WO2022223025A1 - 杂环类衍生物抑制剂、其制备方法和应用 - Google Patents

杂环类衍生物抑制剂、其制备方法和应用 Download PDF

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Publication number
WO2022223025A1
WO2022223025A1 PCT/CN2022/088466 CN2022088466W WO2022223025A1 WO 2022223025 A1 WO2022223025 A1 WO 2022223025A1 CN 2022088466 W CN2022088466 W CN 2022088466W WO 2022223025 A1 WO2022223025 A1 WO 2022223025A1
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Prior art keywords
alkyl
amino
cycloalkyl
alkoxy
membered
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PCT/CN2022/088466
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English (en)
French (fr)
Chinese (zh)
Inventor
高鹏
曾蜜
王少宝
俞文胜
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
Original Assignee
Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Application filed by Jiangsu Hansoh Pharmaceutical Group Co Ltd, Shanghai Hansoh Biomedical Co Ltd filed Critical Jiangsu Hansoh Pharmaceutical Group Co Ltd
Priority to JP2023564007A priority Critical patent/JP2024514338A/ja
Priority to MX2023012054A priority patent/MX2023012054A/es
Priority to AU2022261029A priority patent/AU2022261029A1/en
Priority to CN202280007892.0A priority patent/CN116601148A/zh
Priority to EP22791130.2A priority patent/EP4328225A4/en
Priority to US18/555,468 priority patent/US20240228490A1/en
Priority to KR1020237039621A priority patent/KR20240005756A/ko
Priority to BR112023019797A priority patent/BR112023019797A2/pt
Priority to CA3215823A priority patent/CA3215823A1/en
Priority to IL307824A priority patent/IL307824A/en
Publication of WO2022223025A1 publication Critical patent/WO2022223025A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
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    • 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
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    • 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
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    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/4965—Non-condensed pyrazines
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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    • 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
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    • 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
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Definitions

  • the invention belongs to the field of biomedicine, and in particular relates to a heterocyclic derivative inhibitor and a preparation method and application thereof.
  • R a1 , R a2 and R a3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl , cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;
  • R b is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, oxo, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkyne radical, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R b1 , -(CH 2 ) n OR b1 , -(CH 2 ) n C(O)R b1 , -( CH 2 ) n C(O)OR b1 , -(CH 2 ) n S(O) m R b1 , -(CH 2 ) n NR b2 R b3 , -(CH 2 ) n NR b2 C(O)OR b3 , -(CH 2 ) n NR b2 C(O)OR b3
  • p is each independently 0 or 1;
  • L 2 is a bond or -(CH 2 ) n (CR aa R bb ) n2 -;
  • R 11 , R 22 and R 33 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkane alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally may be further substituted;
  • R b1 , R b2 and R b3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl , cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;
  • R is independently selected from hydrogen, deuterium , halogen, nitro, hydroxy, mercapto, oxo, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkyne radical, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R d1 , -(CH 2 ) n OR d1 , -(CH 2 ) n C(O)R d1 , -( CH 2 ) n C(O)OR d1 , -(CH 2 ) n S(O) m R d1 , -(CH 2 ) n NR d2 R d3 , -(CH 2 ) n NR d2 C(O)OR d3 , -(CH 2 ) n NR d2 C(O)OR d3 ,
  • n1 and n2 are each independently 0, 1, 2, 3 or 4;
  • n5 and n6 are independently 0, 1 or 2;
  • Ring C is
  • Ring D is a 6-10 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl; more preferably, Ring D is a 5-membered heteroaryl, 6-membered heteroaryl membered heteroaromatic ring, benzene ring, 5-membered heteroaromatic ring and 6-membered heteroaromatic ring, 6-membered heteroaromatic ring and 6-membered heteroaromatic ring, 6-membered heteroaromatic ring and 6-membered heterocyclic ring, 6-membered heteroaromatic ring and 5-membered heteroaromatic ring Member Heterocycle, Benzo-5-membered Heterocycle, Benzo-6-membered Heteroaromatic Ring, Benzo-6-membered Heterocycle; 3-14-membered Heterocycle, 6-10-membered Heterocycle, 5-10-membered Heterocycle The heteroatoms in the heteroary
  • Ring D is selected from the following groups:
  • Ring D is
  • R 1 is selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1 -6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl , C 6-12 aryl, 5-12 membered heteroaryl, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n S(O) m R 11 , -(CH 2 ) n NR 22 R 33 , -(CH 2 ) n NR 22 C(O)OR
  • R 1 is selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1 -6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl , C 6-12 aryl, 5-12 membered heteroaryl, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n S(O) m R 11 , -(CH 2 ) n NR 22 R 33 , -(CH 2 ) n NR 22 C(O)OR
  • R 44 , R 55 and R 66 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 membered aryl or 5-12 membered heteroaryl, optionally by deuterium, halogen, Substituted with one or more substituents of amino, hydroxyl, cyano, nitro, C 1-6 alkyl and C 3-12 cycloalkyl.
  • R 1 is selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1 -6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl , C 6-12 aryl, 5-12-membered heteroaryl, optionally can be further substituted by one or more substituents in hydroxyl, halogen, amino, C 1-6 alkyl and 3-12-membered heterocyclic replaced.
  • R 1 is selected from hydrogen, deuterium, C 1-3 deuterated alkyl, C 1-3 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl or oxo 4-6 membered heterocyclyl.
  • R 1 is selected from the group consisting of hydrogen, deuterium, C 1-6 deuterated alkyl, C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl.
  • R1 is selected from hydrogen, -CH3 , -CD3 , -CH2CN , ethyl, methoxy, cyano, cyclopropyl,
  • R1 is selected from hydrogen, -CH3 , -CD3 , ethyl, methoxy, cyano, cyclopropyl,
  • Ra is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, oxo, cyano, amino, C1-6 alkyl, C1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3- 12-membered heterocyclyl, C 6-12 -membered aryl, 5-12-membered heteroaryl, -(CH 2 ) n R a1 , -(CH 2 ) n OR a1 , -(CH 2 ) n C(O)R a1 , -(CH 2 ) n C(O)OR a1 , -(CH 2 ) n S(O) m R a1 , -(CH 2 ) n NR a2 R a3 ,
  • Ra is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, oxo, cyano, amino, C1-3 alkyl, C1-3 deuterated Alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, 3- 6-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, -(CH 2 ) n R a1 , -(CH 2 ) n OR a1 , -(CH 2 ) n C(O)R a1 , -(CH 2 ) n C(O)OR a1 , -(CH 2 ) n S(O) m R a1 , -(CH 2 ) n NR a2 R a3 , -(CH(CH 2 )
  • R a1 , R a2 and R a3 are independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-6 alkyl, C 1- 6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl , 3-12-membered heterocyclic group, C 6-12 -membered aryl group or 5-12-membered heteroaryl group, the amino group, C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 halogenated alkyl group base, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -12
  • R is independently selected from hydrogen, deuterium , halogen, nitro, hydroxy, mercapto, oxo, cyano, amino optionally substituted with C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl.
  • R is independently selected from hydrogen, deuterium , halogen, nitro, hydroxy, mercapto, oxo, cyano, amino, C1-3 alkyl, C3-6 cycloalkane base.
  • Ra is independently selected from hydrogen, ethyl, oxo, cyclopropyl, methyl, methoxy, ethynyl, propynyl, trifluoromethyl, or cyano.
  • Ra is independently selected from hydrogen, ethyl, oxo, cyclopropyl, methyl, methoxy, ethynyl, trifluoromethyl, or cyano.
  • Ra is independently selected from hydrogen, ethyl, oxo, cyclopropyl and methyl.
  • x is 1, 2 or 3.
  • R is independently selected from hydrogen, deuterium , halogen, nitro, hydroxy, mercapto, oxo, cyano, amino, C1-6 alkyl, C1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3- 12-membered heterocyclyl, C 6-12 -membered aryl, 5-12-membered heteroaryl, -(CH 2 ) n R b1 , -(CH 2 ) n OR b1 , -(CH 2 ) n C(O)R b1 , -(CH 2 ) n C(O)OR b1 , -(CH 2 ) n S(O) m R b1 , -(CH 2 ) n NR b2 R b3 ,
  • R is independently selected from hydrogen, deuterium , halogen, nitro, hydroxy, mercapto, oxo, cyano, amino, C1-6 alkyl, C1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3- 12-membered heterocyclyl, C 6-12 -membered aryl, 5-12-membered heteroaryl, -(CH 2 ) n R b1 , -(CH 2 ) n OR b1 , -(CH 2 ) n C(O)R b1 , -(CH 2 ) n C(O)OR b1 , -(CH 2 ) n S(O) m R b1 , -(CH 2 ) n NR b2 R b3 ,
  • R b is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, sulfhydryl, oxo, cyano, amino, C 1-3 alkyl, C 1-3 deuterated Alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, 3- 6-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, -(CH 2 ) n R b1 , -(CH 2 ) n OR b1 , -(CH 2 ) n C(O)R b1 , -(CH 2 ) n C(O)OR b1 , -(CH 2 ) n S(O) m R b1 , -(CH 2 ) n NR b2 R
  • R b1 , R b2 and R b3 are independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-6 alkyl, C 1- 6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl , 3-12-membered heterocyclic group, C 6-12 -membered aryl group or 5-12-membered heteroaryl group, the amino group, C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 halogenated alkyl group base, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -12
  • R b is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, oxo, cyano, amino, C 1-3 alkyl, C 1-3 haloalkyl , C 3-6 cycloalkyl.
  • y is 1.
  • R is independently selected from hydrogen, deuterium , halogen, nitro, hydroxy, mercapto, oxo, cyano, amino, C1-6 alkyl, C1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3- 12-membered heterocyclyl, C 6-12 -membered aryl, 5-12-membered heteroaryl, -(CH 2 ) n R c1 , -(CH 2 ) n OR c1 , -(CH 2 ) n C(O)R c1 , -(CH 2 ) n C(O)OR c1 , -(CH 2 ) n S(O) m R c1 , -(CH 2 ) n NR c2 R c3 ,
  • R is independently selected from hydrogen, deuterium , halogen, nitro, hydroxy, mercapto, oxo, cyano, amino, C1-6 alkyl, C1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3- 12-membered heterocyclyl, C 6-12 -membered aryl, 5-12-membered heteroaryl, -(CH 2 ) n R c1 , -(CH 2 ) n OR c1 , -(CH 2 ) n C(O)R c1 , -(CH 2 ) n C(O)OR c1 , -(CH 2 ) n S(O) m R c1 , -(CH 2 ) n NR c2 R c3 ,
  • R is independently selected from hydrogen, deuterium , halogen, nitro, hydroxy, mercapto, oxo, cyano, amino, C1-3 alkyl, C1-3 deuterated Alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, 3- 6-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, -(CH 2 ) n R c1 , -(CH 2 ) n OR c1 , -(CH 2 ) n C(O)R c1 , -(CH 2 ) n C(O)OR c1 , -(CH 2 ) n S(O) m R c1 , -(CH 2 ) n NR c2 R c3 , -
  • R c1 , R c2 and R c3 are independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-6 alkyl, C 1- 6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl , 3-12-membered heterocyclic group, C 6-12 -membered aryl group or 5-12-membered heteroaryl group, the amino group, C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 halogenated alkyl group base, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -12
  • R is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, oxo, cyano, amino optionally substituted with C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 3-6 cycloalkyl.
  • Rc is independently selected from hydrogen, deuterium, F, chloro, hydroxy, methyl, methoxy, oxo, and cyano.
  • Rc is independently selected from hydrogen, deuterium, F, hydroxy, methyl, methoxy, oxo, and cyano.
  • Rc is independently selected from hydrogen, F, hydroxy, methyl, methoxy, oxo, and cyano.
  • Rc is independently selected from hydrogen, F, methyl, oxo, and cyano.
  • Rc is independently selected from hydrogen, F, methyl and oxo.
  • R d is independently selected from hydrogen, deuterium, halo, nitro, hydroxy, sulfhydryl, oxo, cyano, amino, C 1-6 alkyl, C 1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3- 12-membered heterocyclyl, C 6-12 -membered aryl, 5-12-membered heteroaryl, -(CH 2 ) n R d1 , -(CH 2 ) n OR d1 , -(CH 2 ) n C(O)R d1 , -(CH 2 ) n C(O)OR d1 , -(CH 2 ) n S(O) m R c1 , -(CH 2 ) n NR d2
  • R d is independently selected from hydrogen, deuterium, halo, nitro, hydroxy, sulfhydryl, oxo, cyano, amino, C 1-6 alkyl, C 1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3- 12-membered heterocyclyl, C 6-12 -membered aryl, 5-12-membered heteroaryl, -(CH 2 ) n R d1 , -(CH 2 ) n OR d1 , -(CH 2 ) n C(O)R d1 , -(CH 2 ) n C(O)OR d1 , -(CH 2 ) n S(O) m R c1 , -(CH 2 ) n NR d2
  • R d is independently selected from hydrogen, deuterium, halo, nitro, hydroxy, sulfhydryl, oxo, cyano, amino, C 1-3 alkyl, C 1-3 deuterated Alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, 3- 6-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, -(CH 2 ) n R d1 , -(CH 2 ) n OR d1 , -(CH 2 ) n C(O)R d1 , -(CH 2 ) n C(O)OR d1 , -(CH 2 ) n S(O) m R c1 , -(CH 2 ) n NR d2 R
  • R d1 , R d2 and R d3 are independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, C 1-6 alkyl, C 1- 6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl , 3-12-membered heterocyclic group, C 6-12 -membered aryl group or 5-12-membered heteroaryl group, the amino group, C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 halogenated alkyl group base, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -12 ary
  • R is independently selected from hydrogen, deuterium , halogen, nitro, hydroxy, mercapto, oxo, cyano, amino optionally substituted with C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 3-6 cycloalkyl.
  • Rd is independently selected from hydrogen, deuterium, cyclopropyl, isopropyl, cyano, F, Cl, methyl, -CD3 , -NHCH3 , -NHCD3 , Methoxy and oxo.
  • Rd is independently selected from hydrogen, cyclopropyl, cyano, F, Cl, methyl, -NHCH3 , methoxy and oxo.
  • Rd is independently selected from hydrogen, cyclopropyl, cyano, F, methyl, -NHCH3 , methoxy and oxo.
  • Rd is independently selected from hydrogen, cyclopropyl, cyano, F, methyl, methoxy, and oxo.
  • w is 1 or 2.
  • w is 1.
  • M 1 is C or CR 2 ;
  • M 3 is N or CR 4 ;
  • R 1 is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n NR 22 R 33 or -( CH 2 ) n NR 22 C(O)OR 33 ;
  • R 11 , R 22 and R 33 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3- 12-membered heterocyclyl, C 6-12 aryl or 5-12-membered heteroaryl;
  • R 2 , R 3 , R 4 and R 5 are the same or different, each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino optionally substituted with C 1-3 alkyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 membered aryl or 5-12 membered heteroaryl; preferably, R 2 , R 3 , R 4 and R 5 are independently is hydrogen, deuterium, halogen, C 1-3 alkyl or C 3-6 cycloalkyl;
  • R b is selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, oxo, cyano, amino optionally substituted with C 1-3 alkyl, C 1-6 alkyl, C 1-6 haloalkyl , C 1-6 alkoxy or C 3-6 cycloalkyl;
  • R c is selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, oxo, cyano, amino optionally substituted with C 1-3 alkyl, C 1-6 alkyl, C 1-6 haloalkyl , C 1-6 alkoxy or C 3-6 cycloalkyl;
  • R d is selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, oxo, cyano, amino optionally substituted with C 1-3 alkyl, C 1-6 alkyl, C 1-6 haloalkyl , C 1-6 alkoxy or C 3-6 cycloalkyl;
  • R 6 and R 7 are connected with adjacent carbon atoms to form a C 3-6 cycloalkyl group, and the C 3-6 cycloalkyl group is optionally replaced by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, One or more substitutions of cyano and amino;
  • R 6 and R 8 are connected with adjacent carbon atoms to form a C 3-6 cycloalkyl group, and the C 3-6 cycloalkyl group is optionally replaced by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, One or more substitutions of cyano and amino;
  • n5 and n6 are independently 0, 1 or 2;
  • w 1 or 2
  • y 1 or 2
  • M 6 is N or C-CN.
  • the compound represented by the general formula (I) is the compound represented by the general formula (VI):
  • L 2 is a key or O
  • M 2 is N or CR 3 ;
  • M 4 is N or CR 5 ;
  • R 11 , R 22 and R 33 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3- 12-membered heterocyclyl, C 6-12 aryl or 5-12-membered heteroaryl;
  • R 2 , R 3 , R 4 and R 5 are the same or different, each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino optionally substituted with C 1-3 alkyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 membered aryl or 5-12 membered heteroaryl; preferably, R 2 , R 3 , R 4 and R 5 are independently is hydrogen, deuterium, halogen, C 1-3 alkyl or C 3-6 cycloalkyl;
  • R d is selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, oxo, cyano, amino optionally substituted with C 1-3 alkyl, C 1-6 alkyl, C 1-6 haloalkyl , C 1-6 alkoxy or C 3-6 cycloalkyl;
  • R 6 , R 7 , R 8 and R 9 are the same or different, each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino optionally substituted with C 1-3 alkyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 membered aryl or 5-12 membered heteroaryl; preferably, R 6 , R 7 , R 8 and R 9 are independently is hydrogen, deuterium, halogen, C 1-3 alkyl or C 3-6 cycloalkyl;
  • R 6 and R 8 are connected with adjacent carbon atoms to form a C 3-6 cycloalkyl group, and the C 3-6 cycloalkyl group is optionally replaced by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, One or more substitutions of cyano and amino;
  • w 1 or 2;
  • z 1 or 2
  • M1 is CH or C.
  • M 1 is CH or CD.
  • R6, R7 , R8 , and R9 are independently hydrogen, methyl, ethyl, methoxy, ethynyl, propynyl, or cyclopropyl; alternatively, R 6.
  • R 7 is connected with adjacent carbon atoms to form a cyclopropyl group; or, R 6 and R 8 are connected with adjacent carbon atoms to form a cyclopropyl group.
  • R1 is -NHCH3 or -NH - cyclopropyl.
  • Rd is hydrogen, fluoro, chloro or cyclopropyl.
  • Rd is hydrogen or cyclopropyl.
  • the compound represented by the general formula (I) is a compound represented by the general formula (V):
  • M 1 is C or CR 2 ;
  • M 3 is N or CR 4 ;
  • M 4 is N or CR 5 ;
  • R 1 is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n NR 22 R 33 or -( CH 2 ) n NR 22 C(O)OR 33 ;
  • R 1 is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1- 6 -hydroxyalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12-membered heteroaryl; preferably, R 1 is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-10 membered heterocycle group; more preferably, R 1
  • R 11 , R 22 and R 33 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3- 12-membered heterocyclyl, C 6-12 aryl or 5-12-membered heteroaryl;
  • R c is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, oxo, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl;
  • z 1 or 2
  • n 0, 1, 2 or 3.
  • M2 is CH.
  • M4 is CH.
  • R 11 , R 22 and R 33 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-3 Alkenyl, C 2-3 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl.
  • R 1 is -NHCH 3
  • R 1 is selected from C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, -R 11 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -NR 22 R 33 or -(CH 2 ) n NR 22 C(O)OR 33 ;
  • R c is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, oxo, cyano, amino, C 1-3 alkyl, C 1-3 haloalkyl or C 3-3 cycloalkyl;
  • the compound is further represented by general formula (IX):
  • ring D is a 9-10-membered heterocyclic group, a C 6-10 -membered aryl group or a 9-10-membered heteroaryl group; preferably a 6-membered heteroaromatic ring and a 6-membered heteroaromatic ring, a 6-membered heteroaromatic ring and a 6-membered heteroaromatic ring Heterocycle or 6-membered heteroaromatic and 5-membered heterocycle; more preferably
  • the compound represented by the general formula (I) is the compound represented by the general formula (VIII):
  • M 1 is N, C or CR 2 ;
  • M 2 is N or CR 3 ;
  • M 6 is N or CR 10 ;
  • M 7 is CR 12 or N
  • R 2 , R 3 , R 10 , R 12 and R 13 are the same or different and are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, optionally surrounded by one or more C 1- 3 alkyl substituted amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl; preferably, R 2 , R 3 , R 10 , R 12 and R 13 are the same or different, each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino optionally substituted with one or more C 1-3 alkyl groups , C 1-3 alkyl, C 1-3 deuterated
  • R b is selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, oxo, cyano, amino optionally substituted with one or more C 1-3 alkyl, C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy or C 3-6 cycloalkyl; preferably hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, oxo, cyano, optionally substituted by one or more C 1-3 alkyl substituted amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy;
  • R c is selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, oxo, cyano, amino optionally substituted with one or more C 1-3 alkyl, C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy or C 3-6 cycloalkyl; preferably hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, oxo, cyano, optionally substituted by one or more C 1-3 alkyl substituted amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy;
  • R d is selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, oxo, cyano, amino optionally substituted with one or more C 1-3 alkyl, C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy or C 3-6 cycloalkyl; preferably hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, oxo, cyano, optionally substituted by one or more C 1-3 alkyl substituted amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy;
  • w, y and z are each independently 1, 2, 3 or 4.
  • M 2 is preferably CH.
  • M 6 is preferably N or CH.
  • M 7 is preferably CH or N.
  • R c is preferably hydrogen.
  • R d is preferably hydrogen, deuterium, F, Cl, methyl, -CD 3 , -NHCH 3 .
  • w is preferably 1 or 2.
  • y is preferably 1.
  • the present invention also provides a method for preparing the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: the compound is represented by the general formula (III), and the compound is represented by the general formula (III-1)
  • the compound shown and the compound shown in general formula (III-2) can be reacted as described below,
  • the reaction is carried out under the conditions of a base and a catalyst;
  • the base is preferably DIPEA;
  • the catalyst is preferably potassium iodide;
  • M 1 , M 2 , M 5 , M 6 , R b , R c , R d , L 1 , L 2 , L 3 , R 1 , ring D, n5, n6, y, z and w are as previously described.
  • the present invention also provides a compound of general formula (III-2),
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of any of the indicated compounds of general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable salts thereof.
  • the present invention further relates to any one of the compounds of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or the use of said pharmaceutical composition in the preparation of PARP inhibitor drugs; wherein said The PARP is preferably PARP1.
  • the present invention further relates to a compound represented by the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment of cancer, ischemic disease or neurodegenerative disease , wherein the cancer is preferably selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastric cancer, colorectal cancer, gastrointestinal cancer and lung cancer.
  • the cancer is preferably selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastric cancer, colorectal cancer, gastrointestinal cancer and lung cancer.
  • the present invention further relates to a compound represented by the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the treatment of cancer, ischemic disease or neurodegenerative disease.
  • the present invention also relates to a method of therapeutically preventing and/or treating ischemic disease, neurodegenerative disease, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer or lung cancer, comprising administering to a patient A therapeutically effective dose of the compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition.
  • the gastrointestinal cancer is selected from gastric cancer and colorectal cancer.
  • the present invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions including, but not limited to, conditions associated with PARP kinase dysfunction.
  • PARP is preferably PARP1 or PARP2.
  • the present invention also relates to a method of treating a cancer condition in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative.
  • the methods relate to the treatment of disorders such as cancer, ischemic disease or neurodegenerative disease.
  • the method relates to the treatment of breast, ovarian, pancreatic, prostate, blood, gastrointestinal or lung cancer; preferably, the gastrointestinal cancer is selected from gastric cancer and colorectal cancer.
  • the methods relate to the treatment of ovarian or breast cancer.
  • the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms , most preferably an alkyl group of 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group, the present invention is preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl , deuterated alkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
  • spirocycloalkyl refers to a 5- to 20-membered monocyclic polycyclic group sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings are fully conjugated ⁇ electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups.
  • spirocycloalkyl More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring linked to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) heteroatoms of m (wherein m is an integer from 0 to 2), excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon; wherein said ring atoms may further be boron or P (O) p (where p is an integer from 0 to 2).
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably tetrahydrofuranyl, pyrazolidine, morpholinyl, piperazinyl and pyranyl.
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected with other groups through a single bond, or through a ring Any two or more atoms above are further cyclo-linked to other cycloalkyl, heterocyclyl, aryl and heteroaryl groups.
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group.
  • Non-limiting examples of spiroheterocyclyl include:
  • fused heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more of the rings may contain one or more Double bonds, but none of the rings have a fully conjugated pi-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), the remaining rings Atom is carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclyl group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings have a complete common A pi-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon.
  • m is an integer from 0 to 2
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl groups include:
  • heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered, such as benzene base and naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrrolyl, thienyl , thiazolyl and pyrimidinyl.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl,
  • Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • Haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • Haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • Alkenyl refers to an alkenyl group, also known as an alkenyl group, wherein the alkenyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkanethio group, carboxyl group or carboxylate group.
  • Alkynyl refers to (CH ⁇ C-), wherein the alkynyl group may be further substituted with other related groups such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, Carboxyl or carboxylate.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Carboxyl refers to -C(O)OH.
  • THF tetrahydrofuran
  • EtOAc refers to ethyl acetate
  • MeOH refers to methanol
  • TFA trifluoroacetic acid
  • MeCN refers to acetonitrile
  • DMA refers to N,N-dimethylacetamide.
  • Et2O refers to diethyl ether.
  • DCE 1,2 dichloroethane
  • DIPEA N,N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • Cbz-Cl refers to benzyl chloroformate
  • Pd2(dba )3 refers to tris(dibenzylideneacetone)dipalladium.
  • Dppf refers to 1,1'-bisdiphenylphosphinoferrocene.
  • HATU refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • KHMDS refers to potassium hexamethyldisilazide
  • LiHMDS refers to lithium bistrimethylsilylamide.
  • MeLi refers to methyl lithium
  • n-BuLi refers to n-butyllithium
  • NaBH(OAc) 3 refers to sodium triacetoxyborohydride.
  • X is selected from A, B, or C
  • X is selected from A, B and C
  • X is A, B or C
  • X is A, B and C
  • X is A, B and C
  • the hydrogen atom in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds involved in the present invention can also be replaced by deuterium atom.
  • Optional or “optionally” means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or instances where it does not.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was four Methylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • CDCl 3 deuterated chloroform
  • TMS Methylsilane
  • the starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art.
  • the first step the preparation of ethyl 6-formyl-5-nitronicotinate
  • the third step preparation of ethyl 7-ethyl-6-carbonyl-5,6,7,8-tetrahydro-1,5-naphthalene-3-carboxylate
  • the fourth step preparation of ethyl 7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthalene-3-carboxylate
  • 1,4-Diethyl 7-ethyl-6-carbonyl-5,6,7,8-tetrahydro-1,5-naphthalene-3-carboxylate (2.8 g, 11.3 mmol) in To the oxane solution (50 mL), DDQ (2.85 g, 12.5 mmol) was added, and the mixture was heated to 110° C. and stirred for 4 hours.
  • the fifth step the preparation of 3-ethyl-7-(hydroxymethyl)-1,5-naphthalene-2(1H)-one
  • Step 7 1'-(tert-butyl)6-methyl 3',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate preparation
  • the eighth step preparation of tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate
  • the first step preparation of tert-butyl 4-(6-(methylcarbamoyl)pyridin-3-yl)piperidine-1-carboxylate
  • the first step Preparation of tert-butyl 4-(8-chloro-1,7-naphthyridin-3-yl)piperazine-1-carboxylate
  • the reaction solution was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (100 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was After concentration under reduced pressure, the target compound 4-(8-chloro-1,7-naphthyridin-3-yl)piperazine-1-carboxylate tert-butyl ester (510 mg, 35.7%) was isolated by silica gel column chromatography.
  • reaction solution was concentrated under reduced pressure, DCM and water were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure to obtain the crude target compound 4-(8-(methylamino)-1,7-naphthyridine-3- yl)piperazine-1-carboxylate tert-butyl ester (500 mg), which was used directly in the next step.
  • N-Cyclopropyl-1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthalen-3-yl)methyl)-1',2' Refer to Example 1 for the preparation method of 3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide.
  • N-methyl-1'-((2'-carbonyl-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-[1,5]naphthalene]-7 '-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide was prepared by referring to Example 1.
  • N-(cyanomethyl)-1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthalen-3-yl)methyl)-1' Refer to Example 1 for the preparation method of 2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide.
  • Example 1 1'-(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-(2,2,2-trifluoroethyl) Refer to Example 1 for the preparation method of -1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide.
  • Example 1 1'-(3-Ethyl-2-oxo-2,3-dihydro-1H-pyridine[2,3-b][1,4]oxazin-7-yl)methyl)-2-fluoro
  • Example 1 for the preparation method of -N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide.
  • Test Example 1 Determination of Inhibitory Activity of Compounds of the Invention on PARP1 Enzyme
  • the purpose of this test example is to measure the inhibitory activity of the compound on PARP1 enzyme.
  • PARP1Chemiluminescent Assay Kit was purchased from BPS bioscience, Cat. No. 80569
  • PBS was purchased from Gibco, Cat. No. 10010023
  • chemiluminescence method was used to detect the inhibitory activity of compounds on PARP1 enzyme.
  • This experiment was carried out in a 384-well plate.
  • the 384-well plate was coated with histones: 5 ⁇ histone solution was diluted 5 times with PBS, added to a 384-well ELISA plate, 25 ⁇ L per well, and incubated overnight at 4 degrees Celsius. Wash the coated ELISA plate with 1 ⁇ PBST buffer and then block with blocking solution (blocking buffer 3 in the kit) for 30 to 120 minutes, 100 ⁇ L per well, and wash 3 to 6 times with 1 ⁇ PBST buffer.
  • reaction solution was poured out, washed with 1 ⁇ PBST buffer, and Streptavidin-HRP solution diluted 50 times with Blocking buffer 3 was added, 25 ⁇ L per well, and incubated at room temperature for 30 minutes. After pouring off the reaction solution, wash 3 to 6 times with 1 ⁇ PBST buffer. Add ECL substrate A and ELISA ECL substrate B 1:1 mixed luminescence reaction solution, 50 ⁇ L per well. Chemiluminescence readings were performed immediately using a BioTek Synergy H1 or Envision instrument.
  • Example PARP1 IC50 (nM) Example 1 0.93 Example 2 0.76 Example 3 0.40 Example 6 2.90 Example 17 4.50
  • Example 23 3.30 Example 24 1.70 Example 29 0.98 Example 30 1.40 Example 31 1.00 Example 32 1.00 Example 33 0.91 Example 34 1.60 Example 35 1.00 Example 36 0.80 Example 42 1.30 Example 45 0.80 Example 46 0.60 Example 53 0.96 Example 56 1.30 Example 57 2.80 Example 58 0.90 Example 59 0.80 Example 65 2.20 Example 66 1.70 Example 67 2.10 Example 79 3.30 Example 80 5.00 Example 81 0.90 Example 82 0.60 Example 83 1.40 Example 84 2.70 Example 85 3.50 Example 86 5.10 Example 87 4.90 Example 88 5.00 Example 90 2.70 Example 91 3.00 Example 93 2.10
  • the compounds shown in the present invention show excellent biological activity in the PARP1 enzyme inhibition assay.
  • the purpose of this test example is to measure the inhibitory activity of the compound on PARP2 enzyme.
  • PARP2 Chemiluminescent Assay Kit was purchased from BPS bioscience, Cat. No. 80552
  • PBS was purchased from Gibco, Cat. No. 10010023
  • IC50 values were obtained by taking readings with a BioTek Synergy H1 or Envision instrument, recording chemiluminescence readings, calculating inhibition rates, and fitting the concentrations and inhibition rates to a nonlinear regression curve using Graphpad Prism software.
  • Test Example 3 Determination of the inhibitory effect of the compounds of the present invention on the proliferation activity of BRCA2 Knockout DLD-1 cells
  • the purpose of this test case is to measure the inhibitory effect of the compound on the proliferation activity of BRCA2 Knockout DLD-1 cells.

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US11795173B1 (en) 2022-04-28 2023-10-24 Xinthera, Inc. Substituted pyridines as PARP1 inhibitors
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CN117658983A (zh) * 2022-09-01 2024-03-08 浙江文达医药科技有限公司 选择性parp1抑制剂
TW202416977A (zh) * 2022-09-30 2024-05-01 大陸商中國醫藥研究開發中心有限公司 含氮雜環類化合物及其醫藥用途
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
JP2025535834A (ja) * 2022-11-02 2025-10-28 スアンズ バイオファーマシューティカル カンパニー，リミテッド 多環式ポリ（ａｄｐリボース）ポリメラーゼ選択的阻害剤
CN117903159A (zh) * 2022-12-30 2024-04-19 成都硕德药业有限公司 一种内酰胺类衍生物、其制备方法及用途
CN116375700B (zh) * 2023-01-10 2024-12-17 中国科学院成都生物研究所 一种4-氮杂吲哚啉类化合物及其合成方法与应用
EP4673448A1 (en) * 2023-03-01 2026-01-07 Impact Therapeutics (Shanghai), Inc. Substituted nitrogen-containing tricyclic compounds as parp inhibitors and the use thereof
CN119462669A (zh) * 2023-08-11 2025-02-18 上海海和药物研究开发股份有限公司 稠合三环类化合物、其药物组合物和用途
CN121335891A (zh) * 2023-08-17 2026-01-13 Dic株式会社 化合物和使用该化合物的液晶组合物、液晶显示装置、传感器、液晶透镜、光通信装置和天线
WO2025168048A1 (zh) * 2024-02-08 2025-08-14 上海璎黎药业有限公司 一种三键结构化合物、其药物组合物及其应用
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JP2024514223A (ja) * 2021-04-19 2024-03-28 シンセラ， インコーポレイテッド Ｐａｒｐ１阻害薬及びその使用
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
WO2023088408A1 (zh) * 2021-11-19 2023-05-25 成都百裕制药股份有限公司 选择性parp1抑制剂及其应用
JP2024540600A (ja) * 2021-11-19 2024-10-31 康百達（四川）生物医薬科技有限公司 選択的ｐａｒｐ１阻害剤およびその用途
JP7762306B2 (ja) 2021-11-19 2025-10-29 康百達（四川）生物医薬科技有限公司 選択的ｐａｒｐ１阻害剤およびその用途
AU2022390101B2 (en) * 2021-11-19 2026-02-19 Kangbaida (Sichuan) Biotechnology Co., Ltd. Selective parp1 inhibitor and application thereof
WO2023109521A1 (zh) * 2021-12-17 2023-06-22 凯复(苏州)生物医药有限公司 Parp抑制剂、包含其的药物组合物及其用途
US12384780B2 (en) 2022-01-21 2025-08-12 Xinthera, Inc. PARP1 inhibitors and uses thereof
US11939329B2 (en) 2022-01-21 2024-03-26 Xinthera, Inc. PARP1 inhibitors and uses thereof
US12054479B1 (en) 2022-03-14 2024-08-06 Slap Pharmaceuticals Llc Multicyclic compounds
US11795173B1 (en) 2022-04-28 2023-10-24 Xinthera, Inc. Substituted pyridines as PARP1 inhibitors
WO2023207284A1 (en) * 2022-04-28 2023-11-02 Ningbo Newbay Technology Development Co., Ltd Piperazine derivatives as parp1 inhibitiors
US12421241B2 (en) 2022-04-28 2025-09-23 Xinthera, Inc. Substituted pyridines as PARP1 inhibitors
US12006322B2 (en) 2022-04-28 2024-06-11 Xin Thera, Inc. Substituted pyridines as PARP1 inhibitors
CN115919859B (zh) * 2022-07-14 2024-01-05 四川海思科制药有限公司 一种杂芳基衍生物的药物组合物及其在医药上的应用
CN115919859A (zh) * 2022-07-14 2023-04-07 四川海思科制药有限公司 一种杂芳基衍生物的药物组合物及其在医药上的应用
WO2024050370A1 (en) * 2022-08-30 2024-03-07 1Cbio, Inc. Heterocyclic compounds and methods of use thereof
WO2024067694A1 (zh) * 2022-09-30 2024-04-04 中国医药研究开发中心有限公司 含氮杂环类化合物及其医药用途
WO2024083218A1 (zh) * 2022-10-20 2024-04-25 成都赜灵生物医药科技有限公司 取代四氢吡啶类化合物及其用途
JP2025535816A (ja) * 2022-10-20 2025-10-28 成都▲ざ▼▲霊▼生物医▲薬▼科技有限公司 縮合複素環化合物及びその使用
WO2024099364A3 (en) * 2022-11-09 2024-06-13 Laekna Therapeutics Shanghai Co., Ltd. Fused multicyclic compounds and their use as parp1 inhibitors
WO2024178127A1 (en) * 2023-02-21 2024-08-29 1Cbio, Inc. Heterocyclic compounds and methods of use thereof
WO2024178125A1 (en) * 2023-02-21 2024-08-29 1Cbio, Inc. Heterocyclic compounds and methods of use thereof
WO2024188265A1 (zh) * 2023-03-13 2024-09-19 江苏豪森药业集团有限公司 哌啶烯类化合物在制备治疗癌症的药物中的应用
WO2025026195A1 (zh) * 2023-07-28 2025-02-06 广东东阳光药业股份有限公司 取代的含氮双环化合物及其用途
WO2025103407A1 (zh) * 2023-11-16 2025-05-22 江苏豪森药业集团有限公司 抗体药物偶联物和多腺苷二磷酸核糖聚合酶抑制剂的联合应用
WO2025265123A1 (en) * 2024-06-21 2025-12-26 Protheragen Inc. Parp1 inhibitors for the treatment of diseases
WO2026002281A1 (zh) * 2024-06-28 2026-01-02 上海翰森生物医药科技有限公司 哌啶烯类化合物联合用药在制备治疗癌症的药物中的用途

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