US20080015182A1 - Potent PARP Inhibitors - Google Patents

Potent PARP Inhibitors Download PDF

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US20080015182A1
US20080015182A1 US11/765,776 US76577607A US2008015182A1 US 20080015182 A1 US20080015182 A1 US 20080015182A1 US 76577607 A US76577607 A US 76577607A US 2008015182 A1 US2008015182 A1 US 2008015182A1
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Prior art keywords
quinazolin
alkyl
pyrazolo
oxo
aryl
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Thomas Penning
Sheela Thomas
Philip Hajduk
Daryl Sauer
Kathy Sarris
Vincent Giranda
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Abbott Laboratories
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Abbott Laboratories
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Priority to US11/765,776 priority Critical patent/US20080015182A1/en
Assigned to ABBOTT LABORATORIES reassignment ABBOTT LABORATORIES ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: THOMAS, SHEELA A., GIRANDA, VINCENT L., HAJDUK, PHILIP J., PENNING, THOMAS D., SARRIS, KATHY, SAUER, DARYL R.
Publication of US20080015182A1 publication Critical patent/US20080015182A1/en
Priority to US12/476,849 priority patent/US8183250B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
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    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
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    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to 1H-benzimidazole-4-carboxamides, their preparation, and their use as inhibitors of the enzyme poly(ADP-ribose)polymerase for the preparation of drugs.
  • PARP inhibitors Target for a broad spectrum of disorders. PARP inhibitors have demonstrated efficacy in numerous models of disease, particularly in models of ischemia reperfusion injury, inflammatory disease, degenerative diseases, protection from adverse effects of cytoxic compounds, and the potentiation of cytotoxic cancer therapy. PARP has also been indicated in retroviral infection and thus inhibitors may have use in antiretroviral therapy.
  • PARP inhibitors have been efficacious in preventing ischemia reperfusion injury in models of myocardial infarction, stroke, other neural trauma, organ transplantation, as well as reperfusion of the eye, kidney, gut and skeletal muscle. Inhibitors have been efficacious in inflammatory diseases such as arthritis, gout, inflammatory bowel disease, CNS inflammation such as MS and allergic encephalitis, sepsis, septic shock, hemmorhagic shock, pulmonary fibrosis, and uveitis. PARP inhibitors have also shown benefit in several models of degenerative disease including diabetes (as well as complications) and Parkinsons disease.
  • PARP inhibitors can ameliorate the liver toxicity following acetominophen overdose, cardiac and kidney toxicities from doxorubicin and platinum based antineoplastic agents, as well as skin damage secondary to sulfur mustards. In various cancer models, PARP inhibitors have been shown to potentiate radiation and chemotherapy by increasing cell death of cancer cells, limiting tumor growth, decreasing metastasis, and prolonging the survival of tumor-bearing animals.
  • the present invention provides compounds of Formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, NR A R B , and (NR A R B )carbonyl;
  • X is aryl, arylalkyl, alkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, NR C R D , (NR C R D )carbonyl, (NR C R D )alkyl, (NR C R D )carbonylalkyl, or -alkyl-CO 2 G 1 ; wherein if X is aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, cycloalkyl, or cycloalkylalkyl then X may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z, independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN
  • G 1 is hydrogen, alkyl, alkenyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, or heterocyclealkyl; wherein the aryl, the aryl moiety of arylalkyl, the heteroaryl, the heteroaryl moiety of heteroarylakyl, the cycloalkyl, the cycloalkyl moiety of cycloalkylalkyl, the heterocycle, and the heterocycle moiety of heterocyclealkyl are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbon
  • R C and R D are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylcarbonyloxyalkylcarbonyl, arylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocyclealkylcarbonyl, (NR A R B )alkyl, and (NR A R B )alkylcarbonyl; wherein if R C or R D are aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heteroaryl, heteroarylalky
  • R A and R B are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, and alkylcarbonyl;
  • n 1.
  • the present invention provides compounds of Formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 , R 2 , R 3 and R 4 are hydrogen
  • X is aryl, arylalkyl, alkyl, heteroaryl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, cycloalkyl, (NR C R D )carbonyl, or (NR C R D )alkyl; wherein if X is aryl, arylalkyl, heteroaryl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, or cycloalkyl, then X may be unsubstituted or substituted with 1 or 2 substituents, Z, independently selected from the group consisting of alkyl, nitro, —CN, halogen, alkoxy, alkoxycarbonyl, aryl, arylalkyl, arylalkoxycarbonyl, carboxy, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, NR C R D , (
  • R C and R D are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylcarbonyloxyalkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl, haloalkyl, haloalkylcarbonyl, heteroaryl, heteroarylcarbonyl, heterocyclealkyl, heterocyclecarbonyl, heterocyclealkylcarbonyl, (NR A R B )alkyl, and (NR A R B )alkylcarbonyl; wherein if R C or R D are arylalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclealkyl, heterocyclecarbonyl, or heterocyclealkylcarbonyl, then R C or R D may be unsubstituted or substituted with one substituent selected from the group consisting of alkoxy,
  • R A and R B are independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl;
  • n 1.
  • the present invention provide compounds of Formula (I) where X is selected from the group consisting of aryl, heteroaryl, heterocycle, and cycloalkyl.
  • the present invention provides compounds of Formula (II) or a therapeutically acceptable salt thereof, wherein
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, NR A R B , and (NR A R B )carbonyl;
  • X is aryl, arylalkyl, alkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, NR C R D , (NR C R D )carbonyl, (NR C R D )alkyl, (NR C R D )carbonylalkyl, or -alkyl-CO 2 G 1 ; wherein if X is aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, cycloalkyl, or cycloalkylalkyl then X may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z, independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN
  • aryl and the heteroaryl moieties of Z are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, formyl, halogen, and haloalkyl, and the heterocycle and cycloalkyl moieties of Z are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, oxo, formyl, halogen, and haloalkyl;
  • G 1 is hydrogen, alkyl, alkenyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, or heterocyclealkyl; wherein the aryl, the aryl moiety of arylalkyl, the heteroaryl, the heteroaryl moiety of heteroarylakyl, the cycloalkyl, the cycloalkyl moiety of cycloalkylalkyl, the heterocycle, and the heterocycle moiety of heterocyclealkyl are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbon
  • R C and R D are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylcarbonyloxyalkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocyclealkylcarbonyl, (NR A R B )alkyl, and (NR A R B )alkylcarbonyl; wherein if R C or R D are aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heteroaryl, heteroarylalky
  • R A and R B are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, and alkylcarbonyl.
  • the present invention provides compounds of Formula (III) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, NR A R B , and (NR A R B )carbonyl;
  • X is aryl, arylalkyl, alkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, NR C R D , (NR C R D )carbonyl, (NR C R D )alkyl, (NR C R D )carbonylalkyl, or -alkyl-CO 2 G 1 ; wherein if X is aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, cycloalkyl, or cycloalkylalkyl then X may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z, independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN
  • G 1 is hydrogen, alkyl, alkenyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, or heterocyclealkyl; wherein the aryl, the aryl moiety of arylalkyl, the heteroaryl, the heteroaryl moiety of heteroarylakyl, the cycloalkyl, the cycloalkyl moiety of cycloalkylalkyl, the heterocycle, and the heterocycle moiety of heterocyclealkyl are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbon
  • R C and R D are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylcarbonyloxyalkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocyclealkylcarbonyl, (NR A R B )alkyl, and (NR A R B )alkylcarbonyl; wherein if R C or R D are aryl, arylalkyl, arylalkylcarbonyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclealkyl, hetero
  • R A and R B are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, and alkylcarbonyl.
  • the present invention provides compounds of Formula (II) wherein X is aryl or arylalkyl wherein the aryl or arylalkyl may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z, independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
  • the present invention provides compounds of Formula (II) wherein X is heteroaryl which may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z, independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl,
  • the present invention provides compounds of Formula (II) wherein X is heterocycle or heterocyclealkyl wherein the heterocycle or heterocyclealkyl may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z, independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl, heteroaryl, heteroarylcarbonyl, heteroarylcarbonyl, heteroarylcarbonyl,
  • the present invention provides compounds of Formula (III) wherein X is heteroarylcarbonyl, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, (NR C R D )carbonyl, (NR C R D )alkyl, or aryl wherein if X is heteroarylcarbonyl, heterocyclealkyl, heterocyclecarbonyl, or aryl, then X may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z, independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl, arylalkylcarbonyl, carboxy,
  • the present invention provides compounds of Formula (I) wherein R 1 , R 2 , R 3 and R 4 are hydrogen.
  • the present invention provides compounds of Formula (II) wherein R 1 , R 2 , R 3 and R 4 are hydrogen.
  • the present invention provides compounds of Formula (III) wherein R 1 , R 2 , R 3 and R 4 are hydrogen. In another embodiment, the present invention provides compounds selected from the group consisting of
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.
  • the present invention provides a method of inhibiting PARP in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for decreasing tumor volume in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating leukemia, colon cancer, glioblastomas, lymphomas, melanomas, carcinomas of the breast, or cervical carcinomas in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of potentiation of cytotoxic cancer therapy in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of potentiation of radiation therapy in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating ischemia reperfusion injury associated with, but not limited to, myocardial infarction, stroke, other neural trauma, and organ transplantation, in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of reperfusion including, but not limited to, reperfusion of the eye, kidney, gut and skeletal muscle, in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating inflammatory diseases including, but not limited to, arthritis, gout, inflammatory bowel disease, CNS inflammation, multiple sclerosis, allergic encephalitis, sepsis, septic shock, hemmorhagic shock, pulmonary fibrosis, and uveitis in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • inflammatory diseases including, but not limited to, arthritis, gout, inflammatory bowel disease, CNS inflammation, multiple sclerosis, allergic encephalitis, sepsis, septic shock, hemmorhagic shock, pulmonary fibrosis, and uveitis
  • the present invention provides a method of treating immunological diseases or disorders such as rheumatoid arthritis and septic shock in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating degenerative disease including, but not limited to, diabetes and Parkinsons disease, in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating hypoglycemia in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating retroviral infection in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating liver toxicity following acetominophen overdose in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating cardiac and kidney toxicities from doxorubicin and platinum based antineoplastic agents in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating skin damage secondary to sulfur mustards in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to prepare a medicament for inhibiting the PARP enzyme in a mammal in recognized need of such treatment.
  • the present invention provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to prepare a medicament for inhibiting tumor growth in a mammal in recognized need of such treatment.
  • the present invention provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating cancer in a mammal in recognized need of such treatment.
  • the present invention provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating leukemia, colon cancer, glioblastomas, lymphomas, melanomas, carcinomas of the breast, or cervical carcinomas in a mammal in a mammal in recognized need of such treatment.
  • the present invention provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to prepare a medicament for potentiation of cytotoxic cancer therapy in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to prepare a medicament for potentiation of radiation in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating ischemia reperfusion injury associated with, but not limited to, myocardial infarction, stroke, other neural trauma, and organ transplantation, in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating reperfusion including, but not limited to, reperfusion of the eye, kidney, gut and skeletal muscle, in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating inflammatory diseases including, but not limited to, arthritis, gout, inflammatory bowel disease, CNS inflammation, multiple sclerosis, allergic encephalitis, sepsis, septic shock, hemmorhagic shock, pulmonary fibrosis, and uveitis in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • inflammatory diseases including, but not limited to, arthritis, gout, inflammatory bowel disease, CNS inflammation, multiple sclerosis, allergic encephalitis, sepsis, septic shock, hemmorhagic shock, pulmonary fibrosis, and uveitis
  • inflammatory diseases including, but not limited to, arthritis, gout, inflammatory bowel disease, CNS inflammation, multiple sclerosis, allergic encephalitis,
  • the present invention provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating immunological diseases or disorders such as rheumatoid arthritis and septic shock in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating degenerative disease including, but not limited to, diabetes and Parkinsons disease, in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating hypoglycemia in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating retroviral infection in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating liver toxicity following acetaminophen overdose in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating cardiac and kidney toxicities from doxorubicin and platinum based antineoplastic agents in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating skin damage secondary to sulfur mustards in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.
  • alkenyl as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.
  • alkoxy as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • alkoxyalkyl as used herein, means at least one alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
  • alkoxycarbonyl as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
  • alkoxycarbonylalkyl as used herein, means an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • alkyl as used herein, means a saturated, straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • alkylcarbonyl as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
  • alkylcarbonylalkyl as used herein, means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through a alkyl group, as defined herein.
  • alkylcarbonyloxy means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy.
  • alkylcarbonyloxyalkyl as used herein, means an alkylcarbonyloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • alkylcarbonyloxyalkylcarbonyl as used herein, means an alkylcarbonyloxyalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group.
  • alkylenyl as used herein, means a divalent group derived from a saturated, straight or branched chain hydrocarbon of from 1 to 6 carbon atoms. Representative examples include, but are not limited to, —CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH(CH 3 )CH 2 —.
  • alkynyl as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond.
  • Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
  • aryl means a phenyl group or a naphthyl group.
  • arylalkyl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, 1-methyl-3-phenylpropyl, and 2-naphth-2-ylethyl.
  • arylalkoxy as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • arylalkoxycarbonyl as used herein, means an arylalkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • arylalkylcarbonyl as used herein, means an arylalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • the alkyl of arylalkylcarbonyl groups of the present invention may be substituted with an alkoxy substituent.
  • arylcarbonyl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • carbonyl as used herein, means a —C(O)— group.
  • cyano as used herein, means a —CN group.
  • carboxyalkyl as used herein, means a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • carboxyalkylcarbonyl as used herein, means a carboxyalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • cycloalkyl as used herein, means a saturated cyclic hydrocarbon group containing from 3 to 8 carbons, examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • cycloalkylalkoxy as used herein, means a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • cycloalkylalkyl as used herein, means a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.
  • cycloalkylcarbonyl as used herein, means a cycloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • halo or “halogen” as used herein, means —Cl, —Br, —I or —F.
  • haloalkyl as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, 3-chloropropyl, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
  • haloalkoxy means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
  • haloalkylcarbonyl as used herein, means a haloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • heteroaryl means a monocyclic heteroaryl ring or a bicyclic heteroaryl ring.
  • the monocyclic heteroaryl ring is a 5 or 6 membered ring.
  • the 5 membered ring has two double bonds and contains one, two, three or four heteroatoms independently selected from the group consisting of N, O, and S.
  • the 6 membered ring has three double bonds and contains one, two, three or four heteroatoms independently selected from the group consisting of N, O, and S.
  • the bicyclic heteroaryl ring consists of the 5 or 6 membered heteroaryl ring fused to a phenyl group or the 5 or 6 membered heteroaryl ring is fused to another 5 or 6 membered heteroaryl ring.
  • Nitrogen heteroatoms contained within the heteroaryl may be optionally oxidized to the N-oxide.
  • the heteroaryl is connected to the parent molecular moiety through any carbon atom contained within the heteroaryl while maintaining proper valence.
  • heteroaryl include, but are not limited to, benzothienyl, beizoxadiazolyl, cinnolinyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naplithyridinyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, pyridinium N-oxide, quinolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, and triazinyl.
  • heteroarylalkyl as used herein, means a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of heteroarylalkyl include, but are not limited to, pyridinymethyl.
  • heteroarylcarbonyl as used herein, means a heteroaryl, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • heteroarylcarbonylalkyl as used herein, means a heteroarylcarbonyl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • heterocycle or “heterocyclic” as used herein, means a monocyclic or bicyclic heterocyclic ring.
  • the monocyclic heterocyclic ring consists of a 3, 4, 5, 6, 7, or 8 membered ring containing at least one heteroatom independently selected from O, N, and S.
  • the 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S.
  • the 5 membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of 0, N and S.
  • the 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O , N and S.
  • the bicyclic heterocyclic ring consists of a monocyclic heterocyclic ring fused to a cycloalkyl group or the monocyclic heterocyclic ring fused to a phenyl group or the monocyclic heterocyclic ring fused to another monocyclic heterocyclic ring.
  • the heterocycle is connected to the parent molecular moiety through any carbon or nitrogen atom contained within the heterocycle while maintaining proper valence.
  • heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, thi
  • heterocyclealkyl as used herein, means a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • heterocyclealkylcarbonyl as used herein, means a heterocyclealkyl, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • heterocyclecarbonyl as used herein, means a heterocycle, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • heterocyclecarbonylalkyl as used herein, means a heterocyclecarbonyl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • hydroxy as used herein, means an —OH group.
  • hydroxyalkyl as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.
  • nitro as used herein, means a —NO 2 group.
  • NR A R B means two groups, R A and R B , which are appended to the parent molecular moiety through a nitrogen atom.
  • (NR A R B )alkyl as used herein, means a NR A R B group, as defined herein, appended to the parent molecular moiety through an alkyl group.
  • (NR A R B )carbonyl as used herein, means a NR A R B group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of (NR A R B )carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.
  • (NR A R B )carbonylalkyl as used herein, means a (NR A R B )carbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • (NR A R B )alkylcarbonyl as used herein, means a (NR A R B )alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • NR C R D means two groups, R C and R D , which are appended to the parent molecular moiety through a nitrogen atom.
  • (NR C R D )alkyl as used herein, means a NR C R D group, as defined herein, appended to the parent molecular moiety through an alkyl group.
  • (NR C R D )carbonyl as used herein, means a NR C R D group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of (NR C R D )carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.
  • (NR C R D )carbonylalkyl as used herein, means a (NR C R D )carbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • oxo as used herein, means a ⁇ O moiety.
  • Stereoisomers can exist as stereoisomers, wherein asymmetric or chiral centers are present.
  • Stereoisomers are designated (R) or (S) depending on the configuration of substituents around the chiral carbon atom.
  • the terms (R) and (S) used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., (1976), 45: 13-30, hereby incorporated by reference.
  • the present invention contemplates various stereoisomers and mixtures thereof and are specifically included within the scope of this invention.
  • Stereoisomers include enantiomers, diastereomers, and mixtures of enantiomers or diastereomers.
  • Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
  • Nicotinamide[2,5′,8-3H]adenine dinucleotide and strepavidin SPA beads were purchased from Amersham Biosiences (UK) Recombinant Human Poly(ADP-Ribose) Polymerase (PARP) purified from E.coli and 6-Biotin-17-NAD + , were purchase from Trevigen, Gaithersburg, MD. NAD + , Histone, aminobenzamide, 3-amino benzamide and Calf Thymus DNA (dcDNA) were purchased from Sigma, St. Louis, Mo. Stem loop oligonucleotide containing MCAT sequence was obtained from Qiagen.
  • the oligos were dissoloved to 1 mM in annealing buffer containing 10 mM Tris HCl pH 7.5, 1 mM EDTA, and 50 mM NaCl, incubated for 5min at 95° C., and followed by annealing at 45° C. for 45 minutes.
  • Histone H1 (95% electrophoretically pure) was purchased from Roche, Indianapolis, Ind.
  • Biotinylated histone H1 was prepared by treating the protein with Sulfo-NHS-LC-Biotin from Pierce Rockford, Ill.
  • the biotinylation reaction was conducted by slowly and intermittently adding 3 equivalents of 10 mM Sulfo-NHS-LC-Biotin to 100 ⁇ M Histone H1 in phosphate-buffered saline, pH 7.5, at 4° C. with gentle vortexing over 1 min followed by subsequent 4° C. incubation for 1 hr.
  • Streptavidin coated (FlashPlate Plus) microplates were purchased from Perkin Elmer, Boston, Mass.
  • PARP1 assay was conducted in PARP assay buffer containing 50 mM Tris pH 8.0, 1 mM DTT, 4 mM MgCl 2 .
  • PARP reactions contained 1.5 ⁇ M [ 3 H]-NAD + (1.6 uCi/mmol), 200 nM biotinylated histone H1, 200 nM s1DNA, and 1 nM PARP enzyme.
  • Auto reactions utilizing SPA bead-based detection were carried out in 100 ⁇ l volumes in white 96 well plates. Reactions were initiated by adding 50 ⁇ l of 2 ⁇ NAD + substrate mixture to 50 ⁇ l of 2 ⁇ enzyme mixture containing PARP and DNA.
  • C41 cells were treated with a compound of the present invention for 30 minutes in 96 well plate.
  • PARP was then activated by damaging DNA with 1 mM H 2 O 2 for 10 minutes.
  • the cells were then washed with ice-cold PBS once and fixed with pre-chilled methanol:acetone (7:3) at ⁇ 20° C. for 10 minutes.
  • the plates were rehydrated with PBS and blocked 5% non-fat dry milk in PBS-tween (0.05%) (blocking solution) for 30 minutes at room temperature.
  • the cells were incubated with anti-PAR antibody 10H (1:50) in Blocking solution at 37° C.
  • the cellular assay measures the formation of poly ADP-ribose by PARP within cells and demonstrates that compounds of the present invention penetrate cell membranes and inhibit PARP in intact cells.
  • the EC 50s for representative compounds of the present invention are provided in Table 2. TABLE 2 Cellular Activity EC 50 (nM) 16 9.6 1.1 >1000 24 >1000 106
  • the compounds of the present invention have numerous therapeutic applications related to, ischemia reperfusion injury, inflammatory diseases, degenerative diseases, protection from adverse effects of cytotoxic compounds, and potentiation of cytotoxic cancer therapy.
  • compounds of the present invention potentiate radiation and chemotherapy by increasing cell death of cancer cells, limiting tumor growth, decreasing metastasis, and prolonging the survival of tumor-bearing mammals.
  • Compounds of Formula (I) can treat leukemia, colon cancer, glioblastomas, lymphomas, melanomas, carcinomas of the breast, and cervical carcinomas.
  • Other therapeutic applications include, but are not limited to, retroviral infection, arthritis, gout, inflammatory bowel disease, CNS inflammation, multiple sclerosis, allergic encephalitis, sepsis, septic shock, hemmorhagic shock, pulmonary fibrosis, uveitis, diabetes, Parkinsons disease, myocardial infarction, stroke, other neural trauma, organ transplantation, reperfusion of the eye, reperfusion of the kidney, reperfusion of the gut, reperfusion of skeletal muscle, liver toxicity following acetominophen overdose, cardiac and kidney toxicities from doxorubicin and platinum based antineoplastic agents, and skin damage secondary to sulfur mustards.
  • retroviral infection arthritis, gout, inflammatory bowel disease, CNS inflammation, multiple sclerosis, allergic encephalitis, sepsis, septic shock, hemmorhagic shock, pulmonary fibrosis, uveitis, diabetes, Parkinsons disease, myocardial infarction, stroke, other neural trauma
  • a therapeutically effective amount of one of the compounds of the present invention can be employed as a zwitterion or as a pharmaceutically acceptable salt.
  • a “therapeutically effective amount” of the compound of the invention is meant a sufficient amount of the compound to treat or prevent a disease or disorder ameliorated by a PARP inhibitor at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • salts are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well-known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention or separately by reacting the free base of a compound of the present invention with a suitable acid.
  • Representative acids include, but are not limited to acetatic, citric, aspartic, benzoic, benzenesulfonic, butyric, fumaric, hydrochloric, hydrobromic, hydroiodic, lactic, maleic, methanesulfonic, pamoic, pectinic, pivalic, propionic, succinic, tartaric, phosphic, glutamic, and p-toluenesulfonic.
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as decyl
  • a compound of the present invention may be administered as a pharmaceutical composition containing a compound of the present invention in combination with one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • the compositions can be administered parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, drops or transdermal patch), rectally, or bucally.
  • parenteral refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • compositions for parenteral injection comprise pharmaceutically-acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions can also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.
  • Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically-acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
  • Total daily dose of the compositions of the invention to be administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.0001 to 300 mg/kg body weight daily and more usually 1 to 300 mg/kg body weight.
  • the dose, from 0.0001 to 300 mg/kg body, may be given twice a day.
  • CDI carbonyl diimidazole
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • DME 1,2-dimethoxyethane
  • DMF N,N-dimethylforamide
  • DMSO dimethylsulfoxide
  • Et 2 O diethyl ether
  • EtOAc ethyl acetate
  • EtOH ethanol
  • HPLC high pressure liquid chromatography
  • LDA lithium diisopropylamide
  • MeOH for methanol
  • psi pounds per square inch
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • TMS trimethylsilane.
  • reaction conditions and reaction times for each individual step may vary depending on the particular reactants employed and substituents present in the reactants used. Unless otherwise specified, solvents, temperatures and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Reactions may be worked up in the convention manner, e.g. by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but are not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or may be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.
  • This invention is intended to encompass compounds having formula (I) when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.
  • Compound of formula (6) can be obtained by (a) deprotonation of nitrile (3) with a base such as, but not limited to, n-butyl lithium and the (b) contacting the anion obtained from step (a) with an acid chloride (2) or an ester (1) wherein R 101 is C 1-6 alkyl, to provide compound (4).
  • the anion obtained from step (a) can be treated with (1) wherein R 101 is hydrogen, in the presence of a coupling reagent such as, but not limited to, N,N′-carbonyldiimidazole or 1,3-dicyclohexylcarbodiimide to provide compound (4).
  • a 3-cyano-4H-pyrazolo[1,5-a]quinazolin-5-one (7) prepared using the conditions as described in Scheme 1, or purchased, can be reduced to the 3-aminomethyl analog (8) using an appropriate reducing agent such as ammonia in methanol and Raney nickel, under about 60 psi of hydrogen gas.
  • a coupling reagent such as, but not limited to, 1,3-dicyclohexylcarbodiimide
  • a coupling auxiliary such as, but not limited to, 1-hydroxybenzotriazole hydrate
  • a base such as, but not limited to diisopropylethyl amine
  • the reaction is generally performed in a solvent such as, but not limited to, N,N-dimethylacetamide, at ambient temperature or with heating (for example, at about 100-150° C.) and optionally in a microwave reactor.
  • Compound (8) can also be coupled with an acid chloride R 102 COC1 in the presence of a base such as pyridine and in a solvent such as DMF, or alternatively, (8) can be coupled with an anhydride (R 102 CO) 2 O in the presence of a base such as diisopropylethylamine and in a solvent such as methanol.
  • Compound (8) can also be alkylated with an halide of formula R 103 X wherein R 103 is alkyl, aralkyl, heteroarylalkyl, heterocyclealkyl or NR A R B alkyl, in the presence of a base such as sodium ethoxide or can be reacted with an aldehyde R 104 CHO or ketone R 104 R 105 C(O) wherein R 104 and R 105 are alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclealkyl or NR A R B alkyl, under reductive amination conditions, such as sodium cyanoborohydride in methanol, to give the N-alkyl analog (10).
  • a bromo 2- or 3-aryl, heteroaryl, heteroarylalkyl, or aralkyl-4H-pyrazolo[1,5-a]quinazolin-5-one of formula (11), where A is aryl, heteroaryl, heteroarylalkyl, is prepared using the conditions as described in Scheme 1.
  • This compound can be carbonylated under palladium catalysis in the presence of methanol or other alcohols to give the methyl ester (12). Saponification using, for example, sodium hydroxide in ethanol, gave the acid (13).
  • Acid (13) can be converted to amide (14) using an amine NHR C R D under standard peptide coupling conditions such as 1,3-dicyclohexylcarbodiimide or 1,1′-carbonyldiimidazole.
  • Bromide (11) can also be coupled with an aryl or heteroaryl boronic acid or an aryl or heteroaryl trialkylstannane under palladium catalysis conditions to provide compounds of formula (15), where Ar is aryl or heteroaryl.
  • bromide (11) can be converted to nitrile (16) using zinc cyanide under palladium catalysis conditions.
  • Nitrile (16) can be reduced to amine (17) using, for example, Raney nickel and hydrogen.
  • Amines of formula (17) can be further functionalized to amides (18) wherein R 102 is alkyl, arylalkyl, heterocycle, heterocyclealkyl, or NR A R B alkyl, and substituted amines (19) as described for the preparation of (9) and (10) in Scheme 2.
  • a 2- or 3-carboalkoxy-4H-pyrazolo[1,5-a]quinazolin-5-one (20), is prepared using the conditions as described in Scheme 1.
  • This compound can be saponified to the corresponding carboxylic acid (21) under standard acidic (ie, hydrochloric acid) or basic (ie, sodium hydroxide) conditions.
  • Reduction using a reducing agent such as lithium aluminum hydride in tetrahydrofuran provided the alcohol (22).
  • This can be converted to ether (23) wherein R 102 is alkyl, heteroaryl, heterocyclealkyl or (NR A R B )alkyl, under standard Williamson ether synthesis conditions with an alkyl halide or under standard Mitsunobu conditions.
  • acid (21) can be converted to amide (24) using an amine NHR C R D under standard peptide coupling conditions such as 1,3-dicyclohexylcarbodiimide or 1,1′-carbonyldiimidazole.
  • the title compound was prepared as described in EXAMPLE 20, substituting propionaldehyde for formaldehyde.
  • the crude product was purified by flash chromatography on silica gel with 0-10% methanol/dichloromethane/0.1% ammonium hydroxide.
  • the title compound was prepared as described in EXAMPLE 20, substituting EXAMPLE 35 for EXAMPLE 19.
  • the crude product was purified by flash chromatography on silica gel with 0-10% methanol/dichloromethane/0.1% ammonium hydroxide.
  • the title compound was prepared as described in EXAMPLE 21, substituting EXAMPLE 35 for EXAMPLE 19.
  • the crude product was purified by flash chromatography on silica gel with 0-10% methanol/dichloromethane/0.1% ammonium hydroxide.
  • the title compound was prepared as described in EXAMPLE 23, substituting EXAMPLE 35 for EXAMPLE 19.
  • the crude product was purified by flash chromatography on silica gel with 0-10% methanol/dichloromethane/0.1% ammonium hydroxide.
  • the title compound was prepared as described in EXAMPLE 22, substituting EXAMPLE 35 for EXAMPLE 19.
  • the crude product was purified by flash chromatography on silica gel with 0-10% methanol/dichloromethane/0.1% ammonium hydroxide.
  • the title compound was prepared as described in EXAMPLE 20, substituting EXAMPLE 43B for EXAMPLE 19.
  • the crude product was purified by flash chromatography on silica gel with 0-10% methanol/dichloromethane/0.1% ammonium hydroxide.
  • the title compound was prepared as described in EXAMPLE 21, substituting EXAMPLE 43B for EXAMPLE 19.
  • the crude product was purified by flash chromatography on silica gel with 0-10% methanol/dichloromethane/0.1% ammonium hydroxide.
  • the title compound was prepared as described in EXAMPLE 23, substituting EXAMPLE 43B for EXAMPLE 19.
  • the crude product was purified by flash chromatography on silica gel with 0-10% methanol/dichloromethane/0.1% ammonium hydroxide.
  • the title compound was prepared as described in EXAMPLE 20, substituting EXAMPLE 48B for EXAMPLE 19.
  • the crude product was purified by flash chromatography on silica gel with 0-10% methanol/dichloromethane/0.1% ammonium hydroxide.
  • the title compound was prepared as described in EXAMPLE 57B, substituting EXAMPLE 59A for EXAMPLE 57A.
  • the crude product was purified by flash chromatography on silica gel with 10% methanol/dichloromethane/0.1% ammonium hydroxide.
  • EXAMPLE 59 (0.034 g, 0.1 mmol) and 36% formaldehyde in water (0.05 mL, 0.6 mmol) in methanol (2 mL) was treated with sodium cyanoborohydride (0.006 g, 0.1 mmol) and acetic acid (0.2 mL). The mixture was stirred at ambient temperature for 2 hours and concentrated. The crude product was purified by flash chromatography on silica gel with 10% methanol/dichloromethane to provide the title compound.
  • Example 61B A mixture of Example 61B (0.075 g, 0.212 mmol), dicyanozinc (0.03 g, 0.254 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.024 g, 0.021 mmol) in DMF (2 mL) was heated in a microwave (Personal Chemistry SmithSynthesizer) at 150° C. for 10 minutes. The mixture was evaporated and purified by chromatography on silica gel with 10% MeOH/CH 2 Cl 2 to provide the desired product.
  • a microwave Personal Chemistry SmithSynthesizer
  • Example 62 A mixture of Example 62 (0.32 g, 1.066 mmol) and 3 g raney-nickel in methanol ammonia (30 mL) was stirred under a hydrogen atmosphere at 60 psi for 3.5 hr. The mixture was filtered then evaporated and purified by chromatography on silica gel with 10% MeOH/CH 2 Cl 2 to provide the desired product.
  • Example 61B 0.05 g, 0.141 mmol
  • pyridine-3-ylboronic acid 0.018 g, 0.148 mmol
  • cesium fluoride 0.064 g, 0.423 mmol
  • tetrakis(triphenylphosphine)palladium(0) 0.1 g, 0.014 mmol
  • DME 2 mL
  • Example 61B A mixture of Example 61B (0.1 g, 0.282 mmol), pyrrolidin-2-one (0.048 g, 0.565 mmol) cesium carbonate (0.130 g, 0.395 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.026 g, 0.028 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.025 g, 0.043 mmol) in DME (2 mL) was heated in a microwave (Personal Chemistry SmithSynthesizer) at 200° C. for 60 minutes. The mixture was filtered evaporated.
  • a microwave Personal Chemistry SmithSynthesizer
  • Example 61B A mixture of Example 61B (0.1 g, 0.282 mmol), 2-fluoro-4-(tributylstannyl)pyridine (0.11 g, 0.285 mmol) triethylamine (0.11 g, 1.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.039 g, 0.01 mmol) and tri-o-tolylphosphine (0.007 g, 0.023 mmol) in DMF (2 mL) was heated at 100° C. for 6 hr. The mixture was diluted with EtOAc and washed with sat NaHCO 3 , H 2 O and brine, then evaporated.
  • Example 61B A mixture of Example 61B (0.25 g, 0.706 mmol) triethylamine (0.2 ml, 1.542 mmol) and dichlorobis(diphenylphosphino)dipalladium(II)dichloromethane (0.03 g, 0.041 mmol) in methanol (10 mL) under carbon monoxide at 50psi was heated at 100° C. for 3 hr. The mixture was filtered then evaporated and purified by chromatography on silica gel with 10% MeOH/CH 2 Cl 2 to provide the desired product.
  • Example 69A (0.1 g, 0.44 mmol), 1-methyl piperazine (0.045 g, 0.45 mmol) and CDI (0.075 g, 0.53 mmol) in DMF (1 mL) and pyridine (1 mL) was stirred overnight at ambient temperature. The mixture was evaporated and purified by chromatography on silica gel with 10% MeOH/CH 2 Cl 2 to provide the desired product.
  • Example 69B The title compound was prepared as described in Example 69B, substituting pyrrolidine for 1-methyl piperazine in Example 69 B. The mixture was evaporated and purified by chromatography on silica gel with 10% MeOH/CH 2 Cl 2 to provide the desired product.
  • Example 69B The title compound was prepared as described in Example 69B, substituting dimethylamine for 1-methyl piperazine in Example 69B. The mixture was evaporated and purified by chromatography on silica gel with 10% MeOH/CH 2 Cl 2 to provide the desired product.
  • Example 69B The title compound was prepared as described in Example 69B, substituting piperidine for 1-methyl piperazine in Example 69B. The mixture was evaporated and purified by chromatography on silica gel with 10% MeOH/CH 2 Cl 2 to provide the desired product.
  • Example 69B The title compound was prepared as described in Example 69B, substituting cyclopropylamine for 1-methyl piperazine in Example 69 B. The mixture was evaporated and purified by chromatography on silica gel with 10% MeOH/CH 2 Cl 2 to provide the desired product.
  • Example 69B The title compound was prepared as described in Example 69B, substituting ammonia for 1-methyl piperazine in Example 69B. The mixture was evaporated and purified by chromatography on silica gel with 10% MeOH/CH 2 Cl 2 to provide the desired product.
  • Example 69B The title compound was prepared as described in Example 69B, substituting methanamine for 1-methyl piperazine in Example 69B. The mixture was evaporated and purified by chromatography on silica gel with 10% MeOH/CH 2 Cl 2 to provide the desired product.
  • Example 69B The title compound was prepared as described in Example 69B, substituting ethanamine for 1-methyl piperazine in Example 69B. The residue was purified by HPLC on a C18 column with 0-100% CH 3 CN/H 2 O/0.1% TFA to provide the desired product as the trifluoroacetate salt.
  • Example 69B The title compound was prepared as described in Example 69B, substituting phenylmethanamine for 1-methyl piperazine in Example 69B.
  • the residue was purified by HPLC on a C18 column with 0-100% CH 3 CN/H 2 O/0.1% TFA to provide the desired product as the trifluoroacetate salt.
  • Example 69B The title compound was prepared as described in Example 69B, substituting phenethylamine for 1-methyl piperazine in Example 69B.
  • the residue was purified by HPLC on a C18 column with 0-100% CH 3 CN/H 2 O/0.1% TFA to provide the desired product as the trifluoroacetate salt.
  • Example 69B The title compound was prepared as described in Example 69B, substituting azepane for 1-methyl piperazine in Example 69 B. The mixture was evaporated and purified by chromatography on silica gel with 10% MeOH/CH 2 Cl 2 to provide the desired product.
  • Example 69B The title compound was prepared as described in Example 69B, substituting morpholine for 1-methyl piperazine in Example 69B. The mixture was evaporated and purified by chromatography on silica gel with 10% MeOH/CH 2 Cl 2 to provide the desired product.
  • 1 H NMR 500 MHz, DMSO-d 6 ) ⁇ ppm 3.34 (s, 8H) 7.54-7.58 (m, 1H) 7.91-7.95 (m, 1H) 8.08-8.13 (m, 2H) 8.16-8.19 (m, 1H).
  • Example 69B The title compound was prepared as described in Example 69B, substituting tert-butyl piperazine-1-carboxylate for 1-methyl piperazine in Example 69 B.
  • the reaction mix was evaporated then treated with 1 mL CH 2 Cl 2 and 1 mL of TFA and stirred for 1 hr then evaporated.
  • the mixture was evaporated and purified by chromatography on silica gel with 10% MeOH/CH 2 Cl 2 /0.1% NH 4 OH to provide the desired product.
  • Example 69B The title compound was prepared as described in Example 69B, substituting cyclohexylamine for 1-methyl piperazine in Example 69 B. The mixture was evaporated and purified by chromatography on silica gel with 10% MeOH/CH 2 Cl 2 to provide the desired product.
  • Example 69B The title compound was prepared as described in Example 69B, substituting pyridin-4-amine for 1-methyl piperazine in Example 69 B. The mixture was evaporated and purified by chromatography on silica gel with 10% MeOH/CH 2 Cl 2 to provide the desired product.
  • Example 69 The title compound was prepared as described in Example 69, substituting tert-butyl 4-(aminomethyl)piperidine-1-carboxylate for 1-methyl piperazine in Example 69 B.
  • the reaction mix was evaporated then treated with 1 mL CH 2 Cl 2 and 1 mL of TFA and stirred for 1 hr then evaporated.
  • the residue was purified by HPLC on a C18 column with 0-100% CH 3 CN/H 2 O/0.1% TFA to provide the desired product as the trifluoroacetate salt.
  • Example 69B The title compound was prepared as described in Example 69B, substituting tert-butyl piperidin-3-ylmethylcarbamate for 1-methyl piperazine in Example 69 B.
  • the reaction mix was evaporated then treated with 1 mL CH 2 Cl 2 and 1 mL of TFA and stirred for 1 hr then evaporated.
  • the residue was purified by HPLC on a C18 column with 0-100% CH 3 CN/H 2 O/0.1% TFA to provide the desired product as the trifluoroacetate salt.
  • Example 69B The title compound was prepared as described in Example 69B, substituting aniline for 1-methyl piperazine in Example 69 B.
  • the mixture was evaporated and purified by chromatography on silica gel with 10% MeOR/CH 2 Cl 2 to provide the desired product.
  • Example 69B The title compound was prepared as described in Example 69B, substituting 4-aminobutanoic acid for 1-methyl piperazine in Example 69 B. The mixture was evaporated and purified by chromatography on silica gel with 10% MeOH/CH 2 Cl 2 to provide the desired product.
  • Example 68 (0.15 g, 0.45 mmol) was dissolved in EtOH (10 mL), treated with a 1M solution of sodium hydroxide (3 mL, 3 mmol) and the mixture was heated at 80° C. for 18 hr. The mixture was filtered then acidified with acetic acid and 10% HCl. The precipitated product was filtered, washed with H 2 O and Et 2 O then dried well.
  • Example 69B The title compound was prepared as described in Example 69B, substituting 2-(piperidin-1-yl)ethanamine for 1-methyl piperazine in Example 69B. The mixture was evaporated and purified by chromatography on silica gel with 10% MeOH/CH 2 Cl 2 to provide the desired product.
  • Example 90A (0.1 g, 0.39 mmol) and lithium aluminum hydride (0.044 g, 1.16 mmol) in THF (5 mL) was refluxed for 3 h then cooled and quenched with water and 15% NaOH. The mixture was filtered, evaporated and purified by chromatography on silica gel with 10% MeOH/CH 2 Cl 2 to provide the desired product.
  • Example 88 (0.15 g, 0.47 mmol), 2M solution of NH 3 in MeOH (0.5 mL, 0.1 mmol) and CDI (0.076 g, 0.54 mmol) in DMF (1 mL) and pyridine (1 mL) was stirred overnight at ambient temperature then evaporated. The residue was purified by HPLC on a C18 column with 0-100% CH 3 CN/H 2 O/0.1% TFA to provide the desired product as the trifluoroacetate salt.
  • Example 92B A mixture of Example 92B (0.1 g, 0.47 mmol), 2-oxoacetic acid (0.035 g, 0.47 mmol) and sodium cyanoborohydride (0.029 g, 0.45 mmol) in MeOH (2 mL) was refluxed overnight then evaporated. The residue was purified by HPLC on a C 18 column with 0-100% CH 3 CN/H 2 O/0.1% TFA to provide the desired product as the trifluoroacetate salt.
  • Example 92B A mixture of Example 92B (0.1 g, 0.47 mmol), 4-chlorobutanoyl chloride (0.066 g, 0.47 mmol) in DMF (1 mL) and pyridine (1 mL) was stirred overnight at room temperature then evaporated. The residue was purified by HPLC on a C18 column with 0-100% CH 3 CN/H 2 O/0.1% TFA to provide the desired product as the trifluoroacetate salt.
  • Example 92B A mixture of Example 92B (0.1 g, 0.47 mmol) and dihydrofuran-2,5-dione (0.047 g, 0.47 mmol) in CH 3 CN (2 mL) was heated to 80° C. overnight then evaporated. The residue was purified by HPLC on a C18 column with 0-100% CH 3 CN/H 2 O/0.1% TFA to provide the desired product as the trifluoroacetate salt.
  • Example 92B A mixture of Example 92B (0.1 g, 0.47 mmol) and 1-acetylpiperidine-4-carbonyl chloride (0.089 g, 0.47 mmol) in DMF (1 mL) and pyridine (1 mL) was stirred overnight. The precipitated solids were filtered and washed with H 2 O and Et 2 O then dried well.
  • Example 92B A mixture of Example 92B (0.1 g, 0.47 mmol), 1-bromo-4-chlorobutane (0.08 g, 0.47 mmol) and sodium ethoxide (0.032 g, 0.47 mmol) in EtOH (2 mL) was stirred overnight then evaporated. The residue was purified by HPLC on a C18 column with 0-100% CH 3 CN/H 2 O/0.1% TFA to provide the desired product as the trifluoroacetate salt.
  • Example 92B A mixture of Example 92B (0.1 g, 0.47 mmol), acetic anhydride (0.048 g, 0.47 mmol) and diisopropyl ethylamine (0.2 ml, 1.15 mmol) in MeOH (2 ml) was heated to 40° C. overnight. The mixture was evaporated and purified by chromatography on silica gel with 10% MeOH/CH 2 Cl 2 to provide the desired product.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9062061B2 (en) 2011-07-13 2015-06-23 Santen Pharmaceutical Co., Ltd. Compound having PARP inhibitory activity
US9434734B2 (en) 2012-05-21 2016-09-06 Domain Therapeutics Substituted pyrazoloquinazolinones and pyrroloquinazolinones as allosteric modulators of group II metabotropic glutamate receptors

Families Citing this family (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0701273D0 (en) * 2007-01-24 2007-02-28 Angeletti P Ist Richerche Bio New compounds
CA2728466A1 (en) * 2008-06-19 2009-12-23 Wyeth Llc Thienyl- and furanyl-isoquinolinones and methods for using them
SA109300394B1 (ar) 2008-06-19 2013-01-22 ويث ثيازوليل- وأوكسازوليل- أيزوكوينولينونات وطرق لاستخدامها
BR112013005223A2 (pt) * 2010-09-03 2016-05-03 Bayer Ip Gmbh "pirimidinonas e dihidropirimidinonas fusionadas substituídas."
CN104427984A (zh) 2012-01-20 2015-03-18 D·布朗 包括二脱水半乳糖醇和类似物的经取代的己糖醇类于治疗包括多形性胶质母细胞瘤和成神经管细胞瘤的肿瘤疾病和癌症干细胞的用途
CN103013414B (zh) * 2012-12-20 2014-01-08 东华大学 α-氰基-β-乙氧基丙烯酸乙酯改性环氧树脂胶粘剂及其制备方法
JP2016519684A (ja) 2013-04-08 2016-07-07 デニス エム ブラウン 準最適に投与された薬物療法の有効性を改善するための及び／又は副作用を低減するための方法および組成物
CN103224498B (zh) * 2013-05-07 2015-10-28 陈定奔 两种唑并喹唑啉酮稠杂环的新合成方法
CN112472699A (zh) 2013-07-26 2021-03-12 种族肿瘤学公司 改善比生群及衍生物的治疗益处的组合方法
WO2015035062A1 (en) * 2013-09-05 2015-03-12 Genentech, Inc. Antiproliferative compounds
CN106659765B (zh) 2014-04-04 2021-08-13 德玛医药 二脱水半乳糖醇及其类似物或衍生物用于治疗非小细胞肺癌和卵巢癌的用途
PT3130592T (pt) 2014-04-10 2019-11-21 Hubei Bio Pharmaceutical Industrial Tech Institute Inc Análogos do composto 4h-pirazolo[1,5-]benzimidazole como inibidores de parp
CN104974161B (zh) * 2014-04-10 2019-11-01 湖北生物医药产业技术研究院有限公司 作为PARP抑制剂的4H-吡唑并[1,5-α]苯并咪唑化合物的类似物
EP3000814A1 (en) 2014-09-26 2016-03-30 Domain Therapeutics Substituted pyrazoloquinazolinones and pyrroloquinazolinones as allosteric modulators of group II metabotropic glutamate receptors
TW201702218A (zh) 2014-12-12 2017-01-16 美國杰克森實驗室 關於治療癌症、自體免疫疾病及神經退化性疾病之組合物及方法
US11261466B2 (en) 2015-03-02 2022-03-01 Sinai Health System Homologous recombination factors
AU2016333293B2 (en) 2015-09-30 2020-07-30 Hubei Bio-Pharmaceutical Industrial Technological Institute Inc. Salt type and crystal type of 4H-pyrazolo (1, 5-alpha) benzimidazole compound and preparation method and intermediate thereof
CN108727377A (zh) * 2017-04-14 2018-11-02 四川大学 3-氰基吡唑并[1,5-a]嘧啶衍生物及其制备方法和用途
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EP3624805A4 (en) * 2017-05-18 2020-11-18 Tarun M. Kapoor PYRAZOLOCHINAZOLINONE ANTITUMOR AGENTS
WO2019086009A1 (zh) 2017-11-03 2019-05-09 华南农业大学 含氮稠合三环化合物及其作为农林业杀虫剂的应用
CN108976235B (zh) * 2018-09-30 2019-09-17 遵义医科大学 一种喹唑啉酮类化合物及其用途
CN109265463B (zh) * 2018-12-18 2019-03-08 上海肇钰医药科技有限公司 作为parp抑制剂的吡唑并喹唑啉酮衍生物及其用途
CN114053271B (zh) * 2020-07-30 2024-05-07 江苏天士力帝益药业有限公司 一种含有tsl-1502m的药物组合物及其应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4105766A (en) * 1977-08-19 1978-08-08 Sterling Drug Inc. 4,5-Dihydro-5-oxopyrazolo[1,5-a]quinazoline-3-carboxylic acid derivatives
US4112098A (en) * 1977-10-17 1978-09-05 E. R. Squibb & Sons, Inc. Pyrazolo[1,5-c]quinazoline derivatives and related compounds

Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4105966A (en) * 1977-03-29 1978-08-08 The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration Remote lightning monitor system
US4105764A (en) * 1977-08-19 1978-08-08 Sterling Drug Inc. 4,5-Dihydro-5-oxopyrazolo[1,5-A]quinazoline-3-carboxamides
JP2673824B2 (ja) * 1988-12-20 1997-11-05 コニカ株式会社 新規な写真用カプラー
JPH02228604A (ja) * 1989-02-28 1990-09-11 Konica Corp カラーモザイクフイルター
JPH07100265B2 (ja) 1989-04-27 1995-11-01 松下電器産業株式会社 部品装着装置
JPH03114891A (ja) * 1989-09-29 1991-05-16 Konica Corp 感熱転写記録用の縮合環を有するピラゾロピリミジン―５―オン系色素
JP2505303B2 (ja) 1990-06-01 1996-06-05 富士通株式会社 デ―タ転送方法
JPH0437741A (ja) * 1990-06-03 1992-02-07 Konica Corp 新規な染料を含有するハロゲン化銀写真感光材料
JP3114891B2 (ja) 1991-12-27 2000-12-04 株式会社ユニシアジェックス 車両懸架装置
JPH06222527A (ja) * 1993-01-26 1994-08-12 Konica Corp ハロゲン化銀カラー写真感光材料
JP4037941B2 (ja) 1997-10-15 2008-01-23 Ｉｄｅｃ株式会社 制御装置
JP2000131811A (ja) * 1998-08-20 2000-05-12 Konica Corp 画像記録プリント及びハロゲン化銀写真感光材料
EP1157026A1 (en) * 1999-02-22 2001-11-28 Boehringer Ingelheim Pharmaceuticals Inc. Polycyclo heterocyclic derivatives as antiinflammatory agents
GB0017508D0 (en) * 2000-07-17 2000-08-30 Novartis Ag Antimicrobials
AU2003277674A1 (en) * 2002-11-12 2004-06-03 Mochida Pharmaceutical Co., Ltd. Novel parp inhibitors
JP4037741B2 (ja) 2002-11-21 2008-01-23 アルプス電気株式会社 回転型電子部品
US7268138B2 (en) * 2003-05-28 2007-09-11 Mgi Gp, Inc. Compounds, methods and pharmaceutical compositions for inhibiting PARP
US20080280867A1 (en) * 2006-01-17 2008-11-13 Abbott Laboratories Combination therapy with parp inhibitors
US20080293795A1 (en) * 2006-01-17 2008-11-27 Abbott Laboratories Combination therapy with parp inhibitors
US20090029966A1 (en) * 2006-01-17 2009-01-29 Abbott Laboratories Combination therapy with parp inhibitors
US20080146638A1 (en) * 2006-01-17 2008-06-19 Abbott Laboratories Combination therapy with parp inhibitors
JP2008131811A (ja) 2006-11-22 2008-06-05 Sumitomo Electric Ind Ltd モータ用分割コア

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4105766A (en) * 1977-08-19 1978-08-08 Sterling Drug Inc. 4,5-Dihydro-5-oxopyrazolo[1,5-a]quinazoline-3-carboxylic acid derivatives
US4112098A (en) * 1977-10-17 1978-09-05 E. R. Squibb & Sons, Inc. Pyrazolo[1,5-c]quinazoline derivatives and related compounds

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9062061B2 (en) 2011-07-13 2015-06-23 Santen Pharmaceutical Co., Ltd. Compound having PARP inhibitory activity
US9434734B2 (en) 2012-05-21 2016-09-06 Domain Therapeutics Substituted pyrazoloquinazolinones and pyrroloquinazolinones as allosteric modulators of group II metabotropic glutamate receptors

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CA2655561A1 (en) 2007-12-27
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