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WO2022222965A1 - 吡啶衍生物及其在医药上的应用 - Google Patents

吡啶衍生物及其在医药上的应用 Download PDF

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Publication number
WO2022222965A1
WO2022222965A1 PCT/CN2022/087968 CN2022087968W WO2022222965A1 WO 2022222965 A1 WO2022222965 A1 WO 2022222965A1 CN 2022087968 W CN2022087968 W CN 2022087968W WO 2022222965 A1 WO2022222965 A1 WO 2022222965A1
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compound
alkyl
membered
heterocycloalkyl
pharmaceutically acceptable
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PCT/CN2022/087968
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English (en)
French (fr)
Inventor
张靖
魏用刚
周锡兵
高成
孙毅
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成都百裕制药股份有限公司
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Priority to CN202280015678.XA priority Critical patent/CN116867784A/zh
Publication of WO2022222965A1 publication Critical patent/WO2022222965A1/zh

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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 or sparfloxacin
    • 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 3-8 cycloalkyl or C 3-8 heterocycloalkyl, the C 3-8 heterocycloalkyl contains 1 to 4 heteroatoms selected from N, O and S;
  • 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;
  • A is a 4- to 12-membered heterocycle
  • the 4- to 12-membered heterocycle is a 4- to 12-membered monocycle, a 5- to 12-membered spirocycle, a 4- to 12-membered parallel ring, or a 4- to 12-membered bridged ring
  • the 4- to 12-membered heterocycle is The 12-membered heterocycle contains 1 to 4 heteroatoms selected from N, O and S;
  • R 2 is H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, the C 3-8 heterocycloalkyl containing 1 to 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 heterocycloalkyl are optionally 1 or more substituents selected from the group consisting of halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and C 3-8 heterocycloalkyl;
  • n 1 or 2.
  • 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 or 4 to 12 membered heterocycle contains 1, 2, 3 or 4 heteroatoms selected from N, O and S.
  • the R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L is -CH2- , -CH( CH3 )- or -CD2- .
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R 2 is oxolane, oxhexyl, azetidinyl, methyl, ethyl, or propyl; , azetidine, 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, and I involved in the groups and compounds described in this application all include their isotopic conditions, as well as the carbons involved in the groups and compounds described in this application.
  • 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.
  • 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 salts” or “pharmaceutically acceptable salts thereof” means that the compounds of the present application retain the biological effectiveness and properties of free acids or free bases, and the free acids are 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 described herein, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein “other chemical components” means 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;
  • 6-Methyl-5-nitronicotinic acid ethyl ester 1a (purchased from Jiangsu Aikang Biomedical Research and Development Co., Ltd., 10 g, 45.6 mmol) and selenium dioxide (7.6 g, 68.4 mmol) were dissolved in dioxane ( 100 mL), refluxed at 110° C. for 4 h, filtered hot after the reaction, concentrated the filtrate under reduced pressure, and obtained compound 1b (yellow solid, 9.7 g, yield 90%) by column chromatography.
  • 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.
  • Test compound preparation Precisely weigh an appropriate amount of Control Example 1 and Compound 1, and prepare a 0.3 mg/mL transparent and clear solution with a solvent of 5% DMSO+30% HP- ⁇ -CD;
  • Control Example 1 and Compound 1 were administered to each mouse by gavage at a dose of 3 mg/kg, 3 mice in each group. According to the time points before administration (0h), 5min, 15min, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after administration, 0.1 mL of blood was collected from the orbital venous plexus at 10 time points, and the blood samples were centrifuged at 2000g at 4°C. 10min, collect plasma for subsequent detection;
  • the plasma concentration of the prototype drug was determined by LC-MS/MS, and the main pharmacokinetic parameters were calculated by the Winnolin 8.2 non-compartmental model.
  • 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.

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Abstract

本申请式(I)的化合物及其在医药上的应用，该化合物可用于治疗肿瘤。

Description

吡啶衍生物及其在医药上的应用 技术领域
本申请涉及吡啶衍生物及其在医药上的应用。
背景技术
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。
发明内容
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。
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：
Figure PCTCN2022087968-appb-000001
其中：
R 1为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至4个选自N、O和S的杂原子；
L为-NH-、-CO-或-(CR L1R 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个或者多个选自卤素、羟基和氰基的取代基取代；
A为4至12元杂环，所述4至12元杂环为4至12元单环、5至12元螺环、4至12元并环或4至12元桥环，所述4至12元杂环包含1至4个选自N、O和S的杂原子；
R 2为H、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至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环烷基和C 3-8杂环烷基的取代基取代；
n为1或2。
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。
在一个或多个实施方式中，所述C 3-8杂环烷基或4至12元杂环包含1、2、3或4个选自N、O和S的杂原子。
在一个或多个实施方式中，所述R 1为
Figure PCTCN2022087968-appb-000002
在一个或多个实施方式中，L为-CH 2-、-CH(CH 3)-或-CD 2-。
在一个或多个实施方式中，A为
Figure PCTCN2022087968-appb-000003
在一个或多个实施方式中，R 2为氧杂环戊基、氧杂环己基、氮杂环丁基、甲基、乙基或丙基；所述氧杂环戊基、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。
在一个或多个实施方式中，所述化合物为：
Figure PCTCN2022087968-appb-000004
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。
在一个或多个实施方式中，卤素为F、Cl或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：
(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；
(2)任选的一种或多种其他活性成分；以及
(3)药物可接受的载体和/或赋形剂。
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：
Figure PCTCN2022087968-appb-000005
其中：
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；
L选自-NH-、-CO-或者-(CR L1R 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；
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；
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；
n为1或者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：
Figure PCTCN2022087968-appb-000006
其中：
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；
L选自-NH-、-CO-或者-(CR L1R 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；
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；
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；
n为1或者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：
Figure PCTCN2022087968-appb-000007
其中：
R 1选自C 1-6烷基；
L选自-NH-、-CO-或者-(CR L1R 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；
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；
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；
n为1或者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：
Figure PCTCN2022087968-appb-000008
其中：
R 1选自C 1-6烷基；
L选自-NH-、-CO-或者-(CR L1R 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；
X 1、X 2各自独立地选自CR X或者N；
R X选自H、羟基、氰基或者C 1-6烷基；
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；
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；
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；
m为1、2或者3；
n为1或者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：
Figure PCTCN2022087968-appb-000009
其中：
R 1选自C 1-6烷基；
L选自-NH-、-CO-或者-(CR L1R 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 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 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；
n为1或者2。
m为0、1、2或者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：
Figure PCTCN2022087968-appb-000010
其中：
R 1选自C 1-6烷基；
L选自-NH-、-CO-或者-(CR L1R 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 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；
n为1或者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。
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。
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。
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。
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。
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。
本申请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，及本申请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。
“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。
“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。
“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。
“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。
“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。
“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。
“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 PCTCN2022087968-appb-000011
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。
“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。
“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。
“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。
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。
卤素包括F、Cl、Br和I。
“药物可接受的盐”或者“其药物可接受的盐”是指本申请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。
“药物组合物”是指一种或多种本申请所述化合物、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。
“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。
“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。
“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。
“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。
具体实施方式
以下实施例详细说明本申请的技术方案，但本申请的保护范围包括但是不限于此。
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)；
MS的测定用Agilent 6120B(ESI)和Agilent 6120B(APCI)；
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；
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
实施例1
5-(4-((7-环丙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺化合物1
5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide
Figure PCTCN2022087968-appb-000012
第一步
6-甲酰基-5-硝基烟酸乙酯1b
ethyl 6-formyl-5-nitronicotinate
将6-甲基-5-硝基烟酸乙酯1a(购自江苏艾康生物医药研发有限公司，10g，45.6mmol)、二氧化硒(7.6g，68.4mmol)溶于二氧六环(100mL)，在110℃下回流4h，反应完后热过滤，将滤液减压浓缩，柱层析得到化合物1b(黄色固体，9.7g，产率90％)。
LC-MS m/z(ESI)＝225.10[M+1]。
第二步
6-(2-溴-3-乙氧基-3-氧丙烷-1-烯-1-基)-5-硝基烟酸乙酯1c
ethyl 6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)-5-nitronicotinate
将2-溴-2-(二乙氧基磷酰)乙酸乙酯(购自上海迈瑞尔化学技术有限公司，20g，66.6 mmol)溶于四氢呋喃(100mL)，-78℃下缓慢加入钠氢(1.6g，66.6mmol)，缓慢升温至40℃反应10min，再降温到-78℃下缓慢滴加1b(9.7g，44.4mmol)的四氢呋喃溶液，反应15min后加入饱和氯化铵水溶液(100mL)淬灭，乙酸乙酯(100mL×3)萃取，合并有机相减压浓缩，柱层析得到1c(黄色固体，13g，产率81％，E/Z＝10:3)。
1H NMR(400MHz,DMSO-d 6)δ9.42(d,1H),9.23(d,0.3H),8.86(d,1H),8.80(d,0.3H),8.61(s,1H),7.89(s,0.3H),4.46-4.38(m,2.6H),4.34(q,2H),4.16(q,0.6H),1.39-1.34(m,3.9H),1.32(t,3H),1.08(t,0.9H)。
LC-MS m/z(ESI)＝373.00[M+1]。
第三步
5-氨基-6-(2-溴-3-乙氧基-3-氧代丙-1-烯-1-基)烟酸乙酯1d
ethyl 5-amino-6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)nicotinate
化合物1c(13g，34.8mmol)溶于醋酸(130mL)中，加入铁粉(5.8g，104.5mmol)，室温反应2h后加入蒸馏水(100mL)淬灭反应，乙酸乙酯(100mL×3)萃取，合并有机相减压浓缩，得到化合物1d(黄色固体，10g，产率83％)。
LC-MS m/z(ESI)＝343.00[M+1]。
第四步
7-溴-6-氧-5,6-二氢-1,5-萘啶-3-羧酸乙酯1e
ethyl 7-bromo-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate
将化合物1d(10g，29.1mmol)置于反应瓶中，氮气保护下加入溴化氢的醋酸溶液(100mL),50℃下反应4h后减压浓缩，饱和碳酸氢钠水溶液(100mL)淬灭反应，乙酸乙酯(50mL×3)萃取，减压浓缩，柱层析得到化合物1e(黄色固体，2g，产率23％)。
1H NMR(400MHz,DMSO-d 6)δ12.54(s,1H),8.88(d,1H),8.51(s,1H),8.14(d,1H),4.37(q,2H),1.35(t,3H)。
LC-MS m/z(ESI)＝297.00[M+1]。
第五步
7-环丙基-6-氧代-5,6-二氢-1,5-萘啶-3-羧酸乙酯1f
ethyl 7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate
将化合物1e(400mg，1.3mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(购自成都叮当时代医药科技有限公司，328mg，0.40mmol)、碳酸钾(745mg，5.4mmol)、环丙基硼酸(杭州艾康生物技术有限公司，231mg，2.7mmol)溶于二氧六环(4mL)，110℃下回流8h后加水(5mL)淬灭，乙酸乙酯(5mL×3)萃取，减压浓缩柱层析纯化，得到化合物1f(黄色固体，270mg，产率77％)。
1H NMR(400MHz,DMSO-d 6)δ12.07(s,1H),8.85(d,1H),8.12(d,1H),7.46(s,1H),4.36(q,2H),2.25-2.12(m,1H),1.34(t,3H),1.02(dt,2H),0.90(dt,2H)。
LC-MS m/z(ESI)＝259.10[M+1]。
第六步
3-环丙基-7-(羟甲基)-1,5-萘啶-2(1H)-酮1g
3-cyclopropyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one
将化合物1f(270mg，1mmol)溶于四氢呋喃(2mL)，在冰水浴下缓慢滴加四氢铝锂的四氢呋喃溶液(购自安耐吉化学，2mL，2mmol)，滴加完搅拌10min，加入乙酸乙酯(1mL)，减压浓缩柱层析得到化合物1g(黄色固体，100mg，产率44％)。
1H NMR(400MHz,DMSO-d 6)δ11.92(s,1H),8.35(d,1H),7.59(d,1H),7.41(s,1H), 5.45(t,1H),4.60(d,2H),2.16-2.09(m,1H),0.96(dt,2H),0.82(dt,2H)。
LC-MS m/z(ESI)＝217.10[M+1]。
第七步
7-(溴甲基)-3-环丙基-1,5-萘啶-2(1H)-酮1h
7-(bromomethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H)-one
将化合物1g(100mg，0.46mmol)和三苯基膦(购自上海阿达玛斯试剂有限公司，242mg，0.92mmol)溶于二氯甲烷(1mL)，在冰水浴下加入四溴化碳(购自安耐吉化学，306mg，0.92mmol)的二氯甲烷(0.5mL)溶液，反应0.5h，反应液减压浓缩后经柱层析得到化合物1h(黄色固体，100mg，产率78％)。
LC-MS m/z(ESI)＝279.00[M+1]。
第八步
5-(4-((7-环丙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺化合物1
5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide
将化合物1h(100mg，0.36mmol)、N-甲基-5-(哌嗪-1-基)吡啶甲酰胺1i(江苏药泽医药科技有限公司，86mg，0.39mmol)、N,N-二异丙基乙胺(230mg，1.8mmol)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1(白色固体，40mg，产率27％)。
1H NMR(400MHz,DMSO-d 6)δ11.89(s,1H),8.40(d,1H),8.38(d,1H),8.26(d,1H),7.82(d,1H),7.60(d,1H),7.42(s,1H),7.38(dd,1H),3.63(s,2H),2.34-3.31(s,4H),2.77(d,3H),2.56-2.53(d,4H),2.19-2.09(m,1H),0.99-0.91(m,2H),0.84-0.76(m,2H)。
LC-MS m/z(ESI)＝419.20[M+1]。
实施例2
(R)-5-(4-((7-环丙基-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2
(R)-5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
Figure PCTCN2022087968-appb-000013
将化合物2a(22.08mg，0.08mmol)和化合物1h(22.32mg，0.08mmol)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，51.7mg，0.4mmol)，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2(白色固体，26mg，产率71％)。
1H NMR(400MHz,DMSO-d 6)δ12.13(s,1H),8.38(d,2H),8.27(s,1H),7.83(d,1H), 7.60(s,1H),7.40(d,2H),4.47-4.42(m,1H),3.87-3.79(m,2H),3.73-3.68(m,1H),3.63(s,2H),3.59-3.55(m,1H),3.43-3.37(m,4H),2.56-2.54(m,4H),2.17-2.09(m,2H),1.97-1.91(m,1H),0.99-0.93(m,2H),0.82-0.80(m,2H)。
LC-MS m/z(ESI)＝475.24[M+1]。
实施例3
5-(4-((7-环丙基-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3
5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxyethyl)picolinamide
Figure PCTCN2022087968-appb-000014
参考化合物2的合成方法，得到化合物3(白色固体，31mg，产率76％)。
1H NMR(400MHz,DMSO-d 6)δ11.90(s,1H),8.41-8.33(m,2H),8.28(d,1H),7.83(d,1H),7.60(d,1H),7.42(s,1H),7.41-7.38(m,1H),4.79(t,1H),3.63(s,2H),3.49(q,2H),3.37-3.35(m,2H),3.34-3.32(m,4H),2.56-2.53(m,4H),2.18-2.12(m,1H),1.01-0.93(m,2H),0.85-0.80(m,2H)。
LC-MS m/z(ESI)＝449.22[M+1]。
实施例4
5-(4-((7-环丙基-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4
5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-methoxyethyl)picolinamide
Figure PCTCN2022087968-appb-000015
参考化合物2的合成方法，得到化合物4(白色固体，28mg，产率74％)。
1H NMR(400MHz,DMSO-d 6)δ11.90(s,1H),8.36(d,2H),8.28(d,1H),7.83(d,1H),7.60(s,1H),7.45-7.37(m,2H),3.63(s,2H),3.46-3.42(m,4H),3.39-3.35(t,2H),3.33-3.10(m,2H),3.26(s,3H),2.56-2.53(m,4H),2.18-2.11(m,1H),0.99-0.94(m,2H),0.85-0.79(m, 2H)。
LC-MS m/z(ESI)＝463.24[M+1]。
实施例5
(R)-5-(4-((7-环丙基-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5
(R)-5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide
Figure PCTCN2022087968-appb-000016
参考化合物2的合成方法，得到化合物5(白色固体，29mg，产率76％)。
1H NMR(400MHz,DMSO-d6)δ11.89(s,1H),8.41–8.34(m,2H),7.80(d,1H),7.60(s,1H),7.48(d,1H),7.42(s,1H),4.50-4.42(m,1H),3.92–3.77(m,2H),3.74-3.70(m,1H),3.66(s,2H),3.59(dd,1H),2.96-2.93(m,4H),2.60-2.56(m,4H),2.51(s,3H),2.22–2.10(m,2H),1.97-1.89(m,1H),0.99-0.94(m,2H),0.85–0.79(m,2H)。
LC-MS m/z(ESI)＝489.25[M+1]。
实施例6
(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6
(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 PCTCN2022087968-appb-000017
Figure PCTCN2022087968-appb-000018
第一步
3-环丙基-7-(羟甲基-d 2)-1,5-萘啶-2(1H)-酮6a
3-cyclopropyl-7-(hydroxymethyl-d 2)-1,5-naphthyridin-2(1H)-one
参考1g的合成方法，使用四氘锂铝代替四氢锂铝，得到6a(白色固体，700g，产率58％)。
LC-MS m/z(ESI)＝219.1[M+1]。
第二步
7-(溴甲基-d 2)-3-环丙基-1,5-萘啶-2(1H)-酮6b
7-(bromomethyl-d 2)-3-cyclopropyl-1,5-naphthyridin-2(1H)-one
参考1h的合成方法，得到6b(白色固体，310mg，产率69％)。
LC-MS m/z(ESI)＝281.1[M+1]。
第三步
(R)-5-(4-((7-环丙基-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6
(R)-5-(4-((7-cyclopropyl-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2的合成方法，得到化合物6(白色固体，26mg，产率49％)。
1H NMR(400MHz,DMSO-d 6)δ12.13(s,1H),8.38(d,2H),8.27(s,1H),7.83(d,1H),7.60(s,1H),7.40(d,2H),4.47-4.42(m,1H),3.87-3.79(m,2H),3.73-3.68(m,1H),3.59-3.55(m,1H),3.43-3.37(m,4H),2.56-2.54(m,4H),2.17-2.09(m,2H),1.97-1.91(m,1H),0.99-0.93(m,2H),0.82-0.80(m,2H)。
LC-MS m/z(ESI)＝477.2[M+1]。
生物评价
1.PARP1、PARP2活性抑制试验
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：
(1)使用1×组蛋白混合物(histone mixture，50μL/孔)对96孔板进行过夜包被；
(2)弃包被液；每孔加入封闭缓冲液3(Blocking buffer 3)(200μL)，室温孵育90min；
(3)弃封闭液，PBST洗2遍；加25μL主混合物(含2.5μL 10×PARP buffer、2.5μL  10×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；
(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；
(5)弃液体，PBST洗3遍；加入100μL ELISA ECL Substrate A/B混合(各50μL)；
(6)酶标仪检测结果，利用GraphPad Prism 8进行IC 50的计算。
结果表明，本申请化合物对PARP1具有显著的抑制活性，且相对于PARP2具备良好的选择性。
2.PARP1/PARP2捕获(trapping)试验：
2.1 PARP1捕获(trapping)试验：
(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；
(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；
(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；
(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；
(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。
2.2 PARP2捕获(trapping)试验：
(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Greiner公司，货号：784075)中加入该混合液4μL/孔；
(2)用缓冲液制备4×PARP2probe2(购买自Generay公司)，向384孔板中加入4μL/孔；
(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；
(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；
(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。
Figure PCTCN2022087968-appb-000019
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。
结果表明，本申请化合物对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。
3.DLD1 BRCA2-/-细胞增殖抑制实验
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)。
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。
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。
化合物编号 DLD1 BRCA2-/-细胞IC 50(nM)
化合物1 2.00
结果表明，本申请化合物对DLD1 BRCA2-/-细胞增殖具有明显抑制作用。
4.MDA-MB-436细胞增殖抑制实验
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)。
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。
检测结果用GraphPad Prism 8进行曲线拟合并计算IC 50。
化合物编号 MDA-MB-436细胞IC50(nM)
对照例2 ＞10000
化合物1 4.96
化合物4 24.68
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。
结果表明，本申请化合物对MDA-MB-436细胞增殖具有明显抑制作用。
5.小鼠体内药代动力学实验
(1)试验动物：ICR雄鼠，5-6周龄，购自成都达硕实验动物有限公司；
(2)受试物配制：精密称取适量对照例1和化合物1，配置成0.3mg/mL透明澄清的溶液，溶媒为5％DMSO+30％HP-β-CD；
(3)动物给药及采血：每只小鼠按照3mg/kg的剂量，分别灌胃给予对照例1和化合物1，每组3只小鼠。按照给药前(0h)、给药后5min、15min、0.5h、1h、2h、4h、6h、8h、24h，10个采血时间点分别通过眼眶静脉丛采血0.1mL，血样经4℃2000g离心10min，收集血浆用于后续检测；
(4)采用LC-MS/MS法测定血浆内原型药物浓度，Winnolin 8.2非房室模型计算主要药动学参数。
Figure PCTCN2022087968-appb-000020
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。
结果表明，本申请化合物在小鼠体内显示出明显优于对照例的药代动力学特征。
本申请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，不能理解为对本申请的限制，对于本领域技术人员来说，在不脱离本申请原理的前提下，通过对本申请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申请的权利要求书的保护范围内。

Claims (8)

  1. 式(I)的化合物或者其药物可接受的盐或立体异构体：
    Figure PCTCN2022087968-appb-100001
    其中：
    R 1为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至4个选自N、O和S的杂原子；
    L为-NH-、-CO-或-(CR L1R 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个或者多个选自卤素、羟基和氰基的取代基取代；
    A为4至12元杂环，所述4至12元杂环为4至12元单环、5至12元螺环、4至12元并环或4至12元桥环，所述4至12元杂环包含1至4个选自N、O和S的杂原子；
    R 2为H、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至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环烷基和C 3-8杂环烷基的取代基取代；
    n为1或2；
    任选地，所述式(I)的化合物被1个或者多个氘取代。
  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R 1为
    Figure PCTCN2022087968-appb-100002
  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L为-CH 2-、-CH(CH 3)-或-CD 2-。
  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A为
    Figure PCTCN2022087968-appb-100003
  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 2为氧杂环戊基、氧杂环己基、氮杂环丁基、甲基、乙基或丙基；所述氧杂环戊基、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。
  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，所述化合物为：
    Figure PCTCN2022087968-appb-100004
    任选地，所述化合物被1个或者多个氘取代。
  7. 药物组合物，所述药物组合物包含：
    (1)权利要求1至6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；
    (2)任选的一种或多种其他活性成分；以及
    (3)药物可接受的载体和/或赋形剂。
  8. 权利要求1至6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7所述的药物组合物在制备抗肿瘤药物中的用途。
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