WO2022222964A1 - Dérivé de pyridine et son utilisation en médecine - Google Patents

Dérivé de pyridine et son utilisation en médecine Download PDF

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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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English (en)
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/zh
Publication of WO2022222964A1 publication Critical patent/WO2022222964A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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 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.

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Abstract

L'invention concerne un composé de formule (I) et son utilisation en médecine. Le composé peut être utilisé pour traiter une tumeur.
PCT/CN2022/087966 2021-04-23 2022-04-20 Dérivé de pyridine et son utilisation en médecine WO2022222964A1 (fr)

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US11591331B2 (en) 2021-04-19 2023-02-28 Xinthera, Inc. PARP1 inhibitors and uses thereof
US11795173B1 (en) 2022-04-28 2023-10-24 Xinthera, Inc. Substituted pyridines as PARP1 inhibitors
US11802128B2 (en) 2021-10-01 2023-10-31 Xinthera, Inc. Azetidine and pyrrolidine PARP1 inhibitors and uses thereof
US11939329B2 (en) 2022-01-21 2024-03-26 Xinthera, Inc. PARP1 inhibitors and uses thereof

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WO2024067691A1 (fr) * 2022-09-30 2024-04-04 中国医药研究开发中心有限公司 Composé hétérocyclique contenant de l'azote et son utilisation pharmaceutique
CN117946074A (zh) * 2022-10-20 2024-04-30 上海海和药物研究开发股份有限公司 具有parp1抑制活性的化合物及其用途

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US11591331B2 (en) 2021-04-19 2023-02-28 Xinthera, Inc. PARP1 inhibitors and uses thereof
US11802128B2 (en) 2021-10-01 2023-10-31 Xinthera, Inc. Azetidine and pyrrolidine PARP1 inhibitors and uses thereof
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US11795173B1 (en) 2022-04-28 2023-10-24 Xinthera, Inc. Substituted pyridines as PARP1 inhibitors

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