WO2022222964A1 - Pyridine derivative and use thereof in medicine - Google Patents

Pyridine derivative and use thereof in medicine Download PDF

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Publication number
WO2022222964A1
WO2022222964A1 PCT/CN2022/087966 CN2022087966W WO2022222964A1 WO 2022222964 A1 WO2022222964 A1 WO 2022222964A1 CN 2022087966 W CN2022087966 W CN 2022087966W WO 2022222964 A1 WO2022222964 A1 WO 2022222964A1
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compound
alkyl
methyl
piperazin
ethyl
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PCT/CN2022/087966
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French (fr)
Chinese (zh)
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张靖
魏用刚
周锡兵
尹杰
孙毅
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成都百裕制药股份有限公司
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Priority to CN202280015677.5A priority Critical patent/CN116867783A/en
Publication of WO2022222964A1 publication Critical patent/WO2022222964A1/en

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/499—Spiro-condensed pyrazines or piperazines
    • 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
    • A61K31/4995—Pyrazines or piperazines forming part of bridged 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
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This application relates to pyridine derivatives and their use in medicine.
  • PARP (ploy(ADP-ribose) polymerases) is a class of poly ADP-ribose polymerases that catalyzes the poly-ADP-ribosylation of various proteins, which is involved in DNA damage repair, transcription regulation, It plays an important role in many cellular processes such as chromatin reorganization and remodeling.
  • PARP1/PARP2 inhibitors have been successfully launched on the market, no matter whether they are used alone or in combination, side effects such as blood and gastrointestinal tract are still common in clinical practice, resulting in limited clinical application. Therefore, the development of safer and more effective PARP inhibitors is still an urgent clinical problem.
  • One of the objectives of the present application is to provide pyridine derivatives or their pharmaceutically acceptable salts or stereoisomers, as well as pharmaceutical compositions containing the above compounds, and their use in medicine.
  • One or more embodiments of the present application provide a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof:
  • R 1 is C 1-6 alkyl
  • L is -NH-, -CO- or -(CR L1 R L2 ) n -;
  • R L1 and R L2 are each independently H or C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl and cyano;
  • R 3 is H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; the C 3-8 Heterocycloalkyl contains 1-4 heteroatoms selected from N, O and S; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 hetero Cycloalkyl is optionally surrounded by 1 or more selected from H, halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl or C3-8 Substituent substitution of heterocycloalkyl;
  • R 2 is C 1-4 alkyl, C 5-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; the C 3-8 heterocycle
  • the alkyl group contains 1-4 heteroatoms selected from N, O and S; the C 5-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkane group is optionally selected from one or more groups selected from halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and C 3-8 heterocycloalkyl
  • R 2 is C 1-4 alkyl, the C 1-4 alkyl is substituted by 1 or more substituents selected from hydroxyl and C 1-6 alkoxy;
  • n 1 or 2;
  • n 0, 1, 2 or 3.
  • the compound of formula (I) is substituted with 1 or more (eg 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) deuterium.
  • the C3-8 heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms selected from N, O and S.
  • the compound has the structure of formula (II):
  • R 1 is C 1-6 alkyl
  • L is -NH-, -CO- or -(CR L1 R L2 ) n -;
  • R L1 and R L2 are each independently H or C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl and cyano;
  • R 2 is C 1-4 alkyl, C 5-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; the C 3-8 heterocycle
  • the alkyl group contains 1-4 heteroatoms selected from N, O and S; the C 5-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkane group is optionally selected from one or more groups selected from halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and C 3-8 heterocycloalkyl
  • R 2 is C 1-4 alkyl, the C 1-4 alkyl is substituted by 1 or more substituents selected from hydroxyl and C 1-6 alkoxy;
  • n 1 or 2.
  • the compound of formula (II) is substituted with one or more deuteriums.
  • the compound of formula (I) is substituted with 1 or more (eg 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) deuterium.
  • the R 1 is ethyl
  • L is -CH2- or -CD2- .
  • R3 is H, -CH3 , -CD3 , -OCH3 , or -Cl.
  • R 2 is cyclobutyl, oxolane, oxane, azetidinyl, methyl, ethyl, or propyl; the cyclobutyl, oxa Cyclopentyl, oxhexyl, azetidinyl, methyl, ethyl or propyl are optionally substituted with one or more substituents selected from methyl, methoxy and hydroxy.
  • the compound is:
  • the compounds described above are substituted with 1 or more (eg 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) deuterium.
  • the halogen is F, Cl or Br.
  • One or more embodiments of the present application provide a compound represented by the general formula (I') or a stereoisomer thereof:
  • R 1 is selected from C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, and the C 3-8 heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S;
  • L is selected from -NH-, -CO- or -(CR L1 R L2 ) n -;
  • R L1 and R L2 are each independently selected from H or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano ;
  • A is a 4- to 12-membered heterocyclic ring
  • the 4- to 12-membered heterocyclic ring is selected from a 4- to 12-membered monocyclic ring, a 5- to 12-membered spirocyclic ring, a 4- to 12-membered parallel ring, or a 4- to 12-membered bridged ring.
  • the 4- to 12-membered heterocyclic ring may contain 1 to 4 heteroatoms selected from N, O or S;
  • R 2 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, and the C 3-8 heterocycloalkyl can be Contains 1 to 4 heteroatoms selected from N, O or S; said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl optionally further selected by one or more of halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl substituted by the substituent;
  • n 1 or 2.
  • One or more embodiments of the present application provide a compound represented by the general formula (I") or a stereoisomer thereof:
  • R 1 is selected from H, halogen, C 2-6 alkenyl or C 2-6 alkynyl, and said C 2-6 alkenyl or C 2-6 alkynyl is optionally further selected from 1 or more Substituent substitution of halogen or C 1-6 alkyl;
  • L is selected from -NH-, -CO- or -(CR L1 R L2 ) n -;
  • R L1 and R L2 are each independently selected from H or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano ;
  • A is a 4- to 12-membered heterocyclic ring
  • the 4- to 12-membered heterocyclic ring is selected from a 4- to 12-membered monocyclic ring, a 5- to 12-membered spirocyclic ring, a 4- to 12-membered parallel ring, or a 4- to 12-membered bridged ring.
  • the 4- to 12-membered heterocyclic ring may contain 1 to 4 heteroatoms selected from N, O or S;
  • R 2 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, and the C 3-8 heterocycloalkyl can be Contains 1 to 4 heteroatoms selected from N, O or S, said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl optionally further selected by one or more of halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl substituted by the substituent;
  • n 1 or 2.
  • One or more embodiments of the present application provide a compound represented by the general formula (I"') or a stereoisomer thereof:
  • R 1 is selected from C 1-6 alkyl
  • L is selected from -NH-, -CO- or -(CR L1 R L2 ) n -;
  • R L1 and R L2 are each independently selected from H or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano ;
  • A is a 7- to 12-membered heterocyclic ring
  • the 7- to 12-membered heterocyclic ring is selected from a 7- to 12-membered monocyclic ring, a 7- to 12-membered spirocyclic ring, a 7- to 12-membered parallel ring, or a 7- to 12-membered bridged ring
  • the The 7- to 12-membered heterocyclic ring may contain 1 to 4 heteroatoms selected from N, O or S;
  • R 2 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, and the C 3-8 heterocycloalkyl can be Contains 1 to 4 heteroatoms selected from N, O or S, said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl optionally further selected by one or more of halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl substituted by the substituent;
  • n 1 or 2.
  • One or more embodiments of the present application provide a compound represented by the general formula (II') or a stereoisomer thereof:
  • R 1 is selected from C 1-6 alkyl
  • L is selected from -NH-, -CO- or -(CR L1 R L2 ) n -;
  • R L1 and R L2 are each independently selected from H or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano ;
  • X 1 and X 2 are each independently selected from CR X or N;
  • R X is selected from H, hydroxyl, cyano or C 1-6 alkyl
  • R 2 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, and the C 3-8 heterocycloalkyl can be Contains 1 to 4 heteroatoms selected from N, O or S, said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl optionally further selected by one or more of halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl substituted by the substituent;
  • n 1, 2 or 3;
  • n 1 or 2.
  • One or more embodiments of the present application provide a compound represented by the general formula (III') or a stereoisomer thereof:
  • R 1 is selected from C 1-6 alkyl
  • L is selected from -NH-, -CO- or -(CR L1 R L2 ) n -;
  • R L1 and R L2 are each independently selected from H or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano ;
  • R 3 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; the C 1 -6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl are optionally further substituted by 1 or more selected from H, halogen, hydroxyl, cyano, Substituent substitution of C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl;
  • R 2 is selected from C 5-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, and the C 3-8 heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl are optional is further substituted by one or more selected from halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl base substitution;
  • n 1 or 2.
  • n 0, 1, 2, or 3
  • One or more embodiments of the present application provide a compound represented by the general formula (III") or a stereoisomer thereof:
  • R 1 is selected from C 1-6 alkyl
  • L is selected from -NH-, -CO- or -(CR L1 R L2 ) n -;
  • R L1 and R L2 are each independently selected from H or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano ;
  • R 2 is selected from C 5-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, and the C 3-8 heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl are optional is further substituted by one or more selected from halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl base substitution;
  • n 1 or 2.
  • One or more embodiments of the present application provide the use of the above-mentioned compounds of the present application, or pharmaceutically acceptable salts or stereoisomers thereof, or the above-mentioned pharmaceutical compositions in the preparation of anti-tumor or anti-cancer drugs.
  • One or more embodiments of the present application provide the above-described compound of the present application, or a pharmaceutically acceptable salt or stereoisomer thereof, or the above-described pharmaceutical composition, for use as a medicament.
  • One or more embodiments of the present application provide the above-mentioned compound of the present application, or a pharmaceutically acceptable salt or stereoisomer thereof, or the above-mentioned pharmaceutical composition, for use in a method of treating/preventing cancer.
  • One or more embodiments of the present application provide methods of treating/preventing tumors or cancers, comprising using the above-mentioned compound of the present application, or a pharmaceutically acceptable salt or stereoisomer thereof, or the above-mentioned pharmaceutical composition in need thereof object.
  • One or more embodiments of the present application provide methods of inhibiting PARP1 and/or PARP2, comprising administering the above-described compound of the present application, or a pharmaceutically acceptable salt or stereoisomer thereof, or the above-described pharmaceutical composition in need thereof object.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotopic conditions, and the carbons 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 isotopes of carbon include 12 C, 13 C and 14 C, and isotopes of hydrogen include protium (H), deuterium (D, Also known as heavy hydrogen), tritium (T, also known as super-heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • isotopes of carbon include 12 C, 13 C
  • Alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 8 (eg 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms , more preferably an alkyl group of 1 to 6 carbon atoms, further preferably 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 Various branched chain isomers thereof; when the alkyl group is substituted, it may be optionally further substituted by one or more substituents.
  • Alkoxy refers to a group formed by substituting at least one carbon atom in an alkyl group with an oxygen atom.
  • Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropoxy and cyclobutoxy.
  • the definition of alkyl is the same as the definition of "alkyl" described above.
  • Alkenyl means a straight chain consisting of 2 to 20 carbon atoms containing 1 to 10 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds Chain or branched unsaturated aliphatic hydrocarbon groups, preferably alkenyl groups of 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 2 to 12 An alkenyl group of 8 carbon atoms, more preferably an alkenyl group of 2 to 6 carbon atoms.
  • Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-2-yl En-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and undecene -3-base.
  • the alkenyl group may be optionally further substituted with one or more substituents.
  • Alkynyl means a carbon-carbon triple bond containing 1 to 10 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, consisting of 2 to 20 carbon atoms Linear or branched unsaturated aliphatic hydrocarbon groups, preferably alkynyl groups of 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms, more preferably 2 An alkynyl group of to 8 carbon atoms, more preferably an alkynyl group of 2 to 6 carbon atoms.
  • Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl Butyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl , octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl.
  • the alkynyl group may optionally be further substituted with one or more substituents.
  • Aryl means a substituted or unsubstituted aromatic ring, which may be a 5- to 8-membered (eg, 5, 6, 7, 8) , 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, which may be bridged or spirocyclic, non-limiting examples Including phenyl, naphthyl. The aryl group may optionally be further substituted with one or more substituents.
  • Heteroaryl refers to a substituted or unsubstituted aromatic ring, which may be a 3 to 8 membered (eg 3, 4, 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (eg 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (eg 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably 5- to 8-membered heteroaryl, 1 to 4 (eg 1, 2) optionally substituted in the ring of heteroaryl , 3, 4) N, S can be oxidized into various oxidation states.
  • N, S can be oxidized into various oxidation states.
  • Heteroaryl can be attached to a heteroatom or a carbon atom. Heteroaryl can be bridged or spiro, non-limiting examples include cyclopyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyridyl Azinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, pyrrolopyridyl. Heteroaryl groups are optionally further substituted with one or more substituents.
  • Carbocyclyl or “carbocycle” refers to a saturated or unsaturated aromatic or non-aromatic ring. When aromatic, it is as defined above for “aryl”; when non-aromatic, it may be 3 to 10 membered (eg 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, 4 to 12 membered (eg 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) membered) tricyclic ring system, which may be bridged or spiro, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2- Alkenyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexy
  • Heterocyclyl or “heterocycle” refers to a saturated or unsaturated aromatic heterocycle or a non-aromatic heterocycle, and when it is an aromatic heterocycle, its definition is the same as the definition of "heteroaryl” above; when When it is a non-aromatic heterocycle, it can be a 3- to 10-membered (eg 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic, 4- to 12-membered (eg 7, 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group.
  • 1- to 10-membered eg 3, 4, 5, 6, 7, 8, 9, 10-membered
  • 4- to 12-membered eg 7, 8, 9, 10, 11, 12 membered
  • bicyclic ring or 10 to 15 membere
  • Optionally substituted 1 to 4 (eg 1, 2, 3, 4) N, S in the ring of “heterocyclyl” or “heterocycle” can be oxidized to various oxidation states; “heterocyclyl” or A “heterocycle” can be attached to a heteroatom or a carbon atom; a “heterocyclyl” or “heterocycle” can be a bridged ring or a spirocyclic ring.
  • heterocyclyl or “heterocycle” include oxiranyl, glycidyl, azetidinyl, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, oxepanyl, thiepanyl, oxygen nitrogen Heterozoyl, diazepinyl, thiazepinyl, pyridyl, piperidinyl, homopiperidinyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazine base, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thio
  • Cycloalkyl refers to a saturated cyclic hydrocarbon group, the ring of which may be 3 to 10 membered (eg 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (eg 4 , 5, 6, 7, 8, 9, 10, 11, 12 yuan) double ring or 10 to 20 yuan (such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 yuan) and more
  • the ring carbon atoms are preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms.
  • Non-limiting examples of "cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexene group, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl and cycloheptatrienyl, etc.
  • cycloalkyl When cycloalkyl is substituted, it may be optionally further substituted with one or more substituents.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated non-aromatic ring group, which may be a (eg 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring systems, including 1, 2, 3 or 4 heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group.
  • heterocycloalkyl can be oxidized to various oxidation states; “heterocycloalkyl” can be attached to a heteroatom or carbon atom; “heterocycloalkyl” Alkyl” can be bridged or spiro.
  • heterocycloalkyl include oxiranyl, azetidinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxoyl Pentacyclyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl, Tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatri Cyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl.
  • Halogens include F, Cl, Br and I.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” means that a compound of the present invention retains the biological effectiveness and properties of a free acid or free base that is treated with nontoxic inorganic or organic bases , the free base is a salt obtained by reacting with a non-toxic inorganic acid or organic acid.
  • “Pharmaceutical composition” refers to a mixture of one or more of the compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein “other chemical components” refers to pharmaceutically acceptable carrier, excipient, and/or one or more other therapeutic agents.
  • Carrier refers to a material that is not appreciably irritating to the organism and that does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binding agents agent and disintegrant.
  • Steps refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
  • heterocyclyl optionally substituted with an alkyl group means that the alkyl group may, but need not, be present, and the description includes instances where the heterocyclyl group is substituted with an alkyl group, as well as where the heterocyclyl group is not substituted with an alkyl group happening.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm-0.20mm, and the specification used for TLC separation and purification products is 0.4mm -0.5mm;
  • compound 15c was obtained (white solid, 1.1 mg, yield 89%).
  • compound 16b was obtained (yellow solid, 1.2 g, yield 79%).
  • PARP1 chemiluminescence assay purchased from BPS Bioscience, product number: 80551
  • PARP2 chemiluminescence assay purchased from BPS Bioscience company, product number: 80552
  • the results were quantified by chemiluminescence, and the specific experimental protocol was as follows:
  • Blocking buffer 3 200 ⁇ L
  • Comparative Example 1 is compound 25 of J.Med.Chem (2021), 64(19), 14498-14512, which was obtained according to the preparation method of compound 25.
  • DLD-1 BRCA2(-/-) cells (purchased from Horizon Discovery Ltd.) were cultured in 1640 (10% FBS, 1% PS) medium at 37°C, 5% CO 2 . When cells have grown to logarithmic growth phase, resuspend cells and dilute to 15,000 cells/mL with 1640 medium.
  • the above-mentioned 384-well plate was placed in a CO 2 incubator (37° C., 5% CO 2 ) for further cultivation for 7 days, and the 384-well plate was taken out and placed at room temperature for 30 minutes. Add 20 ⁇ L of Celltiter Glo detection solution to each well, shake the plate for 2 minutes, and place at room temperature for 30 minutes. Chemiluminescence values were determined with a microplate reader (PerkinElmer; EnVision).
  • MDA-MB-436 cells (supplier ATCC) were cultured in DMEM medium (10% FBS, 1% PS) at 37°C, 5% CO 2 . When the cells were in logarithmic growth phase, resuspend and dilute the cells to 1500 cells/ml in DMEM medium. Add the compounds to be tested at 40 ⁇ L per well in a 384-well plate (final concentrations are 10000nM, 2000nM, 400nM, 80nM, 16nM, 3.2nM, 0.64nM, 0.128nM, 0.0256nM, 0.00512nM); each concentration gradient is made 2 In 2 replicates, control group 1 (added 0.1% DMSO) and control group 2 (blank medium) were set. 40 ⁇ L of cell suspension was then added to the 384-well plate (control group 2 without cells).
  • the above-mentioned 384-well plate was placed in an incubator (37° C., 5% CO 2 ) for continuous cultivation for 7 days, and then the 384-well plate was taken out and placed at room temperature for 30 min. Add 30 ⁇ L of Celltiter Glo assay kit detection solution to each well, shake with a shaker for 3 min, and place at room temperature for 30 min. Chemiluminescence values were determined with a microplate reader (PerkinElmer; EnVision).
  • Comparative Example 2 is compound 62 of patent WO200905337, which is obtained according to the preparation method of compound 62.

Abstract

A compound of formula (I) and a use thereof in medicine. The compound can be used to treat tumor.

Description

吡啶衍生物及其在医药上的应用Pyridine derivatives and their applications in medicine 技术领域technical field
本申请涉及吡啶衍生物及其在医药上的应用。This application relates to pyridine derivatives and their use in medicine.
背景技术Background technique
PARP(ploy(ADP-ribose)polymerases)是一类聚ADP-核糖聚合酶，催化多种蛋白聚二磷酸腺苷核糖基化(Poly-ADP-ribosylation)，该过程在DNA损伤修复、转录调控、染色质重组和重塑等许多细胞过程中发挥重要作用。目前，虽然有多个PARP1/PARP2抑制剂成功上市，但在临床上无论单独用药还是联用用药，仍然普遍存在血液、胃肠道等副作用，导致临床应用受到限制。因此，开发更安全有效的PARP抑制剂依然是临床亟需解决的问题。一系列研究表明，与PARP1/PARP2抑制剂相比，高选择性PARP1抑制剂具有更好的疗效和更低的毒性，有望减少目前临床上PARP类药物的潜在风险，拓宽临床应用范围，提高患者的生活质量。PARP (ploy(ADP-ribose) polymerases) is a class of poly ADP-ribose polymerases that catalyzes the poly-ADP-ribosylation of various proteins, which is involved in DNA damage repair, transcription regulation, It plays an important role in many cellular processes such as chromatin reorganization and remodeling. At present, although a number of PARP1/PARP2 inhibitors have been successfully launched on the market, no matter whether they are used alone or in combination, side effects such as blood and gastrointestinal tract are still common in clinical practice, resulting in limited clinical application. Therefore, the development of safer and more effective PARP inhibitors is still an urgent clinical problem. A series of studies have shown that, compared with PARP1/PARP2 inhibitors, highly selective PARP1 inhibitors have better efficacy and lower toxicity, which is expected to reduce the potential risks of current clinical PARP drugs, broaden the scope of clinical applications, and improve patient outcomes. quality of life.
发明内容SUMMARY OF THE INVENTION
本申请的目的之一是提供吡啶衍生物或者其药物可接受的盐或立体异构体以及包含上述化合物的药物组合物，以及其在医药上的应用。One of the objectives of the present application is to provide pyridine derivatives or their pharmaceutically acceptable salts or stereoisomers, as well as pharmaceutical compositions containing the above compounds, and their use in medicine.
本申请的一个或多个实施方式提供式(I)的化合物或者其药物可接受的盐或立体异构体：One or more embodiments of the present application provide a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof:
Figure PCTCN2022087966-appb-000001
Figure PCTCN2022087966-appb-000001
其中in
R 1为C 1-6烷基； R 1 is C 1-6 alkyl;
L为-NH-、-CO-或-(CR L1R L2) n-； L is -NH-, -CO- or -(CR L1 R L2 ) n -;
R L1、R L2各自独立地为H或C 1-6烷基，所述C 1-6烷基任选地被1个或多个选自卤素、羟基和氰基的取代基取代； R L1 and R L2 are each independently H or C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl and cyano;
R 3为H、卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或C 3-8杂环烷基；所述C 3-8杂环烷基包含1-4个选自N、O和S的杂原子；所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或C 3-8杂环烷基任选地被1个或多个选自H、卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或C 3-8杂环烷基的取代基取代； R 3 is H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; the C 3-8 Heterocycloalkyl contains 1-4 heteroatoms selected from N, O and S; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 hetero Cycloalkyl is optionally surrounded by 1 or more selected from H, halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl or C3-8 Substituent substitution of heterocycloalkyl;
R 2为C 1-4烷基、C 5-6烷基、C 1-6烷氧基、C 3-8环烷基或C 3-8杂环烷基；所述C 3-8杂环烷基包含1-4个选自N、O和S的杂原子；所述C 5-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基任选地被1个或多个选自卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和C 3-8杂环烷基的取代基取代；当R 2为C 1-4烷基时，所述C 1-4烷基被1个或多个选自羟基和C 1-6烷氧基的取代基取代； R 2 is C 1-4 alkyl, C 5-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; the C 3-8 heterocycle The alkyl group contains 1-4 heteroatoms selected from N, O and S; the C 5-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkane group is optionally selected from one or more groups selected from halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and C 3-8 heterocycloalkyl When R 2 is C 1-4 alkyl, the C 1-4 alkyl is substituted by 1 or more substituents selected from hydroxyl and C 1-6 alkoxy;
n为1或2；n is 1 or 2;
m为0、1、2或3。m is 0, 1, 2 or 3.
在一个或多个实施方式中，所述式(I)的化合物被1个或多个(例如1、2、3、4、5、6、7、8、9或10个)氘取代。In one or more embodiments, the compound of formula (I) is substituted with 1 or more (eg 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) deuterium.
在一个或多个实施方式中，所述C 3-8杂环烷基包含1、2、3或4个选自N、O和S的杂原子。 In one or more embodiments, the C3-8 heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms selected from N, O and S.
在一个或多个实施方式中，所述化合物具有式(II)的结构：In one or more embodiments, the compound has the structure of formula (II):
Figure PCTCN2022087966-appb-000002
Figure PCTCN2022087966-appb-000002
其中in
R 1为C 1-6烷基； R 1 is C 1-6 alkyl;
L为-NH-、-CO-或-(CR L1R L2) n-； L is -NH-, -CO- or -(CR L1 R L2 ) n -;
R L1、R L2各自独立地为H或C 1-6烷基，所述C 1-6烷基任选地被1个或多个选自卤素、羟基和氰基的取代基取代； R L1 and R L2 are each independently H or C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl and cyano;
R 2为C 1-4烷基、C 5-6烷基、C 1-6烷氧基、C 3-8环烷基或C 3-8杂环烷基；所述C 3-8杂环烷基包含1-4个选自N、O和S的杂原子；所述C 5-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基任选地被1个或多个选自卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和C 3-8杂环烷基的取代基取代；当R 2为C 1-4烷基时，所述C 1-4烷基被1个或多个选自羟基和C 1-6烷氧基的取代基取代； R 2 is C 1-4 alkyl, C 5-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; the C 3-8 heterocycle The alkyl group contains 1-4 heteroatoms selected from N, O and S; the C 5-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkane group is optionally selected from one or more groups selected from halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and C 3-8 heterocycloalkyl When R 2 is C 1-4 alkyl, the C 1-4 alkyl is substituted by 1 or more substituents selected from hydroxyl and C 1-6 alkoxy;
n为1或2。n is 1 or 2.
在一个或多个实施方式中，所述式(II)的化合物被1个或者多个氘取代。In one or more embodiments, the compound of formula (II) is substituted with one or more deuteriums.
在一个或多个实施方式中，所述式(I)的化合物被1个或多个(例如1、2、3、4、5、6、7、8、9或10个)氘取代。In one or more embodiments, the compound of formula (I) is substituted with 1 or more (eg 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) deuterium.
在一个或多个实施方式中，所述R 1为乙基。 In one or more embodiments, the R 1 is ethyl.
在一个或多个实施方式中，L为-CH 2-或-CD 2-。 In one or more embodiments, L is -CH2- or -CD2- .
在一个或多个实施方式中，R 3为H、-CH 3、-CD 3、-OCH 3或-Cl。 In one or more embodiments, R3 is H, -CH3 , -CD3 , -OCH3 , or -Cl.
在一个或多个实施方式中，R 2为环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、甲基、乙基或丙基；所述环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、甲基、乙基或丙基任选地被一个或多个选自甲基、甲氧基和羟基的取代基取代。 In one or more embodiments, R 2 is cyclobutyl, oxolane, oxane, azetidinyl, methyl, ethyl, or propyl; the cyclobutyl, oxa Cyclopentyl, oxhexyl, azetidinyl, methyl, ethyl or propyl are optionally substituted with one or more substituents selected from methyl, methoxy and hydroxy.
在一个或多个实施方式中，所述化合物为：In one or more embodiments, the compound is:
Figure PCTCN2022087966-appb-000003
Figure PCTCN2022087966-appb-000003
Figure PCTCN2022087966-appb-000004
Figure PCTCN2022087966-appb-000004
Figure PCTCN2022087966-appb-000005
Figure PCTCN2022087966-appb-000005
在一个或多个实施方式中，上述化合物被1个或者多个(例如1、2、3、4、5、6、7、8、9或10个)氘取代。In one or more embodiments, the compounds described above are substituted with 1 or more (eg 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) deuterium.
在一个或多个实施方式中，卤素为F、Cl或Br。In one or more embodiments, the halogen is F, Cl or Br.
本申请的一个或多个实施方式提供药物组合物，所述药物组合物包含：One or more embodiments of the present application provide a pharmaceutical composition comprising:
(1)本申请的上述化合物或者其药物可接受的盐或立体异构体；(1) the above-mentioned compounds of the present application or their pharmaceutically acceptable salts or stereoisomers;
(2)任选的一种或多种其他活性成分；以及(2) optionally one or more other active ingredients; and
(3)药物可接受的载体和/或赋形剂。(3) A pharmaceutically acceptable carrier and/or excipient.
本申请的一个或多个实施方式提供通式(I’)所示的化合物或者其立体异构体：One or more embodiments of the present application provide a compound represented by the general formula (I') or a stereoisomer thereof:
Figure PCTCN2022087966-appb-000006
Figure PCTCN2022087966-appb-000006
其中：in:
R 1选自C 3-8环烷基或者C 3-8杂环烷基，所述的C 3-8杂环烷基可以包含1至4个选自N、O或S的杂原子； R 1 is selected from C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, and the C 3-8 heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S;
L选自-NH-、-CO-或者-(CR L1R L2) n-； L is selected from -NH-, -CO- or -(CR L1 R L2 ) n -;
R L1、R L2各自独立地选自H或C 1-6烷基，所述的C 1-6烷基任选地进一步被1个或者多个选自卤素、羟基或者氰基的取代基取代； R L1 and R L2 are each independently selected from H or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano ;
A为4至12元杂环，所述的4至12元杂环选自4至12元单环、5至12元螺环、4至12元并环或者4至12元桥环，所述的4至12元杂环可以包含1至4个选自N、O或S的杂原子；A is a 4- to 12-membered heterocyclic ring, and the 4- to 12-membered heterocyclic ring is selected from a 4- to 12-membered monocyclic ring, a 5- to 12-membered spirocyclic ring, a 4- to 12-membered parallel ring, or a 4- to 12-membered bridged ring. The 4- to 12-membered heterocyclic ring may contain 1 to 4 heteroatoms selected from N, O or S;
R 2选自H、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基，所述的C 3-8杂环烷基可以包含1至4个选自N、O或S的杂原子；所述的C 1-6烷基、C 1-6烷氧基、C 3- 8环烷基或者C 3-8杂环烷基任选地进一步被1个或者多个选自卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基的取代基取代； R 2 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, and the C 3-8 heterocycloalkyl can be Contains 1 to 4 heteroatoms selected from N, O or S; said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl optionally further selected by one or more of halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl substituted by the substituent;
n为1或者2。n is 1 or 2.
本申请的一个或多个实施方式提供通式(I”)所示的化合物或者其立体异构体：One or more embodiments of the present application provide a compound represented by the general formula (I") or a stereoisomer thereof:
Figure PCTCN2022087966-appb-000007
Figure PCTCN2022087966-appb-000007
其中：in:
R 1选自H、卤素、C 2-6烯基或者C 2-6炔基，所述的C 2-6烯基或者C 2-6炔基任选地进一步被1个或者多个选自卤素或者C 1-6烷基的取代基取代； R 1 is selected from H, halogen, C 2-6 alkenyl or C 2-6 alkynyl, and said C 2-6 alkenyl or C 2-6 alkynyl is optionally further selected from 1 or more Substituent substitution of halogen or C 1-6 alkyl;
L选自-NH-、-CO-或者-(CR L1R L2) n-； L is selected from -NH-, -CO- or -(CR L1 R L2 ) n -;
R L1、R L2各自独立地选自H或C 1-6烷基，所述的C 1-6烷基任选地进一步被1个或者多个选自卤素、羟基或者氰基的取代基取代； R L1 and R L2 are each independently selected from H or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano ;
A为4至12元杂环，所述的4至12元杂环选自4至12元单环、5至12元螺环、4至12元并环或者4至12元桥环，所述的4至12元杂环可以包含1至4个选自N、O或S的杂原子；A is a 4- to 12-membered heterocyclic ring, and the 4- to 12-membered heterocyclic ring is selected from a 4- to 12-membered monocyclic ring, a 5- to 12-membered spirocyclic ring, a 4- to 12-membered parallel ring, or a 4- to 12-membered bridged ring. The 4- to 12-membered heterocyclic ring may contain 1 to 4 heteroatoms selected from N, O or S;
R 2选自H、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基，所述的C 3-8杂环烷基可以包含1至4个选自N、O或S的杂原子，所述的C 1-6烷基、C 1-6烷氧基、C 3- 8环烷基或者C 3-8杂环烷基任选地进一步被1个或者多个选自卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基的取代基取代； R 2 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, and the C 3-8 heterocycloalkyl can be Contains 1 to 4 heteroatoms selected from N, O or S, said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl optionally further selected by one or more of halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl substituted by the substituent;
n为1或者2。n is 1 or 2.
本申请的一个或多个实施方式提供通式(I”’)所示的化合物或者其立体异构体：One or more embodiments of the present application provide a compound represented by the general formula (I"') or a stereoisomer thereof:
Figure PCTCN2022087966-appb-000008
Figure PCTCN2022087966-appb-000008
其中：in:
R 1选自C 1-6烷基； R 1 is selected from C 1-6 alkyl;
L选自-NH-、-CO-或者-(CR L1R L2) n-； L is selected from -NH-, -CO- or -(CR L1 R L2 ) n -;
R L1、R L2各自独立地选自H或C 1-6烷基，所述的C 1-6烷基任选地进一步被1个或者多个选自卤素、羟基或者氰基的取代基取代； R L1 and R L2 are each independently selected from H or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano ;
A为7至12元杂环，所述的7至12元杂环选自7至12元单环、7至12元螺环、7至12元并环或者7至12元桥环，所述的7至12元杂环可以包含1至4个选自N、O或S的杂原子；A is a 7- to 12-membered heterocyclic ring, and the 7- to 12-membered heterocyclic ring is selected from a 7- to 12-membered monocyclic ring, a 7- to 12-membered spirocyclic ring, a 7- to 12-membered parallel ring, or a 7- to 12-membered bridged ring, and the The 7- to 12-membered heterocyclic ring may contain 1 to 4 heteroatoms selected from N, O or S;
R 2选自H、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基，所述的C 3-8杂环烷基可以包含1至4个选自N、O或S的杂原子，所述的C 1-6烷基、C 1-6烷氧基、C 3- 8环烷基或者C 3-8杂环烷基任选地进一步被1个或者多个选自卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基的取代基取代； R 2 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, and the C 3-8 heterocycloalkyl can be Contains 1 to 4 heteroatoms selected from N, O or S, said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl optionally further selected by one or more of halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl substituted by the substituent;
n为1或者2。n is 1 or 2.
本申请的一个或多个实施方式提供通式(II’)所示的化合物或者其立体异构体：One or more embodiments of the present application provide a compound represented by the general formula (II') or a stereoisomer thereof:
Figure PCTCN2022087966-appb-000009
Figure PCTCN2022087966-appb-000009
其中：in:
R 1选自C 1-6烷基； R 1 is selected from C 1-6 alkyl;
L选自-NH-、-CO-或者-(CR L1R L2) n-； L is selected from -NH-, -CO- or -(CR L1 R L2 ) n -;
R L1、R L2各自独立地选自H或C 1-6烷基，所述的C 1-6烷基任选地进一步被1个或者多个选自卤素、羟基或者氰基的取代基取代； R L1 and R L2 are each independently selected from H or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano ;
X 1、X 2各自独立地选自CR X或者N； X 1 and X 2 are each independently selected from CR X or N;
R X选自H、羟基、氰基或者C 1-6烷基； R X is selected from H, hydroxyl, cyano or C 1-6 alkyl;
当X 1、X 2均为N时，R a选自羟基、氰基、＝O或C 1-6烷基，所述C 1-6烷基任选地进一步被1个或者多个选自羟基、卤素或者氰基的取代基取代； When X 1 and X 2 are both N, R a is selected from hydroxyl, cyano, =O or C 1-6 alkyl, and the C 1-6 alkyl is optionally further selected from 1 or more Substituent substitution of hydroxyl, halogen or cyano;
当X 1、X 2有一个为CR X时，R a选自H、羟基、氰基、＝O或C 1-6烷基，所述C 1-6烷基任选地进一步被1个或者多个选自羟基、卤素或者氰基的取代基取代； When one of X 1 and X 2 is CR X , R a is selected from H, hydroxy, cyano, =O or C 1-6 alkyl, and the C 1-6 alkyl is optionally further replaced by 1 or Multiple substituents selected from hydroxyl, halogen or cyano are substituted;
R 2选自H、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基，所述的C 3-8杂环烷基可以包含1至4个选自N、O或S的杂原子，所述的C 1-6烷基、C 1-6烷氧基、C 3- 8环烷基或者C 3-8杂环烷基任选地进一步被1个或者多个选自卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基的取代基取代； R 2 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, and the C 3-8 heterocycloalkyl can be Contains 1 to 4 heteroatoms selected from N, O or S, said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl optionally further selected by one or more of halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl substituted by the substituent;
m为1、2或者3；m is 1, 2 or 3;
n为1或者2。n is 1 or 2.
本申请的一个或多个实施方式提供通式(III’)所示的化合物或者其立体异构体：One or more embodiments of the present application provide a compound represented by the general formula (III') or a stereoisomer thereof:
Figure PCTCN2022087966-appb-000010
Figure PCTCN2022087966-appb-000010
其中：in:
R 1选自C 1-6烷基； R 1 is selected from C 1-6 alkyl;
L选自-NH-、-CO-或者-(CR L1R L2) n-； L is selected from -NH-, -CO- or -(CR L1 R L2 ) n -;
R L1、R L2各自独立地选自H或C 1-6烷基，所述的C 1-6烷基任选地进一步被1个或者多个选自卤素、羟基或者氰基的取代基取代； R L1 and R L2 are each independently selected from H or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano ;
R 3选自H、卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基；所述的C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基任选地进一步被1个或者多个选自H、卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基的取代基取代； R 3 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; the C 1 -6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl are optionally further substituted by 1 or more selected from H, halogen, hydroxyl, cyano, Substituent substitution of C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl;
R 2选自C 5-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基，所述的C 3-8杂环烷基可以包含1至4个选自N、O或S的杂原子；所述的C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基任选地进一步被1个或者多个选自卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基的取代基取代； R 2 is selected from C 5-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, and the C 3-8 heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl are optional is further substituted by one or more selected from halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl base substitution;
n为1或者2。n is 1 or 2.
m为0、1、2或者3m is 0, 1, 2, or 3
本申请的一个或多个实施方式提供通式(III”)所示的化合物或者其立体异构体：One or more embodiments of the present application provide a compound represented by the general formula (III") or a stereoisomer thereof:
Figure PCTCN2022087966-appb-000011
Figure PCTCN2022087966-appb-000011
其中：in:
R 1选自C 1-6烷基； R 1 is selected from C 1-6 alkyl;
L选自-NH-、-CO-或者-(CR L1R L2) n-； L is selected from -NH-, -CO- or -(CR L1 R L2 ) n -;
R L1、R L2各自独立地选自H或C 1-6烷基，所述的C 1-6烷基任选地进一步被1个或者多个选自卤素、羟基或者氰基的取代基取代； R L1 and R L2 are each independently selected from H or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano ;
R 2选自C 5-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基，所述的C 3-8杂环烷基可以包含1至4个选自N、O或S的杂原子；所述的C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基任选地进一步被1个或者多个选自卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基的取代基取代； R 2 is selected from C 5-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, and the C 3-8 heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl are optional is further substituted by one or more selected from halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl base substitution;
n为1或者2。n is 1 or 2.
本申请的一个或多个实施方式提供本申请的上述化合物或者其药物可接受的盐或立体异构体或上述药物组合物在制备抗肿瘤或抗癌药物中的用途。One or more embodiments of the present application provide the use of the above-mentioned compounds of the present application, or pharmaceutically acceptable salts or stereoisomers thereof, or the above-mentioned pharmaceutical compositions in the preparation of anti-tumor or anti-cancer drugs.
本申请的一个或多个实施方式提供本申请的上述化合物或者其药物可接受的盐或立体异构体或上述药物组合物，其用作药物。One or more embodiments of the present application provide the above-described compound of the present application, or a pharmaceutically acceptable salt or stereoisomer thereof, or the above-described pharmaceutical composition, for use as a medicament.
本申请的一个或多个实施方式提供本申请的上述化合物或者其药物可接受的盐或立体异构体或上述药物组合物，其用于治疗/预防癌症的方法。One or more embodiments of the present application provide the above-mentioned compound of the present application, or a pharmaceutically acceptable salt or stereoisomer thereof, or the above-mentioned pharmaceutical composition, for use in a method of treating/preventing cancer.
本申请的一个或多个实施方式提供治疗/预防肿瘤或癌症的方法，其包括将本申请的上述化合物或者其药物可接受的盐或立体异构体或上述药物组合物用于有此需要的对象。One or more embodiments of the present application provide methods of treating/preventing tumors or cancers, comprising using the above-mentioned compound of the present application, or a pharmaceutically acceptable salt or stereoisomer thereof, or the above-mentioned pharmaceutical composition in need thereof object.
本申请的一个或多个实施方式提供抑制PARP1和/或PARP2的方法，其包括将本申请的上述化合物或者其药物可接受的盐或立体异构体或上述药物组合物用于有此需要的对象。One or more embodiments of the present application provide methods of inhibiting PARP1 and/or PARP2, comprising administering the above-described compound of the present application, or a pharmaceutically acceptable salt or stereoisomer thereof, or the above-described pharmaceutical composition in need thereof object.
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, terms used in the specification and claims have the following meanings.
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括 12C、 13C和 14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括 16O、 17O和 18O，硫的同位素包括 32S、 33S、 34S和 36S，氮的同位素包括 14N和 15N，氟的同位素包括 17F和 19F，氯的同位素包括 35Cl和 37Cl，溴的同位素包括 79Br和 81Br。 The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotopic conditions, and the carbons 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 isotopes of carbon include 12 C, 13 C and 14 C, and isotopes of hydrogen include protium (H), deuterium (D, Also known as heavy hydrogen), tritium (T, also known as super-heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基，优选为1至8个(例如1、2、3、4、5、6、7、8个)碳原子的烷基，更优选为1至6个碳原子的烷基，进一步优选为1至4个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；当烷基被取代基时，可以任选进一步被1个或者多个取代基所取代。"Alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 8 (eg 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms , more preferably an alkyl group of 1 to 6 carbon atoms, further preferably 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 Various branched chain isomers thereof; when the alkyl group is substituted, it may be optionally further substituted by one or more substituents.
“烷氧基”是指烷基中至少1个碳原子被氧原子取代所形成的基团。非限制性实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷基定义与上文所述的“烷基”定义相同。"Alkoxy" refers to a group formed by substituting at least one carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropoxy and cyclobutoxy. The definition of alkyl is the same as the definition of "alkyl" described above.
“烯基”是指含有1至10个(例如1、2、3、4、5、6、7、8、9、10个)碳-碳双键，由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基，优选2至12个(例如2、3、4、5、6、7、8、9、10、11、12个)碳原子的烯基，更优选2至8个碳原子的烯基，进一步优选2至6个碳原子的烯基。非限制性实例包括乙烯基、丙烯-2-基、丁烯-2-基、丁烯-2-基、戊烯-2-基、戊烯-4-基、己烯-2-基、己烯-3基、庚烯-2-基、庚烯-3-基、庚烯-4-基、辛烯-3-基、壬烯-3-基、癸烯-4-基和十一烯-3-基。所述的烯基可以任选进一步被1个或者多个取代基所取代。"Alkenyl" means a straight chain consisting of 2 to 20 carbon atoms containing 1 to 10 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds Chain or branched unsaturated aliphatic hydrocarbon groups, preferably alkenyl groups of 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 2 to 12 An alkenyl group of 8 carbon atoms, more preferably an alkenyl group of 2 to 6 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-2-yl En-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and undecene -3-base. The alkenyl group may be optionally further substituted with one or more substituents.
“炔基”是指含有1至10个(例如1、2、3、4、5、6、7、8、9、或10个)碳-碳叁键，由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基，优选2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子的炔基，更优选2至8个碳原子的炔基，进一 步优选2至6个碳原子的炔基。非限制性实例包括乙炔基、丙炔-1-基、丙炔-2-基、丁炔-1-基、丁炔-2-基、丁炔-3-基、3,3-二甲基丁炔-2-基、戊炔-1-基、戊炔-2-基、己炔-1-基、1-庚炔-1-基、庚炔-3-基、庚炔-4-基、辛炔-3-基、壬炔-3-基、癸炔-4-基、十一炔-3-基、十二炔-4-基。所述的炔基可以任选进一步被一至多个取代基所取代。"Alkynyl" means a carbon-carbon triple bond containing 1 to 10 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, consisting of 2 to 20 carbon atoms Linear or branched unsaturated aliphatic hydrocarbon groups, preferably alkynyl groups of 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms, more preferably 2 An alkynyl group of to 8 carbon atoms, more preferably an alkynyl group of 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl Butyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl , octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl. The alkynyl group may optionally be further substituted with one or more substituents.
“芳基”是指是指取代的或未取代的芳香环，其可以是5至8元(例如5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，其可以是桥环或者螺环，非限制性实例包括苯基、萘基。所述的芳基可以任选进一步被1个或者多个取代基所取代。"Aryl" means a substituted or unsubstituted aromatic ring, which may be a 5- to 8-membered (eg, 5, 6, 7, 8) , 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, which may be bridged or spirocyclic, non-limiting examples Including phenyl, naphthyl. The aryl group may optionally be further substituted with one or more substituents.
“杂芳基”是指取代的或未取代的芳香环，其可以是3至8元(例如3、4、5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1至6个(例如1、2、3、4、5、6个)选自N、O或S的杂原子，优选5至8元杂芳基，杂芳基的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态。杂芳基可以连接在杂原子或者碳原子上，杂芳基可以是桥环或者螺环，非限制性实例包括环吡啶基、呋喃基、噻吩基、吡喃基、吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基苯并咪唑基、苯并吡啶基、吡咯并吡啶基。杂芳基任选进一步被1个或多个取代基所取代。"Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which may be a 3 to 8 membered (eg 3, 4, 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (eg 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (eg 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably 5- to 8-membered heteroaryl, 1 to 4 (eg 1, 2) optionally substituted in the ring of heteroaryl , 3, 4) N, S can be oxidized into various oxidation states. Heteroaryl can be attached to a heteroatom or a carbon atom. Heteroaryl can be bridged or spiro, non-limiting examples include cyclopyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyridyl Azinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, pyrrolopyridyl. Heteroaryl groups are optionally further substituted with one or more substituents.
“碳环基”或“碳环”是指饱和或者不饱和的芳香环或者非芳香环。当为芳香环时，其定义与上文“芳基”的定义相同；当为非芳香环时，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，可以是桥环或者螺环，非限制性实例包括环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基、
Figure PCTCN2022087966-appb-000012
所述的“碳环基”或“碳环”任选进一步被1个或者多个取代基所取代。 "Carbocyclyl" or "carbocycle" refers to a saturated or unsaturated aromatic or non-aromatic ring. When aromatic, it is as defined above for "aryl"; when non-aromatic, it may be 3 to 10 membered (eg 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, 4 to 12 membered (eg 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) membered) tricyclic ring system, which may be bridged or spiro, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2- Alkenyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cycloheptyl cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl,
Figure PCTCN2022087966-appb-000012
Said "carbocyclyl" or "carbocycle" is optionally further substituted with one or more substituents.
“杂环基”或“杂环”是指饱和或不饱和的芳香性杂环或者非芳香性杂环，当为芳香性杂环时，其定义与上文“杂芳基”定义相同；当为非芳香性杂环时，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1至4个(例如1、2、3、4个)选自N、O或S的杂原子，优选3至8元杂环基。“杂环基”或“杂环”的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态；“杂环基”或“杂环”可以连接在杂原子或者碳原子上；“杂环基”或“杂环”可以为桥环或者螺环。“杂环基”或“杂环”的非限制性实例包括环氧乙基、环氧丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、硫杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡啶基、哌啶基、高哌啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、高哌嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、1,3-二噻烷基、二氢呋喃基、二噻戊环基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代吗啉基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的“杂环基”或“杂环”可以 任选进一步被1个或者多个取代基所取代。"Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated aromatic heterocycle or a non-aromatic heterocycle, and when it is an aromatic heterocycle, its definition is the same as the definition of "heteroaryl" above; when When it is a non-aromatic heterocycle, it can be a 3- to 10-membered (eg 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic, 4- to 12-membered (eg 7, 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group. Optionally substituted 1 to 4 (eg 1, 2, 3, 4) N, S in the ring of "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; "heterocyclyl" or A "heterocycle" can be attached to a heteroatom or a carbon atom; a "heterocyclyl" or "heterocycle" can be a bridged ring or a spirocyclic ring. Non-limiting examples of "heterocyclyl" or "heterocycle" include oxiranyl, glycidyl, azetidinyl, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, oxepanyl, thiepanyl, oxygen nitrogen Heterozoyl, diazepinyl, thiazepinyl, pyridyl, piperidinyl, homopiperidinyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazine base, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuranyl , dithiopenyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzoyl Imidazolyl, benzopyridyl, pyrrolopyridyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, indoline, 2H-pyranyl, 4H-pyranyl, Dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiazolinyl, dihydrothienyl, pyrazolidine, imidazolinyl, imidazolidinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H -Indolylquinazinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonane oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl. Said "heterocyclyl" or "heterocycle" may be optionally further substituted with one or more substituents.
“环烷基”是指饱和的环烃基，其环可以为3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至20元(例如10、11、12、13、14、15、16、17、18、19、20元)多环体系，环碳原子优选3至10个碳原子，进一步优选3至8个碳原子。“环烷基”非限制性实例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、1,5-环辛二烯基、1,4-环己二烯基和环庚三烯基等。当环烷基被取代时，可以任选进一步被1个或者多个取代基所取代。"Cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of which may be 3 to 10 membered (eg 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (eg 4 , 5, 6, 7, 8, 9, 10, 11, 12 yuan) double ring or 10 to 20 yuan (such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 yuan) and more In the ring system, the ring carbon atoms are preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexene group, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl and cycloheptatrienyl, etc. When cycloalkyl is substituted, it may be optionally further substituted with one or more substituents.
“杂环烷基”是指取代的或未取代的饱和非芳香环基，其可以是3至8元(例如3、4、5、6、7、8元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1、2、3或4个选自N、O或S的杂原子，优选3至8元杂环基。“杂环烷基”的环中选择性取代的1、2或3个N、S可被氧化成各种氧化态；“杂环烷基”可以连接在杂原子或者碳原子上；“杂环烷基”可以为桥环或者螺环。“杂环烷基”非限制性实例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻烷基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。"Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic ring group, which may be a (eg 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring systems, including 1, 2, 3 or 4 heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group. Optionally substituted 1, 2 or 3 N, S in the ring of "heterocycloalkyl" can be oxidized to various oxidation states; "heterocycloalkyl" can be attached to a heteroatom or carbon atom; "heterocycloalkyl" Alkyl" can be bridged or spiro. Non-limiting examples of "heterocycloalkyl" include oxiranyl, azetidinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxoyl Pentacyclyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl, Tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatri Cyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl.
当上文所述的“烷基”、“烷氧基”、“烯基”、“炔基”、“芳基”、“杂芳基”、“碳环基”、“碳环”、“杂环基”、“杂环”、“环烷基”、“杂环烷基”或者“杂环基”被取代时，可以选进一步被0、1、2、3、4、5、6、7、8、9或者10个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、C 1-6烷基氨基、＝O、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、-NR q4R q5、＝NR q6、-C(＝O)OC 1-6烷基、-OC(＝O)C 1-6烷基、-C(＝O)NR q4R q5、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基、C 5-10杂芳基、-C(＝O)OC 6-10芳基、-OC(＝O)C 6-10芳基、-OC(＝O)C 5-10杂芳基、-C(＝O)OC 5-10杂芳基、-OC(＝O)C 3-8杂环烷基、-C(＝O)OC 3-8杂环烷基、-OC(＝O)C 3-8环烷基、-C(＝O)OC 3-8环烷基、-NHC(＝O)C 3-8杂环烷基、-NHC(＝O)C 6-10芳基、-NHC(＝O)C 5-10杂芳基、-NHC(＝O)C 3-8环烷基、-NHC(＝O)C 3-8杂环烷基、-NHC(＝O)C 2-6烯基或者-NHC(＝O)C 2-6炔基的取代基所取代，且其中所述的取代基C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基、C 5-10杂芳基、-NHC(＝O)C 6-10芳基、-NHC(＝O)C 5-10杂芳基、-NHC(＝O)C 3-8杂环烷基或者-NHC(＝O)C 3-8环烷基任选进一步被1至3个选自OH、F、Cl、Br、I、C 1-6烷基、C 1-6烷氧基、-NR q4R q5或者＝O的取代基所取代；R q1选自C 1-6烷基、C 1-6烷氧基或者C 6-10芳基；R q2、R q3选自H或者C 1-6烷基；其中，R q4、R q5选自H、C 1-6烷基、-NH(C＝NR q1)NR q2R q3、-S(＝O) 2NR q2R q3、-C(＝O)R q1或者-C(＝O)NR q2R q3，其中所述的C 1-6烷基任选进一步被1个或者多个选自OH、F、Cl、Br、I、C 1-6烷基、C 1-6烷氧基、C 6-10芳基、C 5-10杂芳基、C 3-8环烷基或者C 3-8杂环烷基的取代基所取代；或者R q4与R q5及N原子形成一个3至8元杂环，所述杂环可以含有1个或者多个选自N、O或者S的杂原子。 When the above-mentioned "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclyl", "carbocycle", " When "heterocyclyl", "heterocycle", "cycloalkyl", "heterocycloalkyl" or "heterocyclyl" is substituted, it may be further selected by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 alkylamino, =O, C 1-6 alkyl, C 1 -6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -NR q4 R q5 , =NR q6 , -C(=O)OC 1-6 alkyl, -OC(=O)C 1-6 alkyl, -C(=O)NR q4 R q5 , C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, - C(=O)OC 6-10 aryl, -OC(=O)C 6-10 aryl, -OC(=O)C 5-10 heteroaryl, -C(=O)OC 5-10 heteroaryl Aryl, -OC(=O)C 3-8 heterocycloalkyl, -C(=O)OC 3-8 heterocycloalkyl, -OC(=O)C 3-8 cycloalkyl, -C( =O)OC 3-8 cycloalkyl, -NHC(=O)C 3-8 heterocycloalkyl, -NHC(=O)C 6-10 aryl, -NHC(=O)C 5-10 hetero Aryl, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 heterocycloalkyl, -NHC(=O)C 2-6 alkenyl or -NHC(=O ) C 2-6 alkynyl substituents, and wherein the substituents C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, -NHC(=O)C 6-10 aryl, -NHC(=O) C 5-10 heteroaryl, -NHC(=O)C 3-8 heterocycloalkyl or -NHC(=O) C 3-8 cycloalkyl is optionally further selected from 1 to 3 groups selected from OH, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, -NR q4 R q5 or a substituent of =O; R q1 is selected from C 1-6 alkyl, C 1-6 Alkoxy or C 6-10 aryl; R q2 and R q3 are selected from H or C 1-6 alkyl; wherein, R q4 and R q5 are selected from H, C 1-6 alkyl, -NH (C= NR q1 ) NR q2 R q3 , -S(=O) 2 NR q2 R q3 , -C(=O)R q1 or -C(=O)NR q2 R q3 , wherein said C 1-6 alkyl Optionally further selected by one or more selected from OH, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 5-10 heteroaryl R q4 , R q5 and N atom form a 3- to 8 - membered heterocycle, the heterocycle may contain 1 or a plurality of heteroatoms selected from N, O or S.
卤素包括F、Cl、Br和I。Halogens include F, Cl, Br and I.
“药物可接受的盐”或者“其药物可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that a compound of the present invention retains the biological effectiveness and properties of a free acid or free base that is treated with nontoxic inorganic or organic bases , the free base is a salt obtained by reacting with a non-toxic inorganic acid or organic acid.
“药物组合物”是指一种或多种本发明所述化合物、其药物可接受的盐或前药和其它化学组分形成的混合物，其中，“其它化学组分”是指药物可接受的载体、赋形剂和/或一种或多种其它治疗剂。"Pharmaceutical composition" refers to a mixture of one or more of the compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carrier, excipient, and/or one or more other therapeutic agents.
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特 性的材料。"Carrier" refers to a material that is not appreciably irritating to the organism and that does not abrogate the biological activity and properties of the administered compound.
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。"Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binding agents agent and disintegrant.
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。"Stereoisomers" refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生，该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如，“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在，该描述包括其中杂环基被烷基取代的情况，及其中杂环基未被烷基取代的情况。"Optional" or "optionally" or "selective" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not occur what happened. For example, "heterocyclyl optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes instances where the heterocyclyl group is substituted with an alkyl group, as well as where the heterocyclyl group is not substituted with an alkyl group Happening.
具体实施方式Detailed ways
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited thereto.
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10 - 6(ppm)的单位给出。NMR的测定是用Bruker Avance III 400和Bruker Avance 300核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)； The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10 −6 (ppm). NMR was measured by Bruker Avance III 400 and Bruker Avance 300 nuclear magnetic instruments, and the solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), The internal standard is tetramethylsilane (TMS);
MS的测定用Agilent 6120B(ESI)和Agilent 6120B(APCI)；Agilent 6120B (ESI) and Agilent 6120B (APCI) were used for MS determination;
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm；The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm-0.20mm, and the specification used for TLC separation and purification products is 0.4mm -0.5mm;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
实施例1Example 1
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-((1R,3R)-3-羟基环丁基)吡啶酰胺化合物15-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(( 1R,3R)-3-hydroxycyclobutyl)pyridine amide compound 1
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((1R,3R)-3-hydroxycyclobutyl)picolinamide5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((1R,3R)-3 -hydroxycyclobutyl)picolinamide
Figure PCTCN2022087966-appb-000013
Figure PCTCN2022087966-appb-000013
第一步first step
4-(6-((1R,3R)-3-羟基环丁基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯1c4-(6-((1R,3R)-3-hydroxycyclobutyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate tert-butyl ester 1c
tert-butyl 4-(6-(((1R,3R)-3-hydroxycyclobutyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylatetert-butyl 4-(6-(((1R,3R)-3-hydroxycyclobutyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
将5-溴-N-((1R,3R)-3-羟基环丁基)吡啶酰胺化合物1a(1.2g,4.43mmol)、(S)-2-甲基哌嗪-1-羧酸叔丁酯化合物1b(823mg,4.43mmol)溶解于甲苯(15mL)中，加入醋酸钯(购自华捷明生物科技，95.6mg，0.43mmol)、1,1'-联萘-2,2'-双二苯膦(购自成都爱斯特化学技术有限公司，265.2mg，0.43mmol)，将反应体系置换氮气，将反应体系置于120℃油浴锅中反应4h，加入水(20mL)淬灭反应，乙酸乙酯(3×30mL)萃取，收集有机相，旋干，柱层析分析(PE:EA＝2:1)，得到化合物1c(白色固体，1.3g，产率78％)。5-Bromo-N-((1R,3R)-3-hydroxycyclobutyl)pyridineamide compound 1a (1.2g, 4.43mmol), (S)-2-methylpiperazine-1-carboxylate tert-butyl Ester compound 1b (823 mg, 4.43 mmol) was dissolved in toluene (15 mL), palladium acetate (purchased from Huajie Ming Biotechnology, 95.6 mg, 0.43 mmol), 1,1'-binaphthyl-2,2'-bis was added Diphenylphosphine (purchased from Chengdu Esther Chemical Technology Co., Ltd., 265.2 mg, 0.43 mmol), the reaction system was replaced with nitrogen, the reaction system was placed in an oil bath at 120 °C for 4 h, and water (20 mL) was added to quench the reaction , extracted with ethyl acetate (3×30 mL), collected the organic phase, spin-dried, and analyzed by column chromatography (PE:EA=2:1) to obtain compound 1c (white solid, 1.3 g, yield 78%).
1H NMR(400MHz,DMSO-d 6)δ8.56(d,1H),8.28(d,1H),7.82(d,1H),7.41(dd,1H),4.99(d,1H),4.48(q,1H),4.28(q,1H),3.47(t,4H),3.31(dd,4H),2.36-2.26(m,2H),2.12(ddd,2H),1.42(s,9H)。 1 H NMR (400MHz, DMSO-d 6 )δ8.56(d,1H), 8.28(d,1H), 7.82(d,1H), 7.41(dd,1H), 4.99(d,1H), 4.48( q, 1H), 4.28 (q, 1H), 3.47 (t, 4H), 3.31 (dd, 4H), 2.36-2.26 (m, 2H), 2.12 (ddd, 2H), 1.42 (s, 9H).
LC-MS m/z(ESI)＝377.46[M+1]。LC-MS m/z (ESI) = 377.46 [M+1].
第二步second step
N-((1R,3R)-3-羟基环丁基)-5-(哌嗪-1-基)吡啶酰胺1dN-((1R,3R)-3-hydroxycyclobutyl)-5-(piperazin-1-yl)pyridineamide 1d
N-((1R,3R)-3-hydroxycyclobutyl)-5-(piperazin-1-yl)picolinamideN-((1R,3R)-3-hydroxycyclobutyl)-5-(piperazin-1-yl)picolinamide
将化合物1c溶解于盐酸-1,4二氧六环溶液(购自安耐吉化学，4M，15mL)中，室温下搅拌反应8h，过滤反应液并收集滤饼，得到化合物1d(白色固体，1.1g，产率94％)。Compound 1c was dissolved in hydrochloric acid-1,4-dioxane solution (purchased from Annagy Chemical, 4M, 15 mL), and the reaction was stirred at room temperature for 8 h, the reaction solution was filtered and the filter cake was collected to obtain compound 1d (white solid, 1.1 g, 94% yield).
LC-MS m/z(ESI)＝265.33[M+1]。LC-MS m/z (ESI) = 265.33 [M+1].
第三步third step
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-((1R,3R)-3-羟基环丁基)吡啶酰胺化合物15-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(( 1R,3R)-3-hydroxycyclobutyl)pyridine amide compound 1
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((1R,3R)-3-hydroxycyclobutyl)picolinamide5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((1R,3R)-3 -hydroxycyclobutyl)picolinamide
将化合物1d(35.9mg，0.13mmol)和化合物1e(36.7mg，0.13mmol)溶解于乙腈(5mL)中，加入N,N-二异丙基乙胺(购自上海麦克林生化科技有限公司，84mg，1.5mmol)，70℃下反应3h，旋干反应液，粗品经柱层析分离(MeOH:DCM＝1:60到1:15)，得到化合物1(白色固体，36mg，产率62％)。Compound 1d (35.9 mg, 0.13 mmol) and compound 1e (36.7 mg, 0.13 mmol) were dissolved in acetonitrile (5 mL), and N,N-diisopropylethylamine (purchased from Shanghai McLean Biochemical Technology Co., Ltd.) was added. 84 mg, 1.5 mmol), reacted at 70 °C for 3 h, the reaction solution was spin-dried, and the crude product was separated by column chromatography (MeOH:DCM=1:60 to 1:15) to obtain compound 1 (white solid, 36 mg, yield 62%) ).
1H NMR(400MHz,DMSO-d 6)δ11.88(s,1H),8.53(d,1H),8.40(d,1H),8.27(d,1H),7.81(d,1H),7.75(s,1H),7.63(d,1H),7.39(dd,1H),5.00(d,1H),4.47(q,1H),4.28(d,1H),3.65(s,2H),3.33(s,4H),2.59-2.52(m,6H),2.30(ddd,2H),2.11(ddt,2H),1.18(t,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.88(s,1H), 8.53(d,1H), 8.40(d,1H), 8.27(d,1H), 7.81(d,1H), 7.75( s, 1H), 7.63(d, 1H), 7.39(dd, 1H), 5.00(d, 1H), 4.47(q, 1H), 4.28(d, 1H), 3.65(s, 2H), 3.33(s , 4H), 2.59-2.52 (m, 6H), 2.30 (ddd, 2H), 2.11 (ddt, 2H), 1.18 (t, 3H).
LC-MS m/z(ESI)＝463.55[M+1]。LC-MS m/z (ESI) = 463.55 [M+1].
实施例2Example 2
(R)-4-(2-氟-4-((四氢呋喃-3-基)氨甲酰)苯基)哌嗪-1-羧酸叔丁酯化合物2(R)-4-(2-Fluoro-4-((tetrahydrofuran-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate tert-butyl ester compound 2
tert-butyl(R)-4-(2-fluoro-4-((tetrahydrofuran-3-yl)carbamoyl)phenyl)piperazine-1-carboxylatetert-butyl(R)-4-(2-fluoro-4-((tetrahydrofuran-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2022087966-appb-000014
Figure PCTCN2022087966-appb-000014
Figure PCTCN2022087966-appb-000015
Figure PCTCN2022087966-appb-000015
第一步first step
(R)-5-溴-N-(四氢呋喃-3-基)吡啶酰胺2b(R)-5-Bromo-N-(tetrahydrofuran-3-yl)pyridineamide 2b
(R)-5-bromo-N-(tetrahydrofuran-3-yl)picolinamide(R)-5-bromo-N-(tetrahydrofuran-3-yl)picolinamide
将化合物2a(2g，9.9mmol)溶解在二氯甲烷(20mL)中，在冰水浴下，滴加入(R)-四氢呋喃-3-胺，HATU(3.5g,14.8mmol)三乙胺(2ml)溶液，室温下反应90分钟，反应完减压浓缩过柱纯化得到化合物2b(黄色固体，1.9g，产率80％)。Compound 2a (2 g, 9.9 mmol) was dissolved in dichloromethane (20 mL), and (R)-tetrahydrofuran-3-amine, HATU (3.5 g, 14.8 mmol) triethylamine (2 ml) was added dropwise under an ice-water bath The solution was reacted at room temperature for 90 minutes, and after the reaction was completed, it was concentrated under reduced pressure and purified by column to obtain compound 2b (yellow solid, 1.9 g, yield 80%).
LC-MS m/z(ESI)＝270.10[M+1]。LC-MS m/z (ESI) = 270.10 [M+1].
第二步second step
(R)-4-(6-((四氢呋喃-3-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯2c(R)-tert-butyl 4-(6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate 2c
tert-butyl(R)-4-(6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylatetert-butyl(R)-4-(6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法，得到化合物2c(白色固体，2.5g，产率89％)。Referring to the synthesis method of compound 1c, compound 2c (white solid, 2.5 g, yield 89%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ8.43-8.34(m,2H),8.27(d,1H),7.81(d,1H),7.65(d,1H),4.51-4.38(m,1H),3.83(ddd,2H),3.71(td,1H),3.56(dd,1H),3.33(d,3H),2.58-2.50(m,4H),2.14(dtd,1H),1.99-1.85(m,1H),1.49(s,9H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 8.43-8.34(m, 2H), 8.27(d, 1H), 7.81(d, 1H), 7.65(d, 1H), 4.51-4.38(m, 1H) ),3.83(ddd,2H),3.71(td,1H),3.56(dd,1H),3.33(d,3H),2.58-2.50(m,4H),2.14(dtd,1H),1.99-1.85( m, 1H), 1.49 (s, 9H).
LC-MS m/z(ESI)＝377.21[M+1]。LC-MS m/z (ESI) = 377.21 [M+1].
第三步third step
(R)-3-氟-4-(哌嗪-1-基)-N-(四氢呋喃-3-基)苯甲酰胺2d(R)-3-Fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide 2d
(R)-3-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide(R)-3-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide
参考化合物1d的合成方法，得到化合物2d(白色固体，1.6g，产率83％)。Referring to the synthesis method of compound 1d, compound 2d (white solid, 1.6 g, yield 83%) was obtained.
LC-MS m/z(ESI)＝277.16[M+1]。LC-MS m/z (ESI) = 277.16 [M+1].
第四步the fourth step
(R)-4-(2-氟-4-((四氢呋喃-3-基)氨甲酰)苯基)哌嗪-1-羧酸叔丁酯化合物2(R)-4-(2-Fluoro-4-((tetrahydrofuran-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate tert-butyl ester compound 2
tert-butyl(R)-4-(2-fluoro-4-((tetrahydrofuran-3-yl)carbamoyl)phenyl)piperazine-1-carboxylatetert-butyl(R)-4-(2-fluoro-4-((tetrahydrofuran-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate
参考化合物1的合成方法，得到化合物2(白色固体，19mg，产率42％)。Referring to the synthesis method of compound 1, compound 2 (white solid, 19 mg, yield 42%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ11.86(s,1H),8.43-8.34(m,2H),8.27(d,1H),7.83(d,1H),7.74(d,1H),7.62(d,1H),7.39(dd,1H),4.51-4.38(m,1H),3.83(ddd,2H),3.71(td,1H),3.64(s,2H),3.56(dd,1H),3.33(d,3H),2.58-2.50(m,6H),2.14(dtd,1H),1.99-1.85(m,1H),1.18(q,4H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.86(s,1H), 8.43-8.34(m,2H), 8.27(d,1H), 7.83(d,1H), 7.74(d,1H), 7.62(d,1H),7.39(dd,1H),4.51-4.38(m,1H),3.83(ddd,2H),3.71(td,1H),3.64(s,2H),3.56(dd,1H) , 3.33(d,3H), 2.58-2.50(m,6H), 2.14(dtd,1H), 1.99-1.85(m,1H), 1.18(q,4H).
LC-MS m/z(ESI)＝463.24[M+1]。LC-MS m/z (ESI) = 463.24 [M+1].
实施例3Example 3
(S)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(四氢呋喃-3-基) 吡啶酰胺化合物3(S)-5-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-(tetrahydrofuran-3-yl)pyridine amide compound 3
(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3 -yl)picolinamide
Figure PCTCN2022087966-appb-000016
Figure PCTCN2022087966-appb-000016
第一步first step
(S)-5-溴-N-(四氢呋喃-3-基)吡啶酰胺3a(S)-5-Bromo-N-(tetrahydrofuran-3-yl)pyridineamide 3a
(S)-5-bromo-N-(tetrahydrofuran-3-yl)picolinamide(S)-5-bromo-N-(tetrahydrofuran-3-yl)picolinamide
参考化合物2b的合成方法，得到化合物3a(黄色固体，1.7g，产率77％)。Referring to the synthetic method of compound 2b, compound 3a (yellow solid, 1.7 g, yield 77%) was obtained.
LC-MS m/z(ESI)＝270.10[M+1]。LC-MS m/z (ESI) = 270.10 [M+1].
第二步second step
(S)-4-(6-((四氢呋喃-3-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯3b(S)-tert-butyl 4-(6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate 3b
tert-butyl(S)-4-(6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylatetert-butyl(S)-4-(6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法，得到化合物3b(白色固体，1.1g，产率82％)。Referring to the synthesis method of compound 1c, compound 3b (white solid, 1.1 g, yield 82%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ8.43-8.34(m,2H),8.27(d,1H),7.81(d,1H),7.65(d,1H),4.51-4.38(m,1H),3.83(ddd,2H),3.71(td,1H),3.56(dd,1H),3.33(d,3H),2.58-2.50(m,4H),2.14(dtd,1H),1.99-1.85(m,1H),1.49(s,9H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 8.43-8.34(m, 2H), 8.27(d, 1H), 7.81(d, 1H), 7.65(d, 1H), 4.51-4.38(m, 1H) ),3.83(ddd,2H),3.71(td,1H),3.56(dd,1H),3.33(d,3H),2.58-2.50(m,4H),2.14(dtd,1H),1.99-1.85( m, 1H), 1.49 (s, 9H).
LC-MS m/z(ESI)＝377.21[M+1]。LC-MS m/z (ESI) = 377.21 [M+1].
第三步third step
(S)-3-氟-4-(哌嗪-1-基)-N-(四氢呋喃-3-基)苯甲酰胺3c(S)-3-Fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide 3c
(S)-3-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide(S)-3-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide
参考化合物1d的合成方法，得到化合物3c(白色固体，1.2g，产率82％)。Referring to the synthesis method of compound 1d, compound 3c was obtained (white solid, 1.2 g, yield 82%).
LC-MS m/z(ESI)＝277.16[M+1]。LC-MS m/z (ESI) = 277.16 [M+1].
第四步the fourth step
(S)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(四氢呋喃-3-基)吡啶酰胺化合物3(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-(tetrahydrofuran-3-yl)pyridine amide compound 3
(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3 -yl)picolinamide
参考化合物1的合成方法，得到化合物3(白色固体，19mg，产率42％)。Referring to the synthesis method of compound 1, compound 3 (white solid, 19 mg, yield 42%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ11.86(s,1H),8.43-8.34(m,2H),8.27(d,1H),7.83(d,1H),7.74(d,1H),7.62(d,1H),7.39(dd,1H),4.51-4.38(m,1H),3.83(ddd,2H),3.71(td,1H),3.64(s,2H),3.56(dd,1H),3.33(d,3H),2.58-2.50(m,6H),2.14(dtd,1H),1.99-1.85(m,2H),1.18(t,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.86(s,1H), 8.43-8.34(m,2H), 8.27(d,1H), 7.83(d,1H), 7.74(d,1H), 7.62(d,1H),7.39(dd,1H),4.51-4.38(m,1H),3.83(ddd,2H),3.71(td,1H),3.64(s,2H),3.56(dd,1H) , 3.33 (d, 3H), 2.58-2.50 (m, 6H), 2.14 (dtd, 1H), 1.99-1.85 (m, 2H), 1.18 (t, 3H).
LC-MS m/z(ESI)＝463.24[M+1]。LC-MS m/z (ESI) = 463.24 [M+1].
实施例4Example 4
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-甲氧基乙基)吡啶酰胺化合物45-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2 -Methoxyethyl) pyridine amide compound 4
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-methoxyethyl)picolinamide5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-methoxyethyl)picolinamide
Figure PCTCN2022087966-appb-000017
Figure PCTCN2022087966-appb-000017
第一步first step
4-(6-((2-甲氧基乙基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯4b4-(6-((2-Methoxyethyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate tert-butyl ester 4b
tert-butyl 4-(6-((2-methoxyethyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylatetert-butyl 4-(6-((2-methoxyethyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法，得到化合物4b(白色固体，1.7g，产率67％)。Referring to the synthesis method of compound 1c, compound 4b (white solid, 1.7 g, yield 67%) was obtained.
LC-MS m/z(ESI)＝365.45[M+1]。LC-MS m/z (ESI) = 365.45 [M+1].
第二步second step
N-(2-甲氧基乙基)-5-(哌嗪-1-基)吡啶酰胺4cN-(2-Methoxyethyl)-5-(piperazin-1-yl)pyridineamide 4c
N-(2-methoxyethyl)-5-(piperazin-1-yl)picolinamideN-(2-methoxyethyl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法，得到化合物4c(白色固体，1.4g，产率89％)。Referring to the synthesis method of compound 1d, compound 4c (white solid, 1.4 g, yield 89%) was obtained.
LC-MS m/z(ESI)＝265.33[M+1]。LC-MS m/z (ESI) = 265.33 [M+1].
第三步third step
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-甲氧基乙基)吡啶酰胺化合物45-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2 -Methoxyethyl) pyridine amide compound 4
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-methoxyethyl)picolinamide5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-methoxyethyl)picolinamide
参考化合物1的合成方法，得到化合物4(白色固体，41mg，产率67％)。Referring to the synthesis method of compound 1, compound 4 (white solid, 41 mg, yield 67%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ11.21(s,1H),8.68(s,1H),8.62(s,1H),8.39(d,J1H),8.35(s,1H),7.89(d,1H),7.81(d,1H),7.50(s,1H),4.56(s,2H),4.10(d,2H),3.62-3.54(m,4H),3.27-3.14(m,2H),3.26(s,3H),3.14(d,2H),2.57(s,4H),1.20(d,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.21(s,1H), 8.68(s,1H), 8.62(s,1H), 8.39(d,J1H), 8.35(s,1H), 7.89( d, 1H), 7.81(d, 1H), 7.50(s, 1H), 4.56(s, 2H), 4.10(d, 2H), 3.62-3.54(m, 4H), 3.27-3.14(m, 2H) , 3.26(s, 3H), 3.14(d, 2H), 2.57(s, 4H), 1.20(d, 3H).
LC-MS m/z(ESI)＝451.54[M+1]。LC-MS m/z (ESI) = 451.54 [M+1].
实施例5Example 5
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-羟丙基)吡啶酰胺化合物55-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2 -Hydroxypropyl) pyridine amide compound 5
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)picolinamide5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)picolinamide
Figure PCTCN2022087966-appb-000018
Figure PCTCN2022087966-appb-000018
第一步first step
4-(6-((2-羟丙基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯5a4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate tert-butyl ester 5a
tert-butyl 4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylatetert-butyl 4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法，得到化合物5a(白色固体，1.2g，产率67％)。Referring to the synthesis method of compound 1c, compound 5a was obtained (white solid, 1.2 g, yield 67%).
1H NMR(400MHz,DMSO-d 6)δ8.31(dd,2H),7.85(d,1H),7.42(dd,1H),4.84(d,1H),3.76(tt,1H),3.47(t,4H),3.31(ddd,4H),3.13(ddd,1H),2.69(s,1H),1.42(s,9H),1.05(d,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ8.31(dd,2H), 7.85(d,1H), 7.42(dd,1H), 4.84(d,1H), 3.76(tt,1H), 3.47( t, 4H), 3.31 (ddd, 4H), 3.13 (ddd, 1H), 2.69 (s, 1H), 1.42 (s, 9H), 1.05 (d, 3H).
LC-MS m/z(ESI)＝365.45[M+1]。LC-MS m/z (ESI) = 365.45 [M+1].
第二步second step
N-(2-羟丙基)-5-(哌嗪-1-基)吡啶酰胺5bN-(2-hydroxypropyl)-5-(piperazin-1-yl)pyridinamide 5b
N-(2-hydroxypropyl)-5-(piperazin-1-yl)picolinamideN-(2-hydroxypropyl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法，得到化合物5b(白色固体，910mg，产率96％)。Referring to the synthesis method of compound 1d, compound 5b (white solid, 910 mg, yield 96%) was obtained.
LC-MS m/z(ESI)＝265.33[M+1]。LC-MS m/z (ESI) = 265.33 [M+1].
第三步third step
6-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-羟丙基)吡啶酰胺化合物56-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2 -Hydroxypropyl) pyridine amide compound 5
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2- hydroxypropyl)picolinamide5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)picolinamide
参考化合物1的合成方法，得到化合物5(白色固体，60mg，产率68％)。Referring to the synthesis method of compound 1, compound 5 (white solid, 60 mg, yield 68%) was obtained.
LC-MS m/z(ESI)＝451.54[M+1]。LC-MS m/z (ESI) = 451.54 [M+1].
实施例6Example 6
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-羟乙基)吡啶酰胺化合物65-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2 -Hydroxyethyl) pyridine amide compound 6
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxyethyl)picolinamide5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxyethyl)picolinamide
Figure PCTCN2022087966-appb-000019
Figure PCTCN2022087966-appb-000019
第一步first step
5-溴-N-(2-羟乙基)吡啶酰胺6a5-Bromo-N-(2-hydroxyethyl)pyridineamide 6a
5-bromo-N-(2-hydroxyethyl)picolinamide5-bromo-N-(2-hydroxyethyl)picolinamide
参考化合物2b的合成方法，得到化合物6a(黄色固体，1.7g，产率77％)。Referring to the synthesis method of compound 2b, compound 6a (yellow solid, 1.7 g, yield 77%) was obtained.
LC-MS m/z(ESI)＝244.98[M+1]。LC-MS m/z (ESI) = 244.98 [M+1].
第二步second step
4-(6-((2-羟乙基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯6b4-(6-((2-Hydroxyethyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate tert-butyl ester 6b
tert-butyl 4-(6-((2-hydroxyethyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylatetert-butyl 4-(6-((2-hydroxyethyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法，得到化合物6b(白色固体，1.9g，产率86％)。Referring to the synthesis method of compound 1c, compound 6b (white solid, 1.9 g, yield 86%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ8.30(d,1H),7.68(d,1H),7.49-7.12(m,2H),5.25(s,1H),3.12(dd,6H),2.75-2.52(m,6H),1.50(s,9H)。 1 H NMR (400MHz, DMSO-d 6 )δ8.30(d,1H), 7.68(d,1H), 7.49-7.12(m,2H), 5.25(s,1H), 3.12(dd,6H), 2.75-2.52(m, 6H), 1.50(s, 9H).
LC-MS m/z(ESI)＝351.20[M+1]。LC-MS m/z (ESI) = 351.20 [M+1].
第三步third step
N-(2-羟乙基)-5-(哌嗪-1-基)吡啶酰胺6cN-(2-Hydroxyethyl)-5-(piperazin-1-yl)pyridineamide 6c
N-(2-hydroxyethyl)-5-(piperazin-1-yl)picolinamideN-(2-hydroxyethyl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法，得到化合物6c(白色固体，1.2g，产率81％)Referring to the synthesis method of compound 1d, compound 6c was obtained (white solid, 1.2 g, yield 81%)
LC-MS m/z(ESI)＝250.14[M+1]。LC-MS m/z (ESI) = 250.14 [M+1].
第四步the fourth step
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-羟乙基)吡啶酰胺化合物65-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2 -Hydroxyethyl) pyridine amide compound 6
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-
hydroxyethyl)picolinamidehydroxyethyl)picolinamide
将化合物1e(21.3mg，0.08mmol)、化合物6c(22.0mg，0.09mmol)、N,N-二异丙基乙胺(51.6mg，0.4mmol)溶解在乙腈(4mL)中，80℃下反应4h，反应液减压浓缩，经制备色谱得到化合物6(白色固体，16mg，产率46％)。Compound 1e (21.3 mg, 0.08 mmol), compound 6c (22.0 mg, 0.09 mmol), and N,N-diisopropylethylamine (51.6 mg, 0.4 mmol) were dissolved in acetonitrile (4 mL) and reacted at 80 °C 4h, the reaction solution was concentrated under reduced pressure, and compound 6 (white solid, 16 mg, yield 46%) was obtained by preparative chromatography.
1H NMR(400MHz,DMSO-d 6)δ11.85(s,1H),8.49-8.31(m,2H),8.27(d,1H),7.83(d,1H),7.75(q,1H),7.62(d,1H),7.44-7.32(m,1H),4.82(t,1H),3.64(s,2H),3.49(q,2H),3.33(dd,6H),2.54(td,6H),1.17(t,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.85(s, 1H), 8.49-8.31(m, 2H), 8.27(d, 1H), 7.83(d, 1H), 7.75(q, 1H), 7.62(d,1H),7.44-7.32(m,1H),4.82(t,1H),3.64(s,2H),3.49(q,2H),3.33(dd,6H),2.54(td,6H) , 1.17(t, 3H).
LC-MS m/z(ESI)＝437.22[M+1]。LC-MS m/z (ESI) = 437.22 [M+1].
实施例7Example 7
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-((1s,3s)-3-羟基环丁基)吡啶酰胺化合物75-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(( 1s,3s)-3-hydroxycyclobutyl)pyridine amide compound 7
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((1s,3s)-3-hydroxycyclobutyl)picolinamide5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((1s,3s)-3 -hydroxycyclobutyl)picolinamide
Figure PCTCN2022087966-appb-000020
Figure PCTCN2022087966-appb-000020
第一步first step
4-(6-((1s,3s)-3-羟基环丁基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯7b4-(6-((1s,3s)-3-hydroxycyclobutyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate tert-butyl ester 7b
tert-butyl 4-(6-(((1s,3s)-3-hydroxycyclobutyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylatetert-butyl 4-(6-(((1s,3s)-3-hydroxycyclobutyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法，得到化合物7b(白色固体，1.1g，产率76％)。Referring to the synthesis method of compound 1c, compound 7b (white solid, 1.1 g, yield 76%) was obtained.
LC-MS m/z(ESI)＝377.46[M+1]。LC-MS m/z (ESI) = 377.46 [M+1].
第二步second step
N-((1s,3s)-3-羟基环丁基)-5-(哌嗪-1-基)吡啶酰胺7cN-((1s,3s)-3-hydroxycyclobutyl)-5-(piperazin-1-yl)pyridinamide 7c
N-((1s,3s)-3-hydroxycyclobutyl)-5-(piperazin-1-yl)picolinamideN-((1s,3s)-3-hydroxycyclobutyl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法，得到化合物7c(白色固体，0.9g，产率92％)。Referring to the synthesis method of compound 1d, compound 7c was obtained (white solid, 0.9 g, yield 92%).
LC-MS m/z(ESI)＝277.16[M+1]。LC-MS m/z (ESI) = 277.16 [M+1].
第三步third step
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-((1s,3s)-3-羟基环丁基)吡啶酰胺化合物75-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(( 1s,3s)-3-hydroxycyclobutyl)pyridine amide compound 7
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((1s,3s)-3-hydroxycyclobutyl)picolinamide5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((1s,3s)-3 -hydroxycyclobutyl)picolinamide
参考化合物1的合成方法，得到化合物7(白色固体，41mg，产率59％)。Referring to the synthesis method of compound 1, compound 7 (white solid, 41 mg, yield 59%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ11.87(s,1H),8.39(d,2H),8.27(d,1H),7.83-7.73(m,2H),7.62(s,1H),7.39(dd,1H),5.03(d,1H),3.94-3.78(m,2H),3.65(s,2H),3.34-3.31(m,4H),2.56-2.53(m,6H),2.50-2.44(m,2H),1.98-1.85(m,2H),1.18(t,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.87(s,1H), 8.39(d,2H), 8.27(d,1H), 7.83-7.73(m,2H), 7.62(s,1H), 7.39(dd, 1H), 5.03(d, 1H), 3.94-3.78(m, 2H), 3.65(s, 2H), 3.34-3.31(m, 4H), 2.56-2.53(m, 6H), 2.50- 2.44(m, 2H), 1.98-1.85(m, 2H), 1.18(t, 3H).
LC-MS m/z(ESI)＝463.24[M+1]。LC-MS m/z (ESI) = 463.24 [M+1].
实施例8Example 8
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-羟基-2-甲基丙基)吡啶酰胺化合物85-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2 -Hydroxy-2-methylpropyl)picolinamide compound 8
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxy-2-methylpropyl)picolinamide5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxy-2-methylpropyl) )picolinamide
Figure PCTCN2022087966-appb-000021
Figure PCTCN2022087966-appb-000021
第一步first step
5-溴-N-(2-羟基-2-甲基丙基)吡啶酰胺8a5-Bromo-N-(2-hydroxy-2-methylpropyl)pyridineamide 8a
5-bromo-N-(2-hydroxy-2-methylpropyl)picolinamide5-bromo-N-(2-hydroxy-2-methylpropyl)picolinamide
参考化合物2b的合成方法，得到化合物8a(黄色固体，1.4g，产率71％)。Referring to the synthesis method of compound 2b, compound 8a (yellow solid, 1.4 g, yield 71%) was obtained.
LC-MS m/z(ESI)＝274.13[M+1]。LC-MS m/z (ESI) = 274.13 [M+1].
第二步second step
4-(6-((2-羟基-2-甲基丙基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯8b4-(6-((2-Hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate tert-butyl ester 8b
tert-butyl 4-(6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylatetert-butyl 4-(6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法，得到化合物8b(白色固体，1.1g，产率92％)。Referring to the synthesis method of compound 1c, compound 8b (white solid, 1.1 g, yield 92%) was obtained.
LC-MS m/z(ESI)＝379.47[M+1]。LC-MS m/z (ESI) = 379.47 [M+1].
第三步third step
N-(2-羟基-2-甲基丙基)-5-(哌嗪-1-基)吡啶酰胺8cN-(2-Hydroxy-2-methylpropyl)-5-(piperazin-1-yl)pyridinamide 8c
N-(2-hydroxy-2-methylpropyl)-5-(piperazin-1-yl)picolinamideN-(2-hydroxy-2-methylpropyl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法，得到化合物8c(白色固体，920mg，产率89％)Referring to the synthesis method of compound 1d, compound 8c was obtained (white solid, 920 mg, yield 89%)
LC-MS m/z(ESI)＝279.3[M+1]。LC-MS m/z (ESI) = 279.3 [M+1].
第四步the fourth step
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-2-羟基-2-甲基丙基)吡啶酰胺化合物85-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-2- Hydroxy-2-methylpropyl)picolinamide compound 8
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-
hydroxy-2-methylpropyl)picolinamidehydroxy-2-methylpropyl)picolinamide
参考化合物6的合成方法，得到化合物8(白色固体，27mg，产率53％)。Referring to the synthesis method of compound 6, compound 8 (white solid, 27 mg, yield 53%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ11.88(s,1H),8.40(d,1H),8.31(d,1H),8.20(t,1H),7.84(d,1H),7.75(s,1H),7.63(d,1H),7.41(dd,1H),4.70(s,1H),3.65(s,2H),3.35(s,4H),3.23(d,2H),2.59-2.52(m,6H),1.18(t,3H),1.08(s,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.88(s,1H), 8.40(d,1H), 8.31(d,1H), 8.20(t,1H), 7.84(d,1H), 7.75( s, 1H), 7.63(d, 1H), 7.41(dd, 1H), 4.70(s, 1H), 3.65(s, 2H), 3.35(s, 4H), 3.23(d, 2H), 2.59-2.52 (m, 6H), 1.18 (t, 3H), 1.08 (s, 6H).
LC-MS m/z(ESI)＝465.5[M+1]。LC-MS m/z (ESI) = 465.5 [M+1].
实施例9Example 9
(S)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(1-羟基丙烷-2-基)吡啶酰胺化合物9(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-(1-Hydroxypropan-2-yl)pyridine amide compound 9
(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-hydroxypropan-2-yl)picolinamide(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-hydroxypropan -2-yl)picolinamide
Figure PCTCN2022087966-appb-000022
Figure PCTCN2022087966-appb-000022
第一步first step
(S)-5-溴-N-(1-羟基丙烷-2-基)吡啶酰胺9a(S)-5-Bromo-N-(1-hydroxypropan-2-yl)pyridineamide 9a
(S)-5-bromo-N-(1-hydroxypropan-2-yl)picolinamide(S)-5-bromo-N-(1-hydroxypropan-2-yl)picolinamide
参考化合物2b的合成方法，得到化合物9a(黄色固体，1.3g，产率76％)。Referring to the synthesis method of compound 2b, compound 9a (yellow solid, 1.3 g, yield 76%) was obtained.
LC-MS m/z(ESI)＝259.00[M+1]。LC-MS m/z (ESI) = 259.00 [M+1].
第二步second step
(S)-4-(6-((1-羟基丙烷-2-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯9b(S)-tert-butyl 4-(6-((1-hydroxypropan-2-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate 9b
tert-butyl(S)-4-(6-((1-hydroxypropan-2-yl)carbamoyl)pyridin-3-yl)piperazine-1- carboxylatetert-butyl(S)-4-(6-((1-hydroxypropan-2-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法，得到化合物9b(白色固体，1.2g，产率91％)。Referring to the synthesis method of compound 1c, compound 9b (white solid, 1.2 g, yield 91%) was obtained.
LC-MS m/z(ESI)＝365.21[M+1]。LC-MS m/z (ESI) = 365.21 [M+1].
第三步third step
(S)-N-(1-羟基丙烷-2-基)-5-(哌嗪-1-基)吡啶酰胺9c(S)-N-(1-Hydroxypropan-2-yl)-5-(piperazin-1-yl)pyridinamide 9c
(S)-N-(1-hydroxypropan-2-yl)-5-(piperazin-1-yl)picolinamide(S)-N-(1-hydroxypropan-2-yl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法，得到化合物9c(白色固体，860mg，产率88％)Referring to the synthesis method of compound 1d, compound 9c was obtained (white solid, 860 mg, yield 88%)
LC-MS m/z(ESI)＝279.3[M+1]。LC-MS m/z (ESI) = 279.3 [M+1].
1H NMR(400MHz,DMSO-d 6)δ9.53(s,1H),8.37-8.29(m,1H),8.04(d,1H),7.63(dd,1H),3.99(dt,1H),3.77-3.58(m,4H),3.43(qd,2H),3.21-3.10(m,6H),1.19(t,1H),1.14(d,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.53(s,1H), 8.37-8.29(m,1H), 8.04(d,1H), 7.63(dd,1H), 3.99(dt,1H), 3.77-3.58 (m, 4H), 3.43 (qd, 2H), 3.21-3.10 (m, 6H), 1.19 (t, 1H), 1.14 (d, 3H).
第四步the fourth step
(S)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(1-羟基丙烷-2-基)吡啶酰胺化合物9(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-(1-Hydroxypropan-2-yl)pyridine amide compound 9
(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-hydroxypropan-2-yl)picolinamide(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-hydroxypropan -2-yl)picolinamide
参考化合物6的合成方法，得到化合物9(白色固体，23mg，产率54％)。Referring to the synthesis method of compound 6, compound 9 (white solid, 23 mg, yield 54%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ11.87(s,1H),8.39(d,1H),8.27(d,1H),8.10(d,1H),7.84(d,1H),7.74(s,1H),7.62(d,1H),7.38(dd,1H),4.86(t,1H),3.98(ddt,1H),3.63(s,2H),3.43(dq,2H),3.32(t,4H),2.58-2.52(m,6H),1.22-1.08(m,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.87(s,1H), 8.39(d,1H), 8.27(d,1H), 8.10(d,1H), 7.84(d,1H), 7.74( s,1H),7.62(d,1H),7.38(dd,1H),4.86(t,1H),3.98(ddt,1H),3.63(s,2H),3.43(dq,2H),3.32(t , 4H), 2.58-2.52 (m, 6H), 1.22-1.08 (m, 6H).
LC-MS m/z(ESI)＝465.5[M+1]。LC-MS m/z (ESI) = 465.5 [M+1].
实施例10Example 10
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(1-羟基丙烷-2-基)吡啶酰胺化合物10(R)-5-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-(1-Hydroxypropan-2-yl)pyridine amide compound 10
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-hydroxypropan-2-yl)picolinamide(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-hydroxypropan -2-yl)picolinamide
Figure PCTCN2022087966-appb-000023
Figure PCTCN2022087966-appb-000023
第一步first step
(R)-5-溴-N-(1-羟基丙烷-2-基)吡啶酰胺10a(R)-5-Bromo-N-(1-hydroxypropan-2-yl)pyridineamide 10a
(R)-5-bromo-N-(1-hydroxypropan-2-yl)picolinamide(R)-5-bromo-N-(1-hydroxypropan-2-yl)picolinamide
参考化合物2b的合成方法，得到化合物10a(黄色固体，1.4g，产率76％)。Referring to the synthesis method of compound 2b, compound 10a (yellow solid, 1.4 g, yield 76%) was obtained.
LC-MS m/z(ESI)＝259.00[M+1]。LC-MS m/z (ESI) = 259.00 [M+1].
第二步second step
(R)-4-(6-((1-羟基丙烷-2-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯10b(R)-tert-butyl 4-(6-((1-hydroxypropan-2-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate 10b
tert-butyl(R)-4-(6-((1-hydroxypropan-2-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylatetert-butyl(R)-4-(6-((1-hydroxypropan-2-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法，得到化合物10b(白色固体，1.1g，产率90％)。Referring to the synthesis method of compound 1c, compound 10b (white solid, 1.1 g, yield 90%) was obtained.
LC-MS m/z(ESI)＝365.21[M+1]。LC-MS m/z (ESI) = 365.21 [M+1].
第三步third step
(R)-N-(1-羟基丙烷-2-基)-5-(哌嗪-1-基)吡啶酰胺10c(R)-N-(1-Hydroxypropan-2-yl)-5-(piperazin-1-yl)pyridinamide 10c
(R)-N-(1-hydroxypropan-2-yl)-5-(piperazin-1-yl)picolinamide(R)-N-(1-hydroxypropan-2-yl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法，得到化合物10c(白色固体，840mg，产率83％)Referring to the synthesis method of compound 1d, compound 10c was obtained (white solid, 840 mg, yield 83%)
LC-MS m/z(ESI)＝279.3[M+1]。LC-MS m/z (ESI) = 279.3 [M+1].
1H NMR(400MHz,DMSO-d 6)δ9.53(s,1H),8.37-8.29(m,1H),8.04(d,1H),7.63(dd,1H),3.99(dt,1H),3.77-3.58(m,4H),3.43(qd,2H),3.21-3.10(m,6H),1.19(t,1H),1.14(d,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.53(s,1H), 8.37-8.29(m,1H), 8.04(d,1H), 7.63(dd,1H), 3.99(dt,1H), 3.77-3.58 (m, 4H), 3.43 (qd, 2H), 3.21-3.10 (m, 6H), 1.19 (t, 1H), 1.14 (d, 3H).
第四步the fourth step
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(1-羟基丙烷-2-基)吡啶酰胺化合物10(R)-5-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-(1-Hydroxypropan-2-yl)pyridine amide compound 10
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-hydroxypropan-2-yl)picolinamide(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-hydroxypropan -2-yl)picolinamide
参考化合物6的合成方法，得到化合物10(白色固体，27mg，产率62％)。Referring to the synthesis method of compound 6, compound 10 was obtained (white solid, 27 mg, yield 62%).
1H NMR(400MHz,DMSO-d 6)δ11.87(s,1H),8.39(d,1H),8.27(d,1H),8.10(d,1H),7.84(d,1H),7.74(s,1H),7.62(d,1H),7.38(dd,1H),4.86(t,1H),3.98(ddt,1H),3.63(s,2H),3.43(dq,2H),3.32(t,4H),2.58-2.52(m,6H),1.22-1.08(m,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.87(s,1H), 8.39(d,1H), 8.27(d,1H), 8.10(d,1H), 7.84(d,1H), 7.74( s,1H),7.62(d,1H),7.38(dd,1H),4.86(t,1H),3.98(ddt,1H),3.63(s,2H),3.43(dq,2H),3.32(t , 4H), 2.58-2.52 (m, 6H), 1.22-1.08 (m, 6H).
LC-MS m/z(ESI)＝465.5[M+1]。LC-MS m/z (ESI) = 465.5 [M+1].
实施例11Example 11
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-羟丙基)吡啶酰胺化合物11(R)-5-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-(2-hydroxypropyl)pyridine amide compound 11
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)picolinamide(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl) )picolinamide
Figure PCTCN2022087966-appb-000024
Figure PCTCN2022087966-appb-000024
Figure PCTCN2022087966-appb-000025
Figure PCTCN2022087966-appb-000025
第一步first step
(R)-4-(6-((2-羟丙基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯11b(R)-tert-butyl 4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate 11b
tert-butyl(R)-4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylatetert-butyl(R)-4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法，得到化合物11b(白色固体，1.1g，产率81％)。Referring to the synthesis method of compound 1c, compound 11b (white solid, 1.1 g, yield 81%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ8.31(dd,2H),7.85(d,1H),7.42(dd,1H),4.84(d,1H),3.76(tt,1H),3.47(t,4H),3.31(ddd,4H),3.13(ddd,1H),2.69(s,1H),1.42(s,9H),1.05(d,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ8.31(dd,2H), 7.85(d,1H), 7.42(dd,1H), 4.84(d,1H), 3.76(tt,1H), 3.47( t, 4H), 3.31 (ddd, 4H), 3.13 (ddd, 1H), 2.69 (s, 1H), 1.42 (s, 9H), 1.05 (d, 3H).
LC-MS m/z(ESI)＝365.45[M+1]。LC-MS m/z (ESI) = 365.45 [M+1].
第二步second step
(R)-N-(2-羟丙基)-5-(哌嗪-1-基)吡啶酰胺11c(R)-N-(2-hydroxypropyl)-5-(piperazin-1-yl)pyridinamide 11c
(R)-N-(2-hydroxypropyl)-5-(piperazin-1-yl)picolinamide(R)-N-(2-hydroxypropyl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法，得到化合物11c(白色固体，902mg，产率92％)。Referring to the synthesis method of compound 1d, compound 11c (white solid, 902 mg, yield 92%) was obtained.
LC-MS m/z(ESI)＝265.33[M+1]。LC-MS m/z (ESI) = 265.33 [M+1].
第三步third step
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-羟丙基)吡啶酰胺化合物11(R)-5-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-(2-hydroxypropyl)pyridine amide compound 11
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)picolinamide(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl) )picolinamide
参考化合物1的合成方法，得到化合物11(白色固体，42mg，产率72％)。Referring to the synthesis method of compound 1, compound 11 (white solid, 42 mg, yield 72%) was obtained.
1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.40(d,1H),8.35-8.24(m,2H),7.84(d,1H),7.75(s,1H),7.63(d,1H),7.40(dd,1H),4.85(d,1H),3.75(p,1H),3.65(s,2H),3.33(s,4H),3.32-3.27(m,1H),3.13(dt,1H),2.59-2.52(m,6H),1.18(t,3H),1.04(d,3H)。 1 H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.40(d,1H),8.35-8.24(m,2H),7.84(d,1H),7.75(s,1H),7.63 (d, 1H), 7.40(dd, 1H), 4.85(d, 1H), 3.75(p, 1H), 3.65(s, 2H), 3.33(s, 4H), 3.32-3.27(m, 1H), 3.13 (dt, 1H), 2.59-2.52 (m, 6H), 1.18 (t, 3H), 1.04 (d, 3H).
LC-MS m/z(ESI)＝451.54[M+1]。LC-MS m/z (ESI) = 451.54 [M+1].
实施例12Example 12
(S)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-羟丙基)吡啶酰胺化合物12(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-(2-hydroxypropyl)pyridine amide compound 12
(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)picolinamide(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl) )picolinamide
Figure PCTCN2022087966-appb-000026
Figure PCTCN2022087966-appb-000026
第一步first step
(S)-4-(6-((2-羟丙基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯12b(S)-tert-butyl 4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate 12b
tert-butyl(S)-4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylatetert-butyl(S)-4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法，得到化合物12b(白色固体，1.3g，产率84％)。Referring to the synthesis method of compound 1c, compound 12b (white solid, 1.3 g, yield 84%) was obtained.
LC-MS m/z(ESI)＝365.45[M+1]。LC-MS m/z (ESI) = 365.45 [M+1].
第二步second step
(S)-N-(2-羟丙基)-5-(哌嗪-1-基)吡啶酰胺12c(S)-N-(2-hydroxypropyl)-5-(piperazin-1-yl)pyridinamide 12c
(S)-N-(2-hydroxypropyl)-5-(piperazin-1-yl)picolinamide(S)-N-(2-hydroxypropyl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法，得到化合物12c(白色固体，1.1g，产率94％)。Referring to the synthesis method of compound 1d, compound 12c (white solid, 1.1 g, yield 94%) was obtained.
LC-MS m/z(ESI)＝265.33[M+1]。LC-MS m/z (ESI) = 265.33 [M+1].
第三步third step
(S)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-羟丙基)吡啶酰胺化合物12(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-(2-hydroxypropyl)pyridine amide compound 12
(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)picolinamide(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl) )picolinamide
参考化合物1的合成方法，得到化合物12(白色固体，37mg，产率76％)。Referring to the synthesis method of compound 1, compound 12 (white solid, 37 mg, yield 76%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ11.87(s,1H),8.40(d,1H),8.35-8.20(m,2H),7.84(d,1H),7.75(d,1H),7.62(d,1H),7.40(dd,1H),4.84(d,1H),3.75(ddd,1H),3.65(s,2H),3.33(d,4H),3.32-3.28(m,1H),3.13(ddd,1H),2.61-2.51(m,6H),1.18(t,3H),1.04(d,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.87(s, 1H), 8.40(d, 1H), 8.35-8.20(m, 2H), 7.84(d, 1H), 7.75(d, 1H), 7.62(d,1H),7.40(dd,1H),4.84(d,1H),3.75(ddd,1H),3.65(s,2H),3.33(d,4H),3.32-3.28(m,1H) , 3.13 (ddd, 1H), 2.61-2.51 (m, 6H), 1.18 (t, 3H), 1.04 (d, 3H).
LC-MS m/z(ESI)＝451.54[M+1]。LC-MS m/z (ESI) = 451.54 [M+1].
实施例13Example 13
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(四氢-2H-吡喃-4-基)吡啶甲酰胺化合物135-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetra Hydrogen-2H-pyran-4-yl)picolinamide compound 13
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)picolinamide5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydro-2H-pyran-4 -yl)picolinamide
Figure PCTCN2022087966-appb-000027
Figure PCTCN2022087966-appb-000027
第一步first step
4-(6-((四氢-2H-吡喃-4-基)氨基甲酰基)吡啶-3-基)哌嗪-1-羧酸叔丁酯13b4-(6-((Tetrahydro-2H-pyran-4-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate tert-butyl ester 13b
tert-butyl 4-(6-((tetrahydro-2H-pyran-4-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylatetert-butyl 4-(6-((tetrahydro-2H-pyran-4-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法，得到化合物13b(白色固体，1.1g，产率82％)。Referring to the synthesis method of compound 1c, compound 13b was obtained (white solid, 1.1 g, yield 82%).
LC-MS m/z(ESI)＝389.25[M+1]。LC-MS m/z (ESI) = 389.25 [M+1].
第二步second step
N-环己基-5-(哌嗪-1-基)吡啶甲酰胺13cN-Cyclohexyl-5-(piperazin-1-yl)picolinamide 13c
N-cyclohexyl-5-(piperazin-1-yl)picolinamideN-cyclohexyl-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法，得到化合物13c(白色固体，1.0g，产率91％)。Referring to the synthesis method of compound 1d, compound 13c was obtained (white solid, 1.0 g, yield 91%).
LC-MS m/z(ESI)＝288.20[M+1]。LC-MS m/z (ESI) = 288.20 [M+1].
第三步third step
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(四氢-2H-吡喃-4-基)吡啶甲酰胺化合物135-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetra Hydrogen-2H-pyran-4-yl)picolinamide compound 13
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)picolinamide5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydro-2H-pyran-4 -yl)picolinamide
参考化合物1的合成方法，得到化合物13(白色固体，32mg，产率74％)。Referring to the synthesis method of compound 1, compound 13 (white solid, 32 mg, yield 74%) was obtained.
1H NMR(400MHz,DMSO-d6)δ12.21(s,1H),8.68(s,1H),8.33(s,2H),7.93-7.78(m,3H),7.48(d,1H),4.52(s,2H),4.12-3.92(m,3H),3.91-3.82(m,2H),3.63-3.56(m,2H),3.34-3.17(m,4H),3.15-3.08(m,2H),2.59-2.54(m,2H),1.75-1.58(m,4H),1.19(t,3H)。1H NMR (400MHz, DMSO-d6) δ12.21(s,1H), 8.68(s,1H), 8.33(s,2H), 7.93-7.78(m,3H), 7.48(d,1H), 4.52( s,2H),4.12-3.92(m,3H),3.91-3.82(m,2H),3.63-3.56(m,2H),3.34-3.17(m,4H),3.15-3.08(m,2H), 2.59-2.54 (m, 2H), 1.75-1.58 (m, 4H), 1.19 (t, 3H).
LC-MS m/z(ESI)＝477.25[M+1]。LC-MS m/z (ESI) = 477.25 [M+1].
实施例14Example 14
3-乙基-7-((4-(6-(3-羟基氮杂环丁烷-1-羰基)吡啶-3-基)哌嗪-1-基)甲基)-1,5-萘啶-2(1H)-酮化合物143-ethyl-7-((4-(6-(3-hydroxyazetidine-1-carbonyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthalene Pyridin-2(1H)-one compound 14
3-ethyl-7-((4-(6-(3-hydroxyazetidine-1-carbonyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one3-ethyl-7-((4-(6-(3-hydroxyazetidine-1-carbonyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one
Figure PCTCN2022087966-appb-000028
Figure PCTCN2022087966-appb-000028
第一步first step
4-(6-(3-羟基氮杂环丁烷-1-羰基)吡啶-3-基)哌嗪-1-羧酸叔丁酯14b4-(6-(3-Hydroxyazetidine-1-carbonyl)pyridin-3-yl)piperazine-1-carboxylate tert-butyl ester 14b
tert-butyl 4-(6-(3-hydroxyazetidine-1-carbonyl)pyridin-3-yl)piperazine-1-carboxylatetert-butyl 4-(6-(3-hydroxyazetidine-1-carbonyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法，得到化合物14b(白色固体，1.1g，产率87％)。Referring to the synthesis method of compound 1c, compound 14b (white solid, 1.1 g, yield 87%) was obtained.
1H NMR(400MHz,DMSO-d6)δ8.29(d,1H),7.79(d,1H),7.38(dd,1H),5.66(d,1H),4.72(dd,1H),4.54–4.37(m,1H),4.30–4.11(m,2H),3.74(dd,1H),3.45(d,4H),3.31(d,4H),1.42(s,9H)。 1 H NMR (400MHz, DMSO-d6) δ8.29(d,1H), 7.79(d,1H), 7.38(dd,1H), 5.66(d,1H), 4.72(dd,1H), 4.54–4.37 (m, 1H), 4.30–4.11 (m, 2H), 3.74 (dd, 1H), 3.45 (d, 4H), 3.31 (d, 4H), 1.42 (s, 9H).
LC-MS m/z(ESI)＝363.43[M+1]。LC-MS m/z (ESI) = 363.43 [M+1].
第二步second step
(3-羟基氮杂环丁烷-1-基)(5-(哌嗪-1-基)吡啶-2-基)甲酮14c(3-Hydroxyazetidine-1-yl)(5-(piperazin-1-yl)pyridin-2-yl)methanone 14c
(3-hydroxyazetidin-1-yl)(5-(piperazin-1-yl)pyridin-2-yl)methanone(3-hydroxyazetidin-1-yl)(5-(piperazin-1-yl)pyridin-2-yl)methanone
参考化合物1d的合成方法，得到化合物14c(白色固体，1.1g，产率94％)。Referring to the synthesis method of compound 1d, compound 14c (white solid, 1.1 g, yield 94%) was obtained.
LC-MS m/z(ESI)＝265.33[M+1]。LC-MS m/z (ESI) = 265.33 [M+1].
第三步third step
3-乙基-7-((4-(6-(3-羟基氮杂环丁烷-1-羰基)吡啶-3-基)哌嗪-1-基)甲基)-1,5-萘啶-2(1H)-酮化合物143-ethyl-7-((4-(6-(3-hydroxyazetidine-1-carbonyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthalene Pyridin-2(1H)-one compound 14
3-ethyl-7-((4-(6-(3-hydroxyazetidine-1-carbonyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one3-ethyl-7-((4-(6-(3-hydroxyazetidine-1-carbonyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one
参考化合物1的合成方法，得到化合物14(白色固体，37mg，产率76％)。Referring to the synthesis method of compound 1, compound 14 (white solid, 37 mg, yield 76%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ11.87(s,1H),8.40(d,1H),8.27(d,1H),7.78(d,1H),7.75(d,1H),7.62(d,1H),7.36(dd,1H),5.67(d,1H),4.76–4.65(m,1H),4.46(tdd,1H),4.32–4.14(m,2H),3.81–3.68(m,1H),3.64(s,2H),3.33(d,4H),2.54(qd,6H),1.18(t,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.87(s,1H), 8.40(d,1H), 8.27(d,1H), 7.78(d,1H), 7.75(d,1H), 7.62( d, 1H), 7.36 (dd, 1H), 5.67 (d, 1H), 4.76–4.65 (m, 1H), 4.46 (tdd, 1H), 4.32–4.14 (m, 2H), 3.81–3.68 (m, 1H), 3.64(s, 2H), 3.33(d, 4H), 2.54(qd, 6H), 1.18(t, 3H).
LC-MS m/z(ESI)＝449.53[M+1]。LC-MS m/z (ESI) = 449.53 [M+1].
实施例15Example 15
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基-N- (四氢呋喃-3-基)吡啶酰胺化合物15(R)-5-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 6-Methyl-N-(tetrahydrofuran-3-yl)pyridine amide compound 15
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N- (tetrahydrofuran-3-yl)picolinamide
Figure PCTCN2022087966-appb-000029
Figure PCTCN2022087966-appb-000029
第一步first step
(R)-4-(2-甲基-6-((四氢呋喃-3-基)氨基甲酰基)吡啶-3-基)哌嗪-1-羧酸叔丁酯15b(R)-tert-butyl 4-(2-methyl-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate 15b
tert-butyl(R)-4-(2-methyl-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylatetert-butyl(R)-4-(2-methyl-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法，得到化合物15b(白色固体，1.3g，产率84％)。Referring to the synthesis method of compound 1c, compound 15b was obtained (white solid, 1.3 g, yield 84%).
LC-MS m/z(ESI)＝391.23[M+1]。LC-MS m/z (ESI) = 391.23 [M+1].
第二步second step
(R)-6-甲基-5-(哌嗪-1-基)-N-(四氢呋喃-3-基)吡啶酰胺15c(R)-6-Methyl-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyridineamide 15c
(R)-6-methyl-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide(R)-6-methyl-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
参考化合物1d的合成方法，得到化合物15c(白色固体，1.1mg，产率89％)。Referring to the synthesis method of compound 1d, compound 15c was obtained (white solid, 1.1 mg, yield 89%).
LC-MS m/z(ESI)＝291.17[M+1]。LC-MS m/z (ESI) = 291.17 [M+1].
第三步third step
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基-N-(四氢呋喃-3-基)吡啶酰胺化合物15(R)-5-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 6-Methyl-N-(tetrahydrofuran-3-yl)pyridine amide compound 15
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N- (tetrahydrofuran-3-yl)picolinamide
参考化合物1的合成方法，得到化合物15(白色固体，26mg，产率77％)。Referring to the synthesis method of compound 1, compound 15 (white solid, 26 mg, yield 77%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ11.88(s,1H),8.41(s,1H),8.38(d,1H),7.80(d,1H),7.75(s,1H),7.63(s,1H),7.48(d,1H),4.49-4.44(m,1H),3.90–3.79(m,2H),3.74-3.70(m,1H),3.67(s,2H),3.61-3.58(m,1H),2.96-2.94(m,4H),2.64–2.59(m,4H),2.57-2.53(m,2H),2.50(s,3H),2.22–2.11(m,1H),2.05–1.84(m,1H),1.18(t,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.88(s,1H), 8.41(s,1H), 8.38(d,1H), 7.80(d,1H), 7.75(s,1H), 7.63( s, 1H), 7.48(d, 1H), 4.49-4.44(m, 1H), 3.90-3.79(m, 2H), 3.74-3.70(m, 1H), 3.67(s, 2H), 3.61-3.58( m,1H), 2.96-2.94(m,4H), 2.64-2.59(m,4H), 2.57-2.53(m,2H), 2.50(s,3H), 2.22-2.11(m,1H), 2.05- 1.84(m, 1H), 1.18(t, 3H).
LC-MS m/z(ESI)＝477.25[M+1]。LC-MS m/z (ESI) = 477.25 [M+1].
实施例16Example 16
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲氧基-N-(四氢呋喃-3-基)吡啶酰胺化合物16(R)-5-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 6-Methoxy-N-(tetrahydrofuran-3-yl)pyridine amide compound 16
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methoxy-N-(tetrahydrofuran-3-yl)picolinamide(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methoxy-N- (tetrahydrofuran-3-yl)picolinamide
Figure PCTCN2022087966-appb-000030
Figure PCTCN2022087966-appb-000030
第一步first step
叔丁基(R)-4-(4-甲氧基-6-((四氢呋喃-3-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸酯16btert-Butyl(R)-4-(4-methoxy-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate 16b
tert-butyl(R)-4-(4-methoxy-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylatetert-butyl(R)-4-(4-methoxy-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法，得到化合物16b(黄色固体，1.2g，产率79％)。Referring to the synthesis method of compound 1c, compound 16b was obtained (yellow solid, 1.2 g, yield 79%).
LC-MS m/z(ESI)＝407.48[M+1]。LC-MS m/z (ESI) = 407.48 [M+1].
第二步second step
(R)-4-甲氧基-5-(哌嗪-1-基)-N-(四氢呋喃-3-基)吡啶酰胺16c(R)-4-Methoxy-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyridineamide 16c
(R)-4-methoxy-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide(R)-4-methoxy-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
参考化合物1d的合成方法，得到化合物16c(白色固体，920mg，产率86％)。Referring to the synthesis method of compound 1d, compound 16c (white solid, 920 mg, yield 86%) was obtained.
LC-MS m/z(ESI)＝307.37[M+1]。LC-MS m/z (ESI) = 307.37 [M+1].
第三步third step
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲氧基-N-(四氢呋喃-3-基)吡啶酰胺化合物16(R)-5-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 6-Methoxy-N-(tetrahydrofuran-3-yl)pyridine amide compound 16
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methoxy-N-(tetrahydrofuran-3-yl)picolinamide(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methoxy-N- (tetrahydrofuran-3-yl)picolinamide
参考化合物化合物1的合成方法，得到化合物化合物16(白色固体，56mg，产率76％)。Referring to the synthesis method of compound compound 1, compound compound 16 (white solid, 56 mg, yield 76%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ11.88(s,1H),8.40(d,1H),8.12(d,1H),7.75(s,1H),7.62(d,1H),7.55(d,1H),7.25(d,1H),4.52–4.40(m,1H),3.99(s,3H),3.86(qd,2H),3.71(td,1H),3.64(s,2H),3.60(dd,1H),3.10(s,4H),2.54(t,6H),2.17(dtd,1H),2.02–1.84(m,1H),1.18(t,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.88(s,1H), 8.40(d,1H), 8.12(d,1H), 7.75(s,1H), 7.62(d,1H), 7.55( d, 1H), 7.25(d, 1H), 4.52–4.40(m, 1H), 3.99(s, 3H), 3.86(qd, 2H), 3.71(td, 1H), 3.64(s, 2H), 3.60 (dd, 1H), 3.10 (s, 4H), 2.54 (t, 6H), 2.17 (dtd, 1H), 2.02–1.84 (m, 1H), 1.18 (t, 3H).
LC-MS m/z(ESI)＝493.58[M+1]。LC-MS m/z (ESI) = 493.58 [M+1].
实施例17Example 17
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-(甲基-d 3)-N-(四氢呋喃-3-基)吡啶酰胺化合物17 (R)-5-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 6-(Methyl-d 3 )-N-(tetrahydrofuran-3-yl) pyridine amide compound 17
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-(methyl-d 3)-N-(tetrahydrofuran-3-yl)picolinamide (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-(methyl-d 3 )-N-(tetrahydrofuran-3-yl)picolinamide
Figure PCTCN2022087966-appb-000031
Figure PCTCN2022087966-appb-000031
第一步first step
5-氟-6-(甲基-d 3)吡啶甲酸甲酯17b Methyl 5-fluoro-6-(methyl-d 3 )picolinate 17b
methyl 5-fluoro-6-(methyl-d 3)picolinate methyl 5-fluoro-6-(methyl-d 3 )picolinate
取100mL反应瓶干燥，抽换N 2，N 2条件下加入6-溴-5-氟吡啶甲酸甲酯(17a，10mmol)、甲基硼酸-d 3(11mmol)、Pd(dppf)Cl 2(0.5mmol)、K 2CO 3(20mmol)和1,4-二氧六环(50mL)，100℃搅拌反应12小时。反应完成后过滤收集滤液，旋蒸除去溶剂，柱层析分离得到化合物17b(无色油状物，产率70％)。 The 100 mL reaction flask was dried, and N 2 was replaced. Under N 2 , methyl 6-bromo-5-fluoropicolinate (17a, 10 mmol), methylboronic acid-d 3 (11 mmol), Pd(dppf)Cl 2 ( 0.5 mmol), K 2 CO 3 (20 mmol) and 1,4-dioxane (50 mL), and the reaction was stirred at 100° C. for 12 hours. After the completion of the reaction, the filtrate was collected by filtration, the solvent was removed by rotary evaporation, and the compound 17b was obtained by column chromatography (colorless oil, yield 70%).
LC-MS m/z(ESI)＝173.2[M+1]。LC-MS m/z (ESI) = 173.2 [M+1].
第二步second step
4-(6-(甲氧羰基)-2-(甲基-d 3)吡啶-3-基)哌嗪-1-羧酸叔丁酯17c 4-(6-(Methoxycarbonyl)-2-(methyl-d 3 )pyridin-3-yl)piperazine-1-carboxylate tert-butyl ester 17c
tert-butyl 4-(6-(methoxycarbonyl)-2-(methyl-d 3)pyridin-3-yl)piperazine-1-carboxylate tert-butyl 4-(6-(methoxycarbonyl)-2-(methyl-d 3 )pyridin-3-yl)piperazine-1-carboxylate
取50mL反应瓶干燥，抽换N 2，N 2条件下加入17b(5mmol)、K 2CO 3(15mmol)、哌嗪-1-羧酸叔丁酯(10mmol)和20mL DMF，120℃搅拌反应12小时。反应完成后加入100mL水，EA萃取3次，合并有机相Na 2SO 4干燥，旋蒸除去溶剂，组层析分离得到化合物17c(白色固体，产率63％)。 A 50 mL reaction flask was taken and dried, and N 2 was replaced by suction. Under N 2 , 17b (5 mmol), K 2 CO 3 (15 mmol), tert-butyl piperazine-1-carboxylate (10 mmol) and 20 mL of DMF were added, and the reaction was stirred at 120° C. 12 hours. After the reaction was completed, 100 mL of water was added, extracted three times with EA, the combined organic phases were dried over Na 2 SO 4 , and the solvent was removed by rotary evaporation. Compound 17c was isolated by group chromatography (white solid, yield 63%).
LC-MS m/z(ESI)＝339.2[M+1]。LC-MS m/z (ESI) = 339.2 [M+1].
第三步third step
叔丁基(R)-4-(2-(甲基-d 3)-6-((四氢呋喃-3-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸酯17d tert-Butyl (R)-4-(2-(methyl-d 3 )-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate 17d
tert-butyl(R)-4-(2-(methyl-d 3)-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate tert-butyl(R)-4-(2-(methyl-d 3 )-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法，得到化合物17c(黄色固体，1.2g，产率80％)。Referring to the synthesis method of compound 1c, compound 17c (yellow solid, 1.2 g, yield 80%) was obtained.
LC-MS m/z(ESI)＝394.2[M+1]。LC-MS m/z (ESI) = 394.2 [M+1].
第四步the fourth step
(R)-6-(甲基-d 3)-5-(哌嗪-1-基)-N-(四氢呋喃-3-基)吡啶酰胺17e (R)-6-(Methyl-d 3 )-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyridineamide 17e
(R)-6-(methyl-d 3)-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide (R)-6-(methyl-d 3 )-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
参考化合物1d的合成方法，得到化合物17e(黄色固体，1.2g，产率80％)。Referring to the synthesis method of compound 1d, compound 17e (yellow solid, 1.2 g, yield 80%) was obtained.
LC-MS m/z(ESI)＝294.2[M+1]。LC-MS m/z (ESI) = 294.2 [M+1].
第五步the fifth step
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-(甲基-d 3)-N-(四氢呋喃-3-基)吡啶酰胺 (R)-5-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 6-(Methyl-d 3 )-N-(tetrahydrofuran-3-yl)pyridineamide
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-(methyl-d 3)-N-(tetrahydrofuran-3-yl)picolinamide (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-(methyl-d 3 )-N-(tetrahydrofuran-3-yl)picolinamide
参考化合物1的合成方法，得到化合物17(黄色固体，17g，产率39％)。Referring to the synthesis method of compound 1, compound 17 (yellow solid, 17 g, yield 39%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ11.88(s,1H),8.41(s,1H),8.38(d,1H),7.80(d,1H),7.75(s,1H),7.63(s,1H),7.48(d,1H),4.49-4.44(m,1H),3.90–3.79(m,2H),3.74-3.70(m,1H),3.67(s,2H),3.61-3.58(m,1H),2.96-2.94(m,4H),2.64–2.59(m,4H),2.57-2.53(m,2H),2.22–2.11(m,1H),2.05–1.84(m,1H),1.18(t,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.88(s,1H), 8.41(s,1H), 8.38(d,1H), 7.80(d,1H), 7.75(s,1H), 7.63( s, 1H), 7.48(d, 1H), 4.49-4.44(m, 1H), 3.90-3.79(m, 2H), 3.74-3.70(m, 1H), 3.67(s, 2H), 3.61-3.58( m,1H), 2.96-2.94(m,4H), 2.64-2.59(m,4H), 2.57-2.53(m,2H), 2.22-2.11(m,1H), 2.05-1.84(m,1H), 1.18(t, 3H).
LC-MS m/z(ESI)＝480.3[M+1]。LC-MS m/z (ESI) = 480.3 [M+1].
实施例18Example 18
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基-d 2)哌嗪-1-基)-N-(四氢呋喃-3-基)吡啶酰胺化合物18 (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl-d 2 )piperazine-1- yl)-N-(tetrahydrofuran-3-yl)pyridine amide compound 18
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl-d 2)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl-d 2 )piperazin-1-yl)-N-( tetrahydrofuran-3-yl)picolinamide
Figure PCTCN2022087966-appb-000032
Figure PCTCN2022087966-appb-000032
Figure PCTCN2022087966-appb-000033
Figure PCTCN2022087966-appb-000033
第一步first step
3-乙基-7-(羟甲基-d 2)-1,5-萘啶-2(1H)-酮18b 3-Ethyl-7-(hydroxymethyl-d 2 )-1,5-naphthyridin-2(1H)-one 18b
3-ethyl-7-(hydroxymethyl-d 2)-1,5-naphthyridin-2(1H)-one 3-ethyl-7-(hydroxymethyl-d 2 )-1,5-naphthyridin-2(1H)-one
将化合物18a(2.7g，9mmol)溶于四氢呋喃(10mL)，在冰水浴下缓慢滴加四氘锂铝的四氢呋喃溶液(购自安耐吉化学，18mL，18mmol)，滴加完搅拌10min，加入乙酸乙酯(5mL)，减压浓缩柱层析得到得到18b(白色固体，1.2g，产率63％)。Compound 18a (2.7 g, 9 mmol) was dissolved in tetrahydrofuran (10 mL), and a solution of tetradeuterium lithium aluminum in tetrahydrofuran (purchased from Annagy Chemical, 18 mL, 18 mmol) was slowly added dropwise in an ice-water bath, and the solution was stirred for 10 min after the dropwise addition. Ethyl acetate (5 mL) was concentrated under reduced pressure by column chromatography to give 18b (white solid, 1.2 g, 63% yield).
LC-MS m/z(ESI)＝207.2[M+1]。LC-MS m/z (ESI) = 207.2 [M+1].
第二步second step
7-(溴甲基-d 2)-3-乙基-1,5-萘啶-2(1H)-酮18c 7-(Bromomethyl-d 2 )-3-ethyl-1,5-naphthyridin-2(1H)-one 18c
7-(bromomethyl-d 2)-3-ethyl-1,5-naphthyridin-2(1H)-one 7-(bromomethyl-d 2 )-3-ethyl-1,5-naphthyridin-2(1H)-one
将化合物18b(430mg，2mmol)和三苯基膦(购自上海阿达玛斯试剂有限公司，2183mg，4mmol)溶于二氯甲烷(5mL)，在冰水浴下加入四溴化碳(购自安耐吉化学，1.3g，4mmol)的二氯甲烷(2mL)溶液，反应0.5h，反应液减压浓缩后经柱层析得到18c(白色固体，450mg，产率80％)。Compound 18b (430 mg, 2 mmol) and triphenylphosphine (purchased from Shanghai Adamas Reagent Co., Ltd., 2183 mg, 4 mmol) were dissolved in dichloromethane (5 mL), and carbon tetrabromide (purchased from Anton) was added under an ice-water bath. Nagy Chemical, 1.3 g, 4 mmol) in dichloromethane (2 mL), reacted for 0.5 h, the reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain 18c (white solid, 450 mg, yield 80%).
LC-MS m/z(ESI)＝269.1[M+1]。LC-MS m/z (ESI) = 269.1 [M+1].
第三步third step
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基-d 2)哌嗪-1-基)-N-(四氢呋喃-3-基)吡啶酰胺化合物18 (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl-d 2 )piperazine-1- yl)-N-(tetrahydrofuran-3-yl)pyridine amide compound 18
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl-d 2)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl-d 2 )piperazin-1-yl)-N-( tetrahydrofuran-3-yl)picolinamide
参考化合物1的合成方法，得到化合物18(白色固体，46mg，产率49％)。Referring to the synthesis method of compound 1, compound 18 (white solid, 46 mg, yield 49%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ11.86(s,1H),8.43-8.34(m,2H),8.27(d,1H),7.83(d,1H),7.74(d,1H),7.62(d,1H),7.39(dd,1H),4.51-4.38(m,1H),3.83(ddd,2H),3.71(td,1H),3.56(dd,1H),3.33(d,3H),2.58-2.50(m,6H),2.14(dtd,1H),1.99-1.85(m,1H),1.18(q,4H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.86(s,1H), 8.43-8.34(m,2H), 8.27(d,1H), 7.83(d,1H), 7.74(d,1H), 7.62(d,1H),7.39(dd,1H),4.51-4.38(m,1H),3.83(ddd,2H),3.71(td,1H),3.56(dd,1H),3.33(d,3H) , 2.58-2.50 (m, 6H), 2.14 (dtd, 1H), 1.99-1.85 (m, 1H), 1.18 (q, 4H).
LC-MS m/z(ESI)＝465.3[M+1]。LC-MS m/z (ESI) = 465.3 [M+1].
实施例19Example 19
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基-d 2)哌嗪-1-基)-6-(甲基-d 3)-N-(四氢呋喃-3-基)吡啶酰胺化合物19 (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl-d 2 )piperazine-1- yl)-6-(methyl-d 3 )-N-(tetrahydrofuran-3-yl) pyridine amide compound 19
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl-d 2)piperazin-1-yl)-6-(methyl-d 3)-N-(tetrahydrofuran-3-yl)picolinamide (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl-d 2 )piperazin-1-yl)-6-( methyl-d 3 )-N-(tetrahydrofuran-3-yl)picolinamide
Figure PCTCN2022087966-appb-000034
Figure PCTCN2022087966-appb-000034
参考化合物1的合成方法，得到化合物19(白色固体，28mg，产率41％)。Referring to the synthesis method of compound 1, compound 19 (white solid, 28 mg, yield 41%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ11.88(s,1H),8.41(s,1H),8.38(d,1H),7.80(d,1H),7.75(s,1H),7.63(s,1H),7.48(d,1H),4.49-4.44(m,1H),3.90–3.79(m,2H),3.74-3.70(m,1H),3.61-3.58(m,1H),2.96-2.94(m,4H),2.64–2.59(m,4H),2.57-2.53(m,2H),2.22–2.11(m,1H),2.05–1.84(m,1H),1.18(t,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.88(s,1H), 8.41(s,1H), 8.38(d,1H), 7.80(d,1H), 7.75(s,1H), 7.63( s, 1H), 7.48(d, 1H), 4.49-4.44(m, 1H), 3.90-3.79(m, 2H), 3.74-3.70(m, 1H), 3.61-3.58(m, 1H), 2.96- 2.94 (m, 4H), 2.64–2.59 (m, 4H), 2.57–2.53 (m, 2H), 2.22–2.11 (m, 1H), 2.05–1.84 (m, 1H), 1.18 (t, 3H).
LC-MS m/z(ESI)＝482.3[M+1]。LC-MS m/z (ESI) = 482.3 [M+1].
实施例20Example 20
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-((3S,4R)-4-羟基四氢呋喃-3-基)-6-甲基吡啶酰胺化合物205-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(( 3S,4R)-4-hydroxytetrahydrofuran-3-yl)-6-picoline amide compound 20
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-6-methylpicolinamide5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4 -hydroxytetrahydrofuran-3-yl)-6-methylpicolinamide
Figure PCTCN2022087966-appb-000035
Figure PCTCN2022087966-appb-000035
第一步first step
5-溴-6-甲基吡啶甲酸甲酯20bMethyl 5-bromo-6-methylpicolinate 20b
methyl 5-bromo-6-methylpicolinatemethyl 5-bromo-6-methylpicolinate
将20a(2g，9.26mmol)溶解于甲醇(20mL)，然后在冰水浴下缓慢滴加二氯亚砜(20mL)，滴加完将反应瓶置于油浴80℃回流2小时。反应完成后减压浓缩，用饱和碳酸钠溶液调节pH到中性，乙酸乙酯(50mL×3)萃取，合并有机相，干燥，过滤，减压浓缩得到20b(黄色固体，2g，产率94％)。20a (2 g, 9.26 mmol) was dissolved in methanol (20 mL), and then thionyl chloride (20 mL) was slowly added dropwise in an ice-water bath. After the dropwise addition, the reaction flask was placed in an oil bath at 80° C. and refluxed for 2 hours. After the reaction was completed, it was concentrated under reduced pressure, adjusted to neutral pH with saturated sodium carbonate solution, extracted with ethyl acetate (50 mL×3), combined with the organic phases, dried, filtered, and concentrated under reduced pressure to obtain 20b (yellow solid, 2 g, yield 94 %).
1H NMR(400MHz,DMSO-d6)δ8.20(d,1H),7.78(d,1H),3.86(s,3H),2.62(s,3H)。 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (d, 1H), 7.78 (d, 1H), 3.86 (s, 3H), 2.62 (s, 3H).
LC-MS m/z(ESI)＝229.90[M+1]。LC-MS m/z (ESI) = 229.90 [M+1].
第二步second step
4-(6-(甲氧羰基)-2-甲基吡啶-3-基)哌嗪-1-羧酸叔丁酯20c4-(6-(Methoxycarbonyl)-2-methylpyridin-3-yl)piperazine-1-carboxylate tert-butyl ester 20c
tert-butyl 4-(6-(methoxycarbonyl)-2-methylpyridin-3-yl)piperazine-1-carboxylatetert-butyl 4-(6-(methoxycarbonyl)-2-methylpyridin-3-yl)piperazine-1-carboxylate
将20b(2g，8.70mmol)、哌嗪-1-羧酸叔丁酯(1.78g，9.56mmol)、RuPhos Pd G3(364mg，0.44mmol)、碳酸铯(11g，34.8mmol)溶解于二氧六环(40mL)在110℃下回流4小时。反应完成后加入水(50mL)，乙酸乙酯(50mL*3)萃取，合并有机相，干燥，过滤，减压浓缩后使用硅胶(200-300目)柱层析(DCM:EA＝3-1)分离，得到20c(白色固体，2.2g，产率75％)。20b (2 g, 8.70 mmol), tert-butyl piperazine-1-carboxylate (1.78 g, 9.56 mmol), RuPhos Pd G3 (364 mg, 0.44 mmol), cesium carbonate (11 g, 34.8 mmol) were dissolved in dioxane The ring (40 mL) was refluxed at 110 °C for 4 hours. After the reaction was completed, water (50 mL) was added, extracted with ethyl acetate (50 mL*3), the organic phases were combined, dried, filtered, concentrated under reduced pressure, and then used silica gel (200-300 mesh) column chromatography (DCM:EA=3-1 ) was isolated to give 20c (white solid, 2.2 g, 75% yield).
LC-MS m/z(ESI)＝336.20[M+1]。LC-MS m/z (ESI) = 336.20 [M+1].
第三步third step
5-(4-(叔丁氧羰基)哌嗪-1-基)-6-甲基吡啶甲酸20d5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-methylpicolinic acid 20d
5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-methylpicolinic acid5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-methylpicolinic acid
将20c(2.2g，6.5mmol)溶解于(四氢呋喃：甲醇：水＝1：1：1，20mL)中，加入氢氧化锂(0.78g，32.7mmol)，在常温下过夜反应。反应完成后减压浓缩有机相，乙酸乙酯(10mL*2)萃取，收集水相用1M盐酸调节pH至2-3，搅拌30分钟，析出大量固体，过滤，收集滤饼。烘干后得到20d(黄色固体，2g，产率95％)。20c (2.2 g, 6.5 mmol) was dissolved in (tetrahydrofuran:methanol:water=1:1:1, 20 mL), lithium hydroxide (0.78 g, 32.7 mmol) was added, and the reaction was carried out at room temperature overnight. After the reaction was completed, the organic phase was concentrated under reduced pressure, extracted with ethyl acetate (10 mL*2), the aqueous phase was collected and adjusted to pH 2-3 with 1M hydrochloric acid, stirred for 30 minutes, a large amount of solid was precipitated, filtered, and the filter cake was collected. After drying, 20d (yellow solid, 2 g, 95% yield) was obtained.
LC-MS m/z(ESI)＝322.20[M+1]。LC-MS m/z (ESI) = 322.20 [M+1].
第四步the fourth step
4-(6-((3S,4R)-4-羟基四氢呋喃-3-基)氨甲酰)-2-甲基吡啶-3-基)哌嗪-1-羧酸叔丁酯20e4-(6-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)carbamoyl)-2-methylpyridin-3-yl)piperazine-1-carboxylate tert-butyl ester 20e
tert-butyl 4-(6-(((3S,4R)-4-hydroxytetrahydrofuran-3-yl)carbamoyl)-2-methylpyridin-3-yl)piperazine-1-carboxylatetert-butyl 4-(6-(((3S,4R)-4-hydroxytetrahydrofuran-3-yl)carbamoyl)-2-methylpyridin-3-yl)piperazine-1-carboxylate
参考化合物2b的合成方法，得到化合物20e(白色固体，150mg，产率95％)。Referring to the synthesis method of compound 2b, compound 20e (white solid, 150 mg, yield 95%) was obtained.
1H NMR(400MHz,DMSO-d6)δ8.31(d,1H),7.82(d,1H),7.50(d,1H),4.25(p,1H),4.22-4.17(m,1H),3.95(ddd,2H),3.64(dd,1H),3.50-3.48(m,4H),3.13-3.07(m,2H),2.89-2.87(m,4H),2.52(s,3H),1.42(s,9H)。 1 H NMR (400MHz, DMSO-d6)δ8.31(d,1H), 7.82(d,1H), 7.50(d,1H), 4.25(p,1H), 4.22-4.17(m,1H), 3.95 (ddd,2H),3.64(dd,1H),3.50-3.48(m,4H),3.13-3.07(m,2H),2.89-2.87(m,4H),2.52(s,3H),1.42(s , 9H).
LC-MS m/z(ESI)＝407.20[M+1]。LC-MS m/z (ESI) = 407.20 [M+1].
第五步the fifth step
N-((3S，4R)-4-羟基四氢呋喃-3-基)-6-甲基-5-(哌嗪-1-基)吡啶酰胺20fN-((3S,4R)-4-Hydroxytetrahydrofuran-3-yl)-6-methyl-5-(piperazin-1-yl)pyridineamide 20f
N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-6-methyl-5-(piperazin-1-yl)picolinamideN-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-6-methyl-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法，得到化合物20f(白色固体，110mg，产率97％)。Referring to the synthesis method of compound 1d, compound 20f (white solid, 110 mg, yield 97%) was obtained.
LC-MS m/z(ESI)＝307.20[M+1]。LC-MS m/z (ESI) = 307.20 [M+1].
第六步Step 6
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-((3S,4R)-4-羟基四氢呋喃-3-基)-6-甲基吡啶酰胺化合物205-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(( 3S,4R)-4-hydroxytetrahydrofuran-3-yl)-6-picoline amide compound 20
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-6-methylpicolinamide5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4 -hydroxytetrahydrofuran-3-yl)-6-methylpicolinamide
参考化合物6的合成方法，合成分离得到化合物20(白色固体，40mg，产率46％)。Referring to the synthesis method of compound 6, compound 20 (white solid, 40 mg, yield 46%) was synthesized and isolated.
1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.41(s,1H),8.29(d,1H),7.81(d,1H),7.75(s,1H),7.62(s,1H),7.49(d,1H),5.34(d,1H),4.25–4.22(m,1H),4.21–4.16(m,1H), 3.94(ddd,2H),3.67(s,2H),3.63(dd,1H),3.51(dd,1H),2.96–2.93(m,4H),2.64–2.51(m,9H),1.18(t,3H)。 1 H NMR (400MHz, DMSO-d6)δ11.87(s,1H), 8.41(s,1H), 8.29(d,1H), 7.81(d,1H), 7.75(s,1H), 7.62(s ,1H),7.49(d,1H),5.34(d,1H),4.25–4.22(m,1H),4.21–4.16(m,1H), 3.94(ddd,2H),3.67(s,2H), 3.63 (dd, 1H), 3.51 (dd, 1H), 2.96–2.93 (m, 4H), 2.64–2.51 (m, 9H), 1.18 (t, 3H).
LC-MS m/z(ESI)＝493.20[M+1]。LC-MS m/z (ESI) = 493.20 [M+1].
实施例21Example 21
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基-N-(3-甲基四氢呋喃-3-基)吡啶酰胺化合物215-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl -N-(3-Methyltetrahydrofuran-3-yl)pyridine amide compound 21
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(3-methyltetrahydrofuran-3-yl)picolinamide5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(3-methyltetrahydrofuran -3-yl)picolinamide
Figure PCTCN2022087966-appb-000036
Figure PCTCN2022087966-appb-000036
第一步first step
4-(2-甲基-6-((3-甲基四氢呋喃-3-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯21a4-(2-Methyl-6-((3-methyltetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate tert-butyl ester 21a
tert-butyl 4-(2-methyl-6-((3-methyltetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylatetert-butyl 4-(2-methyl-6-((3-methyltetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物2b的合成方法，得到化合物21a(白色固体，140mg，产率90％)。Referring to the synthesis method of compound 2b, compound 21a (white solid, 140 mg, yield 90%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ8.23(s,1H),7.80(d,1H),7.50(d,1H),3.96(d,1H),3.84–3.77(m,2H),3.63(d,1H),3.80–3.48(m,4H),2.88–2.86(m,4H),2.52(s,3H),2.40(dt,1H),1.95(dt,1H),1.47(s,3H),1.42(s,9H)。 1 H NMR (400MHz, DMSO-d 6 )δ8.23(s, 1H), 7.80(d, 1H), 7.50(d, 1H), 3.96(d, 1H), 3.84-3.77(m, 2H), 3.63(d,1H), 3.80–3.48(m,4H), 2.88–2.86(m,4H), 2.52(s,3H), 2.40(dt,1H), 1.95(dt,1H), 1.47(s, 3H), 1.42 (s, 9H).
LC-MS m/z(ESI)＝405.20[M+1]。LC-MS m/z (ESI) = 405.20 [M+1].
第二步second step
6-甲基-N-(3-甲基四氢呋喃-3-基)-5-(哌嗪-1-基)吡啶酰胺21b6-Methyl-N-(3-methyltetrahydrofuran-3-yl)-5-(piperazin-1-yl)pyridineamide 21b
6-methyl-N-(3-methyltetrahydrofuran-3-yl)-5-(piperazin-1-yl)picolinamide6-methyl-N-(3-methyltetrahydrofuran-3-yl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法，得到化合物21b(白色固体，100mg，产率95％)。Referring to the synthesis method of compound 1d, compound 21b (white solid, 100 mg, yield 95%) was obtained.
LC-MS m/z(ESI)＝305.20[M+1]。LC-MS m/z (ESI) = 305.20 [M+1].
第三步third step
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基-N-(3-甲基四氢呋喃-3-基)吡啶酰胺化合物215-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl -N-(3-Methyltetrahydrofuran-3-yl)pyridine amide compound 21
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(3-methyltetrahydrofuran-3-yl)picolinamide5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(3-methyltetrahydrofuran -3-yl)picolinamide
参考化合物6的合成方法，合成分离得到化合物21(白色固体，35mg，产率40％)。Referring to the synthesis method of compound 6, compound 21 was synthesized and isolated (white solid, 35 mg, yield 40%).
1H NMR(400MHz,DMSO-d 6)δ11.87(s,1H),8.41(s,1H),8.21(s,1H),7.79(d,1H),7.75(s,1H),7.62(s,1H),7.49(d,1H),3.96(d,1H),3.85–3.76(m,2H),3.67(s,2H),3.62(d,1H),2.96–2.93(m,4H),2.65–2.51(m,9H),2.43–2.35(m,1H),2.01–1.90(m,1H),1.47(s,3H),1.18(t,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.87(s,1H), 8.41(s,1H), 8.21(s,1H), 7.79(d,1H), 7.75(s,1H), 7.62( s, 1H), 7.49 (d, 1H), 3.96 (d, 1H), 3.85–3.76 (m, 2H), 3.67 (s, 2H), 3.62 (d, 1H), 2.96–2.93 (m, 4H) , 2.65–2.51 (m, 9H), 2.43–2.35 (m, 1H), 2.01–1.90 (m, 1H), 1.47 (s, 3H), 1.18 (t, 3H).
LC-MS m/z(ESI)＝491.30[M+1]。LC-MS m/z (ESI) = 491.30 [M+1].
实施例22Example 22
N-(3-噁唑环[3.1.0]己烷-6-基)-5-(4-((7-乙基-6-氧基-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基吡啶酰胺化合物22N-(3-oxazolecyclo[3.1.0]hexane-6-yl)-5-(4-((7-ethyl-6-oxy-5,6-dihydro-1,5-naphthalene Perid-3-yl)methyl)piperazin-1-yl)-6-methylpyridine amide compound 22
N-(3-oxabicyclo[3.1.0]hexan-6-yl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methylpicolinamideN-(3-oxabicyclo[3.1.0]hexan-6-yl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl )piperazin-1-yl)-6-methylpicolinamide
Figure PCTCN2022087966-appb-000037
Figure PCTCN2022087966-appb-000037
第一步first step
4-(6-((3-噁唑环[3.1.0]己烷-6-基)氨甲酰)-2-甲基吡啶-3-基)哌嗪-1-羧酸叔丁酯22a4-(6-((3-oxazolecyclo[3.1.0]hexane-6-yl)carbamoyl)-2-methylpyridin-3-yl)piperazine-1-carboxylate tert-butyl ester 22a
tert-butyl 4-(6-((3-oxabicyclo[3.1.0]hexan-6-yl)carbamoyl)-2-methylpyridin-3-yl)piperazine-1-carboxylatetert-butyl 4-(6-((3-oxabicyclo[3.1.0]hexan-6-yl)carbamoyl)-2-methylpyridin-3-yl)piperazine-1-carboxylate
参考化合物2b的合成方法，得到化合物22a(白色固体，110mg，产率81％)。Referring to the synthesis method of compound 2b, compound 22a (white solid, 110 mg, yield 81%) was obtained.
1H NMR(400MHz,DMSO-d6)δ8.45(d,1H),7.78(d,1H),7.49(d,1H),3.86(s,1H),3.84(s,1H),3.63(s,1H),3.62(s,1H),3.49–2.40(m,4H),2.93–2.84(m,4H),2.60–2.58(m,1H),2.52(s,3H),1.98–1.97(m,2H),1.42(s,9H)。 1 H NMR (400MHz, DMSO-d6)δ8.45(d,1H), 7.78(d,1H), 7.49(d,1H), 3.86(s,1H), 3.84(s,1H), 3.63(s ,1H),3.62(s,1H),3.49–2.40(m,4H),2.93–2.84(m,4H),2.60–2.58(m,1H),2.52(s,3H),1.98–1.97(m , 2H), 1.42(s, 9H).
LC-MS m/z(ESI)＝403.20[M+1]。LC-MS m/z (ESI) = 403.20 [M+1].
第二步second step
N-(3-氧杂环[3.1.0]己烷-6-基)-6-甲基-5-(哌嗪-1-基)吡啶酰胺22bN-(3-oxacyclo[3.1.0]hexane-6-yl)-6-methyl-5-(piperazin-1-yl)pyridinamide 22b
N-(3-oxabicyclo[3.1.0]hexan-6-yl)-6-methyl-5-(piperazin-1-yl)picolinamideN-(3-oxabicyclo[3.1.0]hexan-6-yl)-6-methyl-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法，得到化合物22b(白色固体，80mg，产率96％)。Referring to the synthesis method of compound 1d, compound 22b (white solid, 80 mg, yield 96%) was obtained.
LC-MS m/z(ESI)＝303.20[M+1]。LC-MS m/z (ESI) = 303.20 [M+1].
第三步third step
N-(3-噁唑环[3.1.0]己烷-6-基)-5-(4-((7-乙基-6-氧基-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基吡啶酰胺化合物22N-(3-oxazolecyclo[3.1.0]hexane-6-yl)-5-(4-((7-ethyl-6-oxy-5,6-dihydro-1,5-naphthalene Perid-3-yl)methyl)piperazin-1-yl)-6-methylpyridine amide compound 22
N-(3-oxabicyclo[3.1.0]hexan-6-yl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methylpicolinamideN-(3-oxabicyclo[3.1.0]hexan-6-yl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl )piperazin-1-yl)-6-methylpicolinamide
参考化合物6的合成方法，合成分离得到化合物22(白色固体，30mg，产率42％)。Referring to the synthesis method of compound 6, compound 22 (white solid, 30 mg, yield 42%) was synthesized and isolated.
1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.44(d,1H),8.41(s,1H),7.78(d,1H),7.75(s,1H),7.62(s,1H),7.48(d,1H),3.85(d,2H),3.67(s,2H),3.62(d,2H),2.94–2.91(m,4H),2.61–2.53(m,7H),2.48(s,3H),1.97–1.96(m,2H),1.18(t,3H)。 1 H NMR (400MHz, DMSO-d6)δ11.87(s,1H), 8.44(d,1H), 8.41(s,1H), 7.78(d,1H), 7.75(s,1H), 7.62(s ,1H),7.48(d,1H),3.85(d,2H),3.67(s,2H),3.62(d,2H),2.94–2.91(m,4H),2.61–2.53(m,7H), 2.48(s, 3H), 1.97–1.96(m, 2H), 1.18(t, 3H).
LC-MS m/z(ESI)＝489.20[M+1]。LC-MS m/z (ESI) = 489.20 [M+1].
实施例23Example 23
(R)-6-氯-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(四氢呋喃-3-基)吡啶酰胺化合物23(R)-6-Chloro-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazine-1 -yl)-N-(tetrahydrofuran-3-yl)pyridine amide compound 23
(R)-6-chloro-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide(R)-6-chloro-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N- (tetrahydrofuran-3-yl)picolinamide
Figure PCTCN2022087966-appb-000038
Figure PCTCN2022087966-appb-000038
第一步first step
5-(4-(叔丁氧羰基)哌嗪-1-基)-6-氯吡啶甲酸23b5-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-6-chloropicolinic acid 23b
5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloropicolinic acid5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloropicolinic acid
参考1c的合成方法，得到23b(白色固体，700mg，产率68％)。Referring to the synthetic method of 1c, 23b was obtained (white solid, 700 mg, 68% yield).
LC-MS m/z(ESI)＝342.1[M+1]。LC-MS m/z (ESI) = 342.1 [M+1].
第二步second step
叔丁基(R)-4-(2-氯-6-((四氢呋喃-3-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸酯23ctert-Butyl(R)-4-(2-chloro-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate 23c
tert-butyl(R)-4-(2-chloro-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylatetert-butyl(R)-4-(2-chloro-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考2b的合成方法，得到23c(白色固体，340mg，产率53％)。Referring to the synthetic method of 2b, 23c was obtained (white solid, 340 mg, 53% yield).
LC-MS m/z(ESI)＝411.2[M+1]。LC-MS m/z (ESI) = 411.2 [M+1].
第三步third step
(R)-6-氯-5-(哌嗪-1-基)-N-(四氢呋喃-3-基)吡啶酰胺23d(R)-6-Chloro-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyridineamide 23d
(R)-6-chloro-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide(R)-6-chloro-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
参考1d的合成方法，得到23d(白色固体，170mg，产率67％)。Referring to the synthetic method of 1d, 23d (white solid, 170 mg, 67% yield) was obtained.
LC-MS m/z(ESI)＝311.2[M+1]。LC-MS m/z (ESI) = 311.2 [M+1].
第四步the fourth step
(R)-6-氯-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(四氢呋喃-3-基)吡啶酰胺化合物23(R)-6-Chloro-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazine-1 -yl)-N-(tetrahydrofuran-3-yl)pyridine amide compound 23
(R)-6-chloro-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide(R)-6-chloro-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N- (tetrahydrofuran-3-yl)picolinamide
参考化合物1的合成方法，得到化合物23(白色固体，23mg，产率55％)。Referring to the synthesis method of compound 1, compound 23 was obtained (white solid, 23 mg, yield 55%).
1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.40(d,2H),7.93(d,1H),7.74(s,1H),7.69–7.55(m,2H),4.45(dt,1H),3.83(ddd,2H),3.74–3.55(m,4H),3.49(t,2H),3.10(t,2H),2.65–2.54(m,6H),2.15(tq,1H),1.93(ddd,1H),1.17(t,3H)。 1 H NMR (400MHz, DMSO-d6) δ 11.87(s, 1H), 8.40(d, 2H), 7.93(d, 1H), 7.74(s, 1H), 7.69–7.55(m, 2H), 4.45 (dt, 1H), 3.83 (ddd, 2H), 3.74–3.55 (m, 4H), 3.49 (t, 2H), 3.10 (t, 2H), 2.65–2.54 (m, 6H), 2.15 (tq, 1H) ), 1.93(ddd, 1H), 1.17(t, 3H).
LC-MS m/z(ESI)＝497.2[M+1]。LC-MS m/z (ESI) = 497.2 [M+1].
实施例24Example 24
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(3-甲基四氢呋喃-3-基)吡啶酰胺化合物245-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(3 -Methyltetrahydrofuran-3-yl)pyridine amide compound 24
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(3-methyltetrahydrofuran-3-yl)picolinamide5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(3-methyltetrahydrofuran-3-yl) )picolinamide
Figure PCTCN2022087966-appb-000039
Figure PCTCN2022087966-appb-000039
第一步first step
5-溴-N-(3-甲基四氢呋喃-3-基)吡啶酰胺24a5-Bromo-N-(3-methyltetrahydrofuran-3-yl)pyridineamide 24a
5-bromo-N-(3-methyltetrahydrofuran-3-yl)picolinamide5-bromo-N-(3-methyltetrahydrofuran-3-yl)picolinamide
参考化合物2b的合成方法，得到化合物24a(黄色固体，1.4g，产率71％)。Referring to the synthesis method of compound 2b, compound 24a was obtained (yellow solid, 1.4 g, yield 71%).
LC-MS m/z(ESI)＝286.14[M+1]。LC-MS m/z (ESI) = 286.14 [M+1].
第二步second step
4-(6-((3-甲基四氢呋喃-3-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯24b4-(6-((3-Methyltetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate tert-butyl ester 24b
tert-butyl 4-(6-((3-methyltetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylatetert-butyl 4-(6-((3-methyltetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法，得到化合物24b(白色固体，1.1g，产率92％)。Referring to the synthesis method of compound 1c, compound 24b was obtained (white solid, 1.1 g, yield 92%).
LC-MS m/z(ESI)＝390.48[M+1]。LC-MS m/z (ESI) = 390.48 [M+1].
第三步third step
N-(3-甲基四氢呋喃-3-基)-5-(哌嗪-1-基)吡啶酰胺24cN-(3-Methyltetrahydrofuran-3-yl)-5-(piperazin-1-yl)pyridineamide 24c
N-(3-methyltetrahydrofuran-3-yl)-5-(piperazin-1-yl)picolinamideN-(3-methyltetrahydrofuran-3-yl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法，得到化合物24c(白色固体，920mg，产率89％)Referring to the synthesis method of compound 1d, compound 24c was obtained (white solid, 920 mg, yield 89%)
LC-MS m/z(ESI)＝291.37[M+1]。LC-MS m/z (ESI) = 291.37 [M+1].
第四步the fourth step
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(3-甲基四氢呋喃-3-基)吡啶酰胺化合物245-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(3 -Methyltetrahydrofuran-3-yl)pyridine amide compound 24
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(3-methyltetrahydrofuran-3-yl)picolinamide5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(3-methyltetrahydrofuran-3-yl) )picolinamide
参考化合物6的合成方法，得到化合物24(白色固体，27mg，产率53％)。Referring to the synthesis method of compound 6, compound 24 (white solid, 27 mg, yield 53%) was obtained.
LC-MS m/z(ESI)＝477.58[M+1]。LC-MS m/z (ESI) = 477.58 [M+1].
实施例25Example 25
N-(2-噁唑环[3.1.0]己烷-6-基)-5-(4-((7-乙基-6-氧基-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶酰胺化合物25N-(2-oxazolecyclo[3.1.0]hexane-6-yl)-5-(4-((7-ethyl-6-oxy-5,6-dihydro-1,5-naphthalene Perid-3-yl)methyl)piperazin-1-yl)pyridinamide compound 25
N-(2-oxabicyclo[3.1.0]hexan-6-yl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamideN-(2-oxabicyclo[3.1.0]hexan-6-yl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl )piperazin-1-yl)picolinamide
Figure PCTCN2022087966-appb-000040
Figure PCTCN2022087966-appb-000040
第一步first step
N-(2-噁唑环[3.1.0]正己烷-6-基)-5-溴哌啶酰胺25aN-(2-oxazolecyclo[3.1.0]n-hexane-6-yl)-5-bromopiperidine amide 25a
N-(2-oxabicyclo[3.1.0]hexan-6-yl)-5-bromopicolinamideN-(2-oxabicyclo[3.1.0]hexan-6-yl)-5-bromopicolinamide
参考化合物2b的合成方法，得到化合物25a(黄色固体，1.1g，产率74％)。Referring to the synthesis method of compound 2b, compound 25a (yellow solid, 1.1 g, yield 74%) was obtained.
LC-MS m/z(ESI)＝284.13[M+1]。LC-MS m/z (ESI) = 284.13 [M+1].
第二步second step
4-(6-((2-噁唑环[3.1.0]己烷-6-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯25b4-(6-((2-oxazolecyclo[3.1.0]hexane-6-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate tert-butyl ester 25b
tert-butyl 4-(6-((2-oxabicyclo[3.1.0]hexan-6-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylatetert-butyl 4-(6-((2-oxabicyclo[3.1.0]hexan-6-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法，得到化合物25b(白色固体，900mg，产率91％)。Referring to the synthesis method of compound 1c, compound 25b (white solid, 900 mg, yield 91%) was obtained.
LC-MS m/z(ESI)＝389.47[M+1]。LC-MS m/z (ESI) = 389.47 [M+1].
第三步third step
N-(2-噁唑环[3.1.0]己烷-6-基)-5-(哌嗪-1-基)吡啶酰胺25cN-(2-oxazolecyclo[3.1.0]hexane-6-yl)-5-(piperazin-1-yl)pyridineamide 25c
N-(2-oxabicyclo[3.1.0]hexan-6-yl)-5-(piperazin-1-yl)picolinamideN-(2-oxabicyclo[3.1.0]hexan-6-yl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法，得到化合物25c(白色固体，670mg，产率81％)Referring to the synthesis method of compound 1d, compound 25c was obtained (white solid, 670 mg, yield 81%)
LC-MS m/z(ESI)＝289.35[M+1]。LC-MS m/z (ESI) = 289.35 [M+1].
第四步the fourth step
N-(2-噁唑环[3.1.0]己烷-6-基)-5-(4-((7-乙基-6-氧基-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶酰胺化合物25N-(2-oxazolecyclo[3.1.0]hexane-6-yl)-5-(4-((7-ethyl-6-oxy-5,6-dihydro-1,5-naphthalene Perid-3-yl)methyl)piperazin-1-yl)pyridinamide compound 25
N-(2-oxabicyclo[3.1.0]hexan-6-yl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamideN-(2-oxabicyclo[3.1.0]hexan-6-yl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl )piperazin-1-yl)picolinamide
参考化合物6的合成方法，得到化合物25(白色固体，27mg，产率53％)。Referring to the synthesis method of compound 6, compound 25 (white solid, 27 mg, yield 53%) was obtained.
LC-MS m/z(ESI)＝475.57[M+1]。LC-MS m/z (ESI) = 475.57 [M+1].
实施例26Example 26
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-((3S，4R)-4-羟基四氢呋喃-3-基)吡啶酰胺化合物265-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(( 3S,4R)-4-hydroxytetrahydrofuran-3-yl)pyridine amide compound 26
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)picolinamide5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4 -hydroxytetrahydrofuran-3-yl)picolinamide
Figure PCTCN2022087966-appb-000041
Figure PCTCN2022087966-appb-000041
第一步first step
5-溴-N-((3S，4R)-4-羟基四氢呋喃-3-基)吡啶酰胺26a5-Bromo-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)pyridineamide 26a
5-bromo-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)picolinamide5-bromo-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)picolinamide
参考化合物2b的合成方法，得到化合物26a(黄色固体，1.1g，产率76％)。Referring to the synthesis method of compound 2b, compound 26a (yellow solid, 1.1 g, yield 76%) was obtained.
LC-MS m/z(ESI)＝288.11[M+1]。LC-MS m/z (ESI) = 288.11 [M+1].
第二步second step
4-(6-((3S，4R)-4-羟基四氢呋喃-3-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯26b4-(6-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate tert-butyl ester 26b
tert-butyl 4-(6-(((3S,4R)-4-hydroxytetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylatetert-butyl 4-(6-(((3S,4R)-4-hydroxytetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法，得到化合物26b(白色固体，900mg，产率92％)。Referring to the synthesis method of compound 1c, compound 26b (white solid, 900 mg, yield 92%) was obtained.
LC-MS m/z(ESI)＝393.46[M+1]。LC-MS m/z (ESI) = 393.46 [M+1].
第三步third step
N-((3S,4R)-4-羟基四氢呋喃-3-基)-5-(哌嗪-1-基)吡啶酰胺26cN-((3S,4R)-4-Hydroxytetrahydrofuran-3-yl)-5-(piperazin-1-yl)pyridinamide 26c
N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-5-(piperazin-1-yl)picolinamideN-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法，得到化合物26c(白色固体，640mg，产率89％)Referring to the synthesis method of compound 1d, compound 26c was obtained (white solid, 640 mg, yield 89%)
LC-MS m/z(ESI)＝293.46[M+1]。LC-MS m/z (ESI) = 293.46 [M+1].
第四步the fourth step
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-((3S,4R)-4-羟基四氢呋喃-3-基)吡啶酰胺化合物265-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(( 3S,4R)-4-hydroxytetrahydrofuran-3-yl)pyridine amide compound 26
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)picolinamide5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4 -hydroxytetrahydrofuran-3-yl)picolinamide
参考化合物6的合成方法，得到化合物26(白色固体，46mg，产率42％)。Referring to the synthesis method of compound 6, compound 26 (white solid, 46 mg, yield 42%) was obtained.
LC-MS m/z(ESI)＝479.55[M+1]。LC-MS m/z (ESI) = 479.55 [M+1].
实施例27Example 27
(R)-5-(4-((7-甲基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(四氢呋喃-3-基)吡啶酰胺化合物27(R)-5-(4-((7-Methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-(tetrahydrofuran-3-yl)pyridine amide compound 27
(R)-5-(4-((7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide(R)-5-(4-((7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3 -yl)picolinamide
Figure PCTCN2022087966-appb-000042
Figure PCTCN2022087966-appb-000042
27a根据专利WO2021013735的中间体14的合成方法，使用三乙基2-膦酰基丙酯替代三乙基2-丁基丙烯酯制备得到，LCMS m/s＝253.10[M+1]。27a was prepared according to the synthesis method of intermediate 14 of patent WO2021013735, using triethyl 2-phosphonopropyl ester instead of triethyl 2-butyl propylene ester, LCMS m/s=253.10 [M+1].
按照化合物1的方法，制备得到化合物27(白色固体，31mg，产率：74％)。According to the method of compound 1, compound 27 was prepared (white solid, 31 mg, yield: 74%).
1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.50(d,1H),8.40(d,1H),7.83(d,1H),7.85-7.76(m,2H),7.32(d,1H),7.18(d,1H),4.48-4.36(m,1H),3.87-3.79(m,2H),3.75–3.63(m,3H),3.56(dd,1H),3.06(s,4H),2.58(s,4H),2.13(d,3H),2.09(d,1H),1.94–1.85(m,1H)。 1 H NMR (400MHz, DMSO-d6) δ 11.87(s, 1H), 8.50(d, 1H), 8.40(d, 1H), 7.83(d, 1H), 7.85-7.76(m, 2H), 7.32 (d,1H),7.18(d,1H),4.48-4.36(m,1H),3.87-3.79(m,2H),3.75-3.63(m,3H),3.56(dd,1H),3.06(s , 4H), 2.58(s, 4H), 2.13(d, 3H), 2.09(d, 1H), 1.94–1.85(m, 1H).
LCMS m/s＝449.53[M+1]。LCMS m/s=449.53 [M+1].
生物评价Biological evaluation
1.PARP1、PARP2活性抑制试验1. PARP1, PARP2 activity inhibition test
通过PARP1化学发光分析(Chemiluminescent assay，购买自BPS Bioscience公司，货号：80551)、PARP2化学发光分析(Chemiluminescent assay，购买自BPS Bioscience公司，货号：80552)分别检测化合物对PARP1、PARP2的抑制活性。利用化学发光对结果进行定量，具体实验方案如下：The inhibitory activities of compounds on PARP1 and PARP2 were detected by PARP1 chemiluminescence assay (Chemiluminescent assay, purchased from BPS Bioscience, product number: 80551) and PARP2 chemiluminescence assay (Chemiluminescent assay, purchased from BPS Bioscience company, product number: 80552). The results were quantified by chemiluminescence, and the specific experimental protocol was as follows:
(1)使用1×组蛋白混合物(histone mixture，50μL/孔)对96孔板进行过夜包被；(1) Coat 96-well plates overnight with 1× histone mix (50 μL/well);
(2)弃包被液；每孔加入封闭缓冲液3(Blocking buffer 3)(200μL)，室温孵育90min；(2) Discard the coating solution; add Blocking buffer 3 (200 μL) to each well, and incubate at room temperature for 90 min;
(3)弃封闭液，PBST洗2遍；加25μL主混合物(含2.5μL 10×PARP buffer、2.5μL10×PARP Assay mixture、5μL活化DNA、15μL ddH2O)、5μL抑制剂(抑制剂初始浓度为10μM，按1:5倍比稀释8个浓度)、20μL酶(2ng/μL)；室温孵育1小时；(3) Discard the blocking solution and wash twice with PBST; add 25 μL of master mix (containing 2.5 μL of 10×PARP buffer, 2.5 μL of 10×PARP Assay mixture, 5 μL of activated DNA, 15 μL of ddH2O), 5 μL of inhibitor (the initial concentration of the inhibitor is 10 μM) , 8 concentrations were diluted 1:5 times), 20 μL enzyme (2ng/μL); incubated at room temperature for 1 hour;
(4)弃液体，PBST洗2遍；加入链霉亲和素(Streptavidin)-HRP封闭缓冲液3(Blocking buffer 3，稀释50倍)50μL；室温孵育30min；(4) Discard the liquid, wash twice with PBST; add 50 μL of Streptavidin-HRP blocking buffer 3 (Blocking buffer 3, diluted 50 times); incubate at room temperature for 30 min;
(5)弃液体，PBST洗3遍；加入100μL ELISA ECL Substrate A/B混合(各50μL)；(5) Discard the liquid, wash 3 times with PBST; add 100 μL ELISA ECL Substrate A/B to mix (50 μL each);
(6)酶标仪检测结果，利用GraphPad Prism 8进行IC 50的计算。 (6) The results of the microplate reader were used to calculate the IC 50 using GraphPad Prism 8.
结果表明，本发明化合物对PARP1具有显著的抑制活性，且相对于PARP2具备良好的选择性。The results show that the compounds of the present invention have significant inhibitory activity against PARP1, and have good selectivity relative to PARP2.
2.PARP1/PARP2捕获(trapping)试验：2. PARP1/PARP2 trapping test:
2.1 PARP1捕获(trapping)试验：2.1 PARP1 trapping test:
(1)用缓冲液制备4×PARP1(购买自BPS Bioscience公司，货号：80501)和Mab anti GST-Tb(购买自cisbio公司，货号：61GSTTLA)混合液，向384孔板(购买自Greiner公司，货号：784075)中加入该混合液4μL/孔；(1) Prepare a mixed solution of 4×PARP1 (purchased from BPS Bioscience, Item No.: 80501) and Mab anti GST-Tb (purchased from cisbio, Item No.: 61GSTTLA) with buffer, and transfer them to a 384-well plate (purchased from Greiner, Inc., Item No.: 784075), add 4 μL/well of the mixture;
(2)用缓冲液制备4×DSB DNA probe-1(购买自Generay)，向384孔板中加入4μL/孔；(2) Prepare 4×DSB DNA probe-1 (purchased from Generay) with buffer, and add 4 μL/well to 384-well plate;
(3)向384孔板中加入4μL/孔抑制(初始浓度为10μM，按1:5倍比稀释10个浓度)，室温孵育1h；(3) Add 4 μL/well of inhibition to the 384-well plate (the initial concentration is 10 μM, 10 concentrations are diluted 1:5 times), and incubate at room temperature for 1 h;
(4)用缓冲液制备4×NAD(购买自Sigma公司，货号：10127965001)，向384孔板中加入4μL/孔，室温孵育10min；(4) Prepare 4×NAD with buffer solution (purchased from Sigma, Cat. No.: 10127965001), add 4 μL/well to a 384-well plate, and incubate at room temperature for 10 min;
(5)结果采用TR-FRET检测，利用GraphPad 5.0拟合曲线，并进行IC50的计算。(5) The results were detected by TR-FRET, the curve was fitted by GraphPad 5.0, and IC50 was calculated.
2.2 PARP2捕获(trapping)试验：2.2 PARP2 trapping test:
(1)用缓冲液制备4×PARP2(购买自BPS Bioscience公司，货号：80502)和Mab anti GST-Tb(购买自cisbio公司，货号：61GSTTLA)混合液，向384孔板(购买自G reiner公司，货号：784075)中加入该混合液4μL/孔；(1) Prepare a mixed solution of 4×PARP2 (purchased from BPS Bioscience, Item No.: 80502) and Mab anti GST-Tb (purchased from cisbio, Item No.: 61GSTTLA) with buffer, and put it into a 384-well plate (purchased from Greiner Co., Ltd. , Item No.: 784075), add 4 μL/well of the mixture;
(2)用缓冲液制备4×PARP2probe2(购买自Generay公司)，向384孔板中加入4μL/孔；(2) 4×PARP2 probe2 (purchased from Generay) was prepared with buffer, and 4 μL/well was added to the 384-well plate;
(3)向384孔板中加入4μL/孔抑制(初始浓度为10μM，按1:5倍比稀释10个浓度)，室温孵育45min；(3) Add 4 μL/well of inhibition to the 384-well plate (the initial concentration is 10 μM, 10 concentrations are diluted 1:5 times), and incubate at room temperature for 45 minutes;
(4)用缓冲液制备4×NAD(购买自Sigma公司，货号：10127965001)，向384孔板中 加入4μL/孔，室温孵育10min；(4) Prepare 4×NAD (purchased from Sigma, Cat. No.: 10127965001) with buffer, add 4 μL/well to a 384-well plate, and incubate at room temperature for 10 min;
(5)结果采用TR-FRET检测，利用GraphPad 5.0拟合曲线，并进行IC50的计算。(5) The results were detected by TR-FRET, the curve was fitted by GraphPad 5.0, and IC50 was calculated.
Figure PCTCN2022087966-appb-000043
Figure PCTCN2022087966-appb-000043
注：对照例1为J.Med.Chem(2021),64(19),14498–14512的化合物25，其按照化合物25的制备方法得到。Note: Comparative Example 1 is compound 25 of J.Med.Chem (2021), 64(19), 14498-14512, which was obtained according to the preparation method of compound 25.
结果表明，本发明化合物对PARP1捕获(trapping)具有显著抑制活性，且相对于PARP2捕获(trapping)具有良好的选择性。The results show that the compounds of the present invention have significant inhibitory activity on PARP1 trapping and have good selectivity relative to PARP2 trapping.
3.DLD1 BRCA2-/-细胞增殖抑制实验3. DLD1 BRCA2-/- cell proliferation inhibition experiment
用1640(10％FBS，1％PS)培养基培养DLD-1 BRCA2(-/-)细胞(购买自Horizon Discovery Ltd.公司)，培养条件为37℃，5％CO 2。当细胞生长至对数生长期时，重悬细胞，并用1640培养基稀释至15000个/mL。使用Echo移液器向384孔白板(PerkinElmer)中每孔加入40nL待测化合物(终浓度分别为10μM、2μM、400nM、80nM、16nM、3.2nM、0.64nM、0.128nM、0.0256nM、0.00512nM)；每个浓度梯度做2个重复，设置对照组1(加入0.1％DMSO)和对照组2(空白培养基)。随后384孔白板(PerkinElmer)每孔加入40μL(600个)细胞悬液(对照组2不加细胞)。 DLD-1 BRCA2(-/-) cells (purchased from Horizon Discovery Ltd.) were cultured in 1640 (10% FBS, 1% PS) medium at 37°C, 5% CO 2 . When cells have grown to logarithmic growth phase, resuspend cells and dilute to 15,000 cells/mL with 1640 medium. Add 40 nL of test compound to each well of a 384-well white plate (PerkinElmer) using an Echo pipette (final concentrations of 10 μM, 2 μM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, 0.0256 nM, 0.00512 nM, respectively) ; Each concentration gradient was repeated twice, and control group 1 (adding 0.1% DMSO) and control group 2 (blank medium) were set. Subsequently, 40 μL (600 cells) of cell suspension was added to each well of a 384-well white plate (PerkinElmer) (control group 2 did not add cells).
将上述384孔板置于CO 2培养箱(37℃，5％CO 2)中继续培养7天，取出384孔板，室温放置30分钟。每孔加入20μL Celltiter Glo检测液，震板机震荡2分钟，室温放置30分钟。用酶标仪(PerkinElmer；EnVision)测定化学发光值。 The above-mentioned 384-well plate was placed in a CO 2 incubator (37° C., 5% CO 2 ) for further cultivation for 7 days, and the 384-well plate was taken out and placed at room temperature for 30 minutes. Add 20 μL of Celltiter Glo detection solution to each well, shake the plate for 2 minutes, and place at room temperature for 30 minutes. Chemiluminescence values were determined with a microplate reader (PerkinElmer; EnVision).
用GraphPad Prism 8.0进行曲线拟合并计算IC 50。酶标仪检测结果，利用GraphPad Prism 8进行IC 50的计算。 Curve fitting and IC50 calculations were performed with GraphPad Prism 8.0. GraphPad Prism 8 was used to calculate the IC50 of the results of the microplate reader.
化合物编号Compound number DLD1 BRCA2-/-细胞IC 50(nM) DLD1 BRCA2-/- cells IC 50 (nM)
化合物1Compound 1 11.6111.61
化合物2Compound 2 9.849.84
化合物3Compound 3 5.495.49
化合物4Compound 4 5.385.38
化合物6Compound 6 11.0011.00
化合物7Compound 7 10.9810.98
结果表明，本发明化合物对DLD1 BRCA2-/-细胞增殖具有明显抑制作用。The results show that the compound of the present invention has obvious inhibitory effect on the proliferation of DLD1 BRCA2-/- cells.
4.MDA-MB-436细胞增殖抑制实验4. MDA-MB-436 cell proliferation inhibition experiment
用DMEM培养基(10％FBS，1％PS)培养MDA-MB-436细胞(供应商ATCC)，培养条件为37℃，5％CO 2。当细胞生长至对数生长期时，用DMEM培养基重悬并稀释细胞至1500个/ml。在384孔板中以每孔40μL加入待测化合物(终浓度分别为10000nM,2000nM,400nM,80nM,16nM,3.2nM,0.64nM,0.128nM,0.0256nM,0.00512nM)；每个浓度梯度做2个重复，设置对照组1(加入0.1％DMSO)和对照组2(空白培养基)。随后向384孔板中加入40μL细胞悬液(对照组2不加细胞)。 MDA-MB-436 cells (supplier ATCC) were cultured in DMEM medium (10% FBS, 1% PS) at 37°C, 5% CO 2 . When the cells were in logarithmic growth phase, resuspend and dilute the cells to 1500 cells/ml in DMEM medium. Add the compounds to be tested at 40 μL per well in a 384-well plate (final concentrations are 10000nM, 2000nM, 400nM, 80nM, 16nM, 3.2nM, 0.64nM, 0.128nM, 0.0256nM, 0.00512nM); each concentration gradient is made 2 In 2 replicates, control group 1 (added 0.1% DMSO) and control group 2 (blank medium) were set. 40 μL of cell suspension was then added to the 384-well plate (control group 2 without cells).
将上述384孔板置于培养箱(37℃，5％CO 2)中连续培养7天，然后取出384孔板，在室温放置30min。每孔加入30μL Celltiter Glo assay kit检测液，用震板机震荡3min，在室温放置30min。用酶标仪(PerkinElmer；EnVision)测定化学发光值。 The above-mentioned 384-well plate was placed in an incubator (37° C., 5% CO 2 ) for continuous cultivation for 7 days, and then the 384-well plate was taken out and placed at room temperature for 30 min. Add 30 μL of Celltiter Glo assay kit detection solution to each well, shake with a shaker for 3 min, and place at room temperature for 30 min. Chemiluminescence values were determined with a microplate reader (PerkinElmer; EnVision).
检测结果用GraphPad Prism 8进行曲线拟合并计算IC 50。 The assay results were curve-fitted with GraphPad Prism 8 and IC50 was calculated.
化合物编号Compound number MDA-MB-436细胞IC 50(nM) MDA-MB-436 cells IC 50 (nM)
对照例2Comparative Example 2 ＞10000>10000
化合物1Compound 1 28.9528.95
化合物2Compound 2 10.5110.51
化合物3Compound 3 16.4116.41
化合物4Compound 4 8.028.02
化合物5Compound 5 19.0719.07
化合物6Compound 6 9.819.81
化合物7Compound 7 18.3318.33
化合物9Compound 9 35.6735.67
化合物11Compound 11 10.6810.68
化合物12Compound 12 15.7515.75
化合物13Compound 13 37.3037.30
化合物15Compound 15 1.831.83
化合物20Compound 20 6.866.86
化合物22Compound 22 39.9739.97
化合物23Compound 23 44.8344.83
化合物25Compound 25 2.012.01
注：对照例2为专利WO200905337的化合物62，其按照化合物62的制备方法得到。Note: Comparative Example 2 is compound 62 of patent WO200905337, which is obtained according to the preparation method of compound 62.
结果表明，本发明化合物对MDA-MB-436细胞增殖具有明显抑制作用。The results show that the compounds of the present invention have obvious inhibitory effect on the proliferation of MDA-MB-436 cells.
本发明说明书对具体实施方案进行了详细描述，本领域技术人员应认识到，上述实施方案是示例性的，不能理解为对本发明的限制，对于本领域技术人员来说，在不脱离本发明原理的前提下，通过对本发明进行若干改进和修饰，这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。The specification of the present invention describes the specific embodiments in detail. Those skilled in the art should realize that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. For those skilled in the art, without departing from the principles of the present invention Under the premise, by carrying out several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims (10)

  1. 式(I)的化合物或者其药物可接受的盐或立体异构体：A compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof:
    Figure PCTCN2022087966-appb-100001
    Figure PCTCN2022087966-appb-100001
    其中in
    R 1为C 1-6烷基； R 1 is C 1-6 alkyl;
    L为-NH-、-CO-或-(CR L1R L2) n-； L is -NH-, -CO- or -(CR L1 R L2 ) n -;
    R L1、R L2各自独立地为H或C 1-6烷基，所述C 1-6烷基任选地被1个或多个选自卤素、羟基和氰基的取代基取代； R L1 and R L2 are each independently H or C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl and cyano;
    R 3为H、卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或C 3-8杂环烷基；所述C 3-8杂环烷基包含1-4个选自N、O和S的杂原子；所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或C 3-8杂环烷基任选地被1个或多个选自H、卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或C 3-8杂环烷基的取代基取代； R 3 is H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; the C 3-8 Heterocycloalkyl contains 1-4 heteroatoms selected from N, O and S; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 hetero Cycloalkyl is optionally surrounded by 1 or more selected from H, halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl or C3-8 Substituent substitution of heterocycloalkyl;
    R 2为C 1-4烷基、C 5-6烷基、C 1-6烷氧基、C 3-8环烷基或C 3-8杂环烷基；所述C 3-8杂环烷基包含1-4个选自N、O和S的杂原子；所述C 5-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基任选地被1个或多个选自卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和C 3-8杂环烷基的取代基取代；当R 2为C 1-4烷基时，所述C 1-4烷基被1个或多个选自羟基和C 1-6烷氧基的取代基取代； R 2 is C 1-4 alkyl, C 5-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; the C 3-8 heterocycle The alkyl group contains 1-4 heteroatoms selected from N, O and S; the C 5-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkane group is optionally selected from one or more groups selected from halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and C 3-8 heterocycloalkyl When R 2 is C 1-4 alkyl, the C 1-4 alkyl is substituted by 1 or more substituents selected from hydroxyl and C 1-6 alkoxy;
    n为1或2；n is 1 or 2;
    m为0、1、2或3；m is 0, 1, 2 or 3;
    任选地，所述式(I)的化合物被1个或多个氘取代。Optionally, the compound of formula (I) is substituted with 1 or more deuterium.
  2. 根据权利要求1所述的化合物或者其药物可接受的盐或立体异构体，其中所述化合物具有式(II)的结构：The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has the structure of formula (II):
    Figure PCTCN2022087966-appb-100002
    Figure PCTCN2022087966-appb-100002
    其中in
    R 1为C 1-6烷基； R 1 is C 1-6 alkyl;
    L为-NH-、-CO-或-(CR L1R L2) n-； L is -NH-, -CO- or -(CR L1 R L2 ) n -;
    R L1、R L2各自独立地为H或C 1-6烷基，所述C 1-6烷基任选地被1个或多个选自卤素、羟基和氰基的取代基取代； R L1 and R L2 are each independently H or C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl and cyano;
    R 2为C 1-4烷基、C 5-6烷基、C 1-6烷氧基、C 3-8环烷基或C 3-8杂环烷基；所述C 3-8杂环烷基包含1-4个选自N、O和S的杂原子；所述C 5-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基任选地被1个或多个选自卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基、 C 3-8环烷基和C 3-8杂环烷基的取代基取代；当R 2为C 1-4烷基时，所述C 1-4烷基被1个或多个选自羟基和C 1-6烷氧基的取代基取代； R 2 is C 1-4 alkyl, C 5-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; the C 3-8 heterocycle The alkyl group contains 1-4 heteroatoms selected from N, O and S; the C 5-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkane The group is optionally selected from one or more groups selected from halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and C 3-8 heterocycloalkyl When R 2 is C 1-4 alkyl, the C 1-4 alkyl is substituted by 1 or more substituents selected from hydroxyl and C 1-6 alkoxy;
    n为1或2；n is 1 or 2;
    任选地，所述式(II)的化合物被1个或者多个氘取代。Optionally, the compound of formula (II) is substituted with one or more deuteriums.
  3. 根据权利要求1所述的化合物或者其药物可接受的盐或立体异构体，其中所述R 1为乙基。 The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said R 1 is ethyl.
  4. 根据权利要求1所述的化合物或者其药物可接受的盐或立体异构体，其中L为-CH 2-或-CD 2-。 The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L is -CH 2 - or -CD 2 -.
  5. 根据权利要求1所述的化合物或者其药物可接受的盐或立体异构体，其中R 3为H、-CH 3、-CD 3、-OCH 3或-Cl。 The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is H, -CH 3 , -CD 3 , -OCH 3 or -Cl.
  6. 根据权利要求1所述的化合物或者其药物可接受的盐或立体异构体，其中R 2为环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、甲基、乙基或丙基；所述环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、甲基、乙基或丙基任选地被一个或多个选自甲基、甲氧基和羟基的取代基取代。 The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is cyclobutyl, oxolane, oxanyl, azetidine, methyl, ethyl or propyl; the cyclobutyl, oxolane, oxanyl, azetidinyl, methyl, ethyl or propyl are optionally selected by one or more of methyl, methyl Substituent substitution of oxy and hydroxy.
  7. 根据权利要求1所述的化合物或者其药物可接受的盐或立体异构体，其中所述卤素为F、Cl或Br。The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the halogen is F, Cl or Br.
  8. 根据权利要求1所述的化合物或者其药物可接受的盐或立体异构体，所述化合物为：The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, which is:
    Figure PCTCN2022087966-appb-100003
    Figure PCTCN2022087966-appb-100003
    Figure PCTCN2022087966-appb-100004
    Figure PCTCN2022087966-appb-100004
    所述化合物任选地被1个或者多个氘取代。The compounds are optionally substituted with one or more deuteriums.
  9. 药物组合物，所述药物组合物包含：A pharmaceutical composition comprising:
    (1)权利要求1至8中任一项所述的化合物或者其药物可接受的盐或立体异构体；(1) The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof;
    (2)任选的一种或多种其他活性成分；以及(2) optionally one or more other active ingredients; and
    (3)药物可接受的载体和/或赋形剂。(3) A pharmaceutically acceptable carrier and/or excipient.
  10. 权利要求1至8中任一项所述的化合物或者其药物可接受的盐或立体异构体或 权利要求9所述的药物组合物在制备抗肿瘤药物中的用途。Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt or stereoisomer thereof or the pharmaceutical composition according to claim 9 in the preparation of an antitumor drug.
PCT/CN2022/087966 2021-04-23 2022-04-20 Pyridine derivative and use thereof in medicine WO2022222964A1 (en)

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