WO2015051766A1

WO2015051766A1 - Amids substituted indazole derivativees as ploy (adp-ribose) polymerase inhibitors

Info

Publication number: WO2015051766A1
Application number: PCT/CN2014/088515
Authority: WO
Inventors: Shaojing Hu; Haijun Li; Yanping Wang; Yinxiang Wang; Yunyan Hu
Original assignee: Betta Pharmaceuticals Co., Ltd
Priority date: 2013-10-12
Filing date: 2014-10-13
Publication date: 2015-04-16
Also published as: TWI522352B; TW201514164A

Abstract

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, 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

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 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) constitutes 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 (Biochem. Biophys. Res. Commun. (1998) 245: 1-10) . 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) turnoveroom temperaturehus, 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 BRCA-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； MoI 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 (MoI 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； MoI 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 MeOSO₂ (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. Rαdiαt. 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 (10mg/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 (1mg/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 (1) : 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.

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,

pharmaceutically acceptable salts, N-oxides, produgs thereof, or mixtures of any of the foregoing, wherein:

A and B are each independently CR₃ or N； R₃ is H, halogen, C_1-6alkyl, halo-substituted C_1-6 alkyl, C_2-6alkenyl, halo-substituted C_2-6alkenyl, C_2-6alkynyl, halo-substituted C_2-6alkynyl or CN；

R₁ is H, OH, C_1-6alkyl or NR₇R₈； R₇ and R₈ are each independently H, C_1-6alkyl, halo-substituted C_1-6alkyl, C_2-6alkenyl, halo-substituted C_2-6alkenyl, C_2-6alkynyl, halo-substituted C_2-6 alkynyl, C_1-6alkoxy, halo-substituted C_1-6alkoxy, or C_1-6alkylcarbonyl；

R₂ is H, halogen, C_1-6alkyl, halo-substituted C_1-6alkyl, C_1-6alkoxy, halo-substituted C_1-6 alkoxy, or CN；

X is

m and n are each independently 1, 2, or 3；

R₄ is H, halogen, C_1-6alkyl, halo-substituted C_1-6alkyl, C_1-6alkoxy, or halo-substituted C_1-6 alkoxy；

R₅ is H, -OH, halogen, C_1-6alkyl, halo-substituted C_1-6alkyl, C_1-6alkoxy, halo-substituted C_1- ₆ alkoxy, C_3-6cycloalkyl, halo-substituted C_3-6cycloalkyl, NR₁₁R₁₂, C_1-6alkyl (NR₁₁R₁₂) , C_1-6 alkoxycarbonyl or

wherein

R₁₁ and R₁₂ are each independently H, C_1-6alkyl, or C_1-6alkoxy.

v is 0, 1 or 2；

R₉ is H, C_1-6alkyl, halo-substituted C_1-6alkyl, C_2-6alkenyl, C_3-6cycloalkyl or C_3-6 cycloalkylC_1-4alkyl；

R₁₀ is H, C_1-4alkyl or C_2-4alkenyl；

or

R₉ and R₁₀, together with the atoms to which they are attached, to form a dihydrofuran ring or tetrahydrofuran ring；

Z is a substituted or unsubstituted 5-15 membered nonaromatic monocycle which includes at least two heteroatoms selected from N, O or S, ；

p is 1 or 2；

each R₆ is independently H, halogen, C_1-6alkyl or halo-substituted C_1-6alkyl.

In certain embodiments, R₁ is H, C_1-6alkyl or OH.

In certain embodiments, R₁ is H, C_1-3alkyl, or OH.

In certain embodiments, R₁ is H, methyl, or OH.

In certain embodiments, R₁ is H.

In certain embodiments, R₂ is H, halogen, C1-6alkyl, C1-6alkoxy, or halo-substituted C1-6alkoxy.

In certain embodiments, R₂ is H, F, C_1-3alkyl, C_1-3alkoxy, or . halo-substituted C_1-3alkoxy.

In certain embodiments, R₂ is H, F, methyl, methoxyl, or chlorine-substituted methoxyl.

In certain embodiments, R₂ is H.

In certain embodiments, A is CR₃.

In certain embodiments, R₃ is H or C1-6alkyl.

In certain embodiments, R₃ is H.

In certain embodiments, B is N.

In certain embodiments, X is

In certain embodiments, R₄ is H, C_1-6alkyl , or C_1-6alkoxy.

In certain embodiments, R₄ is H.

In certain embodiments, R₅ is H, OH, C_1-6alkyl, C_1-6alkoxy, C_1-6 alkyl (NR₁₁R₁₂) , or

In certain embodiments, R₅ is H, OH, C_1-3alkyl, C_1-3alkyl (NR₁₁R₁₂) , or

In certain embodiments, R₅ is

In certain embodiments, v is 0, or 1.

In certain embodiments, v is 0.

In certain embodiments, R₉ is H, C_1-6alkyl, or C_2-6alkenyl.

In certain embodiments, R₉ is H, C_1-4alkyl, or C_2-4alkenyl.

In certain embodiments, R₉ is H, methyl, ethyl, propyl,

or

In certain embodiments, R₁₀ is H, C_1-6alkyl, or C_2-6alkenyl.

In certain embodiments, R₁₀ is H, C_1-3alkyl, or C₂-₃alkenyl.

In certain embodiments, R₁₀ is H, methyl, ethyl,

or

In certain embodiments, R₉ and R₁₀, together with the atoms to which they are attached, to form a dihydrofuran ring or tetrahydrofuran ring.

In certain embodiments, R₅ is C_1-6 alkyl (NR₁₁R₁₂) , and R₁₁ and R₁₂ are independently C_1-3 alkyl.

In certain embodiments, R₁₁ and R₁₂ are all methyl.

In certain embodiments, R₅ is

In certain embodiments, R₅ is H, OH, methyl, ethyl, or

In certain embodiments, R₅ is H.

In certain embodiments, X is

In certain embodiments, p is 1, or 2.

In certain embodiments, p is 2.

In certain embodiments, each R₆ is independently H, or C_1-6alkyl.

In certain embodiments, each R₆ is independently methyl.

In certain embodiments, Z is a substituted or unsubstituted 5-15 membered nonaromatic monocycle which includes at least two heteroatoms selected from O or S.

In certain embodiments, Z is a substituted or unsubstituted 5-15 membered nonaromatic monocycle which includes 2-5 heteroatoms selected from O or S.

In certain embodiments, Z is substituted or unsubstituted 5, 6, 7, 8, 9, 11, 12, or 15 membered nonaromatic monocycle which includes 2, 3, 4, or 5 heteroatoms selected from O or S.

In certain embodiments, Z is 5, 6, 7, 8, 9, 12, or 15 membered nonaromatic monocycle which includes 2, 3, 4, or 5 oxygen atoms.

In certain embodiments, Z is

or

In certain embodiments are provided compounds of Formula II or a therapeutically acceptable salt thereof,

wherein s is 1, 2 or 3； t is 1 or 2； R₅ is H, OH, C_1-6alkyl, C_1-6alkoxy, C_1-6 alkyl (NR₁₁R₁₂) , or

In certain embodiments are provided compounds of Formula II or a therapeutically acceptable salt thereof, wherein t is 1.

In certain embodiments are provided compounds of Formula II or a therapeutically acceptable salt thereof, wherein t is 2.

In certain embodiments are provided compounds of Formula II or a therapeutically acceptable salt thereof, wherein s is 1.

In certain embodiments are provided compounds of Formula II or a therapeutically acceptable salt thereof, wherein s is 3.

In certain embodiments are provided compounds of Formula II or a therapeutically acceptable salt thereof, wherein R₅ is H, OH, C_1-3alkyl, or

In certain embodiments are provided compounds of Formula II or a therapeutically acceptable salt thereof, wherein R₅ is

v is 0； R₉ is H, C_1-4alkyl, or C_2-4alkenyl； and R₁₀ is H, C_1-3alkyl, or C_2-3alkenyl.

In certain embodiments are provided compounds of Formula II or a therapeutically acceptable salt thereof, wherein R₉ is H, methyl, ethyl, propyl,

or

In certain embodiments are provided compounds of Formula II or a therapeutically acceptable salt thereof, wherein R₁₀ is H, methyl, ethyl,

or

In certain embodiments are provided compounds of Formula II or a therapeutically acceptable salt thereof, wherein R₅ is H, OH, methyl, ethyl or

In certain embodiments are provided compounds of Formula II or a therapeutically acceptable salt thereof, wherein R₅ is H.

In certain embodiments are provided compounds of Formula III or a therapeutically acceptable salt thereof,

wherein Z₁ is a substituted or unsubstituted 5, 6, 7, 8, 9, 11, 12, or 15 membered nonaromatic monocycle which includes 2, 3, 4, or 5 heteroatoms selected from O or S.

In certain embodiments are provided compounds of Formula III or a therapeutically acceptable salt thereof, wherein Z₁ is a substituted or unsubstituted 5, 6, 7, 8, 9, 12, or 15 membered nonaromatic monocycle which includes 2, 3, 4, or 5 oxygen atoms.

In certain embodiments are provided compounds of Formula III or a therapeutically acceptable salt thereof, wherein Z₁ is a unsubstituted 5, 6, 7, 8, 9, 12, or 15 membered nonaromatic monocycle which includes 2, 3, 4, or 5 oxygen atoms.

In certain embodiments are provided compounds of Formula III or a therapeutically acceptable salt thereof, wherein Z₁ is

or

The flowing compounds of the invention are provided to give the reader an understanding of the compounds encompassed by the invention.

1) 2- (4- (3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

2) 2- (4- (1- (methoxymethyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

3) 2- (4- (1-methyl-3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

4) 2- (4- (1-ethyl-3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

5) 2- (4- (1-isopropyl-3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

6) 2- (4- (1-hydroxy-3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

7) 2- (4- (1- (ethoxymethyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7- carboxamide hydrochloride

8) 2- (4- (1- (2-methoxyethyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

9) 2- (4- (1- (1-hydroxyallyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

10) 2- (4- (1- (hydroxymethyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

11) 2- (4- (1- (1-hydroxyethyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

12) 2- (4- (1- (1-hydroxypropyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

13) 2- (4- (1- (1-hydroxybutyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamid ehydrochloride

14) 2- (4- (1- (1-hydroxy-3-methylbutyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

15) 2- (4- (1- (1-hydroxybut-3-enyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

16) 2- (4- (1- (1-methoxyethyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

17) 2- (4- (1- (1-methoxypropyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

18) 2- (4- (1- (1-methoxybutyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

19) 2- (4- (1- (1-methoxy-3-methylbutyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

20) 2- (4- (1- (1-methoxybut-3-enyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

21) 2- (4- (1- (1-ethoxybut-3-enyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

22) 2- (4- (1- (1- (allyloxy) allyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

23) 2- (4- (1- (2, 3-dihydrofuran-2-yl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

24) 2- (4- (1- (tetrahydrofuran-2-yl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7- carboxamide hydrochloride

25)2- (4- (1- (methoxymethyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -5-methyl-2H-indazole-7-carboxamide

26) 5-fluoro-2- (4- (1- (methoxymethyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide

27) 5-methoxy-2- (4- (1- (methoxymethyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide

28) 2- (4- (1- (methoxymethyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -N-methyl-2H-indazole-7-carboxamide

29) N-hydroxy-2- (4- (1- (methoxymethyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide

30) 2- (4- (1- (methoxymethyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -3-methyl-2H-indazole-7-carboxamide

31) 3-chloro-2- (4- (1- (methoxymethyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide

32) 2- (4- (1- (2- (dimethylamino) ethyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide

33) 2- (4- (3-azabicyclo [3. 1. 0] hexan-1-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

34) 2- (4- (octahydrocyclopenta [c] pyrrol-3a-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

35) 2- (2, 3-dihydrobenzo [b] [1, 4] dioxin-6-yl) -2H-indazole-7-carboxamide

36) 2- (3, 4-dihydro-2H-benzo [b] [1, 4] dioxepin-7-yl) -2H-indazole-7-carboxamide

37) 2- (2, 3, 4, 5-tetrahydrobenzo [b] [1, 4] dioxocin-8-yl) -2H-indazole-7-carboxamide

38) 2- (benzo [d] [1, 3] dioxol-5-yl) -2H-indazole-7-carboxamide

39) 2- (2, 2-dimethylbenzo [d] [1, 3] dioxol-5-yl) -2H-indazole-7-carboxamide

40) 2- (2, 3, 5, 6, 8, 9-hexahydrobenzo [b] [1, 4, 7, 10] tetraoxacyclododecin-12-yl) -2H-indazole-7-carboxamide

41) 2- (2, 3, 5, 6-tetrahydrobenzo [b] [1, 4, 7] trioxonin-9-yl) -2H-indazole-7-carboxamide

42) 2- (2, 3, 5, 6, 8, 9, 11, 12-octahydrobenzo [b] [1, 4, 7, 10, 13] pentaoxacyclopentadecin-15-yl) -2H-indazole-7-carboxamide

43) 2- (2, 3, 5, 6, 8, 9-hexahydrobenzo [b] [1, 4, 7, 10] tetraoxacyclododecin-12-yl) -2H-indazole-7-carboxamide

44) 2- (2, 3, 4, 6, 7, 8-hexahydrobenzo [b] [1, 4, 8] dioxathiacycloundecin-11-yl) -2H-indazole-7-carboxamide

45) 2- (2, 3, 4, 6, 7, 8-hexahydrobenzo [i] [1, 7, 4] dioxasulfonylcycloundecin-11-yl) -2H-indazole-7-carboxamide；

46) 2- (4- (3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -3a, 7a-dihydro-1H-benzo [d] imidazole-4-carboxamide hydrochloride.

The present invention also provides a pharmaceutical composition comprising a compound comprising a compound of Formula I, II and III and a pharmaceutically acceptable excipient.

The present invention additionally provides a use of the compound of Formula I, II and III or the pharmaceutical composition described herein for the preparation of a medicament.

In some embodiments, a medicament thus prepared can be used as a chemo-or radiosensitizer for cancer treatment.

In some embodiments, a medicament thus prepared can be used in treating, preventing, or delaying the conditions which can be ameliorated by the inhibition of poly (ADP-ribose) polymerase (PARP) .

In some embodiments, a medicament thus prepared can be used in treating, preventing, or delaying the onset or progression of cancer, inflammatory diseases, reperfusion injuries, ischemic conditions, stroke, chronic or acute renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infection, retinal damage, skin senescence or UV-induced skin damage.

In some embodiments, wherein the said diabetes mellitus are 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.

In some embodiments, wherein the said neurodegenerative diseases are 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) .

In some embodiments, wherein the said cancer is solid tumors, blood-borne cancers, acute and chronic leukemias, Lymphomas, central nervous system (CNS) , brain cancers, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, small cell lung cancer, gastric cancer, neuroepithelial tumor, cancer being deficient in Homologous Recombination (HR) dependent DNA double strand break (DSB) repair activity, BRCA-1 or BRCA-2 deficient tumors.

Additionally provides 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 mellitus, neurodegenerative diseases, retroviral infection, retinal damage, skin senescence or UV-induced skin damage, comprises a step of administering to a subject in need thereof an effective amount of a compound of Formula I, II and III, or the pharmaceutical composition comprising a compound of Formula I, II and III, for simultaneous, separate or sequential administration.

In some embodiments, the said inflammatory diseases are 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.

In some embodiments, the said ischemic conditions are those resulted from organ transplantation.

In some embodiments, the said neurodegenerative diseases are 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) .

In some embodiments, the said cancer are solid tumors, blood-borne cancers, acute and chronic leukemias, Lymphomas, central nervous system (CNS) , brain cancers, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, small cell lung cancer, gastric cancer, neuroepithelial tumor, cancer being deficient in Homologous Recombination (HR) dependent DNA double strand break (DSB) repair activity, BRCA-1 or BRCA-2 deficient tumors.

Additionally provides a method, of treating or preventing a cancer, comprising a step of administering to a subject in need thereof an effective amount of a compound of Formula I, II and III, or the pharmaceutical composition comprising a compound of Formula I, II and III for simultaneous, separate or sequential administration.

Additionally proveds a method of treating and/or preventing a cancer being deficient in HR dependent DNA DSB repair pathway, comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound of Formula I, II and III, or the pharmaceutical composition comprising a compound of Formula I, II and III.

In some embodiments, the said cancer comprises one or more cancer cells having a reduced or abrogated ability to repair DNA DSB by HR relative to normal cells.

In some embodiments, the method 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.

In some embodiments, the method, 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.

In some embodiments, the said subject is heterozygous for a mutation in a gene encoding a component of the HR dependent DNA DSB repair pathway.

In some embodiments, the said subject is heterozygous for a mutation in BRCA-1 and/or BRCA-2.

In some embodiments, the said cancer is breast cancer, ovary cancer, pancreatic cancer or prostate cancer.

In some embodiments, the method of treating and/or preventing cancer, further comprising administering to a subject anti-cancer agent or chemotherapeutic agents, for simultaneous, separate or sequential administration

In some embodiments, the method of cancer therapy or for potentiating tumor cells for treatment, further comprises administration of ionizing radiation or chemotherapeutic agent

Additionally provides a method of chemotherapy or radiotherapy, comprising administering to a subject in need of treatment a therapeutically-effective amount of compound of Formula I, II and III , or the pharmaceutical composition comprising a compound of Formula I, II and III.

In some embodiments, whererin the compound of Formula I, II and III or the pharmaceutical composition comprising a compound of Formula I, II and III 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.

In some embodiments, the method comprising administering to the subject a composition comprinsing compound , in the range of about 100 μg to about 250mg per kilogram body weight of the subject per day.

In some embodiments, wherein the instant compounds are also useful in combination with anti-cancer agents or chemotherapeutic agents such as proteasome inhibitors, topoisomerase inhibitors , alkylating agents, anti-mitotic agents, inhibitors of mitotic kinesins, antiproliferative agents, monoclonal antibody, HMG-CoA reductase inhibitors, apoptosis inducing agents , integrin blockers, angiogenesis inhibitors and other therapeutic agents that modulate or inhibit angiogenesis, inhibitor of inherent multidrug resistance (MDR) , anti-emetic agents, an immunologic-enhancing drug.

In some embodiments, wherein the instant compounds are also useful in combination with ionizing radiation and/or in combination with a second compound : 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 present invention also includes within its scope N-oxides of the compounds of Formula I, II and III 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, II and III with oxone in the presence of wet alumina.

The present invention includes within its scope prodrugs of the compounds of Formula I, II and III above. In general, such prodrugs will be functional derivatives of the compounds of Formula I, II and III which are readily convertible in vivo into the required compound of Formula I, II and III. 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, II and III, or 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 a number of different polymorphic forms. When any variable (e. g. R₁ 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.

“Cn-m” refers to the number of carbons in a gropus, wherein n and m are positive integers. “n-membered” refers to the number of atoms in a ring group, for example, pyridinyl is a 6-membered ring group.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C_1- ₆alkyl" is defined to include groups having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement. For example, "C_1-6alkyl" specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl and hexyl and so on. In some embiment, preferred alkyl groups are methyl (-CH₃) and ethyl (-CH₂CH₃) .

As used herein, the term "C_2-6alkenyl" 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. In some embiment preferred alkenyl groups include ethenyl and propenyl.

As used herein, the term "C_2-6alkynyl" 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. In some embiment, preferred alkynyl groups include ethynyl and propynyl.

The term "cycloalkyl" refers to a monocyclic, bicyclic or polycyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "C_3-6cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2, 2-dimethyl-cyclobutyl, 2-methyl-cyclopentyl, cyclohexyl and so on. Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "C_3-6cycloalkylC_1-4alkyl” represents a C_3-6cycloalkyl group of indicated number of carbon atoms attached through C_1-4alkyl group.

"Alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. Examples of suitable alkoxy groups is C_1-6alkoxy which include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy. In some embiment, preferred alkoxy groups are methoxy and ethoxy.

As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.

The terms "haloC_1-6alkyl" , "haloC_2-6alkenyl" , "haloC_2-6alkynyl" and "haloC_1-6alkoxy" mean a C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl or C_1-6alkoxy in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms. In some embiment, preferred are fluoroC_1-6alkyl, fluoroC_2-6alkenyl, fluoroC_2-6alkynyl and fluoroC_1- ₆alkoxy groups, in particular fluoroC_1-3alkyl, for example, CF₃, CHF₂, CH₂F, CH₂CH₂F, CH₂CHF₂, CH₂CF₃ and fluoroC_1-3alkoxy groups, for example, OCF₃, OCHF₂, OCH₂F, OCH₂CH₂F, OCH₂CHF₂ or OCH₂CF₃, and most especially CF₃, OCF₃ and OCHF₂.

As used herein, the term "hydroxyC_1-6alkyl" 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 "C_1-6alkylcarbonyl" or "C_1-6alkoxycarbonyl" denotes a radical, respectively, attached via a carbonyl (C＝O) radical. Suitable examples of "C_1-6alkylcarbonyl" include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl and tert-butylcarbonyl. Examples of "C_1-6alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl. The term "C_6-10arylcarbonyl" 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.

Included in the instant invention is the free base of compounds of Formula I, II and III, 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, II and III. 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. In some embodiment, a pharmaceutically acceptable salt of this invention contains 1 equivalent of a compound of Formula I, II and III 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, N， N-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, II and III 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, II and III or a composition comprising a compound of Formula I, II and III.

The PARP inhibitors of the present invention are useful for the treatment of the diseases specified in WO 2005/082368.

Thus, the present invention provides a compound of Formula I, II and III for use in the manufacture of a medicament for the treatment or prevention of cancer, inflammatory diseases, reperfusion injuries, ischemic conditions, stroke, chornic or acute renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infection, retinal damage, skin senescence or UV-induced skin damage.

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 pro-inflammatory cytokines. Such 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, II and III 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, II and III or a composition comprising at least one compound of Formula I, II and III.

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, II and III or a composition comprising a compound of Formula I, II and III.

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, II and III 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, II and III or a composition comprising a compound of Formula I, II and III.

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, II and III 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, blood-borne cancers, acute and chronic leukemias, Lymphomas, central nervous system (CNS) , brain cancers, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, small cell lung cancer, gastric cancer, neuroepithelial tumor, cancer being deficient in Homologous Recombination (HR) dependent DNA double strand break (DSB) repair activity, BRCA-1 or BRCA-2 deficient tumors.

Solid tumors include 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.

In some embodiment, 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) , RAD5l L1 (NM-002877) , RAD51 C (NM-002876) , RAD51L3 (NM-002878) , DMCl (NM-007068) , XRCC2 (NM7005431) , XRCC3 (NM-005432) , RAD52 (NM-002879) , RAD54L (NM-003579) , RAD54B (NM-012415) , BRCA-1 (NM-007295) , BRCA-2 (NM-000059) , RAD5O (NM-005732) , MREI IA (NM-005590) , NBSl (NM-002485) , ADPRT (PARP-1) , ADPRTL2, (PARP02) CTPS, RPA, RPAl, RPA2, RPA3, XPD, ERCC1, XPF, MMS19, RAD51, RAD51p, RAD51C, RAD5 ID5DMCl, XRCCR, XRCC3, BRCAl, BRCA2, RAD52, RAD54, RAD5O, MRE11, NB51, WRN, BLMKU70, RU80, ATM, ATRCHKl, CHK2, FANCA, FANCB, FANCC, FANCDl, FANCD2, FANCE, FANCF, FANCG, FANCC, FANCDl, 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) .

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, II and III or a composition comprising a compound of Formula I, II and III.

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 MoI 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 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 the present invention may also be useful for the treatment or prevention of cancer or potentiating tumor cells further comprises administration of at least one ionizing radiation or chemotherapeutic agent.

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 intrasternal) ； 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 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^TN 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, II and III 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, II and III 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 250mg 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, II and III and an anticancer agent for simultaneous, separate or sequential administration.

The present invention also provides a compound of Formula I, II and III 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, II and III or a composition comprising a compound of Formula I, II and III 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) , 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. The instant compounds are particularly useful when co-administered with radiation therapy.

Examples of "HDAC inhibitors" include suberoylanilide hydroxamic acid (SAHA) , LAQ824, LBH589, PXDlOl, 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, LYl 17081, toremifene, fulvestrant, 4- [7- (2, 2-dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1-piperidinyl) ethoxy] phenyl] -2H-1-benzopyran-3-yl] -phenyl-2, 2-dimethylpropanoate, 4, 4'-dihydroxybenzophenone-2, 4-dinitrophenyl-hydrazone, and SΗ646. "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 5α-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, α-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, GPXlOO, (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, MENl 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 150mg/m² (of a subject's body surface area) to about 250mg/m². In another embodiment, dacarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 150mg/m² to about 250mg/m².

In an embodiment, the alkylating agent is procarbazine. Procarbazine can be administered to a subject at dosages ranging from about 50mg/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 50mg/m² to about 100mg/m². In an embodiment, the alkylating agent is temozoloamide. Temozolomide can be administered to a subject at dosages ranging from about about 150mg/m² (of a subject's body surface area) to about 200mg/m². In another embodiment, temozolomide is administered orally to an animal once per day for five consecutive days at a dose ranging from about 150mg/m² to about 200mg/m².

Examples of anti-mitotic agents include allocolchicine, halichondrin B, colchicine, colchicine derivative, 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 and peptide aldehydes such asmg 132, mg 115 and PSI.

Examples of microtubule inhibitors/microtubule-stabilising agents include paclitaxel, vindesine sulfate, vincristine, vinblastine, vinorelbine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, cemadotin, RPRl 09881, BMS 184476, vinflunine, 2, 3, 4, 5, 6-pentafluoro-N- (3-fluoro-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, irinotecan, rubitecan, exatecan, gimetecan, silyl-camptothecins, 9-aminocamptothecin, camptothecin, crisnatol, mitomycin C, 6-ethoxypropionyl-3', 4'-O-exo-benzylidene-chartreusin, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3, 4, 5-kl] acridine-2- (6H) propanamine, 1-amino-9-ethyl-5-fluoro-2, 3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [de] pyrano [3', 4': b, 7] -indolizino [1, 2b] quinoline-10, 13 (9H, 15H) dione, lurtotecan, 7- [2- (N-isopropylamino) ethyl] - (20S) camptothecin, BNP1350, BNPIl100, 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, (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, 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-9Η-thioxanthen-4-ylmethyl] formamide, N- (2- (dimethylamino) ethyl) acridine-4-carboxamide, 6- [ [2- (dimethylamino) ethyl] amino] -3-hydroxy-7H-indeno [2, 1-c] quinolin-7-one, and dimesna； non-camptothecin topoisomerase-1 inhibitors such as indolocarbazoles； and dual topoisomerase-1 and II inhibitors such as benzophenazines, XR20 115761MLΝ 576 and benzopyridoindoles. In an embodiment, the topoisomerase inhibitor is irinotecan. Irinotecan can be administered to a subject at dosages ranging from about about 50mg/m² (of a subject's body surface area) to about 150mg/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, raltitrexed, emitefur, decitabine, nolatrexed, pemetrexed, nelzarabine, 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, ecteinascidin, troxacitabine, aminopterin, 5-flurouracil, alanosine, swainsonine, lometrexol, dexrazoxane, methioninase 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 (

see U. S. Pat. Nos. 4,231,938, 4,294,926 and 4,319,039) , simvastatin (

see U. S. Pat. Nos. 4,444,784, 4,820,850 and 4,916,239) , pravastatin (

see U. S. Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589) , fluvastatin (

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 (

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) .

"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-α, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib (PNAS (1992) 89: 7384； JNC/ (1982) 69: 475； Arch. Opthalmol. (1990) 108: 573； Anat. Rec. (1994) 238: 68； FEBS Letters (1995) 372: 83； Clin, Orthop. (1995) 313: 76； J. MoI. Endocrinol. (1996) 16: 107； Jpn. J. Pharmacol. (1997) 75: 105； Cancer Res. (1997) 57: 1625； Cell (1998) 93: 705； Intl. J. MoI. 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-O-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, 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.

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,

and

or a pharmaceutically acceptable salt thereof.

Other examples of angiogenesis inhibitors include, but are not limited to, endostatin, IM862, 5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) oxiranyl] -l-oxaspiro [2, 5] oct-6-yl(chloroacetyl) carbamate, 5-amino-1- [ [3, 5-dichloro-4- (4-chlorobenzoyl) phenyl] methyl] -1H-1, 2, 3-triazole-4-carboxamide, CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, 7, 7- (carbonyl-bis [imino-N-methyl-4, 2-pyrrolocarbonylimino [N-methyl-4, 2-pyrrole] -carbonylimino] -bis- (1, 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 0Cyβ3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the αvβ5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the 0Cyβ3 integrin and the 0Cyβ5 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 OCyβój 0C_vβ8, oqβi, 0C2βl, 0C5βi, 0C6βl and 0C6β4 integrins. The term also refers to antagonists of any combination of α_vβ3, α_vβ5, αvβ6； oc_vβ8, oqβi, 0C2βl, βsoq, 0C6βl and 0C6β4 integrins.

Some specific examples of tyrosine kinase inhibitors include N- (trifluoromethylphenyl) -5-methylisoxazol-4-carboxamide, 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, BIBXl 382, 2, 3, 9, 10, 11, 12-hexahydro-10- (hydroxymethyl) -10-hydroxy-9-methyl-9, 12-epoxy-1H-diindolo [1, 2, 3-fg: 3', 2', 1'-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) -1-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 MeOSO₂ (CΗ₂) -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 l, troglitazone, rosiglitazone, and pioglitazone) , fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NPOI lO, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2- [ (5, 7- dipropyl-3-trifluoromethyl-1, 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, 5^th 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, 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. 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.

In an embodiment, the neurokinin-1 receptor antagonist for use in conjunction with the compounds of the present invention is selected from: 2- (R) - (1- (R) - (3, 5-bis(trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluorophenyl) -4- (3- (5-oxo-1H, 4H-1, 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" acompound) 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, II and III 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-γagonist, 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

General Scheme 1

General Scheme 2

EXAMPLES

Example 1

2- (4- (3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride (Product 1)

Step 1: Synthesis of benzyl prop-2-ynylcarbamate (Compound 1)

Propargylamine hydrochloride (8g) , methylene chloride (300mL) and triethylamine (26.4g) were put into a 1L three-necked flask and fully stirred to dissolve. Then CbzCl (19.4g) in dichloromethane (30mL) was slowly dropwise at 0℃ during a period of 30 mins. After, the reaction mixture was warmed to room temperature and stirred for another 3 hrs. After, the reaction solution was washed with saturated sodium chloride solution, and then separated. Then, the separated organic phase was dried over MgSO₄, filtered, concentrated in vacuum to arrive at a crude product further purified by chromatogram column, to afford 3g Compound 1. MS: 190 (M+H) ⁺.

Step 2: Synthesis of benzyl allyl (prop-2-ynyl) carbamate (Compound 2 )

A 250mL three-necked flask equipped with stirrer, addition funnel and thermometer were charged with compound 1 (3g) and 100mL of THF/DMF (4: 1, v/v) and stirring to dissolve. 760mg of_NaH (60％)_was slowly added in at about 0℃ during a period of 20 mins and stirred for another 30 mins. Then, 3-chloropropene (1.5g)_was added and reacted for 1 hr at room temperature. Then, the reaction was quenched with water, and THF was evaporated in vacuo. The residue was partitioned between sodium chloride solution and ethyl acetate. The separated organic phase was washed with sodium chloride aqueous solution 3 times and dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuum to afford the crude product further purified by chromatogram column (PE: EA ＝ 50: 1) , to arrive at 2.7g Compound 2. MS: 230 (M+H) ⁺.

Step 3: Synthesis of benzyl allyl (3- (4-nitrophenyl) prop-2-ynyl) carbamate (Compound 3)

Compound 2 (2.7g) , p-iodonitrobenzene (2.94g) , triethylamine (1.6g) , PdCl₂ (PPh₃) ₂ (340mg) , CuI (180mg) and DMF (50mL) were put into a 100mL sealed tube under nitrogen. The reaction mixture was heated to 40℃ and stirred overnight. After, the reaction mixture was cooled to room temperature and partitioned between sodium chloride solution and ethyl acetate. The separated organic phase was washed with saturated sodium chloride solution 3 times, and then dried over MgSO₄, filtered, concentrated under reduced pressure to dryness to provide a crude product further purified by chromatogram column (PE: EA＝30: 1) , to afford 3g Compound 3.MS: 351 (M+H) ⁺.

Step 4: Synthesis of benzyl 6- (4-nitrophenyl) -3-azabicyclo [4. 1. 0] hept-4-ene-3-carboxylate (Compound 4)

Compound 3 (3g) , PtCl₂ (300mg) and toluene (50mL) were put into a 100mL sealed tube under nitrogen. The reaction mixture was heated to 80℃ and stirred for 36 hrs. Then, the reaction mixture was concentrated in vacuum to dryness to provide a crude product further purified by chromatogram column, to afford 700mg Compound 4. MS: 351 (M+H) ⁺.

Step 5: Synthesis of benzyl 6- (4-aminophenyl) -3-azabicyclo [4.1.0] hept-4-ene-3-carboxylate (Compound 5)

Compound 4 (700mg) , iron power (560mg) , methanol (50mL) and acetic acid (1mL) were put into a 250mL of one-necked flask with stirring. Then, the reaction mixture was heated to reflux for 2 hrs and then cooled to room temperature. After, the reaction mixture was concentrated in vacuum and the residue was partitioned between water and ethyl acetate. And then the separated organic phase was dried, filtered, and concentrated in vacuum to provide 550mg Compound 5. MS: 321 (M+H) ⁺.

Step 6: Synthesis of (E) -benzyl 6- (4- (3- (methoxycarbonyl) -2-nitro styryl) phenyl) -3-azabicyclo [4. 1. 0] hept-4-ene-3-carboxylate (Compound 6)

Compound 5 (550mg) , methyl 2-nitro-3-formyl-phenyl benzoate (400mg) and ethanol (40mL) were put into a 50mL three-necked flask with stirring. Then the reaction mixture was heated to 70℃ and stirred for 5 hrs. After, the reaction mixture was concentrated in vacuum to provide 850mg Compound 6, No further operation. MS: 511 (M+H) ⁺.

Step 7: Synthesis of methyl 2- (4- (3- (benzyloxycarbonyl) -3-azabicyclo [4. 1. 0] hept-4-en-6-yl) phenyl) -2H-indazole-7-carboxylate (Compound 7)

Compound 6 (500mg) , sodium azide (122mg) and DMF (20mL) were put into an 100mL three-necked flask under nitrogen with stirring. Then the reaction mixture was heated to 95℃ and stirred overnight, and then it was cooled to room temperature. After, the reaction mixture was partitioned between saturated sodium chloride solution and ethyl acetate. Then, the separated organic phase was washed with saturated sodium chloride solution 4 times, dried, filtered and concentrated in vacuum to dryness purified by chromatogram column, to afford 400mg Compound 7. MS: 480 (M+H) ⁺.

Step 8: Synthesis of methyl 2- (4- (3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxylate (Compound 8)

Compound 7 (400mg) , 60mL solution of EA/MeOH (1: 1, v/v) , sodium carbonate (150mg) and 200mg mixture of Pd/C catalysts were put into a 100mL one-necked flask with stirring, and then H₂ was bubbled into the reaction mixture at room temperature overnight. After, the reaction mixture was filtered, and concentrated in vacuum, the residue was washed with ethyl acetate and filtered, and then filtrate was concentrated in vacuum to dryness to provide 300mg Compound 8. MS:348 (M+H) ⁺.

Step 9: Synthesis of methyl 2- (4- (3- (tert-butoxycarbonyl) -3-azabicyclo [4. 1. 0] heptan-6-yl)phenyl) -2H-indazole-7-carboxylate (Compound 9)

Compound 8 (300mg) , dichloromethane (30mL) and triethylamine (110mg) were put into a 100mL two-necked flask with stirring and then the reaction mixture was cooled to 0℃. After, a solution of Boc₂O (210mg) in dichloromethane (5mL) was slowly dropwise via addition funnel while keeping inner temperature at 0℃. Then, the reaction mixture was warmed to room temperature and stirred for another 30 mins. After, the reaction mixture was washed with the chloride sodium solution, dried, filtered and concentrated in vacuum to dryness purified by chromatogram column, to provide 120mg Compound 9. MS: 448 (M+H) +.

Step 10: Synthesis of tert-butyl 6- (4- (7-carbamoyl-2H-indazol-2-yl) phenyl) -3 -azabicyclo [4. 1. 0]heptane-3-carboxylate (Compound 10)

Compound 9 (120mg) and methanol (20mL) were put into a 100mL sealed tube with stirring till to fully dissolved. Then the reaction mixture was cooled to 0℃ and ammonia gas (2.0g) was bubbled into the reaction mixture. After, the reaction system was sealed and then the reaction mixture was heated to 80℃ and stirred overnight. Then, the reaction mixture was concentrated in vacuum to dryness purified by chromatogram column, to provide 100mg Compound 10. MS: 433 (M+H) ⁺.

Step 11: Synthesis of 2- (4- (3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride (Product 1)

A solution of Compound 10 (100mg) in dichloromethane (25mL) was put into a 100mL two-necked flask with stirring and then cooled to 0℃. After, dried hydrogen chloride gas was bubbled into the reaction mixture at 0℃ for 20 mins. Then, the reaction mixture was filtered after stirred at 0℃ for another 30 mins, and the filter cake was dried in vacuum to afford 50mg product 1. ¹H NMR (400MHz, DMSO) : δ 9.30 (1H, s) , 8.78 (2H, d) , 8.55 (1H, s) , 8.10-8.03 (4H, m) , 7.89 (1H, s) , 7.63-7.62 (2H, m) , 7.27 (1H, m) , 3.15-2.84 (4H, m) , 2.33-2.26 (2H, m), 1.51 (1H, m) , 1.20 (2H, m) . MS: 369 (M+H) ⁺.

Example 2

2- (4- (1- (methoxymethyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride (Product 2)

Step 1: Synthesis of benzyl 2- (methoxymethyl) allyl (prop-2-ynyl) carbamate (Compound 11)

Compound 1 (500mg) and 10mL solution of THF/DMF (1: 1, v/v) were put into a 50mL of two-necked flask and fully stirred to dissolve. Then, the reaction mixture was cooled to 0℃, and NaH (130mg) was added in portions. After, the reaction mixture was warmed to room temperature and further stirred for 20 min. Then, the reaction mixture was added in 2 -chloromethyl-4 -methoxy -butene (400mg) and stirred for another1 hr at room temperature. The reaction was complete detected by TLC (PE: EA＝5: 1) , and the reaction mixture was partitioned between sodium chloride solution and ethyl acetate. Further, the separated organic phase was washed with saturated sodium chloride solution, dried, filtered and concentrated in vacuum to dryness purified by chromatogram column (PE:EA＝20:1) , to afford 500mg Compound 11. MS: 274 (M+H) ⁺.

Step 2: Synthesis of benzyl 2- (methoxymethyl) allyl (3- (4-nitrophenyl) prop-2-ynyl) carbamate (Compound 12)

Compound 11 (500mg) , p-iodonitrobenzene (455mg) , triethylamine (245mg ) , PdCl₂ (PPh₃) ₂ (52mg) , CuI (30mg) and DMF (10mL) were put into a 100mL of sealed tube with stirring, and the reaction mixture was heated to 40℃and stirred overnight. After, the reaction mixture was cooled to room temperature, and partitioned between sodium chloride solution and ethyl acetate. Further, the separated organic phase was washed with saturated sodium chloride solution for three times, dried, filtered and concentrated in vacuum to a yellow oil purified by chromatogram column (PE:EA ＝ 15:1) , to provide 400mg Compound 12. MS: 395 (M+H) ⁺.

Step 3: Synthesis of benzyl 1- (methoxymethyl) -6- (4-nitrophenyl) -3-azabicyclo [4. 1. 0] hept-4-ene-3-carboxylate (Compound 13)

Compound 12 (120mg) , PtCl₂ (30mg) , toluene (10mL) was put into a 100mL of sealed tube under nitrogen, , then, the reaction mixture was heated to 80℃ and stirred overnight. Then the reaction mixture was cooled to room temperature, and then dried, filtered, and concentrated in vacuum to dryness purified by chromatogram column, to afford 90mg Compound 13, MS : 395 (M+H) ⁺.

Step 4: Synthesis of benzyl 6- (4-aminophenyl) -1- (methoxymethyl) -3-azabicyclo [4. 1. 0] hept-4-ene-3-carboxylate (Compound 14)

Compound 13 (230mg) , iron power (100mg) , methanol (30mL) and acetic acid (1mL) were put into a 100mL of one-necked flask with stirring, and then the reaction mixture was heated toreflux for 1 hr. After, the reaction mixture was cooled to room temperature, and concentrated in vacuum. Then the residue was partitioned between water and ethyl acetate, the separated organic phase was dried, filtered and concentrated in vacuum to dryness to provide 200mg Compound 14. MS:365 (M+H) ⁺.

Step 5: Synthesis of (E) -benzyl 6- (4- (3- (methoxycarbonyl) -2-nitrostyryl) phenyl) -1- (methoxymethyl) -3-azabicyclo [4. 1. 0] hept-4-ene-3-carboxylate (Compound 15)

Compound 14 (200mg) , methyl 2-nitrophenyl-3-formyl benzoate (120mg) and ethanol (10mL) were put into 50mL of one-necked flask with stirring, and then the reaction mixture was heated to 70℃ and stirred for 5 hrs. After, the reaction mixture was concentrated in vacuum to provide 300mg Compound 15, no further operation. MS: 555 (M+H) ⁺.

Step 6: Synthesis of methyl 2- (4- (3- (benzyloxycarbonyl) -1- (methoxymethyl) -3-azabicyclo [4. 1. 0] hept-4-en-6-yl) phenyl) -2H-indazole-7-carboxylate (Compound 16)

Compound 15 (300mg) , sodium azide (60mg) and DMF (10mL) were put into 50mL of two-necked flask with stirring under nitrogen, , and then the reaction mixture was heated to 95℃ and stirred overnight. After, the reaction mixture was cooled to room temperature, and partitioned between saturated sodium chloride solution and ethyl acetate. Further, the separated organic phase was washed with saturated sodium chloride solution 4 times, dried, filtered and concentrated in vacuum to dryness purified by chromatogram column, to provide 150mg Compound 16. MS: 524 (M+H) ⁺.

Step 7: Synthesis of methyl 2- (4- (1- (methoxymethyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxylate (Compound 17)

Compound 16 (150mg) , 10mL of EA/MeOH (1:1) , sodium carbonate (10mg) and 20mg of Pd/C catalysts were put into a 100mL of one-necked flask with stirring, and H₂ was bubbled into the reaction mixture at room temperature overnight. After, the reaction mixture was filtered and concentrated in vacuum. And then the residue was washed with ethyl acetate, and the mixture solution was filtered, and concentrated in vacuum to dryness to provide 80mg Compound 17. MS: 392 (M+H) ⁺.

Step 8: Synthesis of methyl 2- (4- (3- (tert-butoxycarbonyl) -1- (methoxymethyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxylate (Compound 18)

Compound 17 (80mg) , methylene chloride (20mL) and triethylamine (30mg) were put into 50mL of two-necked flask with stirring, and the reaction mixture was cooled to 0℃. Then, the solution of Boc₂O (50mg) in dichloromethane (5mL) was slowly added dropwise at 0℃ during a period of 15 mins. Then the reaction mixture was warmed to room temperature and stirred for another 30 mins. After, the reaction mixture was washed with chloride sodium, dried, filtered and concentrated in vacuum to dryness to provide 100mg Compound 18. MS: 492 (M+H) ⁺.

Step 9: Synthesis of tert-butyl 6- (4- (7-carbamoyl-2H-indazol-2-yl) phenyl) -1- (methoxymethyl) -3-azabicyclo [4. 1. 0] heptane-3-carboxylate (Compound 19)

A solution of compound 18 (80mg) in 15mL methanol was put into a 100mL of sealed tube. Ammonia (2.0g) was bubbled into the reaction mixture after it was cooled to 0℃. After, the reaction system was sealed and then heated to 70℃ and stirred overnight. Then, the reaction mixture was concentrated in vacuum to provide 80mg Compound 19. MS: 477 (M+H) ⁺.

Step 10: Synthesis of 2- (4- (1- (methoxymethyl) -3-azabicyclo [4. 1. 0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride (Product 2)

A solution of compound 19 (80mg) in dichloromethane (20mL) was put into 50mL of two-necked flask with stirring, and then the reaction mixture was cooled to 0℃. After, dried hydrogen chloride gas was bubbled into the reaction mixture for 30 min. Then, the reaction mixture was filtrated and the filter cake was dried in vacuum to provide 15mg product 2. ¹H NMR (400MHz, DMSO) : δ 9.32 (1H, d) , 8.12-8.10 (2H, d) , 8.10-8.01 (2H, m) , 7.73-7.71 (2H, d) , 7.28-7.25 (1H, m) , 5.67-5.92 (2H, s) 3.51-3.14 (4H, m) , 2.59-2.79 (4H, m) 3.07 (3H, s) . 1.88-1.26 (2H， m) ， 0.27-0.52 (2H, m) MS: 413 (M+H) ⁺.

The desired product of Example 3--Example 32 is synthesized by using the similar sequence and conditions as described for Example 1.

Example 33

2- (4- (3-azabicyclo [3. 1. 0] hexan-1-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride (Product33)

Step 1: Synthesis of (E) -tert-butyl 1- (4- (3- (methoxycarbonyl) -2-nitrobenzyl idene amino) phenyl) -3-azabicyclo [3. 1. 0] hexane-3-carboxylate (Compound 20)

tert-butyl-1- (4-aminophenyl) -3-azabicyclo [3. 1. 0] hexane-3-carboxylate (211mg) , methyl 2-nitro-3-formyl benzoate (178mg) and methanol (6mL) were put into 50mL of one-necked flask under nitrogen, and then the reaction mixture was heated to 75℃ and stirred for 3 hrs. After, the reaction mixture was concentrated in vacuum to dryness to provide 350mg Compound 20, which was used in the next step without further purification. MS: 466 (M+H) ⁺.

Step 2: Synthesis of methyl 2- (4- (3- (tert-butoxycarbonyl) -3-azabicyclo [3. 1. 0] hexan-1-yl) phenyl) -2H-indazole-7-carboxylate (Compound 21)

Compound 20 (350mg) , sodium azide (50mg) and DMF (10mL) were put into a 50mL of one-necked flask under nitrogen, and then the reaction mixture was heated to 95℃ and stirred overnight. After, the reaction mixture was cooled to room temperature, and partitioned between saturated sodium chloride solution and ethyl acetate. Then the separated organic phase was washed with saturated sodium chloride solution 3 times, dried, filtered and concentrated in vacuum to dryness purified by chromatogram column, to provide 160mg Compound 21. MS: 434 (M+H) ⁺.

Step 3: Synthesis of tert-butyl 1- (4- (7-carbamoyl-2H-indazol-2-yl) phenyl) -3-azabicyclo [3. 1. 0] hexane-3-carboxylate (Compound 22)

Compound 21 (160mg) , methanol (15mL) were put into in a 100mL of sealed tube and then the reaction mixture was cooled to 0℃. The reaction system was sealed after 3.0g ammonia was bubbled into the reaction mixture. After, the reaction mixture was heated to 75℃ and stirred for 36 hrs. After, the reaction mixture was concentrated in vacuum to dryness to provide 150mg Compound 22. MS: 419 (M+H) ⁺.

Step 4: Synthesis of 2- (4- (3-azabicyclo [3. 1. 0] hexan-1-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride (Product 33)

A solution of Compound 22 (150mg) in dichloromethane (35mL) was put into a 100mL of three-necked flask with stirring, and then the reaction mixture was cooled to 0℃, and dried hydrogen chloride gas was bubbled into the reaction mixture at 0℃ for 20 mins and stirred for another 30mins. After, the reaction mixture was filtered, and the filter cake was dried in vacuum to dryness to afford 100mg product 33.¹H NMR (400MHz, DMSO) : δ 9.32 (1H, s) , 8.10-8.12 (2H, d) , 8.06-8.04 (1H, d) , 8.02-8.00 (1H, d) , 7.49-7.51 (2H, d) , 7.28-7.25 (1H, m) , 3.77-3.74 (1H, d) , 3.55-3.51 (2H, d) , 3.15-3.47 (1H, d) , 2.25-2.22 (1H, m) 1.50-1.47 (1H, m) , 1.21-1. 16 (1H, m) . MS: 355 (M+H) ⁺.

Example 34

2- (4- (octahydrocyclopenta [c] pyrrol-3a-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride (Product 34)

Step 1: Synthesis of (E) -methyl 3- ( (4- (2-benzyloctahydrocyclopenta [c] pyrrol-3a-yl)phenylimino) methyl) -2-nitrobenzoate (Compound 23)

4- (2-benzyloctahydrocyclopenta [c] pyrrol-3a-yl) aniline (195mg) , methyl 2-nitro-3-aldehyde benzoate (153mg) and ethanol (20mL) were put into a 100mL of one-necked flask with stirring under nitrogen. Then, the reaction mixture was heated to reflux and reacted overnight. After, the reaction mixture was cooled to room temperature and then concentrated in vacuum to dryness to afford 320mg Compound 23, which was used in the next step without further purification. MS: 484 (M+H) ⁺.

Step 2: Synthesis of methyl 2- (4- (2-benzyloctahydrocyclopenta [c] pyrrol-3a-yl) phenyl) -2H-indazole-7-carboxylate (Compound 24)

Compound 23 (300mg) , sodium azide (20mg) and DMF (10mL) were put into a 50mL one-necked flask with stirring under nitrogen. The reaction mixture was heated to 90℃ and stirred overnight, or the reaction was complete detected by TLC (PE:EA＝3:1) . After, the reaction mixture was cooled to room temperature and partitioned between sodium chloride solution and ethyl acetate. The separated organic phase was washed with sodium chloride solution, dried, filtered, and concentrated in vacuum to dryness purified by chromatogram column, to afford 130mg Compound 24. MS: 452 (M+H) ⁺.

Step 3: Synthesis of 2- (4- (2-benzyloctahydrocyclopenta [c] pyrrol-3a-yl) phenyl) -2H-indazole-7-carboxamide (Compound 25)

Compound 24 (80mg) , methanol (15mL) were put into a 100mL sealed tube, and then ammonia gas (2g) was bubbled into the reaction mixture. After, the reaction mixture was heated to 70℃ and stirred overnight. Then, the reaction mixture was concentrated in vacuum to dryness to afford 60mg Compound 25, no further operation. MS: 437 (M+H) ⁺.

Step 4: Synthesis of 2- (4- (octahydrocyclopenta [c] pyrrol-3a-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride (Product 34)

Compound 25 (10mg) , methanol (5mL) and Pd/C (5mg) catalysts were put into a 50mL of one-necked flask with stirring, and then hydrogen gas was bubbled into the reaction mixture at room temperature overnight. After, the reaction mixture was filtered and concentrated in vacuum to dryness to afford 6mg product 34. MS: 384 (M+H) ⁺.

Example 35

2- (2, 3-dihydrobenzo [b] [1, 4] dioxin-6-yl) -2H-indazole-7-carboxamide (Product 35)

Step 1: Synthesis of 2, 3-dihydrobenzo [b] [1, 4] dioxine (Compound 26)

Catechol (2g) , sodium hydroxide (1.8g) and DMF (20mL) were put into a 50mL of two-necked flask and fully stirred to dissolve, then 1, 2-dichloroethane was added (2.7g) . After, The reaction mixture was heated to 90℃ and stirred overnight. Then, the reaction mixture was cooled to room temperature and adjusted to pH 5～6 with dilute hydrochloric acid. And then, the reaction mixture was extracted with ethyl acetate 3 times, further, the organic phase was combined and concentrated in vacuum to dryness purified by chromatogram column, to afford 2.1g Compound 26. MS: 137 (M+H) ⁺.

Step 2: Synthesis of 6-nitro-2, 3-dihydrobenzo [b] [1, 4] dioxine (Compound 27)

Concentrated nitric acid (2.5mL) was put into a 50mL of three-necked flask, and cooled to 0℃. Then, Compound 1 (200mg) was added in portions during a period of 5 mins, and stirred for another 5 minutes. After, the reaction mixture was poured into ice water, filtered, and the filter cake was dried in vacuum to afford 210mg Compound 27, light yellow solid. _MS: 182 (M+H) ⁺.

Step 3: Synthesis of 2, 3-dihydrobenzo [b] [1, 4] dioxin-6-amine (Compound 28)

Compound 27 (200mg) , methanol (20mL) , and Pd/C (100mg ) catalysts were put into a 50mL of one-necked flask, and fully stirred to dissolve. And then hydrogen gas was bubbled into the reaction mixture at room temperature and reacted overnight. After, the reaction mixture was filtered and the filtrate was concentrated in vacuum to afford 190mg Compound 28, which was used in the next step without further purification. MS: 152 (M+H) ⁺.

Step 4: Synthesis of (E) -methyl 3- ( (2, 3-dihydrobenzo [b] [1, 4] dioxin-6-ylimino) methyl) -2-nitrobenzoate (Compound 29)

Compound 28 (190mg) , ethanol (20mL) and methyl 2-nitro-3-formyl-benzoate (20mL) were put in to a 50mL of two-necked flask under nitrogen, and then, the reaction mixture was heated to 75℃ and stirred overnight. After, the reaction mixture was cooled to room temperature and concentrated in vacuum to dryness to afford 220mg Compound 29, which was used in the next step without further purification. MS: 343 (M+H) ⁺.

Step 5: Synthesis of methyl 2- (2, 3-dihydrobenzo [b] [1, 4] dioxin-6-yl) -2H-indazole-7-carboxylate (Compound 30)

Compound 29 (220mg) , DMF (20mL) and sodium azide (60mg) were put into a 50mL of three-necked flask with stirring under nitrogen, and then the reaction mixture was heated to 95℃ and stirred overnight. After, the reaction mixture was cooled to room temperature and then poured into ice-water, further extracted with ethyl acetate. The separated organic phase was concentrated to dryness purified by chromatogram column, to afford 200mg Compound 30. MS: 311 (M+H) ⁺.

Step 6: Synthesis of 2- (2, 3-dihydrobenzo [b] [1, 4] dioxin-6-yl) -2H-indazole-7-carboxamide (Product 35)

A solution of Compound 30 (200mg) in methanol (30mL) was put into a sealed tube, and ammonia gas (2g) was bubbled into the solution. After, the reaction system was sealed and then heated to 70℃ and stirred overnight. After, the reaction mixture was concentrated in vacuum to dryness purified by recrystallized with ethyl acetate/petroleum ether, to afford 120mg product 35. ¹H NMR (400MHz, DMSO, ) : δ 9.22 (1H, s) , 8.54 (1H, br s) , 8.05-8.03 (1H, d) , 8.00-7.98 (1H, d) , 7.85 (1H, br s) , 7.70 (1H, s) , 7.64-7.61 (1H, d) , 7.27-7.23 (1H, d) . , 7.10-7.08 (1H, d) , 4.34 (4H, s) . MS: 296 (M+H) ⁺.

Example 36

2- (3, 4-dihydro-2H-benzo [b] [1, 4] dioxepin-7-yl) -2H-indazole-7-carboxamide (Product 36)

The product 36 is synthesized by using the same sequence and conditions as described for Example 35 and 1, 3-dichloropropane used instead of 1, 2-dichloroethane. ¹H NMR (400MHz, DMSO, ) : δ 9.26 (1H, s) , 8.54 (1H, s) , 8.06-8.04 (1H, d) , 8.00-7.98 (1H, d) , 7.86 (1H, s) , 7. 80-7.79 (1H, d) , 7.76-7.73 (1H, d) , 7.28-7.26 (1H, d) , 7.20-7.18 (1H, d) , 4.27-4.20 (4H, m) , 2.20-2.15 (2H, m) . MS: 310 (M+H) ⁺.

The desired product of Example 37--Example 45.

PHARMACOLOGICAL TESTING

Kinase Assays

Trevigen’s colorimetric assay kit for screening of PARP-1 inhibitors, and quantification of PARP-1 activity. Trevigen’s colorimetric assay kit for screening of PARP-1 inhibitors, and quantification of PARP-1 activity.

Assay Protocol:

A.Ribosylation Reaction

1. Remove strip wells from the wrapper and add 50μL/well of 1x PARP buffer to rehydrate the histones. Incubate at room temperature for 30 minutes. Remove the 1x PARP buffer from the wells by tapping the strip wells on paper towels.

2. Add serial dilutions of inhibitor to appropriate wells.

3. Add diluted PARP enzyme (0.15 Unit/well) to the wells, incubate for 10 minutes at room temperature. (Note: i. Activity control: 0.15 Unit/well PARP enzyme without inhibitors. These wells provide the 100％ activity reference point. ii. Negative control: A negative control without PARP should be prepared to determine background absorbance. )

4. Distribute 25μL of 1xPARP Cocktail into each well using a multichannel pipettor. Incubate the strip wells at room temperature for 60 minutes.

B. Detection

1. Wash strip wells 2 times with 1xPBS+0.1％ Triton X-100 (200μL/well) followed by 2 washes with 1xPBS. Ensure that all the liquid is removed following each wash by tapping strip wells onto paper towels.

2. Add 50μL per well of diluted Strep-HRP. Incubate at room temperature for 60 minutes.

3. Wash strip wells 2 times with 1xPBS + 0.1％ Triton X-100 (200μL/well) followed by 2 washes with 1xPBS. Ensure that all the liquid is removed following each wash by tapping strip wells onto paper towels.

4. Add 50μL per well of pre-warmed TACS-Sapphire^TM colorimetric substrate and incubate, in the dark, for 15 minutes at room temperature. Stop the reactions by adding 50μL per well of 0.2M HCl and read the absorbance at 450 nm.

Result:

Table 1

Example	IC₅₀(nM)
Example	IC₅₀(nM)	1	11.53
2	71.10	1	11.53
2	71.10	3	51.32
4	31.50	3	51.32
4	31.50	5	65.31
6	71.02	5	65.31
6	71.02	7	46.53
8	26.10	7	46.53
8	26.10	9	37.54
10	59.32	9	37.54
10	59.32	11	69.12
12	36.32	11	69.12
12	36.32	13	65.36
14	78.98	13	65.36
14	78.98	15	45.69
16	17.79	15	45.69
16	17.79	17	36.46
18	50.14	17	36.46
18	50.14	19	23.63
20	25.36	19	23.63
20	25.36	21	65.45
22	36.52	21	65.45
22	36.52	23	63.12
21	67.45	23	63.12
21	67.45	25	25.15
26	26.38	25	25.15
26	26.38	27	26.78
28	31.59	27	26.78
28	31.59	29	56.25

Example	IC₅₀(nM)
Example	IC₅₀(nM)	30	48.72
31	45.76	30	48.72
31	45.76	32	20.18
33	2.90	32	20.18
33	2.90	34	23.12
35	31.52	34	23.12
35	31.52	36	8.12
37	51.30	36	8.12
37	51.30	38	62.25
39	39.61	38	62.25
39	39.61	40	45.68
41	60.53	40	45.68
41	60.53	42	30.27
43	25.36	42	30.27
43	25.36	44	48.55
45	52.87	44	48.55
45	52.87	46	11.80

Cell Proliferation Assay

Assay protocol:

Cell proliferation analysis was conducted by the MTS assay protocol. Briefly, Hcc1937, T47D, NCI-H69, HGC27 and MKN45 cells will be cultured in RPMI1640 medium, MDA-MB-436, SK-OV-3, MGC803 cells will be cultured in DMEM medium, SK-N-MC cells will be cultured in MEM medium. All the cells will be cultured in the media supplemented with 10％ FBS, in the temperature of 37℃, 5％ CO₂ and 95％ humidity. The cells will be harvested respectively during the logarithmic growth period and counted with hemocytometer. The cell viability is over 98％ by trypan blue exclusion. Adjust cell concentrations to 1.5×10⁴ or 2×10⁴ cells/ml with respective medium. Add 100μL cell suspensions to 96-well plates (triplicates for each cell concentration), the final cell densities are 1.5×10³ or 2×10³ cells/well. The next day, dissolve the test article or positive drugs with DMSO as stock solution. Dispense 2μL drug solution in 1ml culture media. Add 200μl drug media into 96-well plates after discard the old media. The final concentration of drug will be 0, 0.03, 0.1, 0.3, 1, 3, 10, 30 or 100 μM. The plates will be cultured for another 5-10 days, then measured by means of MTS assay. Prepare MTS/PMS solution immediately prior to use, pipet 20 μLof the mixture into each well of the 96 well assay plate containing 100μL culture media. Incubate the plate for 1-4 hours at 37℃ in a humidified, 5％ CO₂ atmosphere. Record the absorbance at 490 nm using Victor X5 microplate spectrophotometer.

Result:

Table 2

Cellular PAR(poly-ADPribose) assay

In response to DNA damage, PARP-1 which is the main isoform of the PARP family, is rapidly activated. Once activated, NAD⁺ is consumed for the synthesis of the highly negatively charged polymer(PAR). Trevigen’s high throughput chemiluminescent ELISA to quantify PAR in cultured cells with pre-coated plate.

Assay protocol:

A. Preparation of cell extracts

1. Grow 2-10x10⁶ suspension cells or adherent cells in 6 well plate in complete medium. In next day, Add 2mL drug media into 6 well plates after discard the old media.

2. Suspension cells: Transfer the cells to prechilled 5mL microtubes, centrifuge at 1500rpm for 5min at 4℃. Discard the supernatant. Wash the cells one more time with 4 mL of ice cold 1xPBS. Suspend the cell pellets in 1mL of ice cold 1xPBS. Transfer to 1.5mL microtubes and centrifuge at 2000rpm in a microcentrifuge for 5min at 4℃. Discard the supernatant.

Adherent cells: Remove the medium and gently wash the cells with 5mL of PBS. Carefully pipette out the PBS. Repeat this step one more time. Place the plate on ice and immediately scrape the cells with a cell scraper to detachthe cells. Transfer to 1.5mL microtubes and centrifuge at 2000rpm in a microcentrifuge for 5min at 4℃. Discard the supernatant.

3. Resuspend the cell pellet in 50-100μL cell lysis buffer. Incubate the cell suspensions on ice, with periodic vortexing, for 15 minutes.

4. Add 20％ SDS to a final concentration of 1％.

5. Incubate cell extracts at 100℃ for 5 minutes. Cool to room temperature.

6. Add 0.01 volume of 100x Magnesium Cation and 2μL of DNase I. Vortex briefly and incubate at 37℃ for 90 minutes. This step degrades cellular DNA and reduces the viscosity of the extract.

7. Centrifuge at 12000rpm for 10 minutes at 4℃ to remove cellular debris. Save the supernatant.

8. Measure the protein concentration of the extracts with a BCA protein assay. Assay immediately for PAR or aliquot the extracts and store at -80℃.

B. Detection

1. Remove the pre-coated stripwells from the foil pouch.

2. Make serial dilutions of the PAR standard and test samples with sample buffer.

3. Add 50μL/well of the serially diluted PAR standards, diluted test samples and sample buffer (background control) to appropriate wells in duplicate.

4. In order to reach the maximal binding equilibrium, cover the wells with sealing film and incubate the strip wells overnight (16 ± 1 h) at 4℃.

5. Dilute the PAR polyclonal detecting antibody 1:250 fold in Antibody diluent and incubate at 25℃ one hour before use. Bring the incubated stripwells to room temperature. Gently remove the plate sealer and wash strip wells 4 times with PBST (200μL/well). Ensure that all liquid is removed by tapping strip wells onto paper towels.

6. Add 50μL per well of diluted PAR polyclonal detecting antibody. Cover the wells with sealing film and incubate at 25℃ for 2 hours.

7. Dilute the IgG-HRP conjugate 1:250 in Antibody diluent and incubate at 25℃ one hour before use. Gently remove the plate sealer and wash strip wells 4 times with PBST (200μL/well) . Ensure that all the liquid is removed by tapping strip wells onto paper towels.

8. Add 50μL per well of diluted Goat anti-Rabbit IgG-HRP conjugate. Cover the wells with sealing film and incubate at 25℃ for 1.0 hour. Place PeroxyGlow ^TM A and B reagents at 25℃ to pre-warm.

9. Gently remove the plate sealer and wash strip wells 4 times with PBST (200 μL/well) . Ensure that all the liquid is removed by tapping strip wells onto paper towels.

10. Just before use, mix equal volumes of PeroxyGlow^TM A and B together and add 100μL per well. Immediately take chemiluminescent readings.

Table 3

Xenograft tumor models

PARP-1 activity is essential for the repair of single DNA breaks (SSBs) through the base excision repair pathways (BER) . DNA methylating agents, including temozolomide (TMZ) and carboplatin, caused SSBs that required BER, however, if PARP-1 inhibitors are utilized to disable BER, the SSBs caused by the methylating agents could not be repaired. Subsequently these SSBs lead to double DNA breaks. Example 33 is a potent PARP-1 inhibitors, combination with chemotherapeutic drugs can enhanced the activity of therapy effect in vivo xenograft model.

Human breast cancer MX-1 and mouse melanoma B16F10 are expanded in culture, harvested, and injected subcutaneously onto the right flank of BALB/c nude mice and C57 mice. Tumor response is determined by tumor volume measurement performed twice a week during the course of treatment. Tumor volume inhibition (％ growth inhibition) is calculated by comparing treated groups to vehicle control group. Body weight is taken as a general measurement of drug toxicity.

Animals bearing MX-1 xenograft toumors were treated with Example 33 (30, 60, 120mg/kg, po, qd) in combination with carboplatin(10mg/kg, ip). This equated to 68.64％ tumor growth inhibition(TGI) between Example 33 (120mg/kg) combination with carboplatin, compared to a 40.98％ TGI for Example 33 (120mg/kg) and 13.22％ TGI for carboplatin alone. A considerableinhibition of tumor volumes as compared with that of the carboplatin alone group was observed for the carboplatin plus Example 33 (120mg/kg) combination. The B16F10 model, Example 33 (30, 60, 120mg/kg, po) was administered on days 1-11, while TMZ (50mg/kg, po, qd) was administered on days 1-5. Significant inhibition was observed with TGI vaues of 60.0％, 69.3％ and 73.1％ for the 30, 60 and 120mg/kg Example 33 combination groups, compared to a 27.8％ for TMZ alone. The Example 33/carboplatin and TMZ combination were tolerated. , Each treatment group matintain a stable body weight of mice and no emergence of drug toxicity during the experiment.

Although the present invention has been fully described in connection with embodiments thereof, it is to be noted that various change and modifications will become apparent to those skilled in the art. Such changes and modifications are to be understood as being included within the scope of the present invention as defined by the appended claim.

Claims

A compound of Formula I, pharmaceutically acceptable salts, prodrugs thereof, solvates thereof, or mixtures of any of the foregoing,

wherein,

A and B are each independently CR₃ or N； R₃ is H, halogen, C_1-6alkyl, halo-substituted C_1-6 alkyl, C_2-6alkenyl, halo-substituted C_2-6alkenyl, C_2-6alkynyl, halo-substituted C_2-6alkynyl or CN；

R₁ is H, OH, C_1-6alkyl or NR₇R₈； R₇ and R₈ are each independently H, C_1-6alkyl, halo-substituted C_1-6alkyl, C_2-6alkenyl, halo-substituted C_2-6alkenyl, C_2-6alkynyl, halo-substituted C_2-6alkynyl, C_1-6alkoxy, halo-substituted C_1-6alkoxy, or C_1-6alkylcarbonyl；

R₂ is H, halogen, C_1-6alkyl, halo-substituted C_1-6alkyl, C_1-6alkoxy, halo-substituted C_1-6alkoxy, or CN；

X is

m and n are each independently1, 2, or 3；

R₄ is H, halogen, C_1-6alkyl, halo-substituted C_1-6alkyl, C_1-6alkoxy, or halo-substituted C_1-6alkoxy；

R₅ is H, -OH, halogen, C_1-6alkyl, halo-substituted C_1-6alkyl, C_1-6alkoxy, halo-substituted C_1- ₆alkoxy, C_3-6cycloalkyl, halo-substituted C_3-6cycloalkyl, NR₁₁R₁₂, C_1-6alkyl (NR₁₁R₁₂) , C_1-6alkoxycarbonyl or
wherein

R₁₁ and R₁₂ are each independently H, C_1-6alkyl, or C_1-6alkoxy.

v is 0, 1 or 2；

R₉ is H, C_1-6alkyl, halo-substituted C_1-6alkyl, C_2-6alkenyl, C_3-6cycloalkyl or C_3-6 cycloalkylC_1-4alkyl；

R₁₀ is H, C_1-4alkyl or C_2-4alkenyl；

or

R₉ and R₁₀, together with the atoms to which they are attached, to form a dihydrofuran ring or tetrahydrofuran ring；

Z is a substituted or unsubstituted 5-15 membered nonaromatic monocycle which includes at least two heteroatoms selected from N, O or S,；

p is 1 or 2；

each R₆ is independently H, halogen, C_1-6alkyl or halo-substituted C_1-6alkyl.
The compound of Claim 1, wherein R₁ is H, C_1-6alkyl or OH.
The compound of Claim 1 or 2, wherein R₁ is H, C_1-3alkyl, or OH.
The compound of any of Claims 1-3, wherein R₁ is H, methyl, or OH.
The compound of any of Claims 1-4, wherein R₁ is H.
The compound of any of Claims 1-5, R₂ is H, halogen, C_1-6alkyl, C_1-6alkoxy, or halo-substituted C_1-6alkoxy.
The compound of any of Claims 1-6, wherein R₂ is H, F, C_1-3alkyl, C_1-3alkoxy, or . halo-substituted C_1-3alkoxy.
The compound of any of Claims 1-7, wherein R₂ is H, F, methyl, methoxyl, or chlorine-substituted methoxyl.
The compound of any of Claims 1-8, wherein R₂ is H.
The compound of any of Claims 1-9, wherein A is CR₃.
The compound of any of Claims 1-10, wherein R₃ is H or C_1-6alkyl.
The compound of any of Claims 1-11, wherein R₃ is H.
The compound of any of Claims 1-12, wherein B is N.
The compound of any of Claims 1-13, wherein X is
The compound of any of Claims 1-14, wherein R₄ is H, C_1-6alkyl , or C_1-6alkoxy.
The compound of any of Claims 1-15, wherein R₄ is H.
The compound of any of Claims 1-16, wherein R₅ is H, OH, C_1-6alkyl, C_1-6alkoxy, C_1-6 alkyl (NR₁₁R₁₂) , or
The compound of any of Claims 1-17, wherein, R₅ is H, OH, C₁-₃alkyl, C₁-₃alkyl (NR₁₁R₁₂) , or
The compound of any of Claims 1-18, wherein R₅ is
The compound of any of Claims 1-19, wherein v is 0, or 1.
The compound of any of Claims 1-20, wherein v is 0.
The compound of any of Claims 1-21, wherein R₉ is H, C_1-6alkyl, or C_2-6alkenyl.
The compound of any of Claims 1-22, wherein R₉ is H, C_1-4alkyl, or C_2-4alkenyl.
The compound of any of Claims 1-23, wherein R₉ is H, methyl, ethyl, propyl,
The compound of any of Claims 1-24, wherein R₁₀ is H, C_1-6alkyl, or C_2-6alkenyl.
The compound of any of Claims 1-25, wherein R₁₀ is H, C_1-3alkyl, or C_2-3alkenyl.
The compound of any of Claim 1-26, wherein R₁₀ is H, methyl, ethyl,
The compound of any of Claims 1-21, wherein R₉ and R₁₀, together with the atoms to which they are attached, to form a dihydrofuran ring or tetrahydrofuran ring.
The compound of any of Claims 1-18, wherein R₅ is C_1-6 alkyl (NR₁₁R₁₂) , and R₁₁ and R₁₂ are independently C_1-3 alkyl.
The compound of any of Claims 1-18 and 29, wherein R₁₁ and R₁₂ are all methyl.
The compound of any of Claims 1-18 and 29-30, wherein R₅ is
The compound of any of Claims 1-18, wherein R₅ is H, OH, methyl, ethyl, or
The compound of any of Claims 1-18 and 32, wherein R₅ is H.
The compound of any of Claims 1-13, wherein X is
The compound of any of Claims 1-13 and 34, wherein p is 1, or 2.
The compound of any of Claims 1-13 and 34-35, wherein p is 2.
The compound of any of Claims 1-13 and 34-36, wherein each R₆ is independently H, or C_1-6alkyl.
The compound of any of Claims 1-13 and 34-37, wherein each R₆ is independently methyl.
The compound of any of Claims 1-13 and 34-38, wherein Z is a substituted or unsubstituted 5-15 membered nonaromatic monocycle which includes at least two heteroatoms selected from O or S.
The compound of any of Claims 1-13 and 34-39, wherein Z is a substituted or unsubstituted 5-15 membered nonaromatic monocycle which includes 2-5 heteroatoms selected from O or S.
The compound of any of Claims 1-13 and 34-40, wherein Z is substituted or unsubstituted 5, 6, 7, 8, 9, 11, 12, or 15 membered nonaromatic monocycle which includes 2, 3, 4, or 5 heteroatoms selected from O or S.
The compound of any of Claims 1-13 and 34-41, wherein Z is 5, 6, 7, 8, 9, 12, or 15 membered nonaromatic monocycle which includes 2, 3, 4, or 5 oxygen atoms.
The compound of any of Claims 1-13 and 34-42, wherein Z is
The compound of Claim 1, the compound is of Formula II,

Wherein, s is 1, 2 or 3； t is 1 or 2； R₅ is H, OH, C_1-6alkyl, C_1-6alkoxy, C_1-6 alkyl (NR₁₁R₁₂) , or
The compound of Claim 44, wherein t is 1.
The compound of Claim 44, wherein t is 2.
The compound of any of Claims 44-46, wherein s is 1.
The compound of any of Claims 44-46, wherein s is 3.
The compound of any of Claims 44-48, wherein, R₅ is H, OH, C_1-3alkyl, or
The compound of any of Claims 44-49, wherein R₅ is
v is 0； R₉ is H, C_1- ₄alkyl, or C_2-4alkenyl； and R₁₀ is H, C_1-3alkyl, or C_2-3alkenyl.
The compound of any of Claims 44-50, wherein R₉ is H, methyl, ethyl, propyl,
The compound of any of Claims 44-50, wherein R₁₀ is H, methyl, ethyl,
The compound of any of Claims 44-49, wherein R₅ is H, OH, methyl, ethyl or
The compound of any of Claims 44-49, wherein R₅ is H.
The compound of Claim 1, wherein the compound is of Formula III,

Wherein, Z₁ is a substituted or unsubstituted 5, 6, 7, 8, 9, 11, 12, or 15 membered nonaromatic monocycle which includes 2, 3, 4, or 5 heteroatoms selected from O or S.
The compound of Claim 55, wherein Z₁ is a substituted or unsubstituted 5, 6, 7, 8, 9, 12, or 15 membered nonaromatic monocycle which includes 2, 3, 4, or 5 oxygen atoms.
The compound of Claim 55 or 56, wherein Z₁ is a unsubstituted 5, 6, 7, 8, 9, 12, or 15 membered nonaromatic monocycle which includes 2, 3, 4, or 5 oxygen atoms.
The compound of Claim 55, wherein Z₁ is
The compound of any of Claims 55-58, wherein Z₁ is
The compound of Claim 1, wherein the compound is:

1) 2- (4- (3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

2) 2- (4- (1- (methoxymethyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

3) 2- (4- (1-methyl-3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

4) 2- (4- (1-ethyl-3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

5) 2- (4- (1-isopropyl-3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

6) 2- (4- (1-hydroxy-3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

7) 2- (4- (1- (ethoxymethyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

8) 2- (4- (1- (2-methoxyethyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

9) 2- (4- (1- (1-hydroxyallyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

10) 2- (4- (1- (hydroxymethyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

11) 2- (4- (1- (1-hydroxyethyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

12) 2- (4- (1- (1-hydroxypropyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

13) 2- (4- (1- (1-hydroxybutyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

14) 2- (4- (1- (1-hydroxy-3-methylbutyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

15) 2- (4- (1- (1-hydroxybut-3-enyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

16) 2- (4- (1- (1-methoxyethyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

17) 2- (4- (1- (1-methoxypropyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

18) 2- (4- (1- (1-methoxybutyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

19) 2- (4- (1- (1-methoxy-3-methylbutyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

20) 2- (4- (1- (1-methoxybut-3-enyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

21) 2- (4- (1- (1-ethoxybut-3-enyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

22) 2- (4- (1- (1- (allyloxy) allyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

23) 2- (4- (1- (2, 3-dihydrofuran-2-yl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

24) 2- (4- (1- (tetrahydrofuran-2-yl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

25) 2- (4- (1- (methoxymethyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -5-methyl-2H-indazole-7-carboxamide

26) 5-fluoro-2- (4- (1- (methoxymethyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide

27) 5-methoxy-2- (4- (1- (methoxymethyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide

28) 2- (4- (1- (methoxymethyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -N-methyl-2H-indazole-7-carboxamide

29) N-hydroxy-2- (4- (1- (methoxymethyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide

30) 2- (4- (1- (methoxymethyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -3-methyl-2H-indazole-7-carboxamide

31) 3-chloro-2- (4- (1- (methoxymethyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide

32) 2- (4- (1- (2- (dimethylamino) ethyl) -3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -2H-indazole-7-carboxamide

33) 2- (4- (3-azabicyclo [3.1.0] hexan-1-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

34) 2- (4- (octahydrocyclopenta [c] pyrrol-3a-yl) phenyl) -2H-indazole-7-carboxamide hydrochloride

35) 2- (2, 3-dihydrobenzo [b] [1, 4] dioxin-6-yl) -2H-indazole-7-carboxamide

36) 2- (3, 4-dihydro-2H-benzo [b] [1, 4] dioxepin-7-yl) -2H-indazole-7-carboxamide

37) 2- (2, 3, 4, 5-tetrahydrobenzo [b] [1, 4] dioxocin-8-yl) -2H-indazole-7-carboxamide

38) 2- (benzo [d] [1, 3] dioxol-5-yl) -2H-indazole-7-carboxamide

39) 2- (2, 2-dimethylbenzo [d] [1, 3] dioxol-5-yl) -2H-indazole-7-carboxamide

40) 2- (2, 3, 5, 6, 8, 9-hexahydrobenzo [b] [1, 4, 7, 10] tetraoxacyclododecin-12-yl) -2H-indazole-7-carboxamide

41) 2- (2, 3, 5, 6-tetrahydrobenzo [b] [1, 4, 7] trioxonin-9-yl) -2H-indazole-7-carboxamide

42) 2- (2, 3, 5, 6, 8, 9, 11, 12-octahydrobenzo [b] [1, 4, 7, 10, 13] pentaoxacyclopentadecin-15-yl) -2H-indazole-7-carboxamide

43) 2- (2, 3, 5, 6, 8, 9-hexahydrobenzo [b] [1, 4, 7, 10] tetraoxacyclododecin-12-yl) -2H-indazole-7-carboxamide

44) 2- (2, 3, 4, 6, 7, 8-hexahydrobenzo [b] [1, 4, 8] dioxathiacycloundecin-11-yl) -2H-indazole-7-carboxamide

45) 2- (2, 3, 4, 6, 7, 8-hexahydrobenzo [i] [1, 7, 4] dioxasulfonylcycloundecin-11-yl) -2H- indazole-7-carboxamide；

46) 2- (4- (3-azabicyclo [4.1.0] heptan-6-yl) phenyl) -3a, 7a-dihydro-1H-benzo [d] imidazole-4-carboxamide hydrochloride.
A pharmaceutical composition comprising the compound according to any of Claims 1-61, and a pharmaceutically acceptable excipient.
The compound of any of Claims 1-60 or the pharmaceutical composition according to Claim 61 for use as a medicament.
The compound or pharmaceutical composition for use according to Claim 62, wherein the said medicament is used as a chemo-or radiosensitizer for cancer treatment.
The compound or pharmaceutical composition for use according to Claim 62, wherein the said medicament is used in treating , preventing, or delaying the conditions which can be ameliorated by the inhibition of poly (ADP-ribose) polymerase (PARP) .
The compound or pharmaceutical composition for use according to Claim 62, wherein the said medicament is used in treating, preventing, or delaying the onset or progression of cancer, inflammatory diseases, reperfusion injuries, ischemic conditions, stroke, chronic or acute renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infection, retinal damage, skin senescence or UV-induced skin damage.
The compound or pharmaceutical composition for use according to Claim 65, wherein the said inflammatory diseases are 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.
The compound or pharmaceutical composition for use accordint to Claim 65, wherein the said ischemic conditions are conditions resulted from organ transplantation.
The compound or pharmaceutical composition for use according to Claim 65, wherein the said diabetes mellitus are 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.
The compound or pharmaceutical composition for use according to Claim 65, wherein the said neurodegenerative diseases are 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 compound or pharmaceutical composition for use according to Claim 65, wherein the said cancer is solid tumors, blood-borne cancers, acute and chronic leukemias, Lymphomas, central nervous system (CNS) , brain cancers, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, small cell lung cancer, gastric cancer, neuroepithelial tumor, cancer being deficient in Homologous Recombination (HR) dependent DNA double strand break (DSB) repair activity, BRCA-1 or BRCA-2 deficient tumors.
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 mellitus, neurodegenerative diseases, retroviral infection, retinal damage， skin senescence or UV-induced skin damage, comprises a step of administering to a subject in need thereof an effective amount of a compound according to any of Claims 1-60, or the pharmaceutical composition according to Claim 61, for simultaneous, separate or sequential administration.
The method according to Claim 71, the said inflammatory diseases are 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.
The method according to Claim 71, the said ischemic conditions are those resulted from organ transplantation.
The method according to Claim 71, the said diabetes mellitus are 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.
The method according to Claim 71, the said neurodegenerative diseases are 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 method according to Claim 71, the said cancer are solid tumors, blood-borne cancers, acute and chronic leukemias, Lymphomas, central nervous system (CNS) , brain cancers, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, small cell lung cancer, gastric cancer, neuroepithelial tumor, cancer being deficient in Homologous Recombination (HR) dependent DNA double strand break (DSB) repair activity, BRCA-1 or BRCA-2 deficient tumors.
A method, of treating or preventing a cancer, comprising a step of administering to a subject in need thereof an effective amount of a compound according to any of Claims 1-60, or the pharmaceutical composition according to Claim 61 for simultaneous, separate or sequential administration.
A method of treating and/or preventing a cancer being deficient in HR dependent DNA DSB repair pathway, comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to any of Claims 1-60, or the pharmaceutical composition according to Claim 61.
The method according to Claim 77 or 78, the said cancer comprises one or more cancer cells having a reduced or abrogated ability to repair DNA DSB by HR relative to normal cells.
The method according to 79, 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.
The method, 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 according to Claim 80, wherein said cancer cells are deficient in BRCA-1 or BRCA-2.
The method according to any of Claims 77-81, the said subject is heterozygous for a mutation in a gene encoding a component of the HR dependent DNA DSB repair pathway.
The method according to any of Claims 77-81, the said subject is heterozygous for a mutation in BRCA-1 and/or BRCA-2.
The method according to Claims 70 and 76-83, the said cancer is breast cancer, ovary cancer, pancreatic cancer or prostate cancer.
The method according to any of Claims 77-84, of treating and/or preventing cancer, further comprising administering to a subject anti-cancer agent or chemotherapeutic agents, for simultaneous, separate or sequential administration.
The method according to any of Claims 77-85, of cancer therapy or for potentiating tumor cells for treatment, further comprises administration of ionizing radiation or chemotherapeutic agent.
A method of chemotherapy or radiotherapy, comprising administering to a subject in need of treatment a therapeutically-effective amount of compound according to any of Claims 1-60, or the pharmaceutical composition according to claim 61.
The method according to any of Claims 70-86, whererin the compound according to any of Claims 1-60 or the pharmaceutical composition according to Claim 61 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 method according to any of Claims 70-87, comprising administering to the subject a composition comprinsing compound according to any one Claims of 1-60, in the range of about 100 μg to about 250mg per kilogram body weight of the subject per day.
The method according to any of Claims 70-88, wherein the instant compounds are also useful in combination with anti-cancer agents or chemotherapeutic agents such as proteasome inhibitors , topoisomerase inhibitors , alkylating agents, anti-mitotic agents, inhibitors of mitotic kinesins, antiproliferative agents, monoclonal antibody, HMG-CoA reductase inhibitors, apoptosis inducing agents , integrin blockers, angiogenesis inhibitors and other therapeutic agents that modulate or inhibit angiogenesis, inhibitor of inherent multidrug resistance (MDR) , anti-emetic agents, an immunologic-enhancing drug.
The method according to any of Claims 70-89, wherein the instant compounds are also useful in combination with ionizing radiation and/or in combination with a second compound : 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-γagonist, 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.