application in drugs for diseases related to expression level, preferably, the diseases are selected from tumors.
  • the present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite , a pharmaceutically acceptable salt or co-crystal and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification").
  • the present invention also provides a method for treating a disease in a mammal, which comprises administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, Metabolites, pharmaceutically acceptable salts or co-crystals or pharmaceutical compositions.
  • the mammals of the present invention include humans.
  • an "effective dose” or “therapeutically effective dose” in the present application refers to the administration of a sufficient amount of the compound disclosed in the present application, which will relieve the disease or disease to be treated to some extent (such as USP1 activity or expression related diseases one or more symptoms of a tumor).
  • the result is reduction and/or alleviation of signs, symptoms or causes of disease, or any other desired alteration of a biological system.
  • an "effective amount” for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.
  • therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1200 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20 -600mg, 25-600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg, 100-600mg, 200-600mg, 1-500mg , 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70 -500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg
  • the pharmaceutical composition includes but not limited to 1-1500mg, 1-1400mg, 1-1200mg, 1-600mg, 20-400mg, 25-200mg, 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 300mg, 400mg, 480mg, 500mg of the compound of the present invention or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-cry
  • a method for treating a disease in a mammal comprising administering to a subject a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the therapeutically effective dose is preferably 1-1500 mg, and the disease is preferably tumor.
  • a method for treating a disease in a mammal comprises, the compound of the present invention or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal with A daily dose of 1-1500 mg/day is administered to the subject, and the daily dose can be a single dose or divided doses.
  • the daily dose includes but is not limited to 10-1500 mg/day, 10-800 mg/day, 25 -800mg/day, 50-800mg/day, 100-800mg/day, 200-800mg/day, 25-400mg/day, 50-400mg/day, 100-400mg/day, 200-400mg/day, in some implementations
  • the daily dosage includes but not limited to 10mg/day, 20mg/day, 25mg/day, 50mg/day, 100mg/day, 125mg/day, 150mg/day, 200mg/day, 400mg/day, 600mg/day, 800mg /day, 1000mg/day, 1200mg/day.
  • the present invention relates to a kit which may comprise a composition in single or multiple dose form, the kit comprising a compound of the present invention or its stereoisomer, deuterated, solvated, prodrug, metabolite, pharmaceutical acceptable salt or co-crystal, the amount of the compound of the present invention or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal is the same as that in the above-mentioned pharmaceutical composition same amount.
  • R a1 is selected from halogen or OH;
  • R a2 is selected from halogen, preferably from Br, Cl;
  • R a3 is selected from amino protecting group or H;
  • the compound of general formula (Ia-1) and the compound of (Ia-2) obtain the compound of general formula (Ia-3) by substitution reaction, or remove the amino protecting group of the compound of general formula (Ia-2) and then combine with the compound of general formula (Ia -1)
  • the compound obtains the compound of general formula (Ia-3) through a substitution reaction;
  • the compound of general formula (Ia-3) obtains the compound of general formula (Ia-4) through coupling reaction;
  • the compound of general formula (Ia-4) obtains the compound of general formula (Ia-5) by oxidation reaction;
  • the compound of the general formula (Ia-5) is obtained by a reduction reaction to obtain the compound of the general formula (Ia), or the compound of the general formula (Ia-5) is obtained by a reduction reaction and then a substitution reaction to obtain the compound of the general formula (Ia).
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, and I involved in the groups and compounds of the present invention include their isotopes, and the carbon involved in the groups and compounds of the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D, Also called heavy hydrogen), tritium (T, also called super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.
  • the isotopes of carbon include 12 C, 13 C and 14
  • Halogen means F, Cl, Br or I.
  • Halogen substituted refers to F, Cl, Br or I substitution, including but not limited to 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 substituents selected from F, Cl, Br Or substituted by a substituent of I, substituted by 1 to 4 substituents selected from F, Cl, Br or I.
  • Halo-substituted is simply referred to as "halo”.
  • Alkyl refers to a substituted or unsubstituted linear or branched saturated aliphatic hydrocarbon group, including but not limited to an alkyl group of 1 to 20 carbon atoms, an alkyl group of 1 to 8 carbon atoms, an alkyl group of 1 to 6 An alkyl group of carbon atoms, an alkyl group of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched isomers.
  • Alkyl groups appearing herein are defined in accordance with this definition. Alkyl groups can be monovalent, divalent, trivalent or tetravalent.
  • Alkylene refers to substituted or unsubstituted linear and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v - (v is an integer from 1 to 10), examples of alkylene include but not Limited to methylene, ethylene, propylene and butylene, etc.
  • Cycloalkyl means a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclo Heptyl etc. As used herein, cycloalkyl is as defined above. Cycloalkyl groups can be monovalent, divalent, trivalent or tetravalent.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group, including but not limited to 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 atoms selected from N, O or
  • the heteroatoms of S, the selectively substituted N and S in the ring of heterocycloalkyl can be oxidized into various oxidation states.
  • the heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, and the heterocycloalkyl group can be connected to a bridged ring or a spiro ring.
  • Non-limiting examples include ring Oxyethyl, aziridyl, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, Piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl.
  • Heterocycloalkyl can be monovalent, divalent, trivalent or tetravalent
  • alkenyl means a substituted or unsubstituted straight and branched unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, the main chain including but not limited to 2 to 10 1, 2 to 6, or 2 to 4 carbon atoms
  • alkenyl examples include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl , 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-but Alkenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1 -pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octen
  • Alkynyl means a substituted or unsubstituted straight and branched unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, the backbone comprising 2 to 10 carbon atoms , including but not limited to 2 to 6 carbon atoms in the main chain, 2 to 4 carbon atoms in the main chain, examples of alkynyl include but not limited to ethynyl, propargyl, 1-propynyl, 2 -propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl Base-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- Hexynyl, 5-hexynyl, 1-
  • Alkoxy means a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyl Oxygen and Cyclobutoxy.
  • Carbocyclyl or “carbocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring
  • the aromatic ring or non-aromatic ring can be 3 to 8 membered single ring, 4 to 12 membered Bicyclic or 10- to 15-membered tricyclic ring system
  • the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring
  • the aromatic ring or non-aromatic ring is optionally a monocyclic, bridged or spiro ring.
  • Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring,
  • a "carbocyclyl” or “carbocycle” can be monovalent, divalent, trivalent or tetravalent.
  • Heterocyclic group refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring, the aromatic ring or non-aromatic ring can be 3 to 8 membered single ring, 4 to 12 membered A bicyclic ring or a 10- to 15-membered tricyclic ring system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S, and the ring of the heterocyclyl group is selected from sexually substituted N and S can be oxidized into various oxidation states.
  • the heterocyclic group can be connected to a heteroatom or a carbon atom, the heterocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the heterocyclic group can be connected to a bridged ring or a spiro ring.
  • Non-limiting examples include oxirane , aziridyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furyl, thienyl, pyryl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorph Linyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiapentanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl Base, benzimidazolyl, benzo
  • Spiro ring or “spirocyclic group” refers to a polycyclic group that shares one atom (called spiro atom) between substituted or unsubstituted monocyclic rings.
  • a “spirocycle” or “spirocyclyl” can be monovalent, divalent, trivalent or tetravalent.
  • the number of ring atoms in the double ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10.
  • Non-limiting examples include: "Alkyl” or “alkyl” may be monovalent, divalent, trivalent or tetravalent.
  • the number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12 or 5 to 10.
  • Non-limiting examples include
  • a "bridged ring” or “bridged ring group” may be monovalent, divalent, trivalent or tetravalent.
  • Carbospiro refers to a “spirocycle” whose ring system consists only of carbon atoms.
  • the definitions of “carbospirocycle”, “spirocyclic carbocyclyl”, “spirocarbocyclyl” or “carbospirocyclyl” appearing herein are consistent with spirocycle.
  • Carbocyclic “paracyclic carbocyclyl”, “paracarbocyclyl” or “carbocyclyl” refers to a “carbocyclyl” whose ring system consists only of carbon atoms.
  • the definition of “carbocyclyl”, “paracyclic carbocyclyl”, “paracarbocyclyl” or “carbocyclyl” used herein is consistent with that of paracyclyl.
  • Carbobridged ring refers to a “bridged ring” whose ring system consists only of carbon atoms.
  • the definitions of "carbon bridged ring”, “bridged ring carbocyclyl”, “bridged carbocyclyl” or “carbobridged ring” appearing in this article are consistent with those of bridged ring.
  • Heterocyclic group refers to the “heterocyclic group” or “heterocyclic group” of a monocyclic ring system, and the heterocyclic group, "monocyclic heterocyclic group” appearing herein group” or “heteromonocyclic group”, the definition of which is consistent with that of heterocycle.
  • Heterocyclyl refers to “heterocycles” that contain heteroatoms.
  • the definition of heterocyclic ring, “heterocyclic group”, “heterocyclic heterocyclic group” or “heterocyclic group” used herein is consistent with that of parallel ring.
  • Heterospiro refers to a “spirocycle” that contains heteroatoms.
  • heterospirocycle refers to a “spirocycle” that contains heteroatoms.
  • heterospirocycle refers to a “spirocycle” that contains heteroatoms.
  • heterospirocycle refers to a “spirocycle” that contains heteroatoms.
  • heterospirocycle refers to a “spirocycle” that contains heteroatoms.
  • heterospirocycle refers to a "heterospirocyclyl” that contains heteroatoms.
  • Heterobridged ring refers to a “bridged ring” that contains heteroatoms.
  • the definition of heterobridged ring, “heterobridged ring group”, “bridged ring heterocyclyl group” or “heterobridged ring group” used herein is consistent with bridged ring.
  • Aryl or “aromatic ring” refers to a substituted or unsubstituted aromatic hydrocarbon group with a single ring or a condensed ring, and the number of ring atoms in the aromatic ring includes but is not limited to 6 to 18, 6 to 12 or 6 to 10 carbon atoms.
  • the aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring bonded to the parent structure is an aryl ring, non-limiting examples include benzene, naphthalene, "Aryl” or “aromatic ring” may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.
  • heteroaryl examples include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc.
  • the heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples include In this article Where heteroaryl occurs, its definition corresponds to this definition.
  • Heteroaryl groups can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the heteroaryl ring.
  • Constant 1 to 4 heteroatoms selected from O, S, N means containing 1, 2, 3 or 4 heteroatoms selected from O, S, N.
  • Substituted by 0 to X substituents means substituted by 0, 1, 2, 3...X substituents, X is selected from any integer between 1 and 10.
  • substituted by 0 to 4 substituents means substituted by 0, 1, 2, 3 or 4 substituents.
  • substituted by 0 to 5 substituents means substituted by 0, 1, 2, 3, 4 or 5 substituents.
  • the heterobridged ring is optionally further substituted by 0 to 4 substituents selected from H or F means that the heterobridged ring is optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H or F base replaced.
  • X-Y-membered rings (X is selected from integers less than Y and greater than or equal to 3, Y is selected from any integer between 4 and 12) including X, X+1, X+2, X+3, X+4...Y ring of elements.
  • Rings include heterocycles, carbocycles, aryls, aryls, heteroaryls, cycloalkyls, heteromonocycles, heteroheterocycles, heterospirocycles or heterobridged rings.
  • 4--7 membered heteromonocyclic ring refers to 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring
  • 5--10-membered heterocyclic ring refers to 5-, 6-, 7-, and 8-membered heterocyclic rings. , 9- or 10-membered heterocyclic rings.
  • Alkyl optionally substituted by F means that the alkyl group may but not necessarily be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
  • Stepoisomer refers to isomers produced by different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
  • Tautomer refers to a functional group isomer produced by a certain atom in a molecule moving rapidly at two positions, such as keto-enol isomerization and amide-imino alcohol isomerization.
  • Preparation specification refers to the weight of the main drug contained in each tube, tablet or other unit preparation.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • HPLC HPLC-based high pressure liquid chromatography
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.20mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. -0.5mm;
  • the known starting materials of the present invention can be used or synthesized according to methods known in the art, or can be purchased from Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, etc. company.
  • Tf trifluoromethanesulfonyl
  • Ts p-toluenesulfonyl
  • TMS trimethylsilyl
  • SEM THP: Boc: tert-butoxycarbonyl
  • Ms TBS: MTBE: methyl tert-butyl ether
  • Bn DIPEA: N,N-Diisopropylethylamine
  • DMAc N,N-Dimethylacetamide
  • DMSO Dimethylsulfoxide
  • DCM Dichloromethane
  • Cbz Cbz:
  • thionyl chloride (1.23mL, 16.9mmol) was added to 1C (1.6g, 5.63mmol) in dichloromethane (50mL), stirred at room temperature for 30 minutes and then quenched with saturated sodium bicarbonate (70mL) , extracted with dichloromethane (60mL ⁇ 3), combined the organic phases, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1D (1.7g).
  • V/V ethyl acetate/petroleum ether
  • 3C (1.2g, 7.08mmol) and triphenylphosphine (5.57g, 21.24mmo) were dissolved in THF (10mL) and water (1mL), stirred at 60°C for 2h. Cool to room temperature, concentrate under reduced pressure to remove the solvent, dissolve the residue in 5 mL of ethyl acetate, add 5 mL of 4N hydrogen chloride-ethyl acetate solution, precipitate a large amount of solid, filter, dissolve the filter cake in 2 mL of water, add 20 mL of dichloromethane, Under stirring, the pH was adjusted to >8 with saturated aqueous sodium bicarbonate solution, and the organic layer was concentrated under reduced pressure after separation to obtain 3D (0.36 g, yield: 35%).
  • V/V ethyl acetate/petroleum ether
  • 3E (70mg, 0.16mmol) was dissolved in dichloromethane (2mL), pyridine (0.038g, 0.48mmol) was added under ice cooling, trifluoromethanesulfonic anhydride (0.14g, 0.48mmol) was slowly added dropwise, and the temperature was slowly raised to Stir at room temperature for 2h. 20 mL of saturated brine and 20 mL of dichloromethane were added for extraction, and the organic layer was washed with saturated brine (10 mL x 2). Concentration under reduced pressure and removal of solvent gave 3F.
  • lithium bistrimethylsilylamide (0.3mL, 0.3mmol, 1M in THF) was added dropwise to a solution of compound 1 (150mg, 0.27mmol) in tetrahydrofuran (7mL) at -78°C, at -78°C
  • 1,3,2-dioxazolethiophene-2,2-dioxide (50mg, 0.4mmol)
  • react at 0°C for 1h cool down to -78°C
  • add bistrimethylsilylamine dropwise Lithium (0.3mL, 0.3mmol, 1M in THF), stirred at room temperature for 18h.
  • 5D (1.2g, 3.48mmol) was dissolved in 20mL THF, lithium borohydride (0.38g, 17.40mmol) was added, and stirred at 60°C for 2 hours. Cool to room temperature, add saturated ammonium chloride aqueous solution to quench the reaction, add water and ethyl acetate to extract, the organic layer is dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5E (0.9 g, yield: 81%).
  • methanesulfonyl chloride 64mg, 0.56mmol was added to a solution of 5E (0.12g, 0.37mmol) and triethylamine (0.11g, 1.09mmol) in dichloromethane (15mL), and stirred at room temperature for 1 hour . It was quenched by adding 20 mL of saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane (20 mL ⁇ 3).
  • N-bromosuccinimide (0.25g, 1.4mmol) was added to a solution of 5J (0.26g, 0.46mmol) in tert-butanol (6mL) and water (2mL), stirred at room temperature for 2 hours, and then added 10 mL of saturated aqueous sodium thiosulfate was stirred for 5 minutes.
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • 6A (2.4g, 8.44mmol) was dissolved in 50mL THF, lithium borohydride (1.84g, 84.4mmol) was slowly added in an ice-water bath, and stirred at 50°C for 4h. Cool to room temperature, place the reaction bottle in an ice-water bath, slowly add saturated ammonium chloride aqueous solution to quench the reaction, add 20 mL of water, add ethyl acetate (60 mL ⁇ 3) for extraction, collect the organic layer, dry over anhydrous sodium sulfate, and filter , the filtrate was concentrated under reduced pressure to obtain 6B (2.0 g, yield: 92%).
  • 6D (970 mg, 2.48 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (720 mg, 3.72 mmol) were dissolved in 50 mL of 1,4-dioxane and 5 mL of water, and added XPhos Pd G2 (200mg, 0.25mmol) and anhydrous potassium phosphate (1.58g, 7.44mmol) were replaced with nitrogen three times, and reacted at 100°C for 3 hours. Concentrate to remove a large amount of solvent, add 20 mL of water thereto, and extract with ethyl acetate (60 mL ⁇ 3).
  • the eighth step the preparation of the trifluoroacetic acid salt of compound 6
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • lithium bistrimethylsilylamide (0.4mL, 0.4mmol, 1M in THF) was added dropwise to a solution of 5K (150mg, 0.26mmol) in tetrahydrofuran (5mL) at -78°C, and stirred at -78°C After 10 minutes, 1,3,2-dioxazolethiophene-2,2-dioxide (50mg, 0.4mmol) was added, and then the temperature was raised slowly to 0°C for 1h. Lithium bistrimethylsilylamide (0.4 mL, 0.4 mmol, 1M in THF) was added dropwise at -78°C, and the temperature was slowly raised to room temperature and stirred for 1 h.
  • Embodiment 8 is a diagrammatic representation of Embodiment 8
  • Embodiment 9 is a diagrammatic representation of Embodiment 9:
  • Dissolve 10G (0.20g, 0.35mmol) in tetrahydrofuran (10mL), add sodium hydride (0.04g, 1.05mmol) under ice bath, react in ice bath for 30min, add 1,3,2-dioxazolethiophene under ice bath -2,2-dioxide (0.065g, 0.52mmol), stirred at room temperature for 3h.
  • 12A (520mg, 1.74mmol) was dissolved in 8mL THF, sodium borohydride (189.49mg, 8.7mmol) was slowly added at room temperature, and reacted at 60°C for 1 hour. Cool to room temperature, add saturated ammonium chloride aqueous solution to quench the reaction, add water and ethyl acetate to extract, the organic phase is dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 12B (470mg).
  • 12B (470 mg, 1.74 mmol) was dissolved in 5 mL of DCM, and thionyl chloride (1035.04 mg, 8.7 mmol) was slowly added dropwise in an ice-water bath, and the temperature was raised to room temperature to react overnight. Add saturated sodium bicarbonate (20mL) to quench, dichloromethane (30mL ⁇ 3) to extract, combine The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 12C (480mg).
  • 12F (850mg, 2.14mmol) was dissolved in 10mL water and 10mL tert-butanol, after adding NBS (1142.63mg, 6.42mmol), react at room temperature for 2 hours. Water and ethyl acetate were added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 12G (1.1 g, yield 90%).
  • 13A (0.6g, 1.93mmol) was dissolved in THF (10mL), lithium borohydride (0.21g, 9.65mmol) was added, the temperature was raised to 60°C and stirred for 2h. Cool to room temperature, add saturated aqueous ammonium chloride dropwise to quench the reaction, add 20 mL of ethyl acetate and 20 mL of saturated brine for extraction, dry the organic layer over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 13B.
  • 13B (0.54 g, 1.91 mmol) was dissolved in DCM (5 mL), thionyl chloride (2.27 g, 19.10 mmol) was added at room temperature, and stirred overnight at room temperature. Concentrate under reduced pressure, add 20 mL of DCM to the residue, add 20 mL of saturated aqueous sodium bicarbonate solution, stir for 10 min, separate the layers, wash the organic layer with 10 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 13C.
  • 15A (0.6g, 1.85mmol) was dissolved in THF (6mL), lithium borohydride (0.2g, 9.18mmol) was added, and stirred at 60°C for 2h. Cool to room temperature, add saturated ammonium chloride aqueous solution dropwise to quench the reaction, add 20 mL ethyl acetate and 20 mL saturated brine to separate layers, dry the organic layer over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 15B.
  • 15B (0.38g, 1.28mmol) was dissolved in DCM (5mL), thionyl chloride (1.52g, 12.78mmol) was added at room temperature, and stirred overnight at room temperature. Concentrate under reduced pressure, add 20 mL of DCM to the residue, add 20 mL of saturated aqueous sodium bicarbonate solution, stir for 10 minutes and separate the layers. The organic layer is washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 15C.
  • 16A (0.7g, 2.21mmol) was dissolved in THF (6mL), lithium borohydride (0.24g, 11.05mmol) was added, and stirred at 60°C for 2h. Cool to room temperature, add saturated aqueous ammonium chloride dropwise to quench the reaction, add 20 mL of ethyl acetate and 20 mL of saturated brine for extraction, dry the organic layer over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 16B.
  • 16B (0.6g, 2.08mmol) was dissolved in DCM (5mL), thionyl chloride (1237.29mg, 10.40mmol) was added at room temperature, and stirred overnight at room temperature. Concentrate under reduced pressure, add 20 mL of DCM to the residue, add 20 mL of saturated aqueous sodium bicarbonate solution, stir for 10 min, separate the layers, wash the organic layer with 10 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 16C.
  • 17G (80mg, 0.17mmol) and 17D (79.59mg, 0.26mmol) were dissolved in 1,4-dioxane (2mL) and water (0.5mL), and potassium carbonate (70.49mg, 0.51mmol) and Pd(dppf) Cl2 -DCM (13.88 mg, 0.017 mmol). Nitrogen was replaced three times, and reacted at 90°C for 3h.
  • Diisobutylaluminum hydride (2.91mL, 2.91mmol, 1.0M solution in hexanes) was added dropwise to compound 20F (0.3g, 0.97mmol) in tetrahydrofuran (35mL) at 0°C, and reacted at 0°C for 2h.
  • Add 50 mL of water and ethyl acetate (30 mL ⁇ 3) for extraction, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (ethyl acetate/petroleum ether (V/V ) 1/100-1/10), to obtain 20G (0.24g, yield: 88%).
  • Diisobutylaluminum hydride (4.62mL, 4.62mmol, 1.0M solution in hexanes) was added dropwise to 21B (0.5g, 1.54mmol) in tetrahydrofuran (35mL) at 0°C, and reacted at 0°C for 2 hours.
  • Add 50 mL of water and ethyl acetate (30 mL ⁇ 3) for extraction, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (ethyl acetate/petroleum ether (V/V ) 1/100-1/10), to obtain 21C (0.38g, yield: 83%).
  • 21C (380mg, 1.28mmol) was dissolved in 10mL of dichloromethane, and thionyl chloride (0.46g, 3.84mmol) was slowly added dropwise in an ice-water bath, and stirred for 2h under an ice-water bath. It was quenched by adding saturated sodium bicarbonate (20 mL), extracted with dichloromethane (30 mL ⁇ 3), combined the organic phases, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 21D (400 mg).
  • the first step 22B preparation
  • reaction solution was quenched by adding saturated ammonium chloride (20mL), extracted with ethyl acetate (50mL ⁇ 2), the organic phases were combined and dried with anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated under reduced pressure and separated and purified by medium pressure preparation (PE /EA: 0%-10%) gave 22D (0.127g, yield 44%)
  • 24B (1g, 4.65mmol) was dissolved in acetonitrile (10mL), and phosphorus oxychloride (7.13g, 46.50mmol) was slowly added at room temperature. After the addition was complete, it was stirred at 80°C for 4h. Cool to room temperature, pour the reaction solution into ice water, adjust the pH to alkaline with saturated aqueous sodium bicarbonate solution, add 30 mL of ethyl acetate for extraction, dry the organic layer over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 24C.
  • 17G (0.1g, 0.22mmol) and 24E (0.12g, 0.33mmol) were dissolved in 1,4-dioxane (4mL) and water (1mL), and Pd(dppf)Cl 2 ⁇ DCM (0.018 g, 0.022mmol) and potassium carbonate (0.091g, 0.66mmol), after the addition was completed, nitrogen was replaced three times, and stirred overnight at 90°C.
  • 25A (9.42g, 41.44mmol) was dissolved in DMSO (60mL), 2-iodoxybenzoic acid (12.76g, 45.58mmol) was added, and stirred at room temperature for 2h. Add 2-iodylbenzoic acid (6 g, 21.41 mmol), and react in a water bath at 40° C. for 1 h.
  • V/V ethyl acetate/petroleum ether
  • 25H (0.95g, 3.08mmol) was dissolved in 10mL of dichloromethane, and thionyl chloride (1.83g, 15.40mmol) was slowly added dropwise in an ice-water bath, and stirred for 2h under an ice-water bath. It was quenched by adding saturated aqueous sodium bicarbonate (20 mL), extracted with dichloromethane (30 mL ⁇ 3), combined the organic phases, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 25I (0.95 g).
  • 26B (6 g, 25.3 mmol) was dissolved in dichloromethane (100 mL), and Dess-Martin oxidant (16.1 g, 37.95 mmol) was added in portions at 0°C, and reacted at room temperature for 3 h.
  • Add saturated sodium thiosulfate aqueous solution (50mL) to quench, dichloromethane (30mL ⁇ 3) to extract, combine the organic phase, the organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, the residue is purified by silica gel column chromatography (acetic acid Ethyl ester/petroleum ether (V/V) 1/100-1/10) to obtain 26C (3.2 g, yield 54%).
  • 26D (4g, 13.1mmol) was dissolved in hydrochloric acid-dioxane solution (50mL, 4M), and stirred at room temperature for 2h. Concentrate under reduced pressure to obtain the hydrochloride salt of 26E.
  • V/V acetic acid Ethyl ester/petroleum ether
  • Diisobutylaluminum hydride (9.54mL, 9.54mmol, 1.0M solution in hexanes) was added dropwise to 26H (1.1g, 3.18mmol) in tetrahydrofuran (55mL) at 0°C, and reacted at 0°C for 2 hours.
  • Add 50 mL of water and ethyl acetate (30 mL ⁇ 3) for extraction, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (ethyl acetate/petroleum ether (V/V ) 1/100-1/10) to obtain 26I (0.76g, yield: 75%).
  • 26I (760mg, 2.39mmol) was dissolved in 20mL of dichloromethane, and thionyl chloride (0.85g, 7.17mmol) was slowly added dropwise in an ice-water bath, and stirred for 2h under an ice-water bath. It was quenched by adding saturated sodium bicarbonate (20 mL), extracted with dichloromethane (30 mL ⁇ 3), combined the organic phases, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 26J (800 mg).
  • the first step 30A preparation
  • 5G (8g, 28.19mmol) was dissolved in THF (60mL) and water (30mL), and pyridinium tribromide (9.47g, 29.06mmol) was slowly added in an ice-water bath, and stirred for 0.5h in an ice-water bath. After adding water and ethyl acetate and stirring, the layers were separated. The organic phase was washed with saturated brine, saturated aqueous sodium bicarbonate solution and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 30A.
  • 34C (2g, 6.96mmol) was dissolved in DCM (5mL), hydrochloric acid-dioxane solution (10mL, 4M) was added, and stirred at room temperature for 2h. After concentration under reduced pressure, 20 mL of methyl tert-butyl ether was added, stirred for 10 min and then filtered to obtain 34D hydrochloride (1.2 g, yield: 77%).
  • 34E (1.8g, 5.15mmol) was dissolved in DCM (S0, 20mL), and Dess Martin oxidant (2.62g, 6.18mmol) was added in portions at 0°C, and reacted at room temperature for 3 hours.
  • Add 20mL of saturated aqueous sodium thiosulfate solution and stir for 20min, add 20mL of saturated aqueous sodium bicarbonate solution and stir for 10min, separate the layers, dry the organic layer over anhydrous sodium sulfate, concentrate under reduced pressure, and the residue is purified by silica gel column chromatography (ethyl acetate /petroleum ether (V/V) 1/100-1/2) to obtain 34F (1.4g, yield: 78%).
  • a THF solution of diisobutylaluminum hydride (6.9mL, 6.85mmol, 1N) was added dropwise to a solution of 34G (0.9g, 2.74mmol) in THF (10mL) at 0°C, and the temperature was naturally raised to room temperature for 3 hours.
  • 34H (0.21g, 0.70mmol) was dissolved in DCM (4mL), and thionyl chloride (0.41g, 3.44mmol) was slowly added dropwise in an ice-water bath, and stirred at room temperature for 2h.
  • 36A (2.8g, 13.01mmol) was dissolved in DMSO (15mL), 2-iodoxybenzoic acid (4.01g, 14.31mmol) was added, and stirred at 40°C for 2h.
  • 37A (CAS No.: 160033-52-3, 2g, 8.73mmol) was dissolved in THF (10mL), and borane tetrahydrofuran solution (17mL, 17mmol, 1N) was added dropwise under ice-cooling, and stirred at room temperature for 120min.
  • HATU (2.42g, 6.36mmol) was added to 37E hydrochloride (1.16g, 5.30mmol) and monomethyl terephthalate (0.95g, 5.30mmol) in DMF (15mL) solution, stirred at room temperature for 5min, added DIPEA (1.37g, 10.60mmol), stirred for 20min.
  • Add 30 mL of ethyl acetate, wash with saturated brine (20 mL ⁇ 3), concentrate the organic layer under reduced pressure, and purify the residue by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) 1/10-1/ 2) Obtain 37F (1.8 g, yield: 98%).
  • THF solution of diisobutylaluminum hydride (7.7mL, 7.7mmol, 1N) was added dropwise to a THF (10mL) solution of 37H (1g, 3.08mmol) at 0°C, and the temperature was naturally raised to room temperature for 3 hours.
  • Test Example 1 USP1/UAF1 Enzyme Inhibition Activity
  • Ubiquitin rhodamine 110 was used as a substrate to detect the activity of deubiquitinase USP1/UAF1 after drug treatment.
  • the total test system was 20 ⁇ l, and the test buffer was 50 mM Tris-HCl, pH 7.8, 0.5 mM EDTA, 0.01% Bovine Serum Albumin, 1 mM DTT, 0.01% Tween-20.
  • the compound of the present invention has good inhibitory effect on USP1/UAF1 enzymatic activity.
  • Test example 2 MDA-MB-436 cell clone formation test
  • Method 1 In this test, MDA-MB-436 cells are used, and after being treated with test compounds, the ability of cell clone formation is detected.
  • MDA-MB-436 cells ATCC, HTB-130
  • 96-well plate Cornning, 3599
  • 500 cells per well 500 cells per well, and adhered to the wall overnight
  • Continue culturing at 37°C in an incubator without CO 2 On the 7th day, discard the old medium, and re-add the test compound in a gradient dilution.
  • 14 days take out the 96-well plate, discard the culture medium, and use the Crystal violet Assay kit detects cell clones. Detection was at OD 570 nM using a PHERAstar FSX microplate reader (BMG LABTECH).
  • IC50 values were calculated using GraphPad Prism software.
  • Method 2 In this test, MDA-MB-436 cells are used, and after being treated with test compounds, the ability of cell clone formation is detected.
  • MDA-MB-436 cells ATCC, HTB-130
  • 96-well plate Cornning, 3599
  • 500 cells per well 500 cells per well, and adhered to the wall overnight
  • Continue culturing at 37°C in an incubator without CO 2 On the 7th day, discard the old medium, and re-add the test compound in gradient dilution.
  • 11 days take out the 96-well plate, discard the culture medium, and use the Crystal violet Assay kit detects cell clones. Detection was at OD 570 nM using a PHERAstar FSX microplate reader (BMG LABTECH).
  • IC50 values were calculated using GraphPad Prism software.
  • test compound is to MDA-MB-436 cell clone inhibitory activity result Note: A ⁇ 200nM, 200nM ⁇ B ⁇ 500nM, 500nM ⁇ C ⁇ 1000nM
  • the compound of the present invention has a good inhibitory effect on the formation of MDA-MB-436 cell clones.
  • Test animals male ICR mice, 25-30g. purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice were randomly divided into groups according to body weight. One day before the administration, fasting without water for 12-14 hours, and giving food 4 hours after the administration.
  • DMA dimethylacetamide
  • Solutol polyethylene glycol-15-hydroxystearate
  • Saline normal saline
  • MC methylcellulose
  • the compound synthesized by the technology of the present invention has good oral absorption performance in mice, and the oral performance is better than that of the control compound A.
  • the purpose of the experiment administer the test substance to Beagle dogs through a single dose of intravenous and intragastric administration, and determine the concentration of the test substance in the plasma of Beagle dogs. To evaluate the pharmacokinetic characteristics of the test substance in Beagle dogs.
  • mice male Beagle dogs, about 8-11 kg, purchased from Beijing Masi Biotechnology Co., Ltd.
  • Test method On the day of the test, Beagle dogs were randomly divided into groups according to body weight. One day before the administration, fasting without water for 14-18 hours, and giving food 4 hours after the administration. Dosing according to the information in the table below. Vehicle for intravenous administration: 5% DMA + 5% Solutol + 90% Saline; vehicle for intragastric administration: 0.5% MC (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; MC: methylcellulose solution;)
  • Blood collection time points 0, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 24h, 48h, 72h. All samples were stored at -80°C prior to analysis. Samples were quantified by LC-MS/MS.
  • Test Example 5 Rat pharmacokinetic test
  • Test animals male SD rats, 200-250g. purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

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  • Health & Medical Sciences (AREA)
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  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé tel que représenté par la formule générale (I) ou un stéréoisomère, un tautomère, une substance deutérée, un solvate, un promédicament, un métabolite, un sel pharmaceutiquement acceptable ou un eutectique de celui-ci, un intermédiaire de ceux-ci, un procédé de préparation de ceux-ci et une application dans la préparation d'un produit pharmaceutique pour le traitement d'une maladie liée à l'activité ou à l'expression d'USP1.
PCT/CN2023/073285 2022-01-27 2023-01-20 Dérivé azacyclique et son application médicale WO2023143424A1 (fr)

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CN202210132457.2 2022-02-14
CN202210262706.X 2022-03-17
CN202210262706 2022-03-17
CN202210496822 2022-05-12
CN202210496822.8 2022-05-12
CN202210765949.5 2022-07-07
CN202210765949 2022-07-07
CN202211106598.3 2022-09-13
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WO2024032647A1 (fr) * 2022-08-09 2024-02-15 上海济煜医药科技有限公司 Procédé de préparation d'un composé hétérocyclique contenant de l'azote en tant qu'inhibiteur de la protéase 1 spécifique de l'ubiquitine, ainsi que application et utilisation de celui-ci
WO2024051795A1 (fr) * 2022-09-09 2024-03-14 正大天晴药业集团股份有限公司 Dérivé de purinone substitué utilisé en tant qu'inhibiteur de la protéase spécifique de l'ubiquitine
WO2024061213A1 (fr) * 2022-09-20 2024-03-28 正大天晴药业集团股份有限公司 Dérivé hétérocyclique fusionné carbonyle utilisé en tant qu'inhibiteur de protéase spécifique de l'ubiquitine

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WO2017136309A1 (fr) * 2016-02-01 2017-08-10 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de la sgc pour le traitement d'une stéatohépatite non alcoolique (shna)
WO2017200087A1 (fr) * 2016-05-20 2017-11-23 大鵬薬品工業株式会社 Nouveau dérivé de 5h-pyrrolo[2,3-d]pyrimidin-6(7h)-one
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WO2024051795A1 (fr) * 2022-09-09 2024-03-14 正大天晴药业集团股份有限公司 Dérivé de purinone substitué utilisé en tant qu'inhibiteur de la protéase spécifique de l'ubiquitine
WO2024061213A1 (fr) * 2022-09-20 2024-03-28 正大天晴药业集团股份有限公司 Dérivé hétérocyclique fusionné carbonyle utilisé en tant qu'inhibiteur de protéase spécifique de l'ubiquitine

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