WO2012006958A1 - Amids substituted indazole derivativees as ploy(adp-ribose)polymerase inhibitors - Google Patents

Amids substituted indazole derivativees as ploy(adp-ribose)polymerase inhibitors Download PDF

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WO2012006958A1
WO2012006958A1 PCT/CN2011/077165 CN2011077165W WO2012006958A1 WO 2012006958 A1 WO2012006958 A1 WO 2012006958A1 CN 2011077165 W CN2011077165 W CN 2011077165W WO 2012006958 A1 WO2012006958 A1 WO 2012006958A1
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carboxylic acid
alkyl
methyl
indazole
compound according
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PCT/CN2011/077165
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French (fr)
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Shaojing Hu
Haijun Li
Wei LONG
Xiaoyan Shen
Fenlai Tan
Yinxiang Wang
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Zhejiang Beta Pharma Inc.
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Priority to CN201180005360.5A priority Critical patent/CN103052633B/en
Publication of WO2012006958A1 publication Critical patent/WO2012006958A1/en

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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—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
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A—HUMAN NECESSITIES
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • A61P37/00—Drugs for immunological or allergic disorders
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    • A—HUMAN NECESSITIES
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—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 carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to amide substituted indazoles and benzotriazoles which are inhibitors of the enzyme poly(ADP-ribose)polymerase (PARP), previously known as poly(ADP- ribose)synthase and poly(ADP-ribosyl)transferase.
  • PARP poly(ADP-ribose)polymerase
  • the compounds of the present invention are useful as mono-therapies in tumors with specific defects in DNA-repair pathways and as enhancers of certain DNA-damaging agents such as anticancer agents and radiotherapy. Further, the compounds of the present invention are useful for reducing cell necrosis (in stroke and myocardial infarction), regulating inflammation and tissue injury, treating retroviral infections and protecting against the toxicity of chemotherapy.
  • PARP Poly(ADP-ribose) polymerase
  • PARP are nuclear and cytoplasmic enzymes that cleave NAD + to nicotinamide and ADP- ribose to form long and branched ADP-ribose polymers on target proteins, including topoisomerases, histones and PARP itself (Biochem. Biophys. Res. Commun. (1998) 245: 1-10). Poly(ADP-ribosyl)ation has been implicated in several biological processes, including DNA repair, gene transcription, cell cycle progression, cell death, chromatin functions and genomic stability.
  • PARP-1 and PARP-2 The catalytic activity of PARP-1 and PARP-2 has been shown to be promptly stimulated by DNA strand breakages (see Pharmacological Research (2005) 52:25-33).
  • PARP-1 binds to single and double DNA nicks.
  • both PARP-1 and PARP -2 detect DNA strand interruptions can act as nick sensors, provid rapid signals to halt transcription and recruit the enzymes required for DNA repair at the site of damage.
  • PARP inhibitors are useful as chemo- and radiosensitizers for cancer treatment. PARP inhibitors have been reported to be effective in radio sensitizing hypoxic tumor cells (US 5,032,617, US 5,215,738 and US 5,041,653).
  • PARP may also act as a mediator of cell death. Its excessive activation in pathological conditions such as ischemia and reperfusion injury can result in substantial depletion of the intercellular NAD + , which can lead to the impairment of several NAD + dependent metabolic pathways and result in cell death (see Pharmacological Research (2005) 52:44-59). As a result of PARP activation, NAD + levels significantly decline. Extensive PARP activation leads to severe depletion of NAD + in cells suffering from massive DNA damage.
  • poly(ADP-ribose) results in a rapid turnover rate, as once poly(ADP-ribose) is formed, it is quickly degraded by the constitutively active poly(ADP-ribose) glycohydrolase (PARG).
  • PARP and PARG form a cycle that converts a large amount of NAD + to ADP-ribose, causing a drop of NAD + and ATP to less than 20% of the normal level.
  • Such a scenario is especially detrimental during ischemia when deprivation of oxygen has already drastically compromised cellular energy output.
  • Subsequent free radical production during reperfusion is assumed to be a major cause of tissue damage.
  • PARP inhibition is expected to preserve the cellular energy level thereby potentiating the survival of ischemic tissues after insult.
  • Compounds which are inhibitors of PARP are therefore useful for treating conditions which result from PARP mediated cell death, including neurological conditions such as stroke, trauma and Parkinson's disease.
  • PARP inhibitors have been demonstrated as being useful for the specific killing of BRCA-1 and BRC A-2 deficient tumors (Nature (2005) 434:913-916 and 917-921; Cancer Biology & Therapy (2005) 4:934-936).
  • PARP inhibitors have been shown to enhance the efficacy of anticancer drugs (Pharmacological Research (2005) 52:25-33), including platinum compounds such as cisplatin and carboplatin (Cancer Chemother Pharmacol (1993) 33: 157-162; Mol Cancer Ther (2003) 2:371-382). PARP inhibitors have been shown to increase the antitumor activity of topoisomerase I inhibitors such as Irinotecan and Topotecan (Mol Cancer Ther (2003) 2:371-382; and Clin Cancer Res. (2000) 6:2860-2867) and this has been demonstrated in in vivo models (J Natl Cancer Inst (2004) 96:56- 67).
  • TMZ temozolomide
  • PAPR inhibitors have also been shown to prevent the appearance of necrosis induced by selective N3 -adenine methylating agents such as MeOS0 2 (CH 2 )-lexitropsin (Me-Lex) (Pharmacological Research (2005) 52:25-33).
  • PARP inhibitors have been shown to act as radiation sensitizers. PARP inhibitors have been reported to be effective in radiosensitizing (hypoxic) tumor cells and effective in preventing tumor cells from recovering from potentially lethal (Br. J. Cancer (1984) 49(Suppl. VI):34-42; and Int. J. Radiat. Bioi. (1999) 75:91-100) and sub-lethal (Clin. Oncol. (2004) 16(l):29-39) damage of DNA after radiation therapy, presumably by their ability to prevent DNA strand break rejoining and by affecting several DNA damage signaling pathways.
  • PARP inhibitors have also been shown to be useful for treating acute and chronic myocardial diseases (Pharmacological Research (2005) 52:34-43). For instance, it has been demonstrated that single injections of PARP inhibitors have reduced the infarct size caused by ischemia and reperfusion of the heart or skeletal muscle in rabbits. In these studies, a single injection of 3-amino- benzamide (10 mg/kg), either one minute before occlusion or one minute before reperfusion, caused similar reductions in infarct size in the heart (32-42%), while 1,5-dihydroxyisoquinoline (1 mg/kg), another PARP inhibitor, reduced infarct size by a comparable degree (38-48%).
  • PARP inhibitors have been demonstrated as being useful for treating certain vascular diseases, septic shock, ischemic injury and neurotoxicity (Biochim. Biophys. Acta (1989) 1014: 1-7; J. CHn. Invest. (1997) 100:723-735). Oxygen radical DNA damage that leads to strand breaks in DNA, which are subsequently recognized by PARP, is a major contributing factor to such disease states as shown by PARP inhibitor studies (J. Neurosci. Res. (1994) 39:38-46; PNAS (1996) 93:4688-4692). PARP has also been demonstrated to play a role in the pathogenesis of hemorrhagic shock (PNAS (2000) 97: 10203-10208). PARP inhibitors have been demonstrated as being useful for treatment of inflammation diseases (Pharmacological Research (2005) 52:72-82 and 83-92).
  • PARP inhibitors can be used for the treatment or prevention of autoimmune diseases such as Type I diabetes and diabetic complications (Pharmacological Research (2005) 52:60-71).
  • PARP inhibition has been speculated as delaying the onset of aging characteristics in human fibroblasts (Biochem. Biophys. Res. Comm. (1994) 201(2):665-672; Pharmacological Research (2005) 52:93-99). This may be related to the role that PARP plays in controlling telomere function (Nature Gen., (1999) 23(l):76-80).
  • WO 1999/59973 discloses amide substituted benzene rings fused to 5-membered heteroaromatic rings
  • WO2001/85687 discloses amide substituted indoles
  • WO 1997/04771 disclose amide 2000/26192, WO 2000/32579, WO 2000/64878, WO 2000/68206, WO 2001/21615, WO 2002/068407, WO 2003/106430 and WO 2004/096793 disclose amide substituted benzoimidazoles
  • WO 2000/29384 discloses amide substituted benzoimidazoles and indoles
  • EP 0879820 discloses amide substituted benzoxazoles.
  • amide substituted indazoles of the present invention exhibit high levels of inibition of the activity of PARP.
  • the compounds of this invention are useful in the inhibition of poly(ADP-ribose)polymerase (PARP). They are particularly useful as inhibitors of PARP-1 and/or PARP -2.
  • PARP poly(ADP-ribose)polymerase
  • the present invention provides compounds of Formula (I),
  • Ri is selected from hydrogen, Ci_ 6 alkyl, cycloalkyl, alkoxyCi_ 6 alkyl, haloCi_ 6 alkyl, hydroxyCi_ 6 alkyl, NR 4 R 5 , (NR 4 R 5 )alkyl, (NR 4 R 5 )carbonyl, (NR 4 R 5 )carbonylalkyl, alkoxyCi_ 6 alkyl(NR 4 R 5 ) or (NR 4 R 5 )sulfonyl;
  • R 2 is selected from hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkyl, nitro, NR 4 R 5 , or (NR 4 R 5 )carbonyl;
  • R 3 is selected from hydrogen, Ci_ 6 alkyl, C 6 _ioaryl, halogen, cyano, haloCi_ 6 alkyl, or haloCi_ 6 alkoxy; when Ri is NFFNR 4 R 5 , R 3 independently selected from a group consisting of hydrogen, halogen, cyano, haloCi_ 6 alkyl, or haloCi_ 6 alkoxy;
  • X is selected from
  • each R 4 is selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkyl, nitro, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR 5 R 5 , (NR 5 R 6 )alkyl, (NRsR carbonyl, (NR 5 R 6 )carbonylalkyl, and (NRsR sulfony, and wherein when
  • L-T group wherein the L is selected from alkenylene, alkylene, alkynylene, cycloalkylene or spiroheterocycle, and T is selected from heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio or NR 5 R 5 ;
  • R 5 is independently hydrogen, Ci_ 6 alkyl, C 2 _ioalkenyl, haloCi_ 6 alkyl, hydroxyCi_ 6 alkyl, Ci_ 6 alkylcarbonyl, Ci_ 6 alkoxy, haloCi_ 6 alkoxy, Ci_ 6 alkoxycarbonyl, or a ring which is: C 6 -ioaryl; C 6- l oaryloxy; C 6 -ioarylcarbonyl; C3_iocycloalkyl; a 4-membered saturated heterocyclic ring containing one nitrogen (N) atom; a 5 or 6-membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S; a 5 -membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S; a 6 membered heteroaromatic ring containing 1, 2 or 3
  • the compounds of this invention are useful in the inhibition of poly(ADP-ribose)polymerase (PARP). They are particularly useful as inhibitors of PARP-1 and/or PARP-2.
  • PARP poly(ADP-ribose)polymerase
  • the present invention provides compounds of Formula (I),
  • Ri is independently selected from a group consisting of hydrogen, Ci_ 6 alkyl, cycloalkyl, alkoxyCi_ 6 alkyl, haloCi_ 6 alkyl, hydroxyCi_ 6 alkyl, and NR 4 R 5 , (NR 4 Rs)alkyl, (NR 4 Rs)carbonyl, (NR 4 R 5 )carbonylalkyl, alkoxyCi_ 6 alkyl(NR 4 R 5 ) and (NR 4 R 5 )sulfonyl;
  • R 2 is independently selected from a group consisting of each independently selected from the group consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkyl, nitro, NR 4 R 5 , and (NR 4 Rs)carbonyl;
  • R 3 is independently selected from a group consisting of hydrogen, Ci_ 6 alkyl, C 6 _ioaryl, halogen, cyano, haloCi_ 6 alkyl, or haloCi_ 6 alkoxy; when Ri is NFFNR 4 R 5 , R 3 independently selected from a group consisting of hydrogen, halogen, cyano, haloCi_ 6 alkyl, or haloCi_ 6 alkoxy;
  • X is selected from the group consisting of
  • each R4 is selected independently from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkyl, nitro, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR 5 R 6 , (NRsR ⁇ alkyl, (NRsR ⁇ carbonyl, (NRsR ⁇ carbonylalkyl, and (NRsR sulfony
  • L is selected from the group consisting of alkenylene, alkylene, alkynylene, cycloalkylene and spiroheterocycle
  • T is selected from the group consisting of heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio and NR 5 R 6 ;
  • a non-aromatic 6-12 membered monocyclic or bicyclic heterocycle ring having 1 nitrogen atoms is selected from group consisting of ;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl.
  • compounds of Formula (I) or a therapeutically acceptable salt thereof wherein Ri and R 2 are hydrogen, and R 3 is halogen or cyano.
  • R 2 and R 3 are hydrogen
  • Ri is selected from the group consisting of Ci_ 6 alkyl, cycloalkyl, alkoxyCi_ 6 alkyl, haloCi_ 6 alkyl, hydroxyCi_ 6 alkyl, and NR 4 R 5 , (NR 4 R 5 )alkyl, (NR 4 R 5 )carbonyl, (NR 4 R 5 )carbonylalkyl, alkoxyCi_ 6 alkyl(NR 4 R 5 ), and (NR 4 R 5 )sulfonyl.
  • the present invention also includes within its scope N-oxides of the compounds of Formula (I) above.
  • N-oxides may be formed on any available nitrogen atom.
  • the N-oxides may be formed by conventional means, such as reacting the compound of Formula (I) with oxone in the presence of wet alumina.
  • the present invention includes within its scope prodrugs of the compounds of Formula (I) above.
  • prodrugs will be functional derivatives of the compounds of Formula (I) which are readily convertible in vivo into the required compound of Formula (I).
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • a prodrug may be a pharmacologically inactive derivative of a biologically active substance (the "parent drug” or "parent molecule”) that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule.
  • the transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
  • the present invention includes within its scope solvates of the compounds of Formula (I) and salts thereof, for example, hydrates.
  • the compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: EX. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pp.s 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, all such stereoisomers being included in the present invention.
  • the compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted.
  • the compounds may exist in different isomeric forms, all of which are encompassed by the present invention.
  • the compounds may exist in a number of different polymorphic forms.
  • any variable e.g. Ri and R 2 , etc.
  • its definition on each occurrence is independent at every other occurrence.
  • combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn into the ring systems from substituents represent that the indicated bond may be attached to any of the substitutable ring atoms.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • the phrase "optionally substituted” should be taken to be equivalent to the phrase "unsubstituted or substituted with one or more substituents” and in such cases the preferred embodiment will have from zero to three substituents. More particularly, there are zero to two substituents.
  • alkyl is intended to include both branched, straight-chain and cyclic saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • Si_ 6 alkyl is defined to include groups having 1, 2, 3, 4, 5 or 6 carbons in a linear, branched or cyclic arrangement.
  • Ci_ 6 alkyl specifically includes methyl, ethyl, n-propyl, i-propyl, n- butyl, t-butyl, i-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and so on.
  • Preferred alkyl groups are methyl and ethyl.
  • cycloalkyl means a monocyclic, bicyclic or polycyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • C 3 _ 7 cycloalkyl includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2- ethyl-cyclopentyl, cyclohexyl and so on.
  • cycloalkyl includes the groups described immediately above and further includes monocyclic unsaturated aliphatic hydrocarbon groups.
  • cycloalkyl as defined in this embodiment includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl- cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl, 7,7- dimethylbicyclo[2.2.1]heptyl and so on.
  • Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C 2 - 6 alkenyl refers to a non-aromatic hydrocarbon radical, straight or branched, containing from 2 to 6 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present.
  • Alkenyl groups include ethenyl, propenyl, butenyl and 2- methylbutenyl.
  • Preferred alkenyl groups include ethenyl and propenyl.
  • C 2 - 6 alkynyl refers to a hydrocarbon radical straight or branched, containing from 2 to 6 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present.
  • Alkynyl groups include ethynyl, propynyl, butynyl, 3- methylbutynyl and so on.
  • Preferred alkynyl groups include ethynyl and propynyl.
  • Alkoxy represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. “Alkoxy” therefore encompasses the definitions of alkyl above. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t- butoxy. The preferred alkoxy groups are methoxy and ethoxy.
  • CP-ioaryloxy can be construed analogously, and an example of this group is phenoxy.
  • haloCi_ 6 alkyl and "haloCi_ 6 alkoxy” mean a Ci_ 6 alkyl or group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms.
  • fluoro Ci_ 6 alkyl and fluoro Ci_ 6 alkoxy groups in particular fluoroCi_ 3 alkyl and fluoroCi_ 3 alkoxy groups, for example, CF 3 , CHF 2 , CH 2 F, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CH 2 F, OCH 2 CHF 2 or OCH 2 CF 3 , and most especially CF 3 , OCF 3 and OCHF 2 .
  • hydroxyCi_ 6 alkyl means a group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by hydroxy groups. Preferred are CH 2 OH, CH 2 CHOH and CHOHCH 3 .
  • C 6 -ioarylcarbonyl can be construed analogously, and an example of this group is benzoyl.
  • the rings present in the compounds of this invention may be monocyclic or multicyclic, particularly bicyclic. The multicyclic rings may be fused or spiro linked.
  • C 6 -ioaryl is intended to mean any stable monocyclic or bicyclic carbon ring of 6 to 10 atoms, wherein at least one ring is aromatic.
  • aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl and tetrahydrobenzo[7]annulene.
  • the preferred aryl group is phenyl or naphthyl, especially phenyl.
  • heterocycles of this invention are benzimidazolyl, benzofurandionyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, benzoxazolonyl, benzothiazolyl, benzothiadiazolyl, benzodioxolyl, benzoxadiazolyl, benzoisoxazolyl, benzoisothiazolyl, chromenyl, chromanyl, isochromanyl, carbazolyl, carbolinyl, cinnolinyl, epoxidyl, furyl, furazanyl, imidazolyl, indolinyl, indolyl, indolizinyl, isoindolinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,
  • Further examples include azoniaspiro[5.5]undecanyl, azepanyl, octahydroindolizinyl, 12-dihydrospirocyclohexane-l,3-indolyl, azoniabicyclo[3.1.0]hexanyl, diazoniaspiro[4.4]nonanyl, hexahydropyrrolo[3,4-b]pyrrolyl, oxaazoniabicyclo [2.2.
  • a preferred 4-membered saturated heterocycle is azetidinyl.
  • Preferred 5- or 6-membered saturated or partially saturated hetereocycles are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and thiomorpholinyl.
  • a further preferred heterocycle is dihydroimidazolyl.
  • a preferred 7-membered saturated heterocycle is diazepanyl. Further preferred rings are azepanyl and oxazepanyl.
  • Preferred 5-membered heteroaromatic rings are thienyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, furyl and pyrrolyl.
  • Preferred 6 membered heteraromatic rings are pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl.
  • Preferred 6- to 13 -membered saturated, partially saturated or unsaturated hydrocarbon rings are cyclohexyl, cyclohexadienyl, cyclohepyl, cyclooctyl, phenyl, naphthyl, tetrahydronaphthalenyl, dihydroindenyl, fluorenyl, adamantly, tetrahydrobenzo[7]annulenyl, indanyl, and tetrahydroindenyl.
  • Preferred 7- to 13-membered partially saturated or unsaturated heterocyclic rings are tetrahydroquinolinyl, quinolinyl, indolyl, imidazopyridinyl, benzothiazolyl, quinoxalinyl, benzothiadiazolyl, benzoxazolyl, dihydrobenzodioxinyl, benzotriazolyl, benzodioxolyl, dihydroisoindolyl, dihydroindolyl, tetrahydroisoquinolinyl, isoquinolinyl, benzoisothiazolyl, dihydroimidazopyrazinyl, benzothienyl, benzoxadiazolyl, thiazolotriazolyl, dihydrothiazolopyrimidinyl, dihydrobenzoxazinyl, dihydrobenzofuranyl, benzimidazolyl, benzofuranyl, dihydrobenzoxazo
  • Further preferred rings are quinazolinyl and indolizinyl.
  • Further preferred 7- to 15-menbered saturated, partially saturated or unsaturated heterocycles include azoniaspiro[5.5]undecanyl, azepanyl, octahydroindolizinyl, 12-dihydrospirocyclohexane-l,3-indolyl, octahydroisoindolyl, azoniabicyclo[3.1.0]hexanyl, diazoniaspiro[4.4]nonanyl, hexahydropyrrolo[3,4-b]pyrrolyl, oxaazoniabicyclo[2.2.1]heptanyl, diazoniaspriro[5.5]-undecanyl, diazoniaspiro [3.3 ]heptanyl, diazoniaspiro [3.5]nonanyl, diazoniaspiro [4.5]decanyl,
  • halogen refers to fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.
  • the compounds of the present invention can be protonated at the N atom(s) of an amine and/or N containing heterocycle moiety to form a salt.
  • the term "free base" refers to the amine compounds in non-salt form.
  • the encompassed pharmaceutically acceptable salts not only include the salts exemplified for the specific compounds described herein, but also all the typical pharmaceutically acceptable salts of the free form of compounds of Formula (I).
  • the free form of the specific salt compounds described may be isolated using techniques known in the art.
  • the free form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • the free forms may differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise pharmaceutically equivalent to their respective free forms for purposes of the invention.
  • the pharmaceutically acceptable salts of the instant compounds can be synthesized from the compounds of this invention which contain a basic or acidic moiety by conventional chemical methods.
  • the salts of the basic compounds are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt- forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
  • the salts of the acidic compounds are formed by reactions with the appropriate inorganic or organic base.
  • pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed by reacting a basic instant compound with an inorganic, organic acid or polymeric acid.
  • non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, sulfamic, phosphoric, phosphorous, nitric and the like, as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, palmitic, gluconic, phenylacetic, aspartic, cinnamic, pyruvic, ethanesulfonic, acetic, disulfonic, valeric, trifluor
  • Suitable polymeric salts include those derived from the polymeric acids such as tannic acid, carboxymethyl cellulose.
  • a pharmaceutically acceptable salt of this invention contains 1 equivalent of a compound of Formula (I) and 1 , 2 or 3 equivalent of an inorganic or organic acid.
  • pharmaceutically acceptable salts of this invention are the trifluoroacetate or the chloride salts. In an embodiment the salt is trifluoroacetate. In another embodiment the salt is chloride.
  • suitable “pharmaceutically acceptable salts” refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, lysine, betaine caffeine, choline, NiNi-dibenzylethylenediamine, ethylamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, diethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine, dicyclohex
  • the compounds of the present invention are potentially internal salts or zwitterions, since under physiological conditions a deprotonated acidic moiety in the compound, such as a carboxyl group, may be anionic, and this electronic charge might then be balanced off internally against the cationic charge of a protonated or alkylated basic moiety, such as a quaternary nitrogen atom.
  • the invention provides compounds for use in the treatment or prevention of conditions which can be ameliorated by the inhibition of poly(ADP-ribose)polymerase (PARP) (see, for example, Nature Review Drug Discovery (2005) 4:421-440).
  • PARP poly(ADP-ribose)polymerase
  • the present invention provides a compound of Formula (I) for use in the manufacture of a medicament for the treatment or prevention of conditions which can be ameliorated by the inhibition of poly(ADP-ribose)polymerase (PARP).
  • PARP poly(ADP-ribose)polymerase
  • the present invention also provides a method for the treatment or prevention of conditions which can be ameliorated by the inhibition of poly(ADP-ribose)polymerase (PARP), which method comprises administration to a patient in need thereof of an effective amount of a compound of Formula (I) or a composition comprising a compound of Formula (I).
  • the PARP inhibitors of the present invention are useful for the treatment of the diseases specified in WO 2005/082368.
  • the compounds of the invention are useful for the treatment of inflammatory diseases, including conditions resulted from organ transplant rejection, such as chronic inflammatory diseases of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung diseases such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory diseases of the eye including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympatheticophthalmitis and endophthalmitis; chronic inflammatory diseases of the gum, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidney including uremic complications, glomerulonephritis and nephrosis; inflammatory diseases of the skin including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the
  • the inflammatory disease can also be a systemic inflammation of the body, exemplified by gram-positive or gram-negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with proinflammatory cytokines.
  • shock can be induced, e.g. by a chemotherapeutic agent that is administered as a treatment for cancer.
  • the present invention provides a compound of Formula (I) for use in the manufacture of a medicament for treating or preventing inflammatory diseases.
  • the present invention also provides a method for the treatment or prevention of reperfusion injuries, which method comprises administration to a patient in need thereof of an effective amount of a compound of Formula (I) or a composition comprising at least one compound of Formula (I).
  • the compounds of the instant invention may also be useful in the treatment or prevention of ischemic conditions, including those resulted from organ transplantation, such as stable angina, unstable angina, myocardial ischemia, hepatic ischemia, mesenteric artery ischemia, intestinal ischemia, critical limb ischemia, chronic critical limb ischemia, cerebral ischemia, acute cardiac ischemia, ischemia kidney disease, ischemic liver disease, ischemic retinal disorder, septic shock, and an ischemic disease of the central nervous system, such as stroke or cerebral ischemia.
  • organ transplantation such as stable angina, unstable angina, myocardial ischemia, hepatic ischemia, mesenteric artery ischemia, intestinal ischemia, critical limb ischemia, chronic critical limb ischemia, cerebral ischemia, acute cardiac ischemia, ischemia kidney disease, ischemic liver disease, ischemic retinal disorder, septic shock, and an ischemic disease of the central nervous system, such as stroke
  • the present invention also provides a method for the treatment or prevention of stroke, which method comprises administration to a patient in need thereof of an effective amount of a compound of Formula (I) or a composition comprising a compound of Formula (I).
  • the compounds of the instant invention may also be useful for the treatment or prevention of chronic or acute renal failure.
  • the compounds of the instant invention may also be useful for the treatment or prevention of vascular diseases other than cardiovascular diseases, such as peripheral arterial occlusion, thromboangitis obliterans, Reynaud's disease and phenomenon, acrocyanosis, erythromelalgia, venous thrombosis, varicose veins, arteriovenous fistula, lymphedema and lipedema.
  • vascular diseases other than cardiovascular diseases such as peripheral arterial occlusion, thromboangitis obliterans, Reynaud's disease and phenomenon, acrocyanosis, erythromelalgia, venous thrombosis, varicose veins, arteriovenous fistula, lymphedema and lipedema.
  • vascular diseases other than cardiovascular diseases such as peripheral arterial occlusion, thromboangitis obliterans, Reynaud's disease and phenomenon, acrocyanosis, erythromel
  • the present invention also provides a method for the treatment or prevention of cardiovascular diseases, which method comprises administration to a patient in need thereof of an effective amount of a compound of Formula (I) or a composition comprising a compound of Formula (I).
  • the compounds of the invention may also be useful for the treatment and prevention of diabetes mellitus, including Type I diabetes (Insulin Dependent Diabetes Mellitus), Type II diabetes (Non-Insulin Dependent Diabetes Mellitus), gestational diabetes, autoimmune diabetes, insulinopathies, diabetes due to pancreatic disease, diabetes associated with other endocrine diseases (such as Cushing's Syndrome, acromegaly, pheochromocytoma, glucagonoma, primary aldosteronism or somatostatinoma), Type A insulin resistance syndrome, Type B insulin resistance syndrome, lipatrophic diabetes, and diabetes induced by 3-cell toxins.
  • Type I diabetes Insulin Dependent Diabetes Mellitus
  • Type II diabetes Non-Insulin Dependent Diabetes Mellitus
  • gestational diabetes autoimmune diabetes, insulinopathies, diabetes due to pancreatic disease, diabetes associated with other endocrine diseases (such as Cushing's Syndrome, acromegaly, pheochromocytoma, gluca
  • the compounds of this invention may also be useful for the treatment or prevention of diabetic complications, such as diabetic cataract, glaucoma, retinopathy, nephropathy (such as microaluminuria and progressive diabetic nephropathy), polyneuropathy, gangrene of the feet, atherosclerotic coronary arterial disease, peripheral arterial disease, nonketotic hyperglycemic- hyperosmolar coma, mononeuropathies, autonomic neuropathy, foot ulcers, joint problems, and a skin or mucous membrane complication (such as an infection, a shin spot, a candidal infection or necrobiosis lipoidica diabeticorumobesity), hyperlipidemia, hypertension, syndrome of insulin resistance, coronary artery disease, retinopathy, diabetic neuropathy, polyneuropathy, mononeuropathies, autonomic neuropathy, a foot ulcer, a joint problem, a fungal infection, a bacterial infection, and cardiomyopathy.
  • diabetic complications such as
  • the compounds of this invention may also be useful for the treatment or prevention of cancer including solid tumors such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, me
  • the compounds of the present invention may also be used for the treatment of cancer which is deficient in Homologous Recombination (HR) dependent DNA DSB repair activity (see WO 2006/021801).
  • HR Homologous Recombination
  • the HR dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA via homologous mechanisms to reform a continuous DNA helix (Nat. Genet. (2001) 27(3):247- 254).
  • the components of the HR dependent DNA DSB repair pathway include, but are not limited to, ATM (NM-000051), RAD51 (NM-002875), RAD51 LI (NM-002877), RAD51 C (NM-002876), RAD51L3 (NM- 002878), DMC1 (NM-007068), XRCC2 (NM7005431), XRCC3 (NM-005432), RAD52 (NM-002879), RAD54L (NM-003579), RAD54B (NM-012415), BRCA-1 (NM-007295), BRCA-2 (NM-000059), RAD50 (NM-005732), MREI IA (NM-005590), NBS1 (NM-002485), ADPRT (PARP-1), ADPRTL
  • the cancer cells have a BRCA-1 and/or a BRCA-2 deficient phenotype.
  • Cancer cells with this phenotype may be deficient in BRCA-1 and/or BRCA-2, i. e. expression and/or activity of BRCA-1 and/or BRCA-2 may be reduced or abolished in the cancer cells, for example by means of mutation or polymorphism in the encoding nucleic acid, or by means of amplification, mutation or polymorphism in a gene encoding a regulatory factor, for example the EMSY gene which encodes a BRCA-2 regulatory factor (Cell (2003) 115:523-535).
  • BRCA-1 and BRCA-2 are known tumor suppressors whose wild-type alleles are frequently lost in tumors of heterozygous carriers (Oncogene (2002) 21(58): 8981-93; Trends Mol Med., (2002) 8(12):571-6).
  • the association of BRCA-1 and/or BRCA-2 mutations with breast cancer has been well- characterized (Exp CHn Cancer Res. (2002) 21(3 Suppl):9- ⁇ 2).
  • Amplification of the EMSY gene, which encodes a BRCA-2 binding factor is also known to be associated with breast and ovarian cancer. Carriers of mutations in BRCA-1 and/or BRCA-2 are also at elevated risk of cancer of the ovary, prostate and pancreas.
  • BRCA-1 and BRCA-2 The detection of variation in BRCA-1 and BRCA-2 is well- known in the art and is described, for example in EP 699 754; EP 705 903; Genet. Test (1992) 1 :75-83; Cancer Treat Res (2002) 107:29-59; Neoplasm (2003) 50(4):246-50; Ceska Gynekol (2003) 68(1): 11-16). Determination of amplification of the BRCA-2 binding factor EMSY is described in Cell 115:523-535. PARP inhibitors have been demonstrated as being useful for the specific killing of BRCA-1 and BRCA-2 deficient tumors (Nature (2005) 434:913-916 and 917- 920).
  • the present invention also provides a method for the treatment or prevention of BRCA-1 or BRCA-2 deficient tumors, which method comprises administration to a patient in need thereof of an effective amount of a compound of Formula (I) or a composition comprising a compound of Formula (I).
  • the compounds of this invention may be useful for the treatment or prevention of neurodegenerative diseases, including, polyglutamine-expansion-related neurodegeneration, Huntington's disease, Kennedy's disease, spinocerebellar ataxia, dentatorubral-pallidoluysian atrophy (DRPLA), protein-aggregation-related neurodegeneration, Machado-Joseph's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spongiform encephalopathy, a prion-related disease and multiple sclerosis (MS).
  • neurodegenerative diseases including, polyglutamine-expansion-related neurodegeneration, Huntington's disease, Kennedy's disease, spinocerebellar ataxia, dentatorubral-pallidoluysian atrophy (DRPLA), protein-aggregation-related neurodegeneration, Machado-Joseph's disease, Alzheimer's disease, Parkinson's disease, amyotroph
  • the compounds of the present invention may also be useful for the treatment or prevention of retroviral infection (US 5652260), retinal damage (Curr. Eye Res. (2004), 29:403), skin senescence and UV-induced skin damage (US 5589483 and Biochem. Pharmacol (2002) 63:921).
  • the compounds of this invention may be administered to mammals, preferably humans, either alone or in combination with pharmaceutically acceptable carriers, excipients, diluents, adjuvants, fillers, buffers, stabilisers, preservatives and lubricants, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds of this invention may be administered to a subject by any convenient route of administration, whether systemically/peripherally or at the site of desired action, including but not limited to, oral (e.g. by ingestion); topical (including e.g. transdermal, intranasal, ocular, buccal, and sublingual); pulmonary (e.g. by inhalation or insufflation therapy using, e.g. an aerosol, e.g. through mouth or nose); rectal; vaginal; parenteral, (e.g.
  • a depot e.g. subcutaneously or intramuscularly.
  • compositions comprising one or more compounds of this invention and a pharmaceutically acceptable excipient.
  • pharmaceutically acceptable excipient refers to any of a diluent, adjuvant, excipient or carrier with which at least one compound of the present disclosure is administered.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a water soluble taste masking material such as hydroxypropyl-methylcellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate butyrate may be employed.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoo
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxy ethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous solution.
  • the sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase.
  • the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulsion.
  • the injectable solutions or microemulsions may be introduced into a patient's blood stream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound.
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution of 1,3-butanediol.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Compounds of Formula (I) may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • topical application creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula (I) are employed.
  • topical application may include mouth washes and gargles.
  • the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the severity of the individuals symptoms, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient.
  • the amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
  • Administration in vivo can be effected in one dose, continuously or intermittently (e.g. in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.
  • a suitable dose of the active compound is in the range of about 100 ⁇ g to about 250 mg per kilogram body weight of the subject per day. Where the active compound is a salt, an ester, prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
  • the instant compounds are also useful in combination with anti-cancer agents or chemotherapeutic agents.
  • the compounds of this invention may be useful as chemo- and radio- sensitizers for cancer treatment. They are useful for the treatment of mammals who have previously undergone or are presently undergoing treatment for cancer. Such previous treatments include prior chemotherapy, radiation therapy, surgery or immunotherapy, such as cancer vaccines.
  • the present invention provides a combination of a compound of Formula (I) and an anticancer agent for simultaneous, separate or sequential administration.
  • the present invention also provides a compound of Formula (I) for use in the manufacture of a medicament for use as an adjunct in cancer therapy or for potentiating tumor cells for treatment with ionizing radiation or chemotherapeutic agents.
  • the present invention also provides a method of chemotherapy or radiotherapy, which method comprises administration to a patient in need thereof of an effective amount of a compound of Formula (I) or a composition comprising a compound of Formula (I) in combination with ionizing radiation or chemotherapeutic agents.
  • the compounds of this invention can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of the other anticancer agent to a subject in need thereof.
  • the instant compounds and another anticancer agent are administered 1 minute apart,
  • the compounds of this invention and the other anticancer agent can act additively or synergistically.
  • a synergistic combination of the present compounds and another anticancer agent might allow the use of lower dosages of one or both of these agents and/or less frequent dosages of one or both of the instant compounds and other anticancer agents and/or to administer the agents less frequently can reduce any toxicity associated with the administration of the agents to a subject without reducing the efficacy of the agents in the treatment of cancer.
  • a synergistic effect might result in the improved efficacy of these agents in the treatment of cancer and/or the reduction of any adverse or unwanted side-effects associated with the use of either agent alone.
  • cancer agents or chemotherapeutic agents for use in combination with the compounds of the present invention can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
  • Such anticancer agents include, but are not limited to, the following: histone deacetylase (HDAC) inhibitors, estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and survival signaling, apoptosis inducing agents and agents that interfere with cell cycle checkpoints.
  • HDAC histone deacetylase
  • estrogen receptor modulators include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and other angiogenesis
  • HDAC inhibitors include suberoylanilide hydroxamic acid (SAHA), LAQ824, LBH589, PXDIOI, MS275, FK228, valproic acid, butyric acid and CI-994.
  • Estrogen receptor modulators refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism.
  • estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY1 17081, toremifene, fulvestrant, 4-[7- (2,2-dimethyl- 1 -oxopropoxy-4-methyl-2-[4-[2-(l -piperidinyl)ethoxy]phenyl]-2H- 1 -benzopyran-3- yl]-phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.
  • Androgen receptor modulators refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism.
  • Examples of androgen receptor modulators include finasteride and other 5a-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole and abiraterone acetate.
  • Retinoid receptor modulators refers to compounds which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism.
  • retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, a-difluoromethylornithine, ILX23-7553, trans-N-(4'-hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide.
  • Cytotoxic/cytostatic agents refer to compounds which cause cell death or inhibit cell proliferation primarily by interfering directly with the cell's functioning or inhibit or interfere with cell mytosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia activatable compounds, microtubule inhibitors/microtubule-stabilizing agents, inhibitors of mitotic kinesins, inhibitors of kinases involved in mitotic progression, antimetabolites, biological response modifiers; hormonal/anti-hormonal therapeutic agents, haematopoietic growth factors, monoclonal antibody targeted therapeutic agents, topoisomerase inhibitors, proteasome inhibitors and ubiquitin ligase inhibitors.
  • cytotoxic agents include, but are not limited to, cyclophosphamide, chlorambucil carmustine (BCNU), lomustine (CCNU), busulfan, treosulfan, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, aroplatin, oxaliplatin, temozolomide, methyl methanesulfonate, procarbazine, dacarbazine, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cyto
  • the compounds of this invention can be used in combination with alkylating agents.
  • alkylating agents include but are not limited to, nitrogen mustards: cyclophosphamide, ifosfamide, trofosfamide and chlorambucil; nitrosoureas: carmustine (BCNU) and lomustine (CCNU); alkylsulphonates: busulfan and treosulfan; triazenes: dacarbazine, procarbazine and temozolomide; platinum containing complexes: cisplatin, carbop latin, arop latin and oxaliplatin.
  • nitrogen mustards cyclophosphamide, ifosfamide, trofosfamide and chlorambucil
  • nitrosoureas carmustine (BCNU) and lomustine (CCNU)
  • alkylsulphonates busulfan and treosulfan
  • triazenes dacarbazine, procarbazine and temozolomide
  • platinum containing complexes
  • the alkylating agent is dacarbazine.
  • dacarbazine can be administered to a subject at dosages ranging from about 150 mg/m 2 (of a subject's body surface area) to about 250 mg/m 2 .
  • dacarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 150 mg/m 2 to about 250 mg/m 2 .
  • the alkylating agent is procarbazine.
  • Procarbazine can be administered to a subject at dosages ranging from about 50 mg/m 2 (of a subject's body surface area) to about 100mg/m 2 .
  • procarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50 mg/m 2 to about 100 mg/m 2 .
  • the alkylating agent is temozoloamide.
  • Temozolomide can be administered to a subject at dosages ranging from about about 150 mg/m 2 (of a subject's body surface area) to about 200 mg/m 2 .
  • temozolomide is administered orally to an animal once per day for five consecutive days at a dose ranging from about 150 mg/m 2 to about 200 mg/m 2 .
  • anti-mitotic agents examples include allocolchicine, halichondrin B, colchicine, colchicine derivative, dolstatin 10, maytansine, rhizoxin, thiocolchicine and trityl cysteine.
  • hypoxia activatable compound is tirapazamine.
  • proteasome inhibitors include but are not limited to lactacystin, bortezomib, epoxomicin and peptide aldehydes such as MG 132, MG 115 and PSI.
  • microtubule inhibitors/microtubule-stabilising agents include paclitaxel, vindesine sulfate, vincristine, vinblastine, vinorelbine, 3',4'-didehydro-4'-deoxy-8'- norvincaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR1 09881, BMS 184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafiuoro-N-(3-fiuoro-4- methoxyphenyl) benzene sulfonamide, anhydrovinblastine, N,N-dimethyl-L-valyl-L-valyl-N- methyl-L-valyl-L-prolyl-L-proline-t-butylamide, TDX258, the epothilones (see for example
  • topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, exatecan, gimetecan, diflomotecan, silyl- camptothecins, 9-aminocamptothecin, camptothecin, crisnatol, mitomycin C, 6-ethoxypropionyl- 3',4'-0-exo-benzylidene-chartreusin, 9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2- (6H)propanamine, l-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-lH,12H- benzo[de]pyrano[3',4':b,7]-indolizino[l,2
  • the topoisomerase inhibitor is irinotecan.
  • Irinotecan can be administered to a subject at dosages ranging from about about 50 mg/m 2 (of a subject's body surface area) to about 150 mg/m 2 .
  • irinotecan is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50mg/m 2 to about 150mg/m 2 on days 1-5, then again intravenously once per day for five consecutive days on days 28-32 at a dose ranging from about 50mg/m 2 to about 150mg/m 2 , then again intravenously once per day for five consecutive days on days 55-59 at a dose ranging from about 50mg/m 2 to about 150mg/m 2 .
  • inhibitors of mitotic kinesins are described in PCT Publications WO 01/30768, WO 01/98278, WO 02/056880, WO 03/050,064, WO 03/050,122, WO 03/049,527, WO 03/049,679, WO 03/049,678, WO 03/039460, WO 03/079973, WO 03/099211, WO 2004/039774, WO 03/105855, WO 03/106417, WO 2004/087050, WO 2004/058700, WO 2004/058148 and WO 2004/037171, and US applications US 2004/132830 and US 2004/132719.
  • inhibitors of mitotic kinesins include, but are not limited to inhibitors of KSP, inhibitors of MKLPl, inhibitors of CENP-E, inhibitors of MCAK, inhibitors of KIFL4, inhibitors of Mphosphl and inhibitors of Rab6-KIFL.
  • “Inhibitors of kinases involved in mitotic progression” include, but are not limited to, inhibitors of aurora kinase, inhibitors of Polo-like kinases (PLK) (in particular inhibitors of PLK-I), inhibitors of bub- 1 and inhibitors of bub-Rl.
  • Antiproliferative agents includes antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenecytidine, 2'- fluoromethylene-2'-deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N-(3,4- dichlorophenyl)urea,
  • monoclonal antibody targeted therapeutic agents include those therapeutic agents which have cytotoxic agents or radioisotopes attached to a cancer cell specific or target cell specific monoclonal antibody. Examples include Bexxar.
  • HMG-CoA reductase inhibitors refers to inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase.
  • HMG-CoA reductase inhibitors include but are not limited to lovastatin (MEVACOR®; see U.S. Pat. Nos. 4,231,938, 4,294,926 and 4,319,039), simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784, 4,820,850 and 4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat. Nos.
  • HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefore the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention.
  • Prenyl-protein transferase inhibitor refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase).
  • FPTase farnesyl-protein transferase
  • GGPTase-I geranylgeranyl-protein transferase type I
  • GGPTase-II geranylgeranyl-protein transferase type-II
  • prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, US 5,420,245, US 5,523,430, US 5,532,359, US 5,510,510, US 5,589,485, US 5,602,098, European Patent Publ. 0 618 221, European Patent Publ. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ.
  • Angiogenesis inhibitors refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism.
  • angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors FIT-I (VEGFRl) and FIK-I/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon-a, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal antiinflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib (PNAS (1992) 89:7384; JNCI (1982) 69:475; Arch.
  • steroidal anti-inflammatories such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone), carboxyamidotriazole, combretastatin A-4, squalamine, 6-0-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, angiotensin II antagonists (J. Lab. Clin. Med. (1985) 105: 141-145), and antibodies to VEGF (Nature Biotechnology (1999) 17:963-968; Kim et al. Nature (1993) 562:841-844; WO 00/44777; WO 00/61186).
  • agents that modulate or inhibit angiogenesis and may also be used in combination with the compounds of the instant invention include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in Clin. Chem. La. Med. (2000) 38:679-692).
  • agents that modulate or inhibit the coagulation and fibrinolysis pathways include, but are not limited to, heparin (see Thromb. Haemost. (1998) 80: 10-23), low molecular weight heparins and carboxypeptidase U inhibitors (also known as inhibitors of active thrombin activatable fibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. (2001) 101 :329-354).
  • TAFIa inhibitors have been described in PCT Publication WO 03/013,526 and U.S. Ser. No. 60/349,925 (filed January 18, 2002).
  • Agents that interfere with cell cycle checkpoints refer to compounds that inhibit protein kinases that transduce cell cycle checkpoint signals, thereby sensitizing the cancer cell to DNA damaging agents.
  • agents include inhibitors of ATR, ATM, the Chkl and Chk2 kinases and cdk and cdc kinase inhibitors and are specifically exemplified by 7-hydroxystaurosporin, staurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.
  • “Inhibitors of cell proliferation and survival signaling pathway” refer to pharmaceutical agents that inhibit cell surface receptors and signal transduction cascades downstream of those surface receptors.
  • Such agents include inhibitors of inhibitors of EGFR (for example gefitinib and erlotinib), inhibitors of ERB-2 (for example trastuzumab), inhibitors of IGFR (for example those disclosed in WO 03/059951), inhibitors of cytokine receptors, inhibitors of MET, inhibitors of PI3K (for example LY294002), serine/threonine kinases (including but not limited to inhibitors of Akt such as described in (WO 03/086404, WO 03/086403, WO 03/086394, WO 03/086279, WO 02/083675, WO 02/083139, WO 02/083140 and WO 02/083138), inhibitors of Raf kinase (for example BAY-43-9006 ), inhibitors of MEK (for example
  • Apoptosis inducing agents include activators of TNF receptor family members (including the TRAIL receptors).
  • the invention also encompasses combinations with NSAID's which are selective COX-2 inhibitors.
  • NSAID's which are selective inhibitors of COX-2 are defined as those which possess a specificity for inhibiting COX-2 over COX-I of at least 100 folds as measured by the ratio of IC 50 for COX-2 over IC 50 for COX-I evaluated by cell or microsomal assays.
  • Such compounds include, but are not limited to those disclosed in U.S. Pat. 5,474,995, U.S. Pat. 5,861,419, U.S. Pat. 6,001,843, U.S. Pat. 6,020,343, U.S. Pat. 5,409,944, U.S. Pat. 5,436,265, U.S. Pat. 5,536,752, U.S. Pat. 5,550,142, U.S. Pat. 5,604,260, U.S. 5,698,584, U.S. Pat. 5,710,140, WO 94/15932, U.S. Pat. 5,344,991, U.S. Pat. 5,134,142, U.S. Pat. 5,380,738, U.S. Pat. 5,393,790, U.S. Pat. 5,466,823, U.S. Pat. 5,633,272, and U.S. Pat. 5,932,598, all of which are hereby incorporated by reference.
  • Inhibitors of COX-2 that are particularly useful in the instant method of treatment are 5- chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine, or a pharmaceutically acceptable salt thereof.
  • angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-l-oxaspiro[2,5]oct-6- yl(chloroacetyl)carbamate, acetyldinanaline, 5-amino-l-[[3,5-dichloro-4-(4- chlorobenzoyl)phenyl]methyl]- 1 H-l,2,3-triazole-4-carboxamide, CM 101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, 7,7-(carbonyl-bis[imino- N-methyl-4,2-pyrrolocarbonylimino
  • integrated circuit blockers refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the 0CyP3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ 5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the 0CyP3 integrin and the 0CyP5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells.
  • the term also refers to antagonists of the OCyP j 0C v p8, ⁇ ⁇ , 0C2pi, 0C5pi, 0C6pi and 0C6P4 integrins.
  • the term also refers to antagonists of any combination of ⁇ ⁇ ⁇ 3, ⁇ ⁇ ⁇ 5, ⁇ 6 ; 0 ⁇ ⁇ ⁇ 8, ⁇ ⁇ , 0C2pi, fisoq, ( ⁇ 6 ⁇ 1 and ( ⁇ 6 ⁇ 4 integrins.
  • tyrosine kinase inhibitors include N-(trifluoromethylphenyl)-5- methylisoxazol-4-carboxamide, 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one, 17- (allylamino)- 17-demethoxygeldanamycin, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4- morpholinyl)propoxyl]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4- quinazolinamine, BIBX1 382, 2,3,9,10,11,12-hexahydro-l 0-(hydroxymethyl)-10-hydroxy-9- methyl-9, 12-epoxy-lH-diindolo[l,2,3-fg:3',2',r-kl]pyrrolo[
  • the compounds of the present invention are useful for the treatment or prevention of the appearance of necrosis induced by selective N3 -adenine methylating agents such as MeOS0 2 (CH 2 )-lexitropsin (Me-Lex).
  • selective N3 -adenine methylating agents such as MeOS0 2 (CH 2 )-lexitropsin (Me-Lex).
  • Combinations with compounds other than anti-cancer compounds are also encompassed in the instant methods.
  • combinations of the instantly claimed compounds with PPAR- ⁇ (i.e., PPAR-gamma) agonists and PPAR- ⁇ (i.e., PPAR-delta) agonists are useful in the treatment of certain malingnancies.
  • PPAR- ⁇ and PPAR- ⁇ are the nuclear peroxisome proliferator-activated receptors ⁇ and ⁇ .
  • the expression of PPAR- ⁇ on endothelial cells and its involvement in angiogenesis has been reported in the literature (see J. Cardiovasc. Pharmacol. (1998) 31 :909-913; J. Biol. Chem. (1999) 274:9116-9121; Invest.
  • PPAR- ⁇ agonists and PPAR- ⁇ / ⁇ agonists include, but are not limited to, thiazolidinediones (such as DRF2725, CS-OI 1, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR- H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NPOI 10, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-l,2- benzisoxazol-6-yl)oxy]-2-methylpropionic acid (disclosed in USSN 09/782,856), and 2(R)-7-(3-(2- chloro-4-(4-fluorophenoxy)phenoxy
  • Another embodiment of the instant invention is the use of the presently disclosed compounds in combination with gene therapy for the treatment of cancer.
  • Gene therapy can be used to deliver any tumor suppressing gene. Examples of such genes include, but are not limited to, p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Pat. No.
  • a uPA/uPAR antagonist (Adenovirus-Mediated Delivery of a uPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in Mice," Gene Therapy, August (1998) 5(8): 1105-13), and interferon gamma (J Immunol (2000) 164:217-222).
  • the compounds of the instant invention may also be administered in combination with an inhibitor of inherent multidrug resistance (MDR), in particular MDR associated with high levels of expression of transporter proteins.
  • MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853, verapamil and PSC833 (valspodar).
  • a compound of the present invention may be employed in conjunction with anti-emetic agents to treat nausea or emesis, including acute, delayed, late-phase, and anticipatory emesis, which may result from the use of a compound of the present invention, alone or with radiation therapy.
  • a compound of the present invention may be used in conjunction with other antiemetic agents, especially neurokinin- 1 receptor antagonists, 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABA B receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S. Pat. Nos.
  • neurokinin- 1 receptor antagonists especially 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABA B receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S. Pat. Nos.
  • an antidopaminergic such as the phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol.
  • an anti-emesis agent selected from a neurokinin- 1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is administered as an adjuvant for the treatment or prevention of emesis that may result upon administration of the instant compounds.
  • Neurokinin- 1 receptor antagonists of use in conjunction with the compounds of the present invention are fully described, for example, in U.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147; European Patent Publication Nos.
  • the neurokinin- 1 receptor antagonist for use in conjunction with the compounds of the present invention is selected from: 2-(R)-(l-(R)-(3,5- bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluorophenyl)-4-(3-(5-oxo-lH,4H-l ,2,4- triazolo)methyl)morpholine, or a pharmaceutically acceptable salt thereof, which is described in U.S. Pat. No. 5,719,147.
  • a compound of the instant invention may also be administered with an agent useful in the treatment of anemia.
  • an anemia treatment agent is, for example, a continuous eythropoiesis receptor activator (such as epoetin alfa).
  • a compound of the instant invention may also be administered with an agent useful in the treatment of neutropenia.
  • a neutropenia treatment agent is, for example, a hematopoietic growth factor which regulates the production and function of neutrophils such as a human granulocyte colony stimulating factor, (G-CSF).
  • G-CSF human granulocyte colony stimulating factor
  • Examples of a G-CSF include filgrastim.
  • a compound of the instant invention may also be administered with an immunologic- enhancing drug, such as levamisole, isoprinosine and Zadaxin.
  • an immunologic- enhancing drug such as levamisole, isoprinosine and Zadaxin.
  • a compound of the instant invention may also be useful for treating or preventing cancer, including bone cancer, in combination with bisphosphonates (understood to include bisphosphonates, diphosphonates, bisphosphonic acids and diphosphonic acids).
  • bisphosphonates include but are not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate, neridronate, piridronate and tiludronate including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof.
  • the scope of the instant invention encompasses the use of the instantly claimed compounds in combination with ionizing radiation and/or in combination with a second compound selected from: HD AC inhibitors, an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an angiogenesis inhibitor, a PPAR- ⁇ agonist, a PPAR- ⁇ agonist, an anti- viral agent, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic-enhancing drug, an inhibitor of cell proliferation and survival signaling, an agent that interfers with a cell cycle checkpoint, an apoptosis inducing agent and a bisphosphonate.
  • a second compound selected from: HD AC inhibitors, an estrogen receptor modulator, an androgen
  • administration means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.)
  • administration and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treatment refers to the treatment of a mammal afflicted with a pathological condition and refers to an effect that alleviates the condition by killing the cancerous cells, but also to an effect that results in the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure i.e. prophylaxis is also included.
  • pharmaceutically acceptable refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a subject e.g. human
  • Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • the term "adjunct" refers to the use of compounds in conjunction with known therapeutic means. Such means include cytotoxic regimes of drugs and/or ionising radiation as used in the treatment of different cancer types.
  • the active compounds are known to potentiate the actions of a number of cancer chemotherapy treatments, which include the topoisomerase class of poisons (e.g. topotecan, irinotecan, rubitecan), most of the known alkylating agents (e.g. DTIC, temozolamide) and platinum based drugs (e.g. carboplatin, cisplatin) used in treating cancer.
  • the topoisomerase class of poisons e.g. topotecan, irinotecan, rubitecan
  • most of the known alkylating agents e.g. DTIC, temozolamide
  • platinum based drugs e.g. carboplatin, cisplatin
  • a method of treating cancer comprises administering a therapeutically effective amount of a compound of Formula (I) in combination with radiation therapy and/or in combination with a compound selected from: HDAC inhibitors, an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an angiogenesis inhibitor, a PPAR- ⁇ agonist, a PPAR- ⁇ agonist, an anti- viral agent, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic- enhancing drug, an inhibitor of cell proliferation and survival signaling, an agent that interfers with a cell cycle checkpoint, an apoptosis inducing agent and a bisphosphonate.
  • HDAC inhibitors an estrogen receptor modulator, an androgen receptor modulator
  • the compounds of the present invention can be prepared according to Scheme 1 depicts general synthetic routes for compounds of the invention and are not intended to be limiting. More specifically, Scheme 1 depicts synthesis of indazole compounds. Specific examples are described subsequently to these general synthetic descriptions so as to allow one skilled in the art to make and use indazole of the invention. All variables within the formulae are as defined above.
  • the enantiomers may be separated from the racemic mixtures by standard separating methods such as using SFC.
  • Benzaldehyde (1) is commercial available or been prepared by conventional methods known by those skilled in the art.
  • imine formation can be easily achieved by the reaction of benzaldehyde with the corresponding amine 2 in the presence of a catalyst (e.g., 4- methylbenzene sulfonic acid).
  • a catalyst e.g., 4- methylbenzene sulfonic acid.
  • the followed step 2 of Scheme 1 is a ring closure that can be accomplished by treating the key intermediate 3 with sodium azide at elevated temperature to introduce the final nitrogen atom and the resultant extrusion of nitrogen to furnish the indazole ring.
  • step 3 the introduction of halogen of R 3 , such as chloride, bromide and iodine, can be accomplished by the reaction of indazole 4 with reagents such as NBS, NCS or iodine.
  • Compounds as 6, R 3 are cyano, methyl or phenyl groups, can be prepared by the coupling reaction of corresponding, bromide or iodo compounds using condition such as Suzuki coupling or Hartwig coupling.
  • step 5 the conversion of the ester to the primary amide yields the desired amides as the final Compounds 7.
  • step 4 r R 3 Br > CU
  • R 3 CN, Me, phenyl, 6
  • Scheme 2 outlines the general procedures one could use to provide the desired amides such as Compounds 9 of the present invention.
  • the hydrolysis of the key intermediate 4 yields acids 8 in the presence of an alkali metal hydroxide or alkali alkanoxide (e.g., sodium hydroxide, potassium butoxide).
  • an alkali metal hydroxide or alkali alkanoxide e.g., sodium hydroxide, potassium butoxide.
  • the formation of the final amides 9 can be accomplished by the coupling reaction of the acids 8 with proper amines or hydrazines.
  • Step 1 Synthesis of 4-[(3-Methoxycarbonyl-2-nitro-benzylidene)-amino]-piperidine-l- carboxylic acid tert-butyl ester— Compound 3
  • Step 4 Synthesis of 4-(7-Carbamoyl-3-methyl-indazol-2-yl)-piperidine-l-carboxylic acid tert- butyl ester
  • the 2-(l-tert-Butoxycarbonyl-piperidin-4-yl)-3-methyl-2H-indazole-7-carboxylic acid methyl ester 5 was heated in a mixture of THF and 32%aq. NH 3 solution at 70 ° C overnight in a sealed tube.
  • the solvents were reduced in vacuo and the residue purified by flash column chromatography on silica using a gradient of EtO Ac/Petroleum ether from 30:70 to 50:50 to yield the desired (A6) as white solid.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and 3-Amino-piperidine-l-carboxylic acid tert-butyl ester used instead of 4-Amino-piperidine-l-carboxylic acid tert-butyl ester calcd for C14H18N4O requires: 258, found: 259 (M+H) + .
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and 2-Amino-piperidine-l-carboxylic acid tert-butyl ester used instead of 4-Amino-piperidine-l-carboxylic acid tert-butyl ester calcd for Ci 4 Hi 8 N 4 0 requires: 258, found: 259 (M+H) + .
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and 3 -Amino-pyrrolidine- 1-carboxylic acid tert-butyl ester used instead of 4-Amino-piperidine-l-carboxylic acid tert-butyl ester calcd for C13H16N4O (M+H) + 245.2923, found 245.2907 .
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and 2 -Amino-pyrrolidine- 1-carboxylic acid tert-butyl ester used instead of 4-Amino-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci 3 Hi 6 N 4 0 (M+H) + 245.2923, found
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and 4-Amino-4-methylpiperidine- 1-carboxylic acid tert-butyl ester used instead of 4-Amino-piperidine- 1-carboxylic acid tert-butyl ester calcd for C15H20N4O (M+H) + 273.3455, found 273.3457.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and 3 -Amino-3-methylpiperidine- 1-carboxylic acid tert-butyl ester used instead of 4-Amino-piperidine-l-carboxylic acid tert-butyl ester calcd for C15H20N4O (M+H) 273.3455, found 273.3457.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and 3-Amino-3-methylpyrrolidine-l-carboxylic acid tert-butyl ester used instead of 4-Amino-piperidine-l-carboxylic acid tert-butyl ester calcd for C14H18N4O (M+H) + 259.3189, found 259.3176.
  • Step 1 Synthesis of 3-Bromo-2-(l-tert-butoxycarbonyl-piperidin-4-yl)-2H-indazole-7- carboxylic acid methyl ester
  • Step 2 Synthesis of 3-Bromo-2-piperidin-4-yl-2H-indazole-7-carboxylic acid amide
  • Compound 6 A solution of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester (in TFA/DCM 1 : 1 (0.1 M) was stirred at room temperature for 20 min. After evaporation of solvent under reduced pressure and treatment with Et 2 0, the title compound was isolated as a yellowish solid.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester calcd for Ci 3 Hi 5 BrN 4 0 (M+H) + 324.04, found 323.9007.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 2-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester calcd for Ci 3 Hi 5 BrN 4 0 (M+H) + 324.04, found 323.9007.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester calcd for Ci 2 Hi 3 BrN 4 0 (M+H) + 310.1618, found 310.1624
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 2-(7-Carbamoyl-3-bromo-indazol-2-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester calcd for Ci 2 Hi 3 BrN 4 0 (M+H) + 310.1618, found 310.1624.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-4-methylpiperidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci 4 Hi 7 BrN 4 0 (M+H) + 338.2150, found 338.2147.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpiperidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci 4 Hi 7 BrN 4 0 (M+H) + 338.2150, found 338.2147.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci 3 Hi 5 BrN 4 0 (M+H) + 324.1884, found 324.1897.
  • Step 1 Synthesis of 3-Bromo-2-(l-tert-butoxycarbonyl-piperidin-4-yl)-2H-indazole-7- carboxylic acid methyl ester
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci 4 Hi 5 N 5 0 (M+H) + 270.3018, found 270.3027.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci 4 Hi 5 N 5 0 (M+H) + 270.3018, found 270.3027.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for C 13 H 13 N 5 O (M+H) + 256.2752, found 256.2758.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci 3 Hi 3 N 5 0 (M+H) + 256.2752, found 256.2758.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci 5 Hi 7 N 5 0 (M+H) + 284.3284, found 284.3297.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci 5 Hi 7 N 5 0 (M+H) + 284.3284, found 284.3297.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci 4 Hi 5 N 5 0 (M+H) + 270.3018, found 270.3032.
  • Step 1 Synthesis of 3-Bromo-2-(l-tert-butoxycarbonyl-piperidin-4-yl)-2H-indazole-7- carboxylic acid methyl ester
  • 2-(l-tert-Butoxycarbonyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid methyl ester 4 (0.659 g, 2.38 mmol) in 2 mL of acetic acid was added bromine (0.122 mL, 2. 38 mmol) dropwise.
  • the yellow- orange solution was stirred for 15 m, in which time an orange solid precipitated.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci 6 H 23 N 5 0 (M+H) + 302.3867, found 302.3856.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci 6 H 2 3N 5 0 (M+H) + 302.3867, found 302.3872.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci 5 H 2 iN 5 0 (M+H) + 288.3601 , found 288.3624.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci 5 H 2 iN 5 0 (M+H) + 288.3601 , found 288.3624.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for C17H25N5O (M+H) + 316.4133, found 316.4139.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for C17H25N5O (M+H) + 316.4133, found 316.4139.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci 6 H 23 N 5 0 (M+H) + 302.3867, found 302.3873.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for C18H27N5O (M+H) + 330.4399, found 330.4405.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for C18H27N5O (M+H) + 330.4399, found 330.4405.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci 8 H 27 N 5 0 (M+H) + 330.4399, found 330.4405.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoy 0 l-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci 7 H 25 N 5 0 (M+H) + 316.4133, found 316.4139.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for C17H25N5O (M+H) + 316.4133, found 316.4139.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for C19H29N5O (M+H) + 344.4665, found 344.4671.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for C19H29N5O (M+H) + 344.4665, found 344.4671.
  • the desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci 8 H 27 N 5 0 (MH+) 330.4399, found 330.4405.
  • the PARP-1 enzyme -inhibitory activities of the compounds of the present invention were assayed using a PARP Assay kit (4671-096-K) purchased from Trevigen, as described by Lee et al. (Methods Find, Exp. Clin. Pharmacol., 27, 617-622, 2005) as follows.
  • a small volume PS plate (Greiner bio-one, 784101), 384-well plate was coated with histone, and left at 25 ° C for 2 hrs. Then the plate is washed with PBS (7.5 mM Na 2 HP0 4 , 2.5 mM NaH 2 P0 4 , 145 mM NaCl, pH 7.4) four times. To block the nonspecific signal, a Strep-diluent (providedin the kit of Trevigen) was added thereto, and left at 25 ° C for 1 hr.
  • PBS 7.5 mM Na 2 HP0 4 , 2.5 mM NaH 2 P0 4 , 145 mM NaCl, pH 7.4
  • the plate was washed with PBS four times, and various concentrations of the compounds of the Examples were added to a reaction liquid containing PARP-1 enzyme (0.12 unit/well) and PARP cocktail (NAD + , biotinylated NAD + , and activated DNA), and incubated at 25 ° C for 30min. Then, each well was washed with PBS four times.
  • strepavidin- linkedperoxidase Strep-HRP, 1 : 1000 dilution
  • the amount of NAD(P)H accumulated in the cell culture media was measured.
  • Chinese hamster ovary cells Choinese hamster ovary; CHO-K1 were cultured in RPMI media supplemented with 10% fetal bovine serum (FBS). The cultured CHO-K1 cells were seeded at a density of 2.9> ⁇ 10 3 cells/well in 96-well plate, and cultured at 37 ° C and 5% C0 2 for 16 hrs. Then, the cells were treated with various concentrations of the compounds of Examples, and incubated at 37 ° C for 2 hrs.
  • FBS fetal bovine serum
  • DNA damage was induced using 1.5 itiM MMS (Methyl methanesulfonate), and the cells were simultaneously treated with a CCK-8 (Cell count kit-8) solution (DOJINDO, (CKOl- 13)) for colorimetric assay.
  • CCK-8 Cell count kit-8
  • DOJINDO DOE, (CKOl- 13)
  • the amount of NAD(P)H secreted into the culture media was quantified using a Wallac EnvisionTM (PerkinElmer Oy, Turku, Finland) at 450 nm.
  • the results obtained according to various concentrations of the compounds of the present invention are the average values obtained from four wells, and the results were calculated by regression analysis.
  • commercially available DPQ (Sigma) was used as a control to perform the comparative studies.
  • Table 2 represents the result of quantifying the amount of NAD(P)H secreted into culture medium after treating the Chinese hamster ovary cells (CHO-K1) with various concentrations of the compounds of the present invention and then with MMS for 4 hrs.

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Abstract

Amide substituted indazoles and benzotriazoles as inhibitors of the enzyme poly(ADP-ribose)polymerase(PARP). The compounds of the present invention are useful as mono-therapies in tumors with specific defects in DNA-repair pathways, as enhancers of certain DNA-damaging agents such as anticancer agents and radiotherapy, for reducing cell necrosis (in stroke and myocardial infarction), regulating inflammation and tissue injury, treating retroviral infections, and protecting against the toxicity of chemotherapy.

Description

THE DESCRIPTION
AMIDS SUBSTITUTED INDAZOLE DERIVATIVEES AS PLOY(ADP-RIBOSE)POLYMERASE INHIBITORS
Technical Field
The present invention relates to amide substituted indazoles and benzotriazoles which are inhibitors of the enzyme poly(ADP-ribose)polymerase (PARP), previously known as poly(ADP- ribose)synthase and poly(ADP-ribosyl)transferase. The compounds of the present invention are useful as mono-therapies in tumors with specific defects in DNA-repair pathways and as enhancers of certain DNA-damaging agents such as anticancer agents and radiotherapy. Further, the compounds of the present invention are useful for reducing cell necrosis (in stroke and myocardial infarction), regulating inflammation and tissue injury, treating retroviral infections and protecting against the toxicity of chemotherapy.
Background Art
Poly(ADP-ribose) polymerase (PARP) constitute a super family of eighteen proteins containing PARP catalytic domains (Bioessays (2004) 26: 1148). These proteins include PARP-1, PARP-2, PARP-3, tankyrase-1, tankyrase-2, vaultPARP and TiPARP. PARP-1, the founding member, consists of three main domains: an amino (N)-terminal DNA-binding domain (DBD) containing two zinc fingers, the automodification domain, and a carboxy (C)-terminal catalytic domain.
PARP are nuclear and cytoplasmic enzymes that cleave NAD+ to nicotinamide and ADP- ribose to form long and branched ADP-ribose polymers on target proteins, including topoisomerases, histones and PARP itself (Biochem. Biophys. Res. Commun. (1998) 245: 1-10). Poly(ADP-ribosyl)ation has been implicated in several biological processes, including DNA repair, gene transcription, cell cycle progression, cell death, chromatin functions and genomic stability.
The catalytic activity of PARP-1 and PARP-2 has been shown to be promptly stimulated by DNA strand breakages (see Pharmacological Research (2005) 52:25-33). In response to DNA damage, PARP-1 binds to single and double DNA nicks. Under normal physiological conditions there is minimal PARP activity, however, upon DNA damage an immediate activation of PARP activity of up to 500-fold occurs. Both PARP-1 and PARP -2 detect DNA strand interruptions can act as nick sensors, provid rapid signals to halt transcription and recruit the enzymes required for DNA repair at the site of damage. Since radiotherapy and many chemotherapeutic approaches to cancer therapy act by inducing DNA damage, PARP inhibitors are useful as chemo- and radiosensitizers for cancer treatment. PARP inhibitors have been reported to be effective in radio sensitizing hypoxic tumor cells (US 5,032,617, US 5,215,738 and US 5,041,653).
Most of the biological effects of PARP relate to this poly (ADP-ribosyl)ation process which influences the properties and function of the target proteins; to the PAR oligomers that, when cleaved from poly(ADP-ribosyl)ated proteins, confer distinct cellular effects; to the physical association of PARP with nuclear proteins to form functional complexes; and the lowering of the cellular level of its substrate NAD+ (Nature Review (2005) 4:421-440).
Besides being involved in DNA repair, PARP may also act as a mediator of cell death. Its excessive activation in pathological conditions such as ischemia and reperfusion injury can result in substantial depletion of the intercellular NAD+, which can lead to the impairment of several NAD+ dependent metabolic pathways and result in cell death (see Pharmacological Research (2005) 52:44-59). As a result of PARP activation, NAD+ levels significantly decline. Extensive PARP activation leads to severe depletion of NAD+ in cells suffering from massive DNA damage. The short half-life of poly(ADP-ribose) results in a rapid turnover rate, as once poly(ADP-ribose) is formed, it is quickly degraded by the constitutively active poly(ADP-ribose) glycohydrolase (PARG). PARP and PARG form a cycle that converts a large amount of NAD+ to ADP-ribose, causing a drop of NAD+ and ATP to less than 20% of the normal level. Such a scenario is especially detrimental during ischemia when deprivation of oxygen has already drastically compromised cellular energy output. Subsequent free radical production during reperfusion is assumed to be a major cause of tissue damage. Part of the ATP drop, which is typical in many organs during ischemia and reperfusion, could be linked to NAD+ depletion due to poly(ADP- ribose) turnover. Thus, PARP inhibition is expected to preserve the cellular energy level thereby potentiating the survival of ischemic tissues after insult. Compounds which are inhibitors of PARP are therefore useful for treating conditions which result from PARP mediated cell death, including neurological conditions such as stroke, trauma and Parkinson's disease. PARP inhibitors have been demonstrated as being useful for the specific killing of BRCA-1 and BRC A-2 deficient tumors (Nature (2005) 434:913-916 and 917-921; Cancer Biology & Therapy (2005) 4:934-936).
PARP inhibitors have been shown to enhance the efficacy of anticancer drugs (Pharmacological Research (2005) 52:25-33), including platinum compounds such as cisplatin and carboplatin (Cancer Chemother Pharmacol (1993) 33: 157-162; Mol Cancer Ther (2003) 2:371-382). PARP inhibitors have been shown to increase the antitumor activity of topoisomerase I inhibitors such as Irinotecan and Topotecan (Mol Cancer Ther (2003) 2:371-382; and Clin Cancer Res. (2000) 6:2860-2867) and this has been demonstrated in in vivo models (J Natl Cancer Inst (2004) 96:56- 67). PARP inhibitors have been shown to restore susceptibility to the cytotoxic and antiproliferative effects of temozolomide (TMZ) (Curr Med Chem (2002) 9: 1285-1301; Med Chem Rev Online (2004) 1 : 144-150). This has been demonstrated in a number of in vitro models (Br J Cancer (1995) 72:849-856; Br J Cancer (1996) 74: 1030-1036; Mol Pharmacol (1997) 52:249-258; Leukemia (1999) 13:901-909; GHa (2002) 40:44-54; and Clin Cancer Res (2000) 6:2860-2867 and (2004) 10:881-889) and in vivo models (Blood (2002) 99:2241-2244; Clin Cancer Res (2003) 9:5370-5379; J Natl Cancer Inst (2004) 96:56-67). PAPR inhibitors have also been shown to prevent the appearance of necrosis induced by selective N3 -adenine methylating agents such as MeOS02(CH2)-lexitropsin (Me-Lex) (Pharmacological Research (2005) 52:25-33).
PARP inhibitors have been shown to act as radiation sensitizers. PARP inhibitors have been reported to be effective in radiosensitizing (hypoxic) tumor cells and effective in preventing tumor cells from recovering from potentially lethal (Br. J. Cancer (1984) 49(Suppl. VI):34-42; and Int. J. Radiat. Bioi. (1999) 75:91-100) and sub-lethal (Clin. Oncol. (2004) 16(l):29-39) damage of DNA after radiation therapy, presumably by their ability to prevent DNA strand break rejoining and by affecting several DNA damage signaling pathways.
PARP inhibitors have also been shown to be useful for treating acute and chronic myocardial diseases (Pharmacological Research (2005) 52:34-43). For instance, it has been demonstrated that single injections of PARP inhibitors have reduced the infarct size caused by ischemia and reperfusion of the heart or skeletal muscle in rabbits. In these studies, a single injection of 3-amino- benzamide (10 mg/kg), either one minute before occlusion or one minute before reperfusion, caused similar reductions in infarct size in the heart (32-42%), while 1,5-dihydroxyisoquinoline (1 mg/kg), another PARP inhibitor, reduced infarct size by a comparable degree (38-48%). These results make it reasonable to assume that PARP inhibitors could salvage previously ischemic heart or reperfusion injury of skeletal muscle tissue (PNAS (1997) 94:679-683). Similar findings have also been reported in pigs (Eur. J. Pharmacol. (1998) 359: 143-150; Ann. Thorac. Surg. (2002) 73:575-581) and in dogs (Shock. (2004) 21 :426-32).
PARP inhibitors have been demonstrated as being useful for treating certain vascular diseases, septic shock, ischemic injury and neurotoxicity (Biochim. Biophys. Acta (1989) 1014: 1-7; J. CHn. Invest. (1997) 100:723-735). Oxygen radical DNA damage that leads to strand breaks in DNA, which are subsequently recognized by PARP, is a major contributing factor to such disease states as shown by PARP inhibitor studies (J. Neurosci. Res. (1994) 39:38-46; PNAS (1996) 93:4688-4692). PARP has also been demonstrated to play a role in the pathogenesis of hemorrhagic shock (PNAS (2000) 97: 10203-10208). PARP inhibitors have been demonstrated as being useful for treatment of inflammation diseases (Pharmacological Research (2005) 52:72-82 and 83-92).
It has also been demonstrated that efficient retroviral infection of mammalian cells is blocked by the inhibition of PARP activity. Such inhibition of recombinant retroviral vector infections has been shown to occur in various different cell types (J. Virology, (1996) 70(6): 3992-4000). Inhibitors of PARP have thus been developed for use in anti-viral therapies and in cancer treatment (WO 91/18591).
In vitro and in vivo experiments have demonstrated that PARP inhibitors can be used for the treatment or prevention of autoimmune diseases such as Type I diabetes and diabetic complications (Pharmacological Research (2005) 52:60-71).
PARP inhibition has been speculated as delaying the onset of aging characteristics in human fibroblasts (Biochem. Biophys. Res. Comm. (1994) 201(2):665-672; Pharmacological Research (2005) 52:93-99). This may be related to the role that PARP plays in controlling telomere function (Nature Gen., (1999) 23(l):76-80).
The vast majority of PARP inhibitors to date interact with the nicotinamide binding domain of the enzyme and behave as competitive inhibitors with respect to NAD+ (Expert Opin. Ther. Patents (2004) 14: 1531-1551). Structural analogues of nicotinamide, such as benzamide and derivatives were among the first compounds to be investigated as PARP inhibitors. However, these molecules have a weak inhibitory activity and possess other effects unrelated to PARP inhibition. Thus, there is a need to provide potent inhibitors of the PARP enzyme.
Structurally related PARP inhibitors have previously been described. WO 1999/59973 discloses amide substituted benzene rings fused to 5-membered heteroaromatic rings; WO2001/85687 discloses amide substituted indoles; WO 1997/04771, WO 2000/26192, WO 2000/32579, WO 2000/64878, WO 2000/68206, WO 2001/21615, WO 2002/068407, WO 2003/106430 and WO 2004/096793 disclose amide substituted benzoimidazoles; WO 2000/29384 discloses amide substituted benzoimidazoles and indoles; and EP 0879820 discloses amide substituted benzoxazoles.
It has now surprisingly been discovered that amide substituted indazoles of the present invention exhibit high levels of inibition of the activity of PARP.
SUMMARY OF THE INVENTION
The compounds of this invention are useful in the inhibition of poly(ADP-ribose)polymerase (PARP). They are particularly useful as inhibitors of PARP-1 and/or PARP -2. The present invention provides compounds of Formula (I),
Figure imgf000006_0001
Formula I pharmaceutically acceptable salts thereof, N-oxides thereof, produgs thereof, solvates thereof, isomers, polymorphic forms thereof, and mixtures of any of the foregoing, wherein:
Ri is selected from hydrogen, Ci_6alkyl, cycloalkyl, alkoxyCi_6alkyl, haloCi_6alkyl, hydroxyCi_ 6alkyl, NR4R5, (NR4R5)alkyl, (NR4R5)carbonyl, (NR4R5)carbonylalkyl, alkoxyCi_6alkyl(NR4R5) or (NR4R5)sulfonyl;
R2 is selected from hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkyl, nitro, NR4R5, or (NR4R5)carbonyl;
R3 is selected from hydrogen, Ci_6alkyl, C6_ioaryl, halogen, cyano, haloCi_6alkyl, or haloCi_6 alkoxy; when Ri is NFFNR4R5, R3 independently selected from a group consisting of hydrogen, halogen, cyano, haloCi_6alkyl, or haloCi_6alkoxy;
X is selected from
a) an aryl group optionally substituted with 1, 2, or 3 R4, wherein each R4 is selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkyl, nitro, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR5R5, (NR5R6)alkyl, (NRsR carbonyl, (NR5R6)carbonylalkyl, and (NRsR sulfony, and wherein when aryl is phenyl, the phenyl is substituted with at least one substituent selected independently from the group consisting of alkoxyalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio and (NR5R6)alkyl;
b) a heteroaryl group optionally substituted with 1, 2, or 3 R4;
c) a L-T group, wherein the L is selected from alkenylene, alkylene, alkynylene, cycloalkylene or spiroheterocycle, and T is selected from heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio or NR5R5;
d) a non-aromatic 4-13 membered heterocycle ring having 1 to 4 heterocycleatoms selected from nitrogen, sulfur or oxygen atom; wherein the heterocycle is optionally substituted with 1, 2, or 3 R6; wherein each 5 is selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkyl, nitro, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR4R5, (NR4Rs)alkyl, (NR4Rs)carbonyl, (NR4R5)carbonylalkyl and (NR4R5)sulfonyl, and wherein when the heterocycle is bicyclic, the optional substituent(s) are attached to either one or both of the cyclic rings;
R5 is independently hydrogen, Ci_6alkyl, C2_ioalkenyl, haloCi_6alkyl, hydroxyCi_6alkyl, Ci_ 6alkylcarbonyl, Ci_6alkoxy, haloCi_6alkoxy, Ci_6alkoxycarbonyl, or a ring which is: C6-ioaryl; C6- loaryloxy; C6-ioarylcarbonyl; C3_iocycloalkyl; a 4-membered saturated heterocyclic ring containing one nitrogen (N) atom; a 5 or 6-membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S; a 5 -membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S; a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; or a from 7- to 15 -membered unsaturated, partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of which rings being optionally substituted by one or more groups independently selected from (CH2)CR4, and each c is any integer selected from 0-6; wherein R9 is selected from hydrogen, Ci_6alkyl, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkyl, and nitro.
The compounds of this invention are useful in the inhibition of poly(ADP-ribose)polymerase (PARP). They are particularly useful as inhibitors of PARP-1 and/or PARP-2. The present invention provides compounds of Formula (I),
Figure imgf000008_0001
Formula I
pharmaceutically acceptable salts thereof, N-oxides thereof, produgs thereof, solvates thereof, isomers, polymorphic forms thereof, and mixtures of any of the foregoing, wherein:
Ri is independently selected from a group consisting of hydrogen, Ci_6alkyl, cycloalkyl, alkoxyCi_6alkyl, haloCi_6alkyl, hydroxyCi_6alkyl, and NR4R5, (NR4Rs)alkyl, (NR4Rs)carbonyl, (NR4R5)carbonylalkyl, alkoxyCi_6alkyl(NR4R5) and (NR4R5)sulfonyl;
R2 is independently selected from a group consisting of each independently selected from the group consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkyl, nitro, NR4R5, and (NR4Rs)carbonyl;
R3 is independently selected from a group consisting of hydrogen, Ci_6alkyl, C6_ioaryl, halogen, cyano, haloCi_6alkyl, or haloCi_6alkoxy; when Ri is NFFNR4R5, R3 independently selected from a group consisting of hydrogen, halogen, cyano, haloCi_6alkyl, or haloCi_6alkoxy;
X is selected from the group consisting of
a) an aryl group optionally substituted with 1, 2, or 3 R4 , wherein each R4 is selected independently from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkyl, nitro, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR5R6, (NRsR^alkyl, (NRsR^carbonyl, (NRsR^carbonylalkyl, and (NRsR sulfonyl, wherein when aryl is phenyl, the phenyl is substituted with at least one substituent selected independently from the group consisting of alkoxyalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio, (NRsR^alkyl;
b) a heteroaryl group optionally substituted with 1, 2, or 3 R4;
c) a L-T group where L is selected from the group consisting of alkenylene, alkylene, alkynylene, cycloalkylene and spiroheterocycle, and T is selected from the group consisting of heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio and NR5R6;
d) a non-aromatic 6-12 membered monocyclic or bicyclic heterocycle ring having 1 nitrogen atoms is selected from group consisting of ;
Figure imgf000009_0001
Figure imgf000010_0001
wherein n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3; ¾ is selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkyl, nitro, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR^s, (NR4R5)alkyl, (NR4R5)carbonyl, (NR4R5)carbonylalkyl and (NR4R5)sulfonyl, and wherein when the heterocycle is bicyclic, the optional substituent(s) are attached to either one or both of the cyclic rings; R7 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, oxo, heteroaryl, heterocycle, heterocycloalkyl, (NR4R5)alkyl, (NR4R5)carbonyl, (NR4R5)carbonylalkyl, and (NR4R5)sulfonyl; R8 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, oxo, heteroaryl, heterocycle, heterocycloalkyl, (NR4R5)alkyl, (NR4R5)carbonyl, (NR4R5)carbonylalkyl, and (NR4R5)sulfonyl;
wherein R4 and R5 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl.
In certain embodiments are provided compounds of Formula (I) or a therapeutically acceptable salt thereof, wherein Ri and R2 are hydrogen, and R3 is halogen or cyano. In certain embodiments are provided compounds of Formula (I) or a therapeutically acceptable salt thereof, wherein Ri and R2 are hydrogen, and R3 is selected from Ci_6alkyl, C6_ioaryl. In certain embodiments are provided compounds of Formula (I), wherein R2 and R3 are hydrogen, and Ri is selected from the group consisting of Ci_6alkyl, cycloalkyl, alkoxyCi_6alkyl, haloCi_6alkyl, hydroxyCi_6alkyl, and NR4R5, (NR4R5)alkyl, (NR4R5)carbonyl, (NR4R5)carbonylalkyl, alkoxyCi_6alkyl(NR4R5), and (NR4R5)sulfonyl.
The flowing compounds of the invention are provided to give the reader an understanding of the compounds encompassed by the invention.
• 3-Methyl-2-piperidin-4-yl-2H-indazole-7-carboxylic acid amide
• 3-Methyl-2-piperidin-3-yl-2H-indazole-7-carboxylic acid amide
• 3-Methyl-2-piperidin-2-yl-2H-indazole-7-carboxylic acid amide
• 3-Methyl-2-pyrrolidin-3-yl-2H-indazole-7-carboxylic acid amide
• 3-Methyl-2-pyrrolidin-2-yl-2H-indazole-7-carboxylic acid amide
• 3-Methyl-2-(4-methyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid amide
• 3-Methyl-2-(4-methyl-piperidin-3-yl)-2H-indazole-7-carboxylic acid amide
• 3-Methyl-2-(3-methyl-pyrrolidin-3-yl)-2H-indazole-7-carboxylic acid amide
• 3-Bromo-2-piperidin-4-yl-2H-indazole-7-carboxylic acid amide
• 3-Bromo-2-piperidin-3-yl-2H-indazole-7-carboxylic acid amide
• 3-Bromo-2-piperidin-2-yl-2H-indazole-7-carboxylic acid amide
• 3-Bromo-2-pyrrolidin-3-yl-2H-indazole-7-carboxylic acid amide
• 3-Bromo-2-pyrrolidin-2-yl-2H-indazole-7-carboxylic acid amide
• 3-Bromo-2-(4-methyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid amide • 3-Bromo-2-(4-methyl-piperidin-3-yl)-2H-indazole-7-carboxylic acid amide
• 3-Bromo-2-(3-methyl-pyrrolidin-3-yl)-2H-indazole-7-carboxylic acid amide
• 3-Cyano-2-piperidin-4-yl-2H-indazole-7-carboxylic acid amide
• 3-Cyano-2-piperidin-3-yl-2H-indazole-7-carboxylic acid amide
• 3-Cyano-2-piperidin-2-yl-2H-indazole-7-carboxylic acid amide
• 3-Cyano-2-pyrrolidin-3-yl-2H-indazole-7-carboxylic acid amide
• 3-Cyano-2-pyrrolidin-2-yl-2H-indazole-7-carboxylic acid amide
• 3-Cyano-2-(4-methyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid amide
• 3-Cyano-2-(4-methyl-piperidin-3-yl)-2H-indazole-7-carboxylic acid amide
• 3-Cyano-2-(3-methyl-pyrrolidin-3-yl)-2H-indazole-7-carboxylic acid amide
• 3-Methyl-2-piperidin-4-yl-2H-indazole-7-carboxylic acid Ν',Ν'-dimethyl-hydrazide
• 3-Methyl-2-piperidin-3-yl-2H-indazole-7-carboxylic acid Ν',Ν'-dimethyl-hydrazide
• 3-Methyl-2-piperidin-2-yl-2H-indazole-7-carboxylic acid Ν',Ν'-dimethyl-hydrazide
• 3-Methyl-2-pyrrolidin-3-yl-2H-indazole-7-carboxylic acid Ν',Ν'-dimethyl-hydrazide
• 3-Methyl-2-pyrrolidin-2-yl-2H-indazole-7-carboxylic acid Ν',Ν'-dimethyl-hydrazide
• 3-Methyl-2-(4-methyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid Ν',Ν'-dimethyl- hydrazide
• 3-Methyl-2-(4-methyl-piperidin-3-yl)-2H-indazole-7-carboxylic acid Ν',Ν'-dimethyl- hydrazide
• 3-Methyl-2-(3-methyl-pyrrolidin-3-yl)-2H-indazole-7-carboxylic acid Ν',Ν'-dimethyl- hydrazide
• 3-Methyl-2-piperidin-4-yl-2H-indazole-7-carboxylic acid (2-dimethylamino-ethyl)-amide
• 3-Methyl-2-piperidin-3-yl-2H-indazole-7-carboxylic acid (2-dimethylamino-ethyl)-amide
• 3-Methyl-2-piperidin-2-yl-2H-indazole-7-carboxylic acid (2-dimethylamino-ethyl)-amide
• 3-Methyl-2-pyrrolidin-3-yl-2H-indazole-7-carboxylic acid (2-dimethylamino-ethyl)-amide
• 3-Methyl-2-pyrrolidin-2-yl-2H-indazole-7-carboxylic acid (2-dimethylamino-ethyl)-amide
• 3-Methyl-2-(4-methyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid (2-dimethylamino- ethyl)-amide
• 3-Methyl-2-(4-methyl-piperidin-3-yl)-2H-indazole-7-carboxylic acid (2-dimethylamino- ethyl)-amide • 3-Methyl-2-(4-methyl-piperidin-2-yl)-2H-indazole-7-carboxylic acid (2-dimethylamino- ethyl)-amide
• 3-Methyl-2-(3-methyl-pyrrolidin-3-yl)-2H-indazole-7-carboxylic acid (2-dimethylamino- ethyl)-amide
• 3-Phenyl-2-piperidin-4-yl-2H-indazole-7-carboxylic acid amide hydrochloride salt
• 4-(7-Carbamoyl-3-phenyl-indazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester
• 2-(l-Acetyl-piperidin-4-yl)-3-phenyl-2H-indazole-7-carboxylic acid amide
• 4-(7-Carbamoyl-3-methyl-indazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester2-(l-
Acetyl-piperidin-4-yl)-3-methyl-2H-indazole-7-carboxylic acid amide
• 4-[4-(7-Carbamoyl-3-methyl-indazol-2-yl)-piperidine-l-carbonyl]-piperidine-l-carboxylic acid tert-butyl ester
• 3-[4-(7-Carbamoyl-3-methyl-indazol-2-yl)-piperidine-l-carbonyl]-piperidine-l-carboxylic acid tert-butyl ester
• 2-(l-Methyl-piperidin-4-yl)-3-phenyl-2H-indazole-7-carboxylic acid amide
• 4-[4-(7-Carbamoyl-3-phenyl-indazol-2-yl)-piperidine- 1 -carbonylj-piperidine- 1 -carboxylic acid tert-butyl ester
• 3-[4-(7-Carbamoyl-3-phenyl-indazol-2-yl)-piperidine- 1 -carbonylj-piperidine- 1 -carboxylic acid tert-butyl ester
• 3-[4-(7-Carbamoyl-3-methyl-indazol-2-yl)-piperidine-l-carbonyl]-pyrrolidine-l -carboxylic acid tert-butyl ester
• 3-Bromo-2-(4-bromo-phenyl)-2H-indazole-7-carboxylic acid amide
• 3-Chloro-2-(4-pyridin-3-yl-phenyl)-2H-indazole-7-carboxylic acid amide
• 3-Chloro-2-pyrrolidin-3-yl-2H-indazole-7-carboxylic acid amide
The present invention also includes within its scope N-oxides of the compounds of Formula (I) above. In general, such N-oxides may be formed on any available nitrogen atom. The N-oxides may be formed by conventional means, such as reacting the compound of Formula (I) with oxone in the presence of wet alumina. The present invention includes within its scope prodrugs of the compounds of Formula (I) above.
In general, such prodrugs will be functional derivatives of the compounds of Formula (I) which are readily convertible in vivo into the required compound of Formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. A prodrug may be a pharmacologically inactive derivative of a biologically active substance (the "parent drug" or "parent molecule") that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
The present invention includes within its scope solvates of the compounds of Formula (I) and salts thereof, for example, hydrates.
The compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: EX. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pp.s 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, all such stereoisomers being included in the present invention. In addition, the compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted. The compounds may exist in different isomeric forms, all of which are encompassed by the present invention.
The compounds may exist in a number of different polymorphic forms. When any variable (e.g. Ri and R2, etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn into the ring systems from substituents represent that the indicated bond may be attached to any of the substitutable ring atoms.
It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. The phrase "optionally substituted" should be taken to be equivalent to the phrase "unsubstituted or substituted with one or more substituents" and in such cases the preferred embodiment will have from zero to three substituents. More particularly, there are zero to two substituents. A substituent on a saturated, partially saturated or unsaturated heterocycle can be attached at any substitutable position. As used herein, "alkyl" is intended to include both branched, straight-chain and cyclic saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "Ci_6alkyl" is defined to include groups having 1, 2, 3, 4, 5 or 6 carbons in a linear, branched or cyclic arrangement. For example," Ci_6alkyl" specifically includes methyl, ethyl, n-propyl, i-propyl, n- butyl, t-butyl, i-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and so on. Preferred alkyl groups are methyl and ethyl. The term "cycloalkyl" means a monocyclic, bicyclic or polycyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "C3_7cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2- ethyl-cyclopentyl, cyclohexyl and so on. In an embodiment of the invention the term "cycloalkyl" includes the groups described immediately above and further includes monocyclic unsaturated aliphatic hydrocarbon groups. For example, "cycloalkyl" as defined in this embodiment includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl- cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl, 7,7- dimethylbicyclo[2.2.1]heptyl and so on. Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
As used herein, the term "C2-6alkenyl" refers to a non-aromatic hydrocarbon radical, straight or branched, containing from 2 to 6 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present. Alkenyl groups include ethenyl, propenyl, butenyl and 2- methylbutenyl. Preferred alkenyl groups include ethenyl and propenyl.
As used herein, the term "C2-6alkynyl" refers to a hydrocarbon radical straight or branched, containing from 2 to 6 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present. Alkynyl groups include ethynyl, propynyl, butynyl, 3- methylbutynyl and so on. Preferred alkynyl groups include ethynyl and propynyl.
"Alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. "Alkoxy" therefore encompasses the definitions of alkyl above. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t- butoxy. The preferred alkoxy groups are methoxy and ethoxy. The term "CP-ioaryloxy" can be construed analogously, and an example of this group is phenoxy.
The terms "haloCi_6alkyl" and "haloCi_6alkoxy" mean a Ci_6alkyl or group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms. Preferred are fluoro Ci_6alkyl and fluoro Ci_6alkoxy groups, in particular fluoroCi_3alkyl and fluoroCi_3alkoxy groups, for example, CF3, CHF2, CH2F, CH2CH2F, CH2CHF2, CH2CF3, OCF3, OCHF2, OCH2F, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF3, OCF3 and OCHF2.
As used herein, the term "hydroxyCi_6alkyl" means a group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by hydroxy groups. Preferred are CH2OH, CH2CHOH and CHOHCH3.
The term "Ci_6alkylcarbonyl" or "Ci_6alkoxycarbonyl" denotes a radical, respectively, attached via a carbonyl (C=0) radical. Suitable examples of groups include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl and tert-butylcarbonyl. Examples of Ci_6alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and tert- butoxy carbonyl. The term "C6-ioarylcarbonyl" can be construed analogously, and an example of this group is benzoyl. The rings present in the compounds of this invention may be monocyclic or multicyclic, particularly bicyclic. The multicyclic rings may be fused or spiro linked.
As used herein, "C6-ioaryl" is intended to mean any stable monocyclic or bicyclic carbon ring of 6 to 10 atoms, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl and tetrahydrobenzo[7]annulene. The preferred aryl group is phenyl or naphthyl, especially phenyl.
Examples of particular heterocycles of this invention are benzimidazolyl, benzofurandionyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, benzoxazolonyl, benzothiazolyl, benzothiadiazolyl, benzodioxolyl, benzoxadiazolyl, benzoisoxazolyl, benzoisothiazolyl, chromenyl, chromanyl, isochromanyl, carbazolyl, carbolinyl, cinnolinyl, epoxidyl, furyl, furazanyl, imidazolyl, indolinyl, indolyl, indolizinyl, isoindolinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazolinyl, isoxazolinyl, oxetanyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridinyl, pyrimidinyl, triazinyl, tetrazinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinolizinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1 ,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidyl, pyridin-2-onyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrrolinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydroisoquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, dihydroisochromenyl, dihydrochromenyl, dihydroimidazolonyl, dihydrotriazolonyl, dihydrobenzodioxinyl, dihydrothiazolopyrimidinyl, dihydroimidazopyrazinyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl, thiazolidinonyl, imidazolonyl, isoindolinonyl, octahydroquinolizinyl, octahydroisoindolyl, imidazopyridinyl, azabicycloheptanyl, chromenonyl, triazolopyrimidinyl, dihydrobenzoxazinyl, thiazolotriazolyl, azoniabicycloheptanyl, azoniabicyclooctanyl, phthalazinyl, naphthyridinyl, quinazolinyl, pteridinyl, dihydroquinazolinyl, dihydrophthalazinyl, benzisoxazolyl, tetrahydronaphthyridinyl, dibenzo[¾,<i]furanyl, dihydrobenzothiazolyl, imidazothiazolyl, tetrahydroindazolyl, tetrahydrobenzothienyl, hexahydronaphthyridinyl, tetrahydroimidazopyridinyl, tetrahydroimidazopyrazinyl, pyrrolopyridinyl and N-oxides thereof. Further examples include azoniaspiro[5.5]undecanyl, azepanyl, octahydroindolizinyl, 12-dihydrospirocyclohexane-l,3-indolyl, azoniabicyclo[3.1.0]hexanyl, diazoniaspiro[4.4]nonanyl, hexahydropyrrolo[3,4-b]pyrrolyl, oxaazoniabicyclo [2.2. ljheptanyl, diazoniaspriro[5.5]undecanyl, diazoniaspiro[3.3]heptanyl, diazoniaspiro [3.5 Jnonanyl, diazoniaspiro [4.5 ]decanyl, octahydropyrrolo [3 ,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydrocyclopenta[c]pyrrolyl, dihydroindolyl, azoniaspiro[4.5]decanyl, diazoniabicyclo[2.2.2]octanyl, diazoniabicyclo [2.2. ljheptanyl, diazoniabicyclo[3.2.1]octanyl, etrahydrothiophenyl, oxaazoniaspiro[4.5]decanyl and oxazepanyl. Attachment of a heterocyclyl substituent can occur via a carbon atom or via a heteroatom.
A preferred 4-membered saturated heterocycle is azetidinyl.
Preferred 5- or 6-membered saturated or partially saturated hetereocycles are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and thiomorpholinyl. A further preferred heterocycle is dihydroimidazolyl.
A preferred 7-membered saturated heterocycle is diazepanyl. Further preferred rings are azepanyl and oxazepanyl.
Preferred 5-membered heteroaromatic rings are thienyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, furyl and pyrrolyl. Preferred 6 membered heteraromatic rings are pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl.
Preferred 6- to 13 -membered saturated, partially saturated or unsaturated hydrocarbon rings are cyclohexyl, cyclohexadienyl, cyclohepyl, cyclooctyl, phenyl, naphthyl, tetrahydronaphthalenyl, dihydroindenyl, fluorenyl, adamantly, tetrahydrobenzo[7]annulenyl, indanyl, and tetrahydroindenyl. Preferred 7- to 13-membered partially saturated or unsaturated heterocyclic rings are tetrahydroquinolinyl, quinolinyl, indolyl, imidazopyridinyl, benzothiazolyl, quinoxalinyl, benzothiadiazolyl, benzoxazolyl, dihydrobenzodioxinyl, benzotriazolyl, benzodioxolyl, dihydroisoindolyl, dihydroindolyl, tetrahydroisoquinolinyl, isoquinolinyl, benzoisothiazolyl, dihydroimidazopyrazinyl, benzothienyl, benzoxadiazolyl, thiazolotriazolyl, dihydrothiazolopyrimidinyl, dihydrobenzoxazinyl, dihydrobenzofuranyl, benzimidazolyl, benzofuranyl, dihydrobenzoxazolyl, dihydroquinazolinyl, dihydrophthalazinyl, indazolyl, benzisoxazolyl, tetrahydronaphthyridinyl, triazolopyrimidinyl, dibenzo[8,J]furanyl, naphthyridinyl, dihydroquinolinyl, dihydroisochromenyl, dihydrochromenyl, dihydrobenzothiazolyl, imidazothiazolyl, tetrahydroindazolyl, tetrahydrobenzothienyl, hexahydronaphthyridinyl, tetrahydroimidazopyridinyl, tetrahydroimidazopyrazinyl and pyrrolopyridinyl. Further preferred rings are quinazolinyl and indolizinyl. Further preferred 7- to 15-menbered saturated, partially saturated or unsaturated heterocycles include azoniaspiro[5.5]undecanyl, azepanyl, octahydroindolizinyl, 12-dihydrospirocyclohexane-l,3-indolyl, octahydroisoindolyl, azoniabicyclo[3.1.0]hexanyl, diazoniaspiro[4.4]nonanyl, hexahydropyrrolo[3,4-b]pyrrolyl, oxaazoniabicyclo[2.2.1]heptanyl, diazoniaspriro[5.5]-undecanyl, diazoniaspiro [3.3 ]heptanyl, diazoniaspiro [3.5]nonanyl, diazoniaspiro [4.5]decanyl, octahydropyrrolo [3,4-c]pyrrolyl, octahydropyrrolo [3,4-b]pyrro Iyl, octahydrocyclopenta[c]-pyrrolyl, dihydroindolyl, azoniaspiro[4.5]decanyl, diazoniabicyclo[2.2.2]octanyl, diazoniabicyclo[2.2. ljheptanyl, diazoniabicyclo[3.2.1]octanyl, tetrahydrothiophenyl, oxaazoniaspiro[4.5]decanyl and oxazepanyl.
As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.
Included in the instant invention is the free base of compounds of Formula (I), as well as the pharmaceutically acceptable salts and stereoisomers thereof. The compounds of the present invention can be protonated at the N atom(s) of an amine and/or N containing heterocycle moiety to form a salt. The term "free base" refers to the amine compounds in non-salt form. The encompassed pharmaceutically acceptable salts not only include the salts exemplified for the specific compounds described herein, but also all the typical pharmaceutically acceptable salts of the free form of compounds of Formula (I). The free form of the specific salt compounds described may be isolated using techniques known in the art. For example, the free form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free forms may differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise pharmaceutically equivalent to their respective free forms for purposes of the invention.
The pharmaceutically acceptable salts of the instant compounds can be synthesized from the compounds of this invention which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts of the basic compounds are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt- forming inorganic or organic acid in a suitable solvent or various combinations of solvents. Similarly, the salts of the acidic compounds are formed by reactions with the appropriate inorganic or organic base. Thus, pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed by reacting a basic instant compound with an inorganic, organic acid or polymeric acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, sulfamic, phosphoric, phosphorous, nitric and the like, as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, palmitic, gluconic, phenylacetic, aspartic, cinnamic, pyruvic, ethanesulfonic, acetic, disulfonic, valeric, trifluoroacetic and the like. Examples of suitable polymeric salts include those derived from the polymeric acids such as tannic acid, carboxymethyl cellulose. Preferably, a pharmaceutically acceptable salt of this invention contains 1 equivalent of a compound of Formula (I) and 1 , 2 or 3 equivalent of an inorganic or organic acid. More particularly, pharmaceutically acceptable salts of this invention are the trifluoroacetate or the chloride salts. In an embodiment the salt is trifluoroacetate. In another embodiment the salt is chloride. When the compound of the present invention is acidic, suitable "pharmaceutically acceptable salts" refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, lysine, betaine caffeine, choline, NiNi-dibenzylethylenediamine, ethylamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, diethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine, dicyclohexylamine, butylamine, benzylamine, phenylbenzylamine, tromethamine and the like. The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al (1977) J. Pharm. Sci., 'Pharmaceutical Salts', 66: 1-19.
It will also be noted that the compounds of the present invention are potentially internal salts or zwitterions, since under physiological conditions a deprotonated acidic moiety in the compound, such as a carboxyl group, may be anionic, and this electronic charge might then be balanced off internally against the cationic charge of a protonated or alkylated basic moiety, such as a quaternary nitrogen atom.
The invention provides compounds for use in the treatment or prevention of conditions which can be ameliorated by the inhibition of poly(ADP-ribose)polymerase (PARP) (see, for example, Nature Review Drug Discovery (2005) 4:421-440).
Thus, the present invention provides a compound of Formula (I) for use in the manufacture of a medicament for the treatment or prevention of conditions which can be ameliorated by the inhibition of poly(ADP-ribose)polymerase (PARP). The present invention also provides a method for the treatment or prevention of conditions which can be ameliorated by the inhibition of poly(ADP-ribose)polymerase (PARP), which method comprises administration to a patient in need thereof of an effective amount of a compound of Formula (I) or a composition comprising a compound of Formula (I).
The PARP inhibitors of the present invention are useful for the treatment of the diseases specified in WO 2005/082368.
The compounds of the invention are useful for the treatment of inflammatory diseases, including conditions resulted from organ transplant rejection, such as chronic inflammatory diseases of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung diseases such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory diseases of the eye including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympatheticophthalmitis and endophthalmitis; chronic inflammatory diseases of the gum, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidney including uremic complications, glomerulonephritis and nephrosis; inflammatory diseases of the skin including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the central nervous system (CNS), including chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-related neurodegeneration and Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and viral or autoimmune encephalitis; diabetic complications, including, but not limited to, immune-complex vasculitis, systemic lupus erythematosus (SLE); inflammatory diseases of the heart such as cardiomyopathy, ischemic heart disease, hypercholesterolemia, and atherosclerosis; as well as various other diseases that can have significant inflammatory components, including preeclampsia, chronic liver failure, brain and spinal cord trauma and multiple organ dysfunction syndrome (MODS) (multiple organ failure, MOF). The inflammatory disease can also be a systemic inflammation of the body, exemplified by gram-positive or gram-negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with proinflammatory cytokines. Such shock can be induced, e.g. by a chemotherapeutic agent that is administered as a treatment for cancer. Thus, the present invention provides a compound of Formula (I) for use in the manufacture of a medicament for treating or preventing inflammatory diseases.
The present invention also provides a method for the treatment or prevention of reperfusion injuries, which method comprises administration to a patient in need thereof of an effective amount of a compound of Formula (I) or a composition comprising at least one compound of Formula (I).
The compounds of the instant invention may also be useful in the treatment or prevention of ischemic conditions, including those resulted from organ transplantation, such as stable angina, unstable angina, myocardial ischemia, hepatic ischemia, mesenteric artery ischemia, intestinal ischemia, critical limb ischemia, chronic critical limb ischemia, cerebral ischemia, acute cardiac ischemia, ischemia kidney disease, ischemic liver disease, ischemic retinal disorder, septic shock, and an ischemic disease of the central nervous system, such as stroke or cerebral ischemia.
The present invention also provides a method for the treatment or prevention of stroke, which method comprises administration to a patient in need thereof of an effective amount of a compound of Formula (I) or a composition comprising a compound of Formula (I). The compounds of the instant invention may also be useful for the treatment or prevention of chronic or acute renal failure.
The compounds of the instant invention may also be useful for the treatment or prevention of vascular diseases other than cardiovascular diseases, such as peripheral arterial occlusion, thromboangitis obliterans, Reynaud's disease and phenomenon, acrocyanosis, erythromelalgia, venous thrombosis, varicose veins, arteriovenous fistula, lymphedema and lipedema. Thus, the present invention provides a compound of Formula (I) for use in the manufacture of a medicament for the treatment or prevention of vascular diseases other than cardiovascular diseases.
The present invention also provides a method for the treatment or prevention of cardiovascular diseases, which method comprises administration to a patient in need thereof of an effective amount of a compound of Formula (I) or a composition comprising a compound of Formula (I).
The compounds of the invention may also be useful for the treatment and prevention of diabetes mellitus, including Type I diabetes (Insulin Dependent Diabetes Mellitus), Type II diabetes (Non-Insulin Dependent Diabetes Mellitus), gestational diabetes, autoimmune diabetes, insulinopathies, diabetes due to pancreatic disease, diabetes associated with other endocrine diseases (such as Cushing's Syndrome, acromegaly, pheochromocytoma, glucagonoma, primary aldosteronism or somatostatinoma), Type A insulin resistance syndrome, Type B insulin resistance syndrome, lipatrophic diabetes, and diabetes induced by 3-cell toxins. The compounds of this invention may also be useful for the treatment or prevention of diabetic complications, such as diabetic cataract, glaucoma, retinopathy, nephropathy (such as microaluminuria and progressive diabetic nephropathy), polyneuropathy, gangrene of the feet, atherosclerotic coronary arterial disease, peripheral arterial disease, nonketotic hyperglycemic- hyperosmolar coma, mononeuropathies, autonomic neuropathy, foot ulcers, joint problems, and a skin or mucous membrane complication (such as an infection, a shin spot, a candidal infection or necrobiosis lipoidica diabeticorumobesity), hyperlipidemia, hypertension, syndrome of insulin resistance, coronary artery disease, retinopathy, diabetic neuropathy, polyneuropathy, mononeuropathies, autonomic neuropathy, a foot ulcer, a joint problem, a fungal infection, a bacterial infection, and cardiomyopathy. Thus, the present invention provides a compound of Formula (I) for use in the manufacture of a medicament for the treatment or prevention of diabetes.
The compounds of this invention may also be useful for the treatment or prevention of cancer including solid tumors such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms'tumor, cervical cancer, uterine cancer, testicular cancer, small cell lung carcinoma, bladder carcinoma, lung cancer, epithelial carcinoma, skin cancer, melanoma, neuroblastoma and retinoblastoma; blood-borne cancers such as acute lymphoblastic leukemia("ALL"), acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblasts leukemia ("AML"), acute promyelocyte leukemia("APL"), acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocyctic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia("CML"), chronic lymphocytic leukemia("CLL"), hairy cell leukemia and multiple myeloma; acute and chronic leukemias such as lymphoblastic, myelogenous, lymphocytic, myelocytic leukemias; Lymphomas such as Hodgkin's disease, non-Hodgkin's Lymphoma, Multiple myeloma, Waldenstrom's macroglobulinemia, Heavy chain disease and Polycythemia vera; CNS and brain cancers such as glioma, pilocytic astrocytoma, astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, vestibular schwannoma, adenoma, metastatic brain tumor, meningioma, spinal tumor and medulloblastoma.
The compounds of the present invention may also be used for the treatment of cancer which is deficient in Homologous Recombination (HR) dependent DNA DSB repair activity (see WO 2006/021801).
The HR dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA via homologous mechanisms to reform a continuous DNA helix (Nat. Genet. (2001) 27(3):247- 254). The components of the HR dependent DNA DSB repair pathway include, but are not limited to, ATM (NM-000051), RAD51 (NM-002875), RAD51 LI (NM-002877), RAD51 C (NM-002876), RAD51L3 (NM- 002878), DMC1 (NM-007068), XRCC2 (NM7005431), XRCC3 (NM-005432), RAD52 (NM-002879), RAD54L (NM-003579), RAD54B (NM-012415), BRCA-1 (NM-007295), BRCA-2 (NM-000059), RAD50 (NM-005732), MREI IA (NM-005590), NBS1 (NM-002485), ADPRT (PARP-1), ADPRTL2, (PARP02) CTPS, RPA, RPA1, RPA2, RPA3, XPD,ERCC1, XPF, MMS19, RAD51, RAD51p, RAD51C, RAD5 ID5DMC1, XRCCR, XRCC3, BRCA1, BRCA2, RAD52, RAD54, RAD50,MRE11, NB51, WRN, BLMKU70, RU80, ATM, ATRCHK1, CHK2, FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, RADl and RAD9. Other proteins involved in the HR dependent DNA DSB repair pathway include regulatory factors such as EMSY (Cell (2003) 115:523-535).
In another embodiment, the cancer cells have a BRCA-1 and/or a BRCA-2 deficient phenotype. Cancer cells with this phenotype may be deficient in BRCA-1 and/or BRCA-2, i. e. expression and/or activity of BRCA-1 and/or BRCA-2 may be reduced or abolished in the cancer cells, for example by means of mutation or polymorphism in the encoding nucleic acid, or by means of amplification, mutation or polymorphism in a gene encoding a regulatory factor, for example the EMSY gene which encodes a BRCA-2 regulatory factor (Cell (2003) 115:523-535).
BRCA-1 and BRCA-2 are known tumor suppressors whose wild-type alleles are frequently lost in tumors of heterozygous carriers (Oncogene (2002) 21(58): 8981-93; Trends Mol Med., (2002) 8(12):571-6). The association of BRCA-1 and/or BRCA-2 mutations with breast cancer has been well- characterized (Exp CHn Cancer Res. (2002) 21(3 Suppl):9-\2). Amplification of the EMSY gene, which encodes a BRCA-2 binding factor, is also known to be associated with breast and ovarian cancer. Carriers of mutations in BRCA-1 and/or BRCA-2 are also at elevated risk of cancer of the ovary, prostate and pancreas. The detection of variation in BRCA-1 and BRCA-2 is well- known in the art and is described, for example in EP 699 754; EP 705 903; Genet. Test (1992) 1 :75-83; Cancer Treat Res (2002) 107:29-59; Neoplasm (2003) 50(4):246-50; Ceska Gynekol (2003) 68(1): 11-16). Determination of amplification of the BRCA-2 binding factor EMSY is described in Cell 115:523-535. PARP inhibitors have been demonstrated as being useful for the specific killing of BRCA-1 and BRCA-2 deficient tumors (Nature (2005) 434:913-916 and 917- 920).
The present invention also provides a method for the treatment or prevention of BRCA-1 or BRCA-2 deficient tumors, which method comprises administration to a patient in need thereof of an effective amount of a compound of Formula (I) or a composition comprising a compound of Formula (I).
The compounds of this invention may be useful for the treatment or prevention of neurodegenerative diseases, including, polyglutamine-expansion-related neurodegeneration, Huntington's disease, Kennedy's disease, spinocerebellar ataxia, dentatorubral-pallidoluysian atrophy (DRPLA), protein-aggregation-related neurodegeneration, Machado-Joseph's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spongiform encephalopathy, a prion-related disease and multiple sclerosis (MS).
The compounds of the present invention may also be useful for the treatment or prevention of retroviral infection (US 5652260), retinal damage (Curr. Eye Res. (2004), 29:403), skin senescence and UV-induced skin damage (US 5589483 and Biochem. Pharmacol (2002) 63:921).
The compounds of this invention may be administered to mammals, preferably humans, either alone or in combination with pharmaceutically acceptable carriers, excipients, diluents, adjuvants, fillers, buffers, stabilisers, preservatives and lubricants, in a pharmaceutical composition, according to standard pharmaceutical practice.
The compounds of this invention may be administered to a subject by any convenient route of administration, whether systemically/peripherally or at the site of desired action, including but not limited to, oral (e.g. by ingestion); topical (including e.g. transdermal, intranasal, ocular, buccal, and sublingual); pulmonary (e.g. by inhalation or insufflation therapy using, e.g. an aerosol, e.g. through mouth or nose); rectal; vaginal; parenteral, (e.g. by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intr asternal); and by implant of a depot (e.g. subcutaneously or intramuscularly).
The invention also provides pharmaceutical compositions comprising one or more compounds of this invention and a pharmaceutically acceptable excipient. The term "pharmaceutically acceptable excipient" refers to any of a diluent, adjuvant, excipient or carrier with which at least one compound of the present disclosure is administered.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a water soluble taste masking material such as hydroxypropyl-methylcellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate butyrate may be employed.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxy ethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring agents, preservatives and antioxidants. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant. The pharmaceutical compositions may be in the form of a sterile injectable aqueous solution.
The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase. For example, the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulsion.
The injectable solutions or microemulsions may be introduced into a patient's blood stream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution of 1,3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Compounds of Formula (I) may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula (I) are employed. For purposes of this application, topical application may include mouth washes and gargles.
The compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
When a compound according to this invention is administered into a subject, the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the severity of the individuals symptoms, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
Administration in vivo can be effected in one dose, continuously or intermittently (e.g. in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician. In general, a suitable dose of the active compound is in the range of about 100 μg to about 250 mg per kilogram body weight of the subject per day. Where the active compound is a salt, an ester, prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
The instant compounds are also useful in combination with anti-cancer agents or chemotherapeutic agents. The compounds of this invention may be useful as chemo- and radio- sensitizers for cancer treatment. They are useful for the treatment of mammals who have previously undergone or are presently undergoing treatment for cancer. Such previous treatments include prior chemotherapy, radiation therapy, surgery or immunotherapy, such as cancer vaccines.
Thus, the present invention provides a combination of a compound of Formula (I) and an anticancer agent for simultaneous, separate or sequential administration.
The present invention also provides a compound of Formula (I) for use in the manufacture of a medicament for use as an adjunct in cancer therapy or for potentiating tumor cells for treatment with ionizing radiation or chemotherapeutic agents.
The present invention also provides a method of chemotherapy or radiotherapy, which method comprises administration to a patient in need thereof of an effective amount of a compound of Formula (I) or a composition comprising a compound of Formula (I) in combination with ionizing radiation or chemotherapeutic agents. In combination therapy, the compounds of this invention can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of the other anticancer agent to a subject in need thereof. In various embodiments the instant compounds and another anticancer agent are administered 1 minute apart,
10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to
11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart, or no more than 48 hours apart.
The compounds of this invention and the other anticancer agent can act additively or synergistically. A synergistic combination of the present compounds and another anticancer agent might allow the use of lower dosages of one or both of these agents and/or less frequent dosages of one or both of the instant compounds and other anticancer agents and/or to administer the agents less frequently can reduce any toxicity associated with the administration of the agents to a subject without reducing the efficacy of the agents in the treatment of cancer. In addition, a synergistic effect might result in the improved efficacy of these agents in the treatment of cancer and/or the reduction of any adverse or unwanted side-effects associated with the use of either agent alone. Examples of cancer agents or chemotherapeutic agents for use in combination with the compounds of the present invention can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Such anticancer agents include, but are not limited to, the following: histone deacetylase (HDAC) inhibitors, estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and survival signaling, apoptosis inducing agents and agents that interfere with cell cycle checkpoints. The instant compounds are particularly useful when co-administered with radiation therapy.
Examples of "HDAC inhibitors" include suberoylanilide hydroxamic acid (SAHA), LAQ824, LBH589, PXDIOI, MS275, FK228, valproic acid, butyric acid and CI-994. "Estrogen receptor modulators" refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism. Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY1 17081, toremifene, fulvestrant, 4-[7- (2,2-dimethyl- 1 -oxopropoxy-4-methyl-2-[4-[2-(l -piperidinyl)ethoxy]phenyl]-2H- 1 -benzopyran-3- yl]-phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646. "Androgen receptor modulators" refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of androgen receptor modulators include finasteride and other 5a-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole and abiraterone acetate.
"Retinoid receptor modulators" refers to compounds which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism. Examples of such retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, a-difluoromethylornithine, ILX23-7553, trans-N-(4'-hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide.
"Cytotoxic/cytostatic agents" refer to compounds which cause cell death or inhibit cell proliferation primarily by interfering directly with the cell's functioning or inhibit or interfere with cell mytosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia activatable compounds, microtubule inhibitors/microtubule-stabilizing agents, inhibitors of mitotic kinesins, inhibitors of kinases involved in mitotic progression, antimetabolites, biological response modifiers; hormonal/anti-hormonal therapeutic agents, haematopoietic growth factors, monoclonal antibody targeted therapeutic agents, topoisomerase inhibitors, proteasome inhibitors and ubiquitin ligase inhibitors. Examples of cytotoxic agents include, but are not limited to, cyclophosphamide, chlorambucil carmustine (BCNU), lomustine (CCNU), busulfan, treosulfan, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, aroplatin, oxaliplatin, temozolomide, methyl methanesulfonate, procarbazine, dacarbazine, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminedichloro(2-methyl-pyridine)platinum, benzylguanine, glufosfamide, GPXIOO, (trans, trans, trans)- bis-mu-(hexane-l,6-diamine)-mu-[diamine- platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride, diarizidinylspermine, arsenic trioxide, 1-(1 l-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, pinafide, valrubicin, amrubicin, doxorubicin, epirubicin, pirarubicin, antineoplaston, 3'-deamino-3'-morpholino-13-deoxo-10- hydroxycarminomycin, annamycin, galarubicin, elinafide, MEN1 0755 and 4-demethoxy-3- deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin (WO 00/50032).
In an embodiment the compounds of this invention can be used in combination with alkylating agents.
Examples of alkylating agents include but are not limited to, nitrogen mustards: cyclophosphamide, ifosfamide, trofosfamide and chlorambucil; nitrosoureas: carmustine (BCNU) and lomustine (CCNU); alkylsulphonates: busulfan and treosulfan; triazenes: dacarbazine, procarbazine and temozolomide; platinum containing complexes: cisplatin, carbop latin, arop latin and oxaliplatin.
In an embodiment, the alkylating agent is dacarbazine. Dacarbazine can be administered to a subject at dosages ranging from about 150 mg/m2 (of a subject's body surface area) to about 250 mg/m2. In another embodiment, dacarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 150 mg/m2 to about 250 mg/m2.
In an embodiment, the alkylating agent is procarbazine. Procarbazine can be administered to a subject at dosages ranging from about 50 mg/m2 (of a subject's body surface area) to about 100mg/m2. In another embodiment, procarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50 mg/m2 to about 100 mg/m2. In an embodiment, the alkylating agent is temozoloamide. Temozolomide can be administered to a subject at dosages ranging from about about 150 mg/m2 (of a subject's body surface area) to about 200 mg/m2. In another embodiment, temozolomide is administered orally to an animal once per day for five consecutive days at a dose ranging from about 150 mg/m2 to about 200 mg/m2.
Examples of anti-mitotic agents include allocolchicine, halichondrin B, colchicine, colchicine derivative, dolstatin 10, maytansine, rhizoxin, thiocolchicine and trityl cysteine.
An example of a hypoxia activatable compound is tirapazamine.
Examples of proteasome inhibitors include but are not limited to lactacystin, bortezomib, epoxomicin and peptide aldehydes such as MG 132, MG 115 and PSI.
Examples of microtubule inhibitors/microtubule-stabilising agents include paclitaxel, vindesine sulfate, vincristine, vinblastine, vinorelbine, 3',4'-didehydro-4'-deoxy-8'- norvincaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR1 09881, BMS 184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafiuoro-N-(3-fiuoro-4- methoxyphenyl) benzene sulfonamide, anhydrovinblastine, N,N-dimethyl-L-valyl-L-valyl-N- methyl-L-valyl-L-prolyl-L-proline-t-butylamide, TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and 6,288,237) and BMS 188797. Some examples of topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, exatecan, gimetecan, diflomotecan, silyl- camptothecins, 9-aminocamptothecin, camptothecin, crisnatol, mitomycin C, 6-ethoxypropionyl- 3',4'-0-exo-benzylidene-chartreusin, 9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2- (6H)propanamine, l-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-lH,12H- benzo[de]pyrano[3',4':b,7]-indolizino[l,2b]quinoline-10,13(9H,15H)dione, lurtotecan, 7-[2-(N- isopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1 100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane, 2'-dimethylamino-2'-deoxy-etoposide, GL331, N-[2- (dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-l-carboxamide, asulacrine, (5a,5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4- hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3',4':6,7)naphtho(2,3-d)-l,3-dioxol-6- one, 2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium, 6,9-bis[(2- aminoethyl)amino]benzo[g]isoguinoline-5, 10-dione, 5-(3-aminopropylamino)-7, 10-dihydroxy-2- (2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5, 1 -de]acridin-6-one, N-[ 1 -
[2(diethylamino)ethylamino] -7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl] formamide, N-(2- (dimethylamino)ethyl)acridine-4-carboxamide, 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H- indeno[2,l-c] quinolin-7-one, and dimesna; non-camptothecin topoisomerase-1 inhibitors such as indolocarbazoles; and dual topoisomerase-1 and II inhibitors such as benzophenazines, XR 20 115761MLN 576 and benzopyridoindoles. In an embodiment, the topoisomerase inhibitor is irinotecan. Irinotecan can be administered to a subject at dosages ranging from about about 50 mg/m2 (of a subject's body surface area) to about 150 mg/m2. In another embodiment, irinotecan is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50mg/m2 to about 150mg/m2 on days 1-5, then again intravenously once per day for five consecutive days on days 28-32 at a dose ranging from about 50mg/m2 to about 150mg/m2, then again intravenously once per day for five consecutive days on days 55-59 at a dose ranging from about 50mg/m2 to about 150mg/m2.
Examples of inhibitors of mitotic kinesins, and in particular the human mitotic kinesin KSP, are described in PCT Publications WO 01/30768, WO 01/98278, WO 02/056880, WO 03/050,064, WO 03/050,122, WO 03/049,527, WO 03/049,679, WO 03/049,678, WO 03/039460, WO 03/079973, WO 03/099211, WO 2004/039774, WO 03/105855, WO 03/106417, WO 2004/087050, WO 2004/058700, WO 2004/058148 and WO 2004/037171, and US applications US 2004/132830 and US 2004/132719. In an embodiment inhibitors of mitotic kinesins include, but are not limited to inhibitors of KSP, inhibitors of MKLPl, inhibitors of CENP-E, inhibitors of MCAK, inhibitors of KIFL4, inhibitors of Mphosphl and inhibitors of Rab6-KIFL. "Inhibitors of kinases involved in mitotic progression" include, but are not limited to, inhibitors of aurora kinase, inhibitors of Polo-like kinases (PLK) (in particular inhibitors of PLK-I), inhibitors of bub- 1 and inhibitors of bub-Rl.
"Antiproliferative agents" includes antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenecytidine, 2'- fluoromethylene-2'-deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N-(3,4- dichlorophenyl)urea, N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoylJglycylaminoJ-L-glycero-B- L-manno-heptopyranosylJadenine, aplidine, ecteinascidin, troxacitabine, 4-[2-amino-4-oxo-4,6,7,8- tetrahydro-3H-pyrimidino[5,4-b][l,4]thiazin-6-yl-(5)-ethyl]-2,5-thienoyl-L-glutamic acid, aminopterin, 5-flurouracil, alanosine, 1 l-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14- oxa-1,1 l-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-yl acetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase, 2'-cyano-2'-deoxy-N4-palmitoyl-l-B-D-arabinofuranosyl cytosine and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone.
Examples of monoclonal antibody targeted therapeutic agents include those therapeutic agents which have cytotoxic agents or radioisotopes attached to a cancer cell specific or target cell specific monoclonal antibody. Examples include Bexxar.
"HMG-CoA reductase inhibitors" refers to inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductase inhibitors that may be used include but are not limited to lovastatin (MEVACOR®; see U.S. Pat. Nos. 4,231,938, 4,294,926 and 4,319,039), simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784, 4,820,850 and 4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL®; see U.S. Pat. Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164, 5,118,853, 5,290,946 and 5,356,896) and atorvastatin (LIPITOR®; see U.S. Pat. Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952). The structural formulas of these and additional HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89 (5 February 1996) and US Pat. Nos. 4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefore the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention. "Prenyl-protein transferase inhibitor" refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase).
Examples of prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, US 5,420,245, US 5,523,430, US 5,532,359, US 5,510,510, US 5,589,485, US 5,602,098, European Patent Publ. 0 618 221, European Patent Publ. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ. 0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO 95/12572, WO 95/10514, US 5,661,152, WO 95/10515, WO 95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO 96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO 96/00736, US 5,571,792, WO 96/17861, WO 96/33159, WO 96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO 96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO 97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO 97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO 98/02436, and US 5,532,359. For an example of the role of a prenyl-protein transferase inhibitor on angiogenesis see European J. of Cancer (1999), 35(9): 1394-1401.
"Angiogenesis inhibitors" refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism. Examples of angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors FIT-I (VEGFRl) and FIK-I/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon-a, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal antiinflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib (PNAS (1992) 89:7384; JNCI (1982) 69:475; Arch. Opthalmol. (1990) 108:573; Anat. Rec. (1994) 238:68; FEBS Letters (1995) 372:83; Clin, Orthop. (1995) 313:76; J. Mol. Endocrinol. (1996) 16: 107; Jpn. J. Pharmacol. (1997) 75: 105; Cancer Res. (1997) 57: 1625; Cell (1998) 93:705; Intl. J. Mol. Med. (1998) 2:715; J. Biol. Chem. (1999) 274:9116)), steroidal anti-inflammatories (such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone), carboxyamidotriazole, combretastatin A-4, squalamine, 6-0-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, angiotensin II antagonists (J. Lab. Clin. Med. (1985) 105: 141-145), and antibodies to VEGF (Nature Biotechnology (1999) 17:963-968; Kim et al. Nature (1993) 562:841-844; WO 00/44777; WO 00/61186).
Other therapeutic agents that modulate or inhibit angiogenesis and may also be used in combination with the compounds of the instant invention include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in Clin. Chem. La. Med. (2000) 38:679-692). Examples of such agents that modulate or inhibit the coagulation and fibrinolysis pathways include, but are not limited to, heparin (see Thromb. Haemost. (1998) 80: 10-23), low molecular weight heparins and carboxypeptidase U inhibitors (also known as inhibitors of active thrombin activatable fibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. (2001) 101 :329-354). TAFIa inhibitors have been described in PCT Publication WO 03/013,526 and U.S. Ser. No. 60/349,925 (filed January 18, 2002). "Agents that interfere with cell cycle checkpoints" refer to compounds that inhibit protein kinases that transduce cell cycle checkpoint signals, thereby sensitizing the cancer cell to DNA damaging agents. Such agents include inhibitors of ATR, ATM, the Chkl and Chk2 kinases and cdk and cdc kinase inhibitors and are specifically exemplified by 7-hydroxystaurosporin, staurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032. "Inhibitors of cell proliferation and survival signaling pathway" refer to pharmaceutical agents that inhibit cell surface receptors and signal transduction cascades downstream of those surface receptors. Such agents include inhibitors of inhibitors of EGFR (for example gefitinib and erlotinib), inhibitors of ERB-2 (for example trastuzumab), inhibitors of IGFR (for example those disclosed in WO 03/059951), inhibitors of cytokine receptors, inhibitors of MET, inhibitors of PI3K (for example LY294002), serine/threonine kinases (including but not limited to inhibitors of Akt such as described in (WO 03/086404, WO 03/086403, WO 03/086394, WO 03/086279, WO 02/083675, WO 02/083139, WO 02/083140 and WO 02/083138), inhibitors of Raf kinase (for example BAY-43-9006 ), inhibitors of MEK (for example CI- 1040 and PD-098059) and inhibitors of mTOR (for example Wyeth CCI-779 and Ariad AP23573). Such agents include small molecule inhibitor compounds and antibody antagonists.
"Apoptosis inducing agents" include activators of TNF receptor family members (including the TRAIL receptors). The invention also encompasses combinations with NSAID's which are selective COX-2 inhibitors. For purposes of this specification NS AID's which are selective inhibitors of COX-2 are defined as those which possess a specificity for inhibiting COX-2 over COX-I of at least 100 folds as measured by the ratio of IC50 for COX-2 over IC50 for COX-I evaluated by cell or microsomal assays.
Such compounds include, but are not limited to those disclosed in U.S. Pat. 5,474,995, U.S. Pat. 5,861,419, U.S. Pat. 6,001,843, U.S. Pat. 6,020,343, U.S. Pat. 5,409,944, U.S. Pat. 5,436,265, U.S. Pat. 5,536,752, U.S. Pat. 5,550,142, U.S. Pat. 5,604,260, U.S. 5,698,584, U.S. Pat. 5,710,140, WO 94/15932, U.S. Pat. 5,344,991, U.S. Pat. 5,134,142, U.S. Pat. 5,380,738, U.S. Pat. 5,393,790, U.S. Pat. 5,466,823, U.S. Pat. 5,633,272, and U.S. Pat. 5,932,598, all of which are hereby incorporated by reference.
Inhibitors of COX-2 that are particularly useful in the instant method of treatment are 5- chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine, or a pharmaceutically acceptable salt thereof.
Compounds that have been described as specific inhibitors of COX-2 and are therefore useful in the present invention include, but are not limited to: parecoxib, CELEBREX® and BEXTRA® or a pharmaceutically acceptable salt thereof.
Other examples of angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-l-oxaspiro[2,5]oct-6- yl(chloroacetyl)carbamate, acetyldinanaline, 5-amino-l-[[3,5-dichloro-4-(4- chlorobenzoyl)phenyl]methyl]- 1 H-l,2,3-triazole-4-carboxamide, CM 101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, 7,7-(carbonyl-bis[imino- N-methyl-4,2-pyrrolocarbonylimino|TSi-methyl-4,2-pyrrole]-carbonylimino]-bis-(l,3-naphthalene disulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone (SU5416).
As used above, "integrin blockers" refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the 0CyP3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ανβ5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the 0CyP3 integrin and the 0CyP5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells. The term also refers to antagonists of the OCyP j 0Cvp8, ο βί, 0C2pi, 0C5pi, 0C6pi and 0C6P4 integrins. The term also refers to antagonists of any combination of ανβ3, ανβ5,ανβ6; 0ΰνβ8, ο βί, 0C2pi, fisoq, (^6β1 and (^6β4 integrins.
Some specific examples of tyrosine kinase inhibitors include N-(trifluoromethylphenyl)-5- methylisoxazol-4-carboxamide, 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one, 17- (allylamino)- 17-demethoxygeldanamycin, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4- morpholinyl)propoxyl]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4- quinazolinamine, BIBX1 382, 2,3,9,10,11,12-hexahydro-l 0-(hydroxymethyl)-10-hydroxy-9- methyl-9, 12-epoxy-lH-diindolo[l,2,3-fg:3',2',r-kl]pyrrolo[3,4-i][l,6]benzodiazocin-l-one, SH268, genistein, STI571, CEP2563, 4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3- d]pyrimidinemethane sulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, 4- (4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, STI571A, N-4-chlorophenyl-4-(4- pyridylmethyl)-l-phthalazinamine, and EMD121974.
In an embodiment, the compounds of the present invention are useful for the treatment or prevention of the appearance of necrosis induced by selective N3 -adenine methylating agents such as MeOS02(CH2)-lexitropsin (Me-Lex).
Combinations with compounds other than anti-cancer compounds are also encompassed in the instant methods. For example, combinations of the instantly claimed compounds with PPAR-γ (i.e., PPAR-gamma) agonists and PPAR-δ (i.e., PPAR-delta) agonists are useful in the treatment of certain malingnancies. PPAR-γ and PPAR-δ are the nuclear peroxisome proliferator-activated receptors γ and δ. The expression of PPAR-γ on endothelial cells and its involvement in angiogenesis has been reported in the literature (see J. Cardiovasc. Pharmacol. (1998) 31 :909-913; J. Biol. Chem. (1999) 274:9116-9121; Invest. Ophthalmol Vis. Sci. (2000) 41 :2309-2317). More recently, PPAR-γ agonists have been shown to inhibit the angiogenic response to VEGF in vitro; both troglitazone and rosiglitazone maleate inhibit the development of retinal neovascularization in mice. (Arch. Ophthamol. (2001) 119:709-717). Examples of PPAR-γ agonists and PPAR-γ/α agonists include, but are not limited to, thiazolidinediones (such as DRF2725, CS-OI 1, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR- H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NPOI 10, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-l,2- benzisoxazol-6-yl)oxy]-2-methylpropionic acid (disclosed in USSN 09/782,856), and 2(R)-7-(3-(2- chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchromane-2-carboxylic acid (disclosed in USSN 60/235,708 and 60/244,697). Another embodiment of the instant invention is the use of the presently disclosed compounds in combination with anti- viral agents (such as nucleoside analogs including ganciclovir for the treatment of cancer. See WO 98/04290.
Another embodiment of the instant invention is the use of the presently disclosed compounds in combination with gene therapy for the treatment of cancer. For an overview of genetic strategies to treating cancer see Hall et al (Am J Hum Genet (1997) 61 :785-789) and Kufe et al (Cancer Medicine, 5th Ed, pp. 876-889, BC Decker, Hamilton 2000). Gene therapy can be used to deliver any tumor suppressing gene. Examples of such genes include, but are not limited to, p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134, for example), a uPA/uPAR antagonist ("Adenovirus-Mediated Delivery of a uPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in Mice," Gene Therapy, August (1998) 5(8): 1105-13), and interferon gamma (J Immunol (2000) 164:217-222).
The compounds of the instant invention may also be administered in combination with an inhibitor of inherent multidrug resistance (MDR), in particular MDR associated with high levels of expression of transporter proteins. Such MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853, verapamil and PSC833 (valspodar).
A compound of the present invention may be employed in conjunction with anti-emetic agents to treat nausea or emesis, including acute, delayed, late-phase, and anticipatory emesis, which may result from the use of a compound of the present invention, alone or with radiation therapy. For the prevention or treatment of emesis, a compound of the present invention may be used in conjunction with other antiemetic agents, especially neurokinin- 1 receptor antagonists, 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S. Pat. Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, an antidopaminergic, such as the phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol. In an embodiment, an anti-emesis agent selected from a neurokinin- 1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is administered as an adjuvant for the treatment or prevention of emesis that may result upon administration of the instant compounds.
Neurokinin- 1 receptor antagonists of use in conjunction with the compounds of the present invention are fully described, for example, in U.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147; European Patent Publication Nos. EP 0 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430 771, 0 436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0 512 902, 0 514 273, 0 514 274, 0 514 275, 0 514 276, 0 515 681, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 558 156, 0 577 394, 0 585 913,0 590 152, 0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0 707 006, 0 708 101, 0 709 375, 0 709 376, 0 714 891, 0 723 959, 0 733 632 and 0 776 893; PCT International Patent Publication Nos. WO 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181, 93/23380, 93/24465, 94/00440, 94/01402, 94/02461 , 94/02595, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/1 1368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/1 1880, 95/14017, 95/1531 1 , 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 95/33744, 96/05181 , 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661 , 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671 , 97/17362, 97/18206, 97/19084, 97/19942 and 97/21702; and in British Patent Publication Nos. 2 266 529, 2 268 931 , 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293 169, and 2 302 689. The preparation of such compounds is fully described in the aforementioned patents and publications, which are incorporated herein by reference.
In an embodiment, the neurokinin- 1 receptor antagonist for use in conjunction with the compounds of the present invention is selected from: 2-(R)-(l-(R)-(3,5- bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluorophenyl)-4-(3-(5-oxo-lH,4H-l ,2,4- triazolo)methyl)morpholine, or a pharmaceutically acceptable salt thereof, which is described in U.S. Pat. No. 5,719,147.
A compound of the instant invention may also be administered with an agent useful in the treatment of anemia. Such an anemia treatment agent is, for example, a continuous eythropoiesis receptor activator (such as epoetin alfa).
A compound of the instant invention may also be administered with an agent useful in the treatment of neutropenia. Such a neutropenia treatment agent is, for example, a hematopoietic growth factor which regulates the production and function of neutrophils such as a human granulocyte colony stimulating factor, (G-CSF). Examples of a G-CSF include filgrastim.
A compound of the instant invention may also be administered with an immunologic- enhancing drug, such as levamisole, isoprinosine and Zadaxin. A compound of the instant invention may also be useful for treating or preventing cancer, including bone cancer, in combination with bisphosphonates (understood to include bisphosphonates, diphosphonates, bisphosphonic acids and diphosphonic acids). Examples of bisphosphonates include but are not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate, neridronate, piridronate and tiludronate including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof.
Thus, the scope of the instant invention encompasses the use of the instantly claimed compounds in combination with ionizing radiation and/or in combination with a second compound selected from: HD AC inhibitors, an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an angiogenesis inhibitor, a PPAR-γ agonist, a PPAR-δ agonist, an anti- viral agent, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic-enhancing drug, an inhibitor of cell proliferation and survival signaling, an agent that interfers with a cell cycle checkpoint, an apoptosis inducing agent and a bisphosphonate.
The term "administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.), "administration" and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
The term "treatment" refers to the treatment of a mammal afflicted with a pathological condition and refers to an effect that alleviates the condition by killing the cancerous cells, but also to an effect that results in the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e. prophylaxis) is also included.
The term "pharmaceutically acceptable" as used herein pertains to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.
The term "adjunct" refers to the use of compounds in conjunction with known therapeutic means. Such means include cytotoxic regimes of drugs and/or ionising radiation as used in the treatment of different cancer types. In particular, the active compounds are known to potentiate the actions of a number of cancer chemotherapy treatments, which include the topoisomerase class of poisons (e.g. topotecan, irinotecan, rubitecan), most of the known alkylating agents (e.g. DTIC, temozolamide) and platinum based drugs (e.g. carboplatin, cisplatin) used in treating cancer.
Also included in the scope of the claims is a method of treating cancer that comprises administering a therapeutically effective amount of a compound of Formula (I) in combination with radiation therapy and/or in combination with a compound selected from: HDAC inhibitors, an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an angiogenesis inhibitor, a PPAR-γ agonist, a PPAR-δ agonist, an anti- viral agent, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic- enhancing drug, an inhibitor of cell proliferation and survival signaling, an agent that interfers with a cell cycle checkpoint, an apoptosis inducing agent and a bisphosphonate.
Embodiments of the present invention are illustrated by the following Examples. It is to be understood, however, that the embodiments of the invention are not limited to the specific details of these Examples, as other variations thereof will be known, or apparent in light of the instant disclosure, to one of ordinary skill in the art.
All temperatures are expressed in degrees Centigrade unless otherwise indicated.
Modes for Carrying out the Invention
Synthesis
In general, the compounds of the present invention can be prepared according to Scheme 1 depicts general synthetic routes for compounds of the invention and are not intended to be limiting. More specifically, Scheme 1 depicts synthesis of indazole compounds. Specific examples are described subsequently to these general synthetic descriptions so as to allow one skilled in the art to make and use indazole of the invention. All variables within the formulae are as defined above. When the compounds of the present invention have chiral centres, the enantiomers may be separated from the racemic mixtures by standard separating methods such as using SFC.
Benzaldehyde (1) is commercial available or been prepared by conventional methods known by those skilled in the art. In step 1 of Scheme 1, imine formation can be easily achieved by the reaction of benzaldehyde with the corresponding amine 2 in the presence of a catalyst (e.g., 4- methylbenzene sulfonic acid). The followed step 2 of Scheme 1 is a ring closure that can be accomplished by treating the key intermediate 3 with sodium azide at elevated temperature to introduce the final nitrogen atom and the resultant extrusion of nitrogen to furnish the indazole ring. In the step 3, the introduction of halogen of R3, such as chloride, bromide and iodine, can be accomplished by the reaction of indazole 4 with reagents such as NBS, NCS or iodine. Compounds as 6, R3 are cyano, methyl or phenyl groups, can be prepared by the coupling reaction of corresponding, bromide or iodo compounds using condition such as Suzuki coupling or Hartwig coupling. In the step 5, the conversion of the ester to the primary amide yields the desired amides as the final Compounds 7.
General Scheme 1
Figure imgf000043_0001
step 4 r R3 = Br> CU
R3 = CN, Me, phenyl, 6
Alternatively, Scheme 2 outlines the general procedures one could use to provide the desired amides such as Compounds 9 of the present invention. In the step 6 of Scheme 2, the hydrolysis of the key intermediate 4 yields acids 8 in the presence of an alkali metal hydroxide or alkali alkanoxide (e.g., sodium hydroxide, potassium butoxide).
In the final step 7, the formation of the final amides 9 can be accomplished by the coupling reaction of the acids 8 with proper amines or hydrazines.
General Scheme 2
Figure imgf000044_0001
8
EXAMPLES
Example 1
Synthesis of 3-Methyl-2-piperidin-4-yl-2H-indazole-7-carboxylic acid amide
Figure imgf000044_0002
Step 1 : Synthesis of 4-[(3-Methoxycarbonyl-2-nitro-benzylidene)-amino]-piperidine-l- carboxylic acid tert-butyl ester— Compound 3
A mixture of Methyl 3-formyl-2-nitrobenzoate 1 (l .Oeq.) and 4-Amino-piperidine-l- carboxylic acid tert-butyl ester 2 (1.05eq.) in EtOH (0.2M) was stirred at reflux under N2 atmosphere for 2 hr until TLC revealed completation of the reaction (Hexane/EtOAc=75:25). Evaporation of the solvent gave Compound 3 as a white solid which was used in the next step without further purification. 1H NMR (400MHz, CDC13, 300K): δ 8.51 (IH, d, J=7.3 Hz), 8.41 (IH, s), 8.11 (IH, d, J=7.8 Hz), 7.67 (IH, t, J=7.8 Hz), 7.43 (2H, t, J=7.8 Hz), 7.31 (IH, t, J=7.3 Hz), 7.16 (2H, d, J=7.8 Hz), 3.94 (3H, s).
Step 2: Synthesis of 2-(l-tert-Butoxycarbonyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid methyl ester— Compound 4
A mixture of 4-[(3-Methoxycarbonyl-2-nitro-benzylidene)-amino]-piperidine-l-carboxylic acid tert-butyl ester 3 (l .Oeq.) and NaN3 (1.05eq.) in dry DMF (0.3M) was stirred at 90 °C overnight under N2 atmosphere. The crude was reduced in vacuo and the residue purified by flash column chromatography on silica using a gradient of EtO Ac/Petroleum ether from 10:90 to 40:60 to yield the desired Compound 4 as a brown oil. 1H NMR (400MHz, CDC13, 300K): δ 8.50 (1H, s), 8.12 (1H, d, J=7.0 Hz), 7.96-7.90 (3H, m), 7.49 (2H, t, J=7.6 Hz), 7.38 (1H, t, J=7.4 Hz), 7.15 (1H, t, J=7.4 Hz), 4.03 (3H, s). MS (ES) Ci5Hi2N202 requires: 252, found: 253 (M+H)+.
Step 3: Synthesis of 2-(l-tert-Butoxycarbonyl-piperidin-4-yl)-3-methyl-2H-indazole-7- carboxylic acid methyl ester— Compound 5
To a solution of 2-(l-tert-Butoxycarbonyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid methyl ester 4 (5.49g, 26.0mmol) in lOOmL of THF at -78 °C was added a 2.0M solution of lithium diisopropylamide in tetrahydrofuran/heptanes/ethylbenzene (19.5mL, 39.0mmol). The resulting dark orange solution was stirred at 0-5 °C for 15min, then rechilled at -78 °C for 15min. Iodomethane (2.5mL, 40mmol) was added, and the orange solution allowed to slowly warm to room temperature over 17 hr period with stirring. Water (lOOmL) was added, and the mixture was extracted with lOOmL of ether. The organic layer was washed with 200mL of a saturated aqueous NaCl solution, dried over MgS04, filtered, and concentrated to an orange solid. Column chromatography (0-50% EtOAc/hexanes) afforded 7-bromo-2,3-dimethyl-2H-indazole (8: R=R"=Me; 5.28 g, 90%) of as a yellow-stained white solid that was used without further purification.
Step 4: Synthesis of 4-(7-Carbamoyl-3-methyl-indazol-2-yl)-piperidine-l-carboxylic acid tert- butyl ester
The 2-(l-tert-Butoxycarbonyl-piperidin-4-yl)-3-methyl-2H-indazole-7-carboxylic acid methyl ester 5 was heated in a mixture of THF and 32%aq. NH3 solution at 70 °C overnight in a sealed tube. The solvents were reduced in vacuo and the residue purified by flash column chromatography on silica using a gradient of EtO Ac/Petroleum ether from 30:70 to 50:50 to yield the desired (A6) as white solid. 1H NMR (400MHz, DMSO; 300K): δ 9.33 (1H, s), 8.56 (1H, bs), 8.16 (2H, d, J=7.9 Hz), 8.08-8.00 (2H, m), 7.88 (1H, bs), 7.63 (2H, t, J=7.7 Hz), 7.50 (1H, t, 7.4 Hz), 7.27 (1H, t, J=7.9 Hz). MS (ES) Ci4HiiN30 requires: 237, found: 238 (M+H)+.
Step 5: Synthesis of 3-Methyl-2-piperidin-4-yl-2H-indazole-7-carboxylic acid amide Compound 6
A solution of 4-(7-Carbamoyl-3-methyl-indazol-2-yl)-piperidine-l-carboxylic acid tert- butyl ester (in TFA/DCM 1 : 1 (0.1M) was stirred at room temperature for 20min. After evaporation of solvent under reduced pressure and treatment with Et20, the title compound was isolated as a yellowish solid. 1H NMR (D6 DMSO, 300K, 600 MHz): δ (ppm) 8.85 (1H, s), 8.57 (1H, br. s), 8.45 (2H, br. s), 8.01 (1H, d, J=6 Hz), 7.96 (1H, d, J=8 Hz), 7.85 (1H, br. s), 7.25-7.19 (1H, m), 3.34-3.23 (2H, m), 3.07-2.94 (2H, m), 2.85-2.73 (2H, m), 2.26-2.15 (2H, m), 1.65 (3H, s). MS (ES) Ci4Hi8N40 requires: 258, found: 259 (M+H)+.
Example 2
Synthesis of 3-Methyl-2-piperidin-3-yl-2H-indazole-7-carboxylic acid amide
Figure imgf000046_0001
The desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and 3-Amino-piperidine-l-carboxylic acid tert-butyl ester used instead of 4-Amino-piperidine-l-carboxylic acid tert-butyl ester calcd for C14H18N4O requires: 258, found: 259 (M+H)+.
Example 3
Synthesis of 3-Methyl-2-piperidin-2-yl-2H-indazole-7-carboxylic acid amide
Figure imgf000046_0002
The desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and 2-Amino-piperidine-l-carboxylic acid tert-butyl ester used instead of 4-Amino-piperidine-l-carboxylic acid tert-butyl ester calcd for Ci4Hi8N40 requires: 258, found: 259 (M+H)+.
Example 4
Synthesis of 3-Methyl-2-pyrrolidin-3-yl-2H-indazole-7-carboxylic acid amide
Figure imgf000046_0003
The desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and 3 -Amino-pyrrolidine- 1-carboxylic acid tert-butyl ester used instead of 4-Amino-piperidine-l-carboxylic acid tert-butyl ester calcd for C13H16N4O (M+H)+ 245.2923, found 245.2907 .
Example 5
Synthesis of 3-Methyl-2-pyrrolidin- -yl-2H-indazole-7-carboxylic acid amide
Figure imgf000047_0001
The desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and 2 -Amino-pyrrolidine- 1-carboxylic acid tert-butyl ester used instead of 4-Amino-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci3Hi6N40 (M+H)+245.2923, found
245.2907.
Example 6
Synthesis of 3-Methyl-2-(4-methyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid amide
Figure imgf000047_0002
The desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and 4-Amino-4-methylpiperidine- 1-carboxylic acid tert-butyl ester used instead of 4-Amino-piperidine- 1-carboxylic acid tert-butyl ester calcd for C15H20N4O (M+H)+ 273.3455, found 273.3457.
Example 7
Synthesis of 3-Methyl-2-(4-methyl-piperidin-3-yl)-2H-indazole-7-carboxylic acid amide
Figure imgf000047_0003
The desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and 3 -Amino-3-methylpiperidine- 1-carboxylic acid tert-butyl ester used instead of 4-Amino-piperidine-l-carboxylic acid tert-butyl ester calcd for C15H20N4O (M+H) 273.3455, found 273.3457.
Example 8
Synthesis of 3-Methyl-2-(4-methyl-pyrrolidin-2-yl)-2H-indazole-7-carboxylic acid amide
Figure imgf000048_0001
The desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and 3-Amino-3-methylpyrrolidine-l-carboxylic acid tert-butyl ester used instead of 4-Amino-piperidine-l-carboxylic acid tert-butyl ester calcd for C14H18N4O (M+H)+ 259.3189, found 259.3176.
Example 9
Synthesis of 3-Bromo-2-piperidin-4-yl-2H-indazole-7-carboxylic acid amide
Figure imgf000048_0002
Step 1 : Synthesis of 3-Bromo-2-(l-tert-butoxycarbonyl-piperidin-4-yl)-2H-indazole-7- carboxylic acid methyl ester
To a solution of 2-(l-tert-Butoxycarbonyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid methyl ester 4 (0.659 g, 2.38 mmol) in 2 mL of acetic acid was added bromine (0.122 mL, 2.38 mmol) dropwise. The yellow- orange solution was stirred for 15 min, in which time an orange solid precipitated. The mixture was concentrated to a yellow solid, which was partitioned between 20 mL of a 10% aqueous NaOH solution and 20 mL of diethyl ether. The organic layer was washed with 20 mL of a saturated aqueous NaCl solution, dried over MgS04, filtered, and concentrated to a yellow-stained white solid. Column chromatography (0-10% EtOAc/hexanes) afforded 3-bomo-7- (2,4-dichloro-phenyl)-2-methyl-2H-indazole. 1H NMR (400MHz, CDC13, 300K): δ 8.50 (1H, s), 8.12 (1H, d, J=7.0 Hz), 7.96-7.90 (3H, m), 7.49 (2H, t, J=7.6 Hz), 7.38 (1H, t, J=l 7.4 Hz), 7.15 (1H, t, J=7.4 Hz), 4.03 (3H, s). MS (ES) Ci5Hi2N202 requires: 252, found: 253 (M+H)+.
Step 2: Synthesis of 3-Bromo-2-piperidin-4-yl-2H-indazole-7-carboxylic acid amide Compound 6 A solution of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester (in TFA/DCM 1 : 1 (0.1 M) was stirred at room temperature for 20 min. After evaporation of solvent under reduced pressure and treatment with Et20, the title compound was isolated as a yellowish solid. 1H NMR (D6 DMSO, 300K, 600 MHz): δ (ppm) 8.85 (1H, s), 8.57 (1H, br. s), 8.45 (2H, br. s), 8.01 (1H, d, J=6 Hz), 7.96 (1H, d, J=8 Hz), 7.85 (1H, br. s), 7.25-7.19 (1H, m), 3.34-3.23 (2H, m), 3.07-2.94 (2H, m), 2.85-2.73 (2H, m), 2.26-2.15 (2H, m), 1.65 (3H, s). MS (ES) Ci3Hi5BrN40 requires: 323, found: 324 (M+H)+.
Example 10
Synthesis of 3-Bromo-2-piperidin-3-yl-2H-indazole-7-carboxylic acid amide
Figure imgf000049_0001
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester calcd for Ci3Hi5BrN40 (M+H)+ 324.04, found 323.9007.
Example 11
Synthesis of 3-Bromo-2-piperidin-2-yl-2H-indazole-7-carboxylic acid amide
Figure imgf000049_0002
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 2-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester calcd for Ci3Hi5BrN40 (M+H)+ 324.04, found 323.9007.
Example 12
Synthesis of 3-Bromo-2-pyrrolidin-3-yl-2H-indazole-7-carboxylic acid amide
Figure imgf000050_0001
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester calcd for Ci2Hi3BrN40 (M+H)+ 310.1618, found 310.1624
Example 13
Synthesis of 3-Bromo-2-pyrrolidin-2-yl-2H-indazole-7-carboxylic acid amide
Figure imgf000050_0002
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 2-(7-Carbamoyl-3-bromo-indazol-2-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester calcd for Ci2Hi3BrN40 (M+H)+ 310.1618, found 310.1624.
Example 14
Synthesis of 3-Bromo-2-(4-methy -piperidin-4-yl)-2H-indazole-7-carboxylic acid amide
Figure imgf000050_0003
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-4-methylpiperidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci4Hi7BrN40 (M+H)+ 338.2150, found 338.2147.
Example 15
Synthesis of 3-Bromo-2-(4-methyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid amide
Figure imgf000051_0001
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpiperidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci4Hi7BrN40 (M+H)+ 338.2150, found 338.2147.
Example 16:
Synthesis of 3-Bromo-2-(4-methyl-pyrrolidin-3-yl)-2H-indazole-7-carboxylic acid amide
Figure imgf000051_0002
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci3Hi5BrN40 (M+H)+ 324.1884, found 324.1897.
Example 17
Synthesis of 3-Cyano-2-piperidin-4-yl-2H-indazole-7-carboxylic acid amide
Figure imgf000051_0003
Step 1 : Synthesis of 3-Bromo-2-(l-tert-butoxycarbonyl-piperidin-4-yl)-2H-indazole-7- carboxylic acid methyl ester
To a solution of 2-(l-tert-Butoxycarbonyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid methyl ester 4 (0.659 g, 2.38 mmol) in 2 mL of acetic acid was added bromine (0.122 mL, 2.38 mmol) dropwise. The yellow-orange solution was stirred for 15 min, in which time an orange solid precipitated. The mixture was concentrated to a yellow solid, which was partitioned between 20 mL of a 10% aqueous NaOH solution and 20 mL of diethyl ether. The organic layer was washed with 20 mL of a saturated aqueous NaCl solution, dried over MgS04, filtered, and concentrated to a yellow-stained white solid. Column chromatography (0-10% EtOAc/hexanes) afforded 3-bomo-7- (2,4-dichloro-phenyl)-2-methyl-2H-indazole. 1H NMR (400MHz, CDC13, 300K): δ 8.50 (1H, s), 8.12 (1H, d, J=7.0 Hz), 7.96-7.90 (3H, m), 7.49 (2H, t, J=7.6 Hz), 7.38 (1H, t, J=7.4 Hz), 7.15 (1H, t, J=7.4 Hz), 4.03 (3H, s). MS (ES) Ci5Hi2N202 requires: 252, found: 253 (M+H)+.
Step 2: Synthesis of 3-Bromo-2-piperidin-4-yl-2H-indazole-7-carboxylic acid amide Compound 6
A solution of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine-l -carboxylic acid tert-butyl ester (in TFA/DCM 1 : 1 (0.1 M) was stirred at room temperature for 20 min. After evaporation of solvent under reduced pressure and treatment with Et20, the title compound was isolated as a yellowish solid. 1H NMR (D6 DMSO, 300K, 600 MHz): δ (ppm) 8.85 (1H, s); 8.57 (1H, br. s); 8.45 (2H, br. s); 8.01 (1H, d, J=6 Hz); 7.96 (1H, d, J=8 Hz); 7.85 (1H, br. s); 7.25-7.19 (1H, m); 3.34-3.23 (2H, m); 3.07-2.94 (2H, m); 2.85-2.73 (2H, m); 2.26-2.15 (2H, m); 1.65 (3H, s). MS (ES) Ci4Hi5N50 requires: 269, found: 270 (M+H)+.
Example 18
Synthesis of 3-Cyano-2-piperidin-3-yl-2H-indazole-7-carboxylic acid amide
Figure imgf000052_0001
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci4Hi5N50 (M+H)+ 270.3018, found 270.3027.
Example 19
Synthesis of 3-Cyano-2-piperidin-2-yl-2H-indazole-7-carboxylic acid amide
Figure imgf000052_0002
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci4Hi5N50 (M+H)+ 270.3018, found 270.3027.
Example 20
Synthesis of 3-Cyano-2-pyrrolidin-3-yl-2H-indazole-7-carboxylic acid amide
Figure imgf000053_0001
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for C13H13N5O (M+H)+ 256.2752, found 256.2758.
Example 21
Synthesis of 3-Cyano-2-pyrrolidin-3-yl-2H-indazole-7-carboxylic acid amide
Figure imgf000053_0002
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci3Hi3N50 (M+H)+ 256.2752, found 256.2758.
Example 22
Synthesis of 3-Cyano-2-(4-methy -piperidin-4-yl)-2H-indazole-7-carboxylic acid amide
Figure imgf000053_0003
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci5Hi7N50 (M+H)+ 284.3284, found 284.3297.
Example 23
Synthesis of 3-Cyano-2-(4-methyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid amide
Figure imgf000054_0001
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci5Hi7N50 (M+H)+ 284.3284, found 284.3297.
Example 24
Synthesis of 3-Bromo-2-(4-methyl-pyrrolidin-3-yl)-2H-indazole-7-carboxylic acid amide
Figure imgf000054_0002
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci4Hi5N50 (M+H)+ 270.3018, found 270.3032.
Example 25
Synthesis of 3-Methyl-2-piperidin-4-yl-2H-indazole-7-carboxylic acid Ν',Ν'-dimethyl- hydrazide
Figure imgf000054_0003
Step 1 : Synthesis of 3-Bromo-2-(l-tert-butoxycarbonyl-piperidin-4-yl)-2H-indazole-7- carboxylic acid methyl ester To a solution of 2-(l-tert-Butoxycarbonyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid methyl ester 4 (0.659 g, 2.38 mmol) in 2 mL of acetic acid was added bromine (0.122 mL, 2. 38 mmol) dropwise. The yellow- orange solution was stirred for 15 m, in which time an orange solid precipitated. The mixture was concentrated to a yellow solid, which was partitioned between 20 mL of a 10% aqueous NaOH solution and 20 mL of diethyl ether. The organic layer was washed with 20 mL of a saturated aqueous NaCl solution, dried over MgS04, filtered, and concentrated to a yellow-stained white solid. Column chromatography (0-10% EtOAc/hexanes) afforded 3-bomo-7- (2,4-dichloro-phenyl) -2-methyl-2H-indazole. 1H NMR (400MHz, CDC13, 300K): 8.50 (IH, s), 8.12 (1, d, J=7.0 Hz), 7.96-7.90 (3H, m), 7.49 (2H, t, J=7.6 Hz), 7.38 (1, t, J=7.4 Hz), 7.15 (IH, t, J=7.4 Hz), 4.03 (3H, s). MS (ES) Ci5Hi2N202 requires: 252, found: 253 (M+H)+.
Step 2: Synthesis of 3-Bromo-2-piperidin-4-yl-2H-indazole-7-carboxylic acid amide Compound 6
A solution of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester (in TFA/DCM 1 : 1 (0.1 M) was stirred at room temperature for 20 min. After evaporation of solvent under reduced pressure and treatment with Et20, the title compound was isolated as a yellowish solid. 1H NMR (D6 DMSO, 300K, 600 MHz): δ (ppm) 8.85 (1, s), 8.57 (1, br. s), 8.45 (2H, br. s), 8.01 (1, d, J=6 Hz), 7.96 (1, d, J=8 Hz), 7.85 (1, br. s), 7.25-7.19 (1, m), 3.34-3.23 (2H, m), 3.07-2.94 (2H, m), 2.85-2.73 (2H, m), 2.26-2.15 (2H, m), 1.65 (3H, s). MS (ES) Ci6H23N50 re uires: 301, found: 302 (M+H)+.
Figure imgf000055_0001
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci6H23N50 (M+H)+ 302.3867, found 302.3856.
Example 27 Synthesis of 3-Methyl-2-piperidin-2-yl-2H-indazole-7-carboxylic acid Ν',Ν'-dimethyl- hydrazide
Figure imgf000056_0001
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci6H23N50 (M+H)+ 302.3867, found 302.3872.
Example 28
Synthesis of 3-Methyl-2-pyrrolidin-3-yl-2H-indazole-7-carboxylic acid Ν',Ν'-dimethyl- hydrazide
Figure imgf000056_0002
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci5H2iN50 (M+H)+ 288.3601 , found 288.3624.
Example 29
Synthesis of 3-Methyl-2-pyrrolidin-2-yl-2H-indazole-7-carboxylic acid Ν',Ν'-dimethyl- hydrazide
Figure imgf000056_0003
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci5H2iN50 (M+H)+ 288.3601 , found 288.3624. Example 30
Synthesis of 3-Methyl-2-(4-methyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid Ν',Ν'- dimethyl-hydrazide
Figure imgf000057_0001
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for C17H25N5O (M+H)+ 316.4133, found 316.4139.
Example 31
Synthesis of 3-Methyl-2-(4-methyl-piperidin-3-yl)-2H-indazole-7-carboxylic acid Ν',Ν'- dimethyl-hydrazide
Figure imgf000057_0002
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for C17H25N5O (M+H)+ 316.4133, found 316.4139.
Example 32
Synthesis of 3-Methyl-2-(4-methyl-pyrrolidin-4-yl)-2H-indazole-7-carboxylic acid Ν',Ν'- dimethyl-hydrazide
Figure imgf000057_0003
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci6H23N50 (M+H)+ 302.3867, found 302.3873.
Example 33
Synthesis of 3-Methyl-2-piperidin-4-yl-2H-indazole-7-carboxylic acid (2-dimethylamino- ethyl)-amide
Figure imgf000058_0001
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for C18H27N5O (M+H)+ 330.4399, found 330.4405.
Example 34
Synthesis of 3-Methyl-2-piperidin-3-yl-2H-indazole-7-carboxylic acid (2-dimethylamino- ethyl)-amide
Figure imgf000058_0002
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for C18H27N5O (M+H)+ 330.4399, found 330.4405.
Example 35
Synthesis of 3-Methyl-2-piperidin-2-yl-2H-indazole-7-carboxylic acid (2-dimethylamino- ethyl)-amide
Figure imgf000059_0001
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci8H27N50 (M+H)+ 330.4399, found 330.4405.
Example 36:
Synthesis of 3-Methyl-2-pyrrolidin-3-yl-2H-indazole-7-carboxylic acid (2-dimethylamino- ethyl)-amide
Figure imgf000059_0002
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoy 0 l-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci7H25N50 (M+H)+ 316.4133, found 316.4139.
Example 37
Synthesis of 3-Methyl-2-pyrrolidin-4-yl-2H-indazole-7-carboxylic acid (2-dimethylamino- ethyl)-amide
Figure imgf000059_0003
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for C17H25N5O (M+H)+ 316.4133, found 316.4139.
Example 38
Synthesis of 3-Methyl-2-(4-methyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid (2- dimethylamino-ethyl)-amide
Figure imgf000060_0001
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for C19H29N5O (M+H)+ 344.4665, found 344.4671.
Example 39
Synthesis of 3-Methyl-2-(4-methyl-piperidin-3-yl)-2H-indazole-7-carboxylic acid (2- dimethylamino-ethyl)-amide
Figure imgf000060_0002
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for C19H29N5O (M+H)+ 344.4665, found 344.4671.
Example 40
Synthesis of 3-Methyl-2-(4-methyl-pyrrolidin-3-yl)-2H-indazole-7-carboxylic acid (2- dimethylamino-ethyl)-amide
Figure imgf000061_0001
The desired title compound is synthesized by using the same sequence and conditions as described for Example 9 and 3-(7-Carbamoyl-3-bromo-indazol-2-yl)-3-methylpyrrolidine-l- carboxylic acid tert-butyl ester used instead of 4-(7-Carbamoyl-3-bromo-indazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester calcd for Ci8H27N50 (MH+) 330.4399, found 330.4405.
Figure imgf000061_0002
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
PHARMACOLOGICAL TESTING
Poly(ADP-ribose)polymerase-l [PARP-1] Enzyme Inhibition Assay
The PARP-1 enzyme -inhibitory activities of the compounds of the present invention were assayed using a PARP Assay kit (4671-096-K) purchased from Trevigen, as described by Lee et al. (Methods Find, Exp. Clin. Pharmacol., 27, 617-622, 2005) as follows.
A small volume PS plate (Greiner bio-one, 784101), 384-well plate was coated with histone, and left at 25 °C for 2 hrs. Then the plate is washed with PBS (7.5 mM Na2HP04, 2.5 mM NaH2P04, 145 mM NaCl, pH 7.4) four times. To block the nonspecific signal, a Strep-diluent (providedin the kit of Trevigen) was added thereto, and left at 25 °C for 1 hr. Then, the plate was washed with PBS four times, and various concentrations of the compounds of the Examples were added to a reaction liquid containing PARP-1 enzyme (0.12 unit/well) and PARP cocktail (NAD+, biotinylated NAD+, and activated DNA), and incubated at 25 °C for 30min. Then, each well was washed with PBS four times. To measure the ribosylation activity of PARP enzyme, strepavidin- linkedperoxidase (Strep-HRP, 1 : 1000 dilution) was added, and incubated at 37 °C for 30 min. The plate was washed with PBS four times, and then TACS-Sapphire substrate was added thereto, followed by incubation at 25 °C for 10 min for the colorimetric reaction. Finally, 0.2 N HC1 was added to terminate the reaction. Histone ribosylation by PARP-1 enzyme was quantified using a Wallac Envision™ (PerkinElmer Oy, Turku, Finland) at 450 nm. The results obtained according to various concentrations of the compounds of the present invention are average values obtained from three wells, and the result analysis was performed using SigmaPlot 10 (Systat Software Inc., USA) to calculate the IC50 values of the compounds. In addition, commercially available DPQ (Sigma) was used as a control to perform the comparative studies. The results are shown in Table 1.
Table 1
Figure imgf000065_0001
PARP Enzyme Inhibition Assay using cells
To confirm the PARP-1 enzyme-inhibitory activities of the compounds of the present invention, the amount of NAD(P)H accumulated in the cell culture media was measured.
Chinese hamster ovary cells (Chinese hamster ovary; CHO-K1) were cultured in RPMI media supplemented with 10% fetal bovine serum (FBS). The cultured CHO-K1 cells were seeded at a density of 2.9>< 103 cells/well in 96-well plate, and cultured at 37 °C and 5% C02 for 16 hrs. Then, the cells were treated with various concentrations of the compounds of Examples, and incubated at 37 °C for 2 hrs. DNA damage was induced using 1.5 itiM MMS (Methyl methanesulfonate), and the cells were simultaneously treated with a CCK-8 (Cell count kit-8) solution (DOJINDO, (CKOl- 13)) for colorimetric assay. At 3, 4, and 5 hrs after the treatment with MMS, the amount of NAD(P)H secreted into the culture media was quantified using a Wallac Envision™ (PerkinElmer Oy, Turku, Finland) at 450 nm. The results obtained according to various concentrations of the compounds of the present invention are the average values obtained from four wells, and the results were calculated by regression analysis. In addition, commercially available DPQ (Sigma) was used as a control to perform the comparative studies.
Table 2 represents the result of quantifying the amount of NAD(P)H secreted into culture medium after treating the Chinese hamster ovary cells (CHO-K1) with various concentrations of the compounds of the present invention and then with MMS for 4 hrs.
Table 2
Figure imgf000066_0001

Claims

THE CLAIMS claimed is
At least one compound of formula I,
Figure imgf000067_0001
Formula I
pharmaceutically acceptable salts thereof, N-oxides thereof, produgs thereof, solvates thereof, isomers thereof, polymorphic forms thereof, and mixtures of any of the foregoing, wherein:
Ri is selected from hydrogen, Ci_6alkyl, cycloalkyl, alkoxyCi_6alkyl, halosubstitutedCi_6alkyl, hydroxyCi_6alkyl, NR4R5, (NR4R5)alkyl, -(CH2)i~6(NR4R5), (NR4R5)carbonyl,
(NR4R5)carbonylalkyl, alkoxyCi_6 alkyl(NR4R5) or (NR4R5)sulfonyl;
R2 is selected from hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, halosubstituted-alkoxy, halosubstituted-alkyl, hydroxyl, hydroxyalkyl, nitro, NR4R5, or (NR4R5)carbonyl;
R3 is selected from hydrogen, Ci_6alkyl, C6_ioaryl, halogen, cyano, halosubstitutedCi_6alkyl, or halosubstitutedCi_6alkoxy;
X is selected from:
a) an aryl group optionally or an aryl group substituted with 1R4, 2R4, or 3R4; or
b) a heteroaryl group optionally substituted with 1R4, 2R4, or 3R4; or
c) a L-T group, wherein L is selected from alkenylene, alkylene, alkynylene, cycloalkylene or spiroheterocycle, and T is selected from the group consisting of heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy,
heterocycloalkylthio, heterocyclooxy, heterocyclothio, or NR5R6; or
d) a non-aromatic 4-13 membered heterocycle ring having 1 to 3 heteroatoms selected from nitrogen, sulfur or oxygen atom, wherein the heterocycle is optionally substituted with IR5, 2R6, or wherein
Each R4 is selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, halosubstituted alkoxy, halosubstituted alkyl, halogen, hydroxyl, hydroxyalkyl, nitro, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR5R6, (NR5R6)alkyl, (NR5R6)carbonyl, (NR5R6)carbonylalkyl, or (NR5R6)sulfonyl;
Each R5 is independently selected from hydrogen, Ci_6alkyl, C2_ioalkenyl, halosubstitutedCi_6 alkyl, hydroxyCi_6alkyl, Ci_6alkylcarbonyl, Ci_6alkoxy, halosubstitutedCi_6alkoxy, Ci_6alkoxy- carbonyl, or a ring selected from C6-ioaryl; C6-ioaryloxy; C6-ioarylcarbonyl; C3-iocyclo-alkyl; a 4- membered saturated heterocyclic ring containing one nitrogen atom; a 5 or 6-membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from N, O or S; a 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, not more than one heteroatom of which is O or S; a 6- membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; or a from 7- to 15-membered unsaturated, partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O or S; any of which rings being optionally substituted by one or more groups independently selected from (CH2)mR9, and wherein m is any integer selected from 0- 6; R9 is selected from hydrogen, Ci_6alkyl, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, halosubstituted-alkoxy, halosubstituted-alkyl, hydroxyl, hydroxyalkyl, or nitro, NR4R5, or (NR4R5)carbonyl;
Each R6 is selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carbonylalkyl alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, halosubstituted-alkoxy, aryl, arylalkyl, alkylaryl, cyano, halogen, nitro, oxo, halosubstituted alkyl, heteroarylalkoxy, hydroxyalkyl, heteroaryl, hydrogen, hydroxyl, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, carbonylheterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR4R5, (NR4R5)alkyl, (NR4R5)carbonyl, (NR4R5)carbonylalkyl or (NR4R5)sulfonyl, and wherein when the heterocycle is bicyclic, the optional substituent(s) are attached to either one or both of the cyclic rings.
2. The at least one compound according to claim 1, wherein Ri is selected from C3_ locycloalkyl, Ci_4 alkyl, alkoxyCi_4alkyl, halosubstitutedCi_4alkyl, hydroxyCi_4 alkyl, (NR4R5)Ci_ ealkyl, (NR4R5)Ci_6 carbonylalkyl, -(CH2)i~4(NR4R5), or alkoxyC2_4alkyl(NR4R5).
3. The at least one compound according to claim 1, wherein Ri is selected from hydrogen,
Figure imgf000068_0001
4. The at least one compound according to claim 1, wherein Ri is selected from -
Figure imgf000068_0002
or NR4R5, and the said R4 and R5 are methyl.
5. The at least one compound according to claim 1, wherein Ri is hydrogen.
6. The at least one compound according to claim 1, wherein R2 is selected from C2-4alkenyl, Ci_4alkoxy, Ci_4alkyl, Ci_4Cycloalkyl, C2-4alkynyl, halosubstituted-alkoxy, halosubstituted Ci_4alkyl, or hydroxy Ci_4alkyl.
7. The at least one compound according to claim 1, wherein R2 is selected from hydrogen, halogen, cyano, hydroxyl, or nitro.
8. The at least one compound according to claim 1, wherein R2 is selected from hydrogen, NR4R5, or (NR4R5)carbonyl.
9. The at least one compound according to claim 1, wherein R2 is H.
10. The at least one compound according to claim 1, wherein R3 is selected from Ci_4alkyl, C6-8 aryl, hydrogen, cyano, halogen, halosubstitutedCi_4alkyl, or halosubstitutedCi_4alkoxy.
11. The at least one compound according to claim 1 , wherein R3 is selected from hydrogen, cyano, or halogen.
12. The at least one compound according to claim 1, wherein R3 is selected from Ci_4alkyl, or Ce-saryl.
13. The at least one compound according to claim 1, wherein R3 is methyl, phenyl, hydrogen, bromo, chlorine, or cyano.
14. The at least one compound according to claim 13, wherein Ri is hydrogen.
15. The at least one compound according to any one of claims 1—13, wherein X is a C6-i2aryl or a C6_i2aryl substituted with 1R4, 2R4, or 3R4.
16. The at least one compound according to any one of claims 1—13, wherein X is a phenyl or a phenyl substituted with IR4, 2R4, or 3R4.
17. The at least one compound according to claim 15 or 16, wherein R4 is selected from Ci_6 alkoxy, alkoxy Ci_6 alkyl, Ci_6alkoxycarbonyl, alkoxycarbonyl Ci_6alkyl, Ci_6alkyl, C2_6alkynyl, C6- i0aryl, C3_i0 cycloalkyl, halosubstitutedCi_6alkoxy, halosubstitutedCi_6alkyl, hydroxyCi_6alkyl, C5_ i2heteroaryl, (NRs Ci-ealkyl, or (NRsR carbonylCi-ealkyl.
18. The at least one compound according to claim 17, wherein the R4 is selected from alkoxyCi_6alkyl, C4_i2heteroaryl, C4-i2heterocycle, or (NRs Ci-ealkyl.
19. The at least one compound according to any one of claims 1—13, wherein X is a phenyl substituted with halo or heteroaryl containing at least one N or O atom.
20. The at least one compound according to any one of claims 1— 13, wherein X is a phenyl substituted with bromo or heteroaryl containing at least one N atom.
21. The at least one compound according to any one of claims 1— 13, wherein X is a phenyl substituted with bromo or heteroaryl containing at least one N atom.
22. The at least one compound according to any one of claims 1— 13, wherein X is a 5-12 membered heteroaryl or a 5-12 membered heteroaryl substituted with IR4, 2R4, or 3R4.
23. The at least one compound according to any one of claims 1— 13, wherein X is a 5-7 membered heteroaryl or a 5-7 membered heteroaryl substituted with IR4, 2R4, or 3R4
24. The at least one compound according to claim 22 or 23, wherein R4 is selected from Ci_6 alkoxy, alkoxyCi_6 alkyl, Ci_6alkoxycarbonyl, alkoxycarbonylCi_6alkyl, Ci_6alkyl, C2_6alkynyl, C6-1o aryl, C3-10 cycloalkyl, halosubstitutedCi_6alkoxy, halosubstitutedCi_6alkyl, hydroxyCi_6alkyl, C6-12 heteroaryl, (NR5R6)Ci_6alkyl, or (NRsR carbonylCi-ealkyl.
25. The at least one compound according to claim 22 or 23, wherein R4 is selected from cyano, hydroxyl, nitro, or halogen.
26. The at least one compound according to any one of claims 1— 13, wherein X is a L-T group, the L is selected from C2_6alkenylene, Ci_6alkylene, C2_6alkynylene, C4-i2cycloalkylene or C5-12 spiroheterocycle.
27. The at least one compound according to any one of claims 1— 13, wherein X is a L-T group, the T is selected from heteroC6-i2aryl, hetero C6-i2arylalkoxy, hetero C6-i2aryloxy, hetero C6- 12 arylthio, hetero C3_i2cycle, hetero C3_i2cycloalkoxy, hetero C3_i2cycloalkylthio, hetero C3-12 cyclooxy, or hetero C3_i2cyclothio.
28. The at least one compound according to claim 22, wherein T is selected from heteroC6_i2 aryl, hetero C6-i2arylalkoxy, heteroC6_i2aryloxy, or heteroC6_i2arylthio.
29. The at least one compound according to claim 22, wherein T is selected from heteroC3_i2 cycle, heteroC3_i2cycloalkoxy, heteroC3_i2cycloalkylthio, heteroC3_i2cyclooxy, or heteroC3_i2 cyclothio.
30. The at least one compound according to any one of claims 1— 13, wherein X is a L-T group, the L is selected from C2_6alkenylene, Ci_6alkylene, C2_6alkynylene, C4-i2cycloalkylene or C5-12 spiroheterocycle.
31. The at least one compound according to any one of claims 1— 13, wherein X is a non- aromatic 5-10 membered heterocycle ring or a non-aromatic 5-10 membered heterocycle ring substituted with 1R6, 2R6, or 3R6, and the heterocycle has 1 to 3 heteroatoms selected from nitrogen, sulfur or oxygen atom.
32. The at least one compound according to claim 31 , wherein X is a non-aromatic 5~6 membered unsaturated heterocycle containing 1 , or 2 nitrogen atoms optionally substituted with 1R6, or 2R6; a 5-6 membered saturated, partially saturated or unsaturated hydrocarbon ring optionally substituted with 1R6, or IR^; or a 5-6 membered unsaturated or partially saturated heterocyclic ring containing 1, or 2 heteroatoms selected from N optionally substituted with 1R6, or 2Rs.
33. The at least one compound according to claim 32, wherein X is a non-aromatic 5~6 membered unsaturated heterocycle containing 1 , or 2 nitrogen atoms optionally substituted with 1R6; a 5-6 membered saturated, partially saturated or unsaturated hydrocarbon ring optionally substituted with lR^; or a 5-6 membered unsaturated or partially saturated heterocyclic ring containing 1, or 2 heteroatoms selected from N optionally substituted with 1R6.
34. The at least one compound according to any one of claims 1— 13, wherein X is a halo substituted aryl or pyridinyl substituted aryl.
35. The at least one compound according to any one of claims 1— 13, wherein X is a halo substituted phenyl or pyridinyl substituted phenyl.
36. The at least one compound according to any one of claims 1— 13, wherein X is selected from group consisting of
Figure imgf000071_0001
Figure imgf000072_0001
and wherein
n is selected from 0, 1, 2 or 3;
m is selected from 0, 1, 2 or 3;
p is selected from 0, 1, 2 or 3;
R7 is selected from hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, substituted or unsubstituted carbonylalkyl, alkyl, alkynyl, substituted or unsubstituted aryl, arylalkyl, alkylaryl, cycloalkyl, cycloalkylalkyl, halosubstituted-alkyl, hydroxyalkyl, oxo, heteroaryl, heterocycle, heterocycloalkyl, substituted or unsubstituted carbonylaryl, substituted or unsubstituted carbonylheteroaryl, substituted or unsubstituted carbonylheterocyclo, (NR4R5)alkyl, (NR4R5)carbonyl, (NR4R5)sulfonyl, or (NR4R5)carbonylalkyl;
R8 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, halosubstituted-alkyl, hydroxyalkyl, oxo, heteroaryl, heterocycle, heterocycloalkyl, (NR4R5)alkyl, (NR4R5)carbonyl, (NR4R5)carbonylalkyl, or (NR4R5)sulfonyl.
37. The at least one compound according to claim 36, wherein, the ¾ is selected from Ci_ 6alkenyl, Ci_6alkyl, C2_6alkynyl, C6_i3aryl.
38. The at least one compound according to claim 36, wherein, the ¾ is hydrogen.
39. The at least one compound according to claim 36, wherein, the ¾ is Ci_6alkyl.
40. The at least one compound according to claim 36, wherein, the R6 is methyl.
41. The at least one compound according to claim 36, wherein R7 is selected from hydrogen, C2_6alkenyl, Ci_6 alkoxy, Ci_6alkoxyCi_6alkyl, Ci_6alkoxycarbonyl, substituted or unsubstituted carbonylCi_6alkyl, substituted or unsubstituted carbonylC6_ioaryl,Ci_6alkyl, C2_6alkynyl, substituted or unsubstitutedC6_ioaryl, substituted or unsubstituted carbonylheterocyclo, Ci_6alkylC6_ioaryl, substituted or unsubstitutedC5_i2heteroaryl, or (NR4R5)Ci_6alkyl.
42. The at least one compound according to claim 36, wherein R7 is selected from hydrogen, alkylphenyl, Ci_4alkoxycarbonyl, carbonylCi_4alkyl, substituted carbonylheterocyclo.
43. The at least one compound according to claim 36, wherein R7 is selected from methylene phenyl, t-BOC, or carbonylmethyl.
44. The at least one compound according to claim 36, wherein R7 is substituted carbonylpiperidinyl.
45. The at least one compound according to claim 36, wherein R7 is carbonylpiperidinyl and whose H of N was substituted with t-BOC.
46. The at least one compound according to claim 36, wherein Rg is selected from C2_6alkenyl, Ci_6 alkoxy, alkoxyCi_6carbonyl, Ci_6alkyl, C2_6alkynyl, C6-ioaryl, C3_iocycloalkyl, halosubstitutedCi_6 alkyl, hydroxyCi_6alkyl, heteroC4_i2aryl, C4-i3heterocycle, or (NR4R5)Ci_6alkyl.
47. The at least one compound according to claim 36, wherein R8 is selected from hydrogen, Ci_6 alkoxycarbonylCi_6alkyl, arylCi_6alkyl, oxo, heteroC3_6cycloalkyl, (NR4Rs)carbonylCi_6alkyl, or (NR4R5)sulfonyl.
48. The at least one compound of any one claims of 1-13, wherein X is selected from piperidinyl, pyrrolidinyl, or pyridinyl.
49. The at least one compound according to claim 1, wherein the compound is selected from
• 3-Methyl-2-piperidin-4-yl-2H-indazole-7-carboxylic acid amide;
• 3-Methyl-2-piperidin-3-yl-2H-indazole-7-carboxylic acid amide;
• 3-Methyl-2-piperidin-2-yl-2H-indazole-7-carboxylic acid amide;
• 3-Methyl-2-pyrrolidin-3-yl-2H-indazole-7-carboxylic acid amide;
• 3-Methyl-2-pyrrolidin-2-yl-2H-indazole-7-carboxylic acid amide;
• 3-Methyl-2-(4-methyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid amide;
• 3-Methyl-2-(4-methyl-piperidin-3-yl)-2H-indazole-7-carboxylic acid amide;
• 3-Methyl-2-(3-methyl-pyrrolidin-3-yl)-2H-indazole-7-carboxylic acid amide;
• 3-Bromo-2-piperidin-4-yl-2H-indazole-7-carboxylic acid amide;
• 3-Bromo-2-piperidin-3-yl-2H-indazole-7-carboxylic acid amide;
• 3-Bromo-2-piperidin-2-yl-2H-indazole-7-carboxylic acid amide;
• 3-Bromo-2-pyrrolidin-3-yl-2H-indazole-7-carboxylic acid amide;
• 3-Bromo-2-pyrrolidin-2-yl-2H-indazole-7-carboxylic acid amide;
• 3-Bromo-2-(4-methyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid amide;
• 3-Bromo-2-(4-methyl-piperidin-3-yl)-2H-indazole-7-carboxylic acid amide;
• 3-Bromo-2-(3-methyl-pyrrolidin-3-yl)-2H-indazole-7-carboxylic acid amide;
• 3-Cyano-2-piperidin-4-yl-2H-indazole-7-carboxylic acid amide;
• 3-Cyano-2-piperidin-3-yl-2H-indazole-7-carboxylic acid amide;
• 3-Cyano-2-piperidin-2-yl-2H-indazole-7-carboxylic acid amide;
• 3-Cyano-2-pyrrolidin-3-yl-2H-indazole-7-carboxylic acid amide;
• 3-Cyano-2-pyrrolidin-2-yl-2H-indazole-7-carboxylic acid amide;
• 3-Cyano-2-(4-methyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid amide;
• 3-Cyano-2-(4-methyl-piperidin-3-yl)-2H-indazole-7-carboxylic acid amide;
• 3-Cyano-2-(3-methyl-pyrrolidin-3-yl)-2H-indazole-7-carboxylic acid amide;
• 3-Methyl-2-piperidin-4-yl-2H-indazole-7-carboxylic acid Ν',Ν'-dimethyl-hydrazide;
• 3-Methyl-2-piperidin-3-yl-2H-indazole-7-carboxylic acid Ν',Ν'-dimethyl-hydrazide;
• 3-Methyl-2-piperidin-2-yl-2H-indazole-7-carboxylic acid Ν',Ν'-dimethyl-hydrazide; • 3-Methyl-2-pyrrolidin-3-yl-2H-indazole-7-carboxylic acid Ν',Ν'-dimethyl-hydrazide;
• 3-Methyl-2-pyrrolidin-2-yl-2H-indazole-7-carboxylic acid Ν',Ν'-dimethyl-hydrazide;
• 3-Methyl-2-(4-methyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid Ν',Ν'-dimethyl- hydrazide;
• 3-Methyl-2-(4-methyl-piperidin-3-yl)-2H-indazole-7-carboxylic acid Ν',Ν'-dimethyl- hydrazide;
• 3-Methyl-2-(3-methyl-pyrrolidin-3-yl)-2H-indazole-7-carboxylic acid Ν',Ν'-dimethyl- hydrazide;
• 3-Methyl-2-piperidin-4-yl-2H-indazole-7-carboxylic acid (2-dimethylamino-ethyl)-amide;
• 3-Methyl-2-piperidin-3-yl-2H-indazole-7-carboxylic acid (2-dimethylamino-ethyl)-amide;
• 3-Methyl-2-piperidin-2-yl-2H-indazole-7-carboxylic acid (2-dimethylamino-ethyl)-amide;
• 3-Methyl-2-pyrrolidin-3-yl-2H-indazole-7-carboxylic acid (2-dimethylamino-ethyl)-amide;
• 3-Methyl-2-pyrrolidin-2-yl-2H-indazole-7-carboxylic acid (2-dimethylamino-ethyl)-amide;
• 3-Methyl-2-(4-methyl-piperidin-4-yl)-2H-indazole-7-carboxylic acid (2-dimethylamino- ethyl)-amide;
• 3-Methyl-2-(4-methyl-piperidin-3-yl)-2H-indazole-7-carboxylic acid (2-dimethylamino- ethyl)-amide;
• 3-Methyl-2-(4-methyl-piperidin-2-yl)-2H-indazole-7-carboxylic acid (2-dimethylamino- ethyl)-amide;
• 3-Methyl-2-(3-methyl-pyrrolidin-3-yl)-2H-indazole-7-carboxylic acid (2-dimethylamino- ethyl)-amide.
• 3-Phenyl-2-piperidin-4-yl-2H-indazole-7-carboxylic acid amide hydrochloride salt
• 4-(7-Carbamoyl-3-phenyl-indazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester
• 2-(l-Acetyl-piperidin-4-yl)-3-phenyl-2H-indazole-7-carboxylic acid amide
• 4-(7-Carbamoyl-3-methyl-indazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester2-(l- Acetyl-piperidin-4-yl)-3-methyl-2H-indazole-7-carboxylic acid amide
• 4-[4-(7-Carbamoyl-3-methyl-indazol-2-yl)-piperidine-l-carbonyl]-piperidine-l-carboxylic acid tert-butyl ester
• 3-[4-(7-Carbamoyl-3-methyl-indazol-2-yl)-piperidine-l-carbonyl]-piperidine-l-carboxylic acid tert-butyl ester
• 2-(l-Methyl-piperidin-4-yl)-3-phenyl-2H-indazole-7-carboxylic acid amide • 4-[4-(7-Carbamoyl-3-phenyl-indazol-2-yl)-piperidine- 1 -carbonylj-piperidine- 1 -carboxylic acid tert-butyl ester
• 3-[4-(7-Carbamoyl-3-phenyl-indazol-2-yl)-piperidine- 1 -carbonylj-piperidine- 1 -carboxylic acid tert-butyl ester
• 3-[4-(7-Carbamoyl-3-methyl-indazol-2-yl)-piperidine-l-carbonyl]-pyrrolidine-l -carboxylic acid tert-butyl ester
• 3-Bromo-2-(4-bromo-phenyl)-2H-indazole-7-carboxylic acid amide
• 3-Chloro-2-(4-pyridin-3-yl-phenyl)-2H-indazole-7-carboxylic acid amide
• 3-Chloro-2-pyrrolidin-3-yl-2H-indazole-7-carboxylic acid amide
50. The at least one compound according to any one of claims 1-49, wherein said isomers are racemates, racemic mixtures, tautomers, optical isomers, stereoisomers, or an individual diastereomer, and mixtures thereof.
51. The at least one compound according to claim 1-49, wherein said salts are acid salts, base salts, polymeric salts, internals salt or zwitterions.
52. A pharmaceutical composition comprising the at least one compound according to any one of claims 1-51, or a pharmactically acceptable salt; stereoisomer or tautomer thereof, and at least one pharmaceutically acceptable excipient.
53. A use of the at least one compound according to any one of claims 1-51 or the at least one pharmaceutical composition according to claim 52, is for the manufacture of a medicament for the treatment or prevention of conditions which can be ameliorated by the inhibition of poly(ADP- ribose) polymerase (PARP).
54. The use according to claim 53, the compound or the pharmaceutical composition is for the manufacture of a medicament for the treatment or prevention of cancer, inflammatory diseases, reperfusion injuries, ischemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes, neurodegenerative diseases, retroviral infection, retinal damage or skin senescence and UV-induced skin damage.
55. The use according to claim 54, is as a chemo- or radiosensitizer for cancer treatment.
56. A method of treating or preventing cancer, inflammatory diseases, reperfusion injuries, ischemic conditions, stroke, chronic or acute renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes, neurodegenerative diseases, retroviral infection, retinal damage or skin senescence and UV-induced skin damage, comprises a step of administering to a subject in need thereof an effective amount of a at least one compound according to any one of claims 1-51, or the pharmaceutical composition according to claim 52, for simultaneous, separate or sequential administration.
57. The method according to claim 56, for the treatment and/or prevention inflammatory diseases, wherein the said inflammatory diseases are selected from conditions resulted from organ transplant rejection, inflammatory bowel diseases, inflammatory lung diseases, inflammatory diseases of the eye, chronic inflammatory diseases of the gum, inflammatory diseases of the kidney, inflammatory diseases of the skin, inflammatory diseases of the central nervous system, diabetic complications, inflammatory diseases of the heart, various other diseases that can have significant inflammatory components or systemic inflammation of the body.
58. The method according to claim 56, for the treatment and/or prevention of ischemic conditions, wherein said ischemic conditions are those resulted from organ transplantation.
59. The method according to claim 56, for the treatment and/or prevention diabetes mellitus, wherein said diabetes mellitus are selected from Type I diabetes (Insulin Dependent Diabetes Mellitus), Type II diabetes (Non-Insulin Dependent Diabetes Mellitus), gestational diabetes, autoimmune diabetes, insulinopathies, diabetes due to pancreatic disease, diabetes associated with other endocrine diseases, Type A insulin resistance syndrome, Type B insulin resistance syndrome, lipatrophic diabetes, or diabetes induced by 3-cell toxins.
60. The method according to claim 56, for the treatment and/or prevention neurodegenerative diseases, wherein said neurodegenerative diseases are selected from polyglutamine-expansion- related neurodegeneration, Huntington's disease, Kennedy's disease, spinocerebellar ataxia, dentatorubral-pallidoluysian atrophy (DRPLA), protein-aggregation-related neurodegeneration, Machado-Joseph's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spongiform encephalopathy, a prion-related disease and multiple sclerosis (MS).
61. The method according to claim 56, for the treatment and/or prevention, wherein said cancer are selected from solid tumors, blood-borne cancers, acute and chronic leukemias,
Lymphomas, central nervous system (CNS) and brain cancers, cancer being deficient in
Homologous Recombination (HR) dependent DNA double strand break (DSB) repair activity, BRCA-1 or BRCA-2 deficient tumors.
62. The method according to claim 61, of treating or preventing cancer, comprising a step of administering to a subject in need thereof an effective amount of a at least one compound according to any one of claims 1-56, or the at least one pharmaceutical composition according to claim 52, for simultaneous, separate or sequential administration.
63. A method according to claim 61, of treating and/or preventing of treating and/or preventing a cancer deficient in HR dependent DNA DSB repair pathway, comprising
administering to a subject in need of treatment a therapeutically-effective amount of a at least one compound according to any one of claims 1-56, or the at least one pharmaceutical composition according to claim 52.
64. The method according to claim 61, of treating and/or preventing a cancer deficient in Homologous HR dependent DNA DSB repair pathway, wherein the cancer comprises one or more cancer cells having a reduced or abrogated ability to repair DNA DSB by HR relative to normal cells
65. The method according to claim 61, of treating and/or preventing a cancer comprising one or more cancer cells having a reduced or abrogated ability to repair DNA DSB by HR relative to normal cells, wherein said cancer cells have a BRCA-1 or BRCA-2 deficient phenotype.
66. The method according to claim 65, of treating and/or preventing a cancer comprising one or more cancer cells having a reduced or abrogated ability to repair DNA DSB by HR relative to normal cells, wherein said cancer cells are deficient in BRCA-1 or BRCA-2.
67. The method according to claim 61, of treating and/or preventing a cancer deficient in Homologous HR dependent DNA DSB repair pathway, wherein said subject is heterozygous for a mutation in a gene encoding a component of the HR dependent DNA DSB repair pathway.
68. The method according to claim 61, of treating and/or preventing a cancer deficient in HR dependent DNA DSB repair pathway, wherein said subject is heterozygous for a mutation in BRCA-1 and/or BRCA-2.
69. The method according to claim 61, of treating and/or preventing a cancer deficient in HR dependent DNA DSB repair pathway, wherein said cancer is selecterd from breast cancer, ovary cancer, pancreatic cancer or prostate cancer.
70. The method according to claim 62, of treating and/or preventing cancer, further comprising administering to a subject at least one anti-cancer agent or chemotherapeutic agents, for simultaneous, separate or sequential administration.
71. The method according to claim 62, of cancer therapy or for potentiating tumor cells for treatment, further comprises administration of at least one ionizing radiation or chemotherapeutic agent.
72. The method of chemotherapy or radiotherapy, comprising administering to a subject in need of treatment a therapeutically-effective amount of at least one compound according toany one of claims 1-56, or the pharmaceutical composition according to claim 52.
73. The method according to any one of claims 56-72, for the treatment and/or prevention inflammatory diseases, reperfusion injuries, ischemic conditions, stroke, chronic or acute renal failure, cardiovascular diseases, vascular diseases, diabetes mellitus, diabetic complications, cancer, neurodegenerative disease, retroviral infection, retinal damage, skin senescence or UV-induced skin damage, in human, comprising administering to the subject a composition comprinsing at least one compound according to any one claims of 1-56, in the range of about 100 μg to about 250 mg per kilogram body weight of the subject per day.
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WO2015051766A1 (en) * 2013-10-12 2015-04-16 Betta Pharmaceuticals Co., Ltd Amids substituted indazole derivativees as ploy (adp-ribose) polymerase inhibitors
US11072596B2 (en) * 2017-06-14 2021-07-27 Selection Bioscience Llc Poly(ADP-ribose) polymerase inhibitor, preparation method and use

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015051766A1 (en) * 2013-10-12 2015-04-16 Betta Pharmaceuticals Co., Ltd Amids substituted indazole derivativees as ploy (adp-ribose) polymerase inhibitors
US11072596B2 (en) * 2017-06-14 2021-07-27 Selection Bioscience Llc Poly(ADP-ribose) polymerase inhibitor, preparation method and use

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