TW200836731A - Amide substituted indazoles as poly (ADP-ribose) polymerase (PARP) inhibitors - Google Patents

Abstract

The present invention relates to compounds of formula I: and pharmaceutically acceptable salts, stereoisomers or tautomers thereof which are inhibitors of poly (ADP-ribose) polymerase (PARP) and thus useful for the treatment of cancer, inflammatory diseases, reperfusion injuries, ischemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes, neurodegenerative diseases, retroviral infection, retinal damage or skin senescence and UV-induced skin damage, and as chemo- and/or radiosensitizers for cancer treatment.

Description

200836731 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to guanamine substituted carbazoles, which are previously known as poly(ADP-ribose) synthase and poly(ADP-ribosyl)transferase enzymes. Inhibitor of poly(ADP-ribose) polymerase (PARP). The compounds of the present invention are useful as monotherapy for tumors with specific defects in the DNA repair pathway and as inhibitors of certain DNA damaging agents such as anticancer agents and radiation therapy. Moreover, the compounds of the invention are useful for reducing cell necrosis (in stroke and myocardial infarction), down-regulating inflammation and tissue damage, treating retroviral infections, and resisting chemotherapy toxicity. [Prior Art] Poly(ADP-ribose) polymerase (PARP) constitutes a superfamily of 18 proteins containing the catalytic domain of PARP (5/ο α (2004) 26:1148). Such proteins include PARP-1, PARP-2, PARP-3, tankyrase-1, terminal anchor polymerase-2, vaultPARP and TiPARP. PARP-1 (basal member) is composed of three main domains: an amino group (N)-terminal DNA-binding domain (DBD) containing two words, a self-modifying domain, and a carboxyl group (C)_end Catalytic domain. PARP is a nuclear and cytoplasmic enzyme that cleaves NAD+ into nicotinamide and ADP-ribose to form a branched-length ADP-ribose polymer on the target protein, including topoisomerase, histone, and PARP. Self-Ties. (1998) 245:1-10) Anthraquinone (ADP-ribosyl) polymerization is involved in several biological processes including DNA repair, gene transcription, cell cycle progression, cell death, chromatin function, and gene 127700.doc 200836731 . The catalytic activity of PARP-1 and PARP-2 has been rapidly stimulated by DNA strand breaks (see Corpse (2005) 52: 25-33). In response to DNA damage, PARP-1 binds to single-stranded and double-stranded DNA gaps. Under normal physiological conditions, PARP has minimal activity, however, when DNA is damaged, PARP activity is instantly activated up to 500-fold. Both PARP-1 and PARP-2 can detect DNA strand breaks, so they can be used as gap receptors to provide a fast signal for stopping transcription and to supplement the enzymes required for DNA repair. Since many chemical treatments and radiation treatments for cancer treatment play a role in DNA damage, PARP inhibitors can be used as chemical sensitizers and radiosensitizers for cancer treatment. It is reported that PARP inhibitors are effective for radiosensitizing hypoxic tumor cells (U.S. Patent No. 5,032,617, U.S. Patent No. 5,215,738, and U.S. Patent No. 5,041,653). Related: Can affect the target egg. This (ADP-ribosyl) polymerization process of nature and function of white; PAR oligomers that produce different cellular effects upon cleavage of (ADP-ribosyl) polymeric proteins; physical association of PARP and nuclear proteins that form functional complexes Reduced cell levels; (TVaiwre (2005) 4:421-440). In addition to participating in DNA repair, PARP can also be used as a mediator of cell death. Over-activation of PARP under pathological conditions such as ischemia and reperfusion injury can result in substantial loss of NAD+ between cells, which can result in several NAD+-dependent metabolic pathways being impaired and leading to cell death (see (2005) 52). :44-59). As a result of PARP live 127700.doc 200836731, NAD + levels decreased significantly. Excessive PARP activation can cause severe NAD+ deficiency in cells that are severely damaged by DNA. The shorter half-life of poly(ADP-ribose) produces a rapid conversion rate, which is due to the rapid degradation of the constitutively active poly(ADP-ribose) sugar hydrolase (PARG) as a result of the formation of poly(ADP-ribose). PARP and PARG form a cycle that converts a large amount of NAD+ to ADP-ribose, resulting in a reduction in NAD+ and ATP to less than 20% of normal levels. This condition is particularly detrimental during ischemia, when oxygen loss has severely compromised cellular energy output. I believe that the subsequent free radical generation in the reperfusion process is the main cause of tissue damage. Partial ATP reduction (commonly seen in many organs during ischemia and reperfusion) may be associated with NAD+ deficiency caused by poly(ADP-ribose) turnover. Therefore, it is expected that PARP inhibition can maintain cellular energy levels, thereby enhancing the survival rate of ischemic tissue after injury. Thus, compounds that are PARP inhibitors are useful in the treatment of conditions caused by PARP-mediated cell death, including neurological disorders such as stroke, trauma, and Parkinson's disease. Parkerson's disease has been demonstrated to be useful for PARP inhibitors. Killing BRCA-1 and BRCA-2 deficient tumors with π (2005) 434: 913-916 and 917-921; Cancer Biology & Therapy (2005) 4: 934-936) ° PARP inhibitors have been shown to promote anticancer The efficacy of the drug (Pharmacological Research (2005) 52:25-33), such as the start compound C/zemoi/zer P/mrmwo/ (1993) 33:157-162 and Mo /C still cw 772er (2003) 2:371-382). PARP inhibitors have been shown to increase the antitumor activity of topoisomerase I inhibitors such as irinotecan 127700.doc 200836731 (Irinotecan) and topotecan (Mo/C(10)cer 77^r (2003) 2:371 -382; and C7z> (2000) 6:2860_2867) and this has been demonstrated in an in vivo model (J Cancer /wi (2004) 96:56-67). It has been demonstrated that PARP inhibitors can restore to temozolomide (temozolomide) ( TMZ) Sensitivity to cytotoxic and anti-proliferative effects (see Cw " Med C/zem (2002) 9: 1285-1301 and MW C/zem (2004) 1: 144-150). This has been in many in vitro models (Heart J Cancer (1995) 72: 849-856; Br J Cancer (1996) 74: 1030-1036; Mol Pharmacol (1997) 52: 249-258; Leukemia (1999) 13: 901 -909; G/k (2002) 40:44_54; and C7z> C training cer and (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 and J TVai/ Cancer //7W (2004) 96:56-67). It has also been demonstrated that PAPR inhibitors prevent the appearance of necrosis caused by selective #3-adenine methylation reagents such as Me0S02(CH2)-lexitropsin (Me-Lex) (corpse/zarm/(9g/ca/ Tiaearc/z (2005) 52:25-33) PAR has been shown to be useful as a radiosensitizer for PARP inhibitors. It has been reported that PARP inhibitors are effective in radiosensitizing (hypoxic) tumor cells and effectively preventing tumor cells from being treated with radiation. Potential death from DNA (5r. J. Cancer (1984) 49 (Supplement VI): 34-42; and /W. J. Shan·αί. 5/oz·· (1999) 75:91-100) and Sublethal death (C7h· Ομο/· (2004) 16(1): 29-39) damage recovery, presumably by virtue of its ability to prevent re-binding of DNA strand breaks and by affecting several DNA-damaging signaling pathways 127700.doc 200836731 PARP inhibitors have also been shown to be useful in the treatment of acute and chronic cardiomyopathy (see I Pharmacological (2005) 52: 34-43). For example, it has been demonstrated that PARP inhibitors alone in rabbits have been shown to be Reinfusion of the heart or skeletal muscle and reduction of infarct size caused by ischemia. In these studies, 1 minute before occlusion or reperfusion A single injection of 3-amino-benzamide (10 mg/kg) in the first minute resulted in a similar reduction in infarct size (32-42%) in the heart and another PARP inhibitor 1,5-dihydroxyisoquinoline (1 mg/kg) reduces the infarct size to a considerable extent (38-48%). Based on these results, it is reasonable to set the PARP inhibitor to rescue the reperfusion injury of the previously ischemic heart or skeletal muscle tissue. 1997) 94: 679-683). In pigs (five J. corpse Aarmaeo/. (1998) 359: 143-150 and d. Swrg. (2002) 73: 575-581) and in dogs (572 〇) Similar findings have been reported in ci (2004) 21:426-32. PARP inhibitors have been shown to be useful in the treatment of certain vascular diseases, septic shock, ischemic injury and neurotoxicity. Acta (1989) 1014:1-7 J. Clin, Invest. (1997) 100: 723-73 5). Oxygen free radical DNA damage leading to DNA strand breaks (which can be subsequently identified by PARP) is a major contributor to these pathologies, as evidenced by the PARP Inhibitors Institute (J. Λα. (1994) 39:38- 46 and corpse 45 (1996) 93: 468 8-4692). PARP has also been shown to play an important role in the pathogenesis of hemorrhagic shock (see P. (2000) 97: 10203-10208). PARP inhibitors have been shown to be useful in the treatment of inflammatory diseases (see (2005) 52: 72-82 Spear 83-92). It has also been shown that by inhibiting PARP activity, mammalian cells can be blocked by 127700.doc -10- 200836731 Retroviral infection. Inhibition of these recombinant retroviral mediator infections has been shown to occur in a variety of different cell classes (J. hro/ogj;, (1996) 70(6): 3 992-4000). Therefore, PARP inhibitors for antiviral therapy and cancer treatment have been developed (WO 91/18591). In vitro and in vivo experiments have demonstrated that PARP inhibitors can be used to treat or prevent autoimmune diseases such as type 1 diabetes and diabetic complications (Pharmacological Research (20Q5) 52:60-7. It is speculated that PARP inhibition can delay human fibroblasts. Aging characteristics appear (Biochem. Biophys. Res. Comm· (Ϊ994) 20ί(2)'665-672 Anti-Pharmacological Research (2005) 52:93-99) ° ilt can be used in the control of telomere Role-dependent Ge/7·, (1999) 23(1): 76-80). The vast majority of PARP inhibitors interact regularly with the nicotinamide binding domain of the enzyme and are equivalent to a competitive inhibitor of NAD+ (5χρπί 77ζπ·尸如 (2004) 14:153 1-155 1). Structural analogs of the nicotinamide such as benzamide and derivatives belong to the primary compound to be studied as a PARP inhibitor. However, these molecules have weak inhibitory activity and have other effects that are not associated with PARP inhibition. Therefore, there is a need to provide potent inhibitors of PARP enzymes.

Structurally related PARP inhibitors have been previously described. WO 1999/59973 discloses a guanamine-substituted benzene ring fused to a 5-membered heteroaromatic ring; W0200 1/85687 discloses a guanidine-substituted oxime; WO 1997/04771, WO 2000/26192, WO 2000/32579 WO 2000/64878, WO 2000/68206, WO 2001/21615, WO 2002/068407, WO 127700.doc -11 - 200836731 2 003/1 06430 and WO 2004/096793 disclose benzimidazole substituted by decylamine; WO 2000/29384 discloses benzimidazole and hydrazine substituted with decylamine; and European Patent EP 0879820 discloses benzoxazole substituted with decylamine. It has now surprisingly been found that the indoleamine substituted oxazoles of the present invention exhibit particularly high levels of inhibition of poly(ADP-ribose) polymerase (PARP) activity. As a result, the compounds of the present invention are especially useful as inhibitors of PARP-1 and/or PARP-2. These compounds also showed particularly good levels of cellular activity, demonstrating good antiproliferative effects in BRCA1 and BRCA2-deficient cell lines. "' [Invention] The present invention provides a compound of formula I:

Wherein: R1 is hydrogen or fluorine; and R2 is hydrogen or fluorine; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. In one embodiment, R1 is hydrogen. In another embodiment, R1 is fluoro. In one embodiment, R2 is hydrogen. In another embodiment, R2 is fluoro. In one embodiment, R1 is hydrogen and R2 is hydrogen or fluorine. In another embodiment, R1 is fluoro and R2 is hydrogen or fluoro. 127700.doc -12- 200836731 In another embodiment, R1 is hydrogen and R2 is hydrogen. In another embodiment, R1 is hydrogen and R2 is fluorine. In another embodiment, R1 is fluoro and R2 is fluoro. In another embodiment, R1 is hydrogen or fluorine and R2 is hydrogen. In another embodiment, R1 is hydrogen or fluorine and R2 is fluorine. The invention also provides a compound of formula II: CONH.

(Π) wherein R1 and R2 are as defined above; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. The invention also provides a compound of formula III:

Wherein R1 and R2 are as defined above; or a pharmaceutically acceptable salt or tautomer thereof. The invention also provides a compound of formula IV:

(IV) 127700.doc -13- 200836731 wherein R1 and R2 are as defined above; or a pharmaceutically acceptable salt or tautomer thereof. [Embodiment] The preferred identities of the formulae II, III and IV are as defined above for the formula (with necessary modifications). The invention also encompasses within its scope N-oxides of the compounds of formula I above. In general, such N-oxides can be formed on any of the available nitrogen atoms. The N-oxides can be formed by conventional methods (e.g., by reacting a compound of formula j with an oxone in the presence of moist soil). The present invention encompasses, in its scope, prodrugs of the above formula. In general, such peony may be a functional derivative of a compound of formula I which is readily converted in vivo to the desired formula. A conventional procedure for selecting and preparing suitable prodrug derivatives is described, for example, in "Design 〇f pr〇drugsn,"

Written by Bundgaard, Elsevier, 1985. The prodrug may be a pharmacologically inert derivative of a biologically active substance ("parent drug" or "parent molecule,", which is required to be converted in vivo to release the active drug and which has improved delivery properties over the parent drug molecule. In vivo transformation can be the result, for example, of certain metabolic processes (e.g., chemical or enzymatic hydrolysis of a carboxylic acid ester, phosphate or sulfate, or reduction or oxidation of a sensitive functional group). The present invention encompasses within its scope solvates of the compounds and salts thereof, for example, hydrates. The compounds of the present invention may have an asymmetric center, a palm axis, and a palm plane (as described in the following: EL·Eliel and s H. wiien,

Stereochemistry of Carbon Compounds ^ John Wiley & Sons ^? 127700.doc -14- 200836731 New York, tearing 'Pages (1) 9-(10)), and as racemic isomers, racemic mixtures, and as individual diastereoisomers Isomers are present along with all possible isomers and mixtures thereof, including optical isomers, and all such stereoisomers are encompassed by the present invention. Furthermore, the compounds disclosed herein can be considered as tautomers and both tautomeric forms are encompassed within the scope of the invention, even if only one tautomeric structure is illustrated. The compounds may exist in different isomeric forms, and all such isomeric forms are encompassed by the present invention. These compounds can exist in many different polymorphic forms. As used herein, C!·6 alkyl represents a branched, straight-chain, and cyclic saturated aliphatic hydrocarbon group containing one, two, three, four, five, or six gorgon atoms. For example, nCi_6 alkyl" specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, di-butyl, iso-butyl, pentyl, hexyl, cyclopropyl. , cyclobutyl, cyclopentyl and cyclohexyl, etc. Preferred alkyl groups are methyl and ethyl. Specific compounds belonging to the scope of the invention are: 3-{4-[7-(aminocarbonyl) chloride -2//-carbazol-2-yl]phenyl}hexahydroacridine rust; 2-{4_[(3R)-hexahydropyridin-3-yl]phenylcarbazole-7-formamide; -{4-[(38)_hexahydropyridin-3-yl]phenyl}-2孖-carbazole-7-formamide; 3-{4-[7-(aminocarbonyl)-trifluoroacetate- 5-fluoro-27/-oxazol-2-yl]phenyl} hexahydrogen ratio σ 镔; 5-fluoro-2-(3-fluoro-4-hexahydropyridin-3-ylphenyl)-2 Open-carbazole-7-formamide trifluoroacetate; 127700.doc -15- 200836731 3-{4-[7-(aminocarbonyl)-2H-indazol-2-yl]phenyl trifluoroacetate } hexahydrobaridine rust; 5-fluoro-2-(4-hexahydropyridin-3-ylphenyl)-2Η·carbazole-7-carbamamine; chlorinated (3S)-3-{4-[ 7-(Aminocarbonyl)-2Η·oxazol-2-yl]phenyl}hexahydropyridinium; gasification (3R)-3-{4-[7-(aminocarbonyl)-2Η-carbazole -2-yl]phenyl}hexahydropyridine rust; (R) -5-fluoro-2-(4-hexahydropyridin-3-ylphenyl)-2-indole-indazole-7-carboxamide; (S)-5-fluoro-2-(4-hexahydro) Pyridin-3-ylphenyl)-2indole-carbazole-7-formamide; (R)-5-fluoro-2-{3·fluoro-4_hexahydroacridin-3-ylphenyl}-2Η - carbazole-7-formamide; (S) -5-fluoro-2-{3-fluoro-4-hydropyridin-3-ylphenyl}-2 oxime-carbazole-7-carboxamide; The pharmaceutically acceptable salts, free bases or tautomers thereof. Stereoisomers of such compounds are also provided. The specific compounds of the invention are: 3-{4-[7-(aminocarbonyl)- 2//-carbazol-2-yl]phenyl}hexahydropyridinium pyridine; or a pharmaceutically acceptable free base or tautomer thereof. Also provided are stereoisomers of the compound. The compound is: 2-d[(3R)-hexahydroacridin-3-yl]phenylpyrazole·7-formamide; or a pharmaceutically acceptable salt, free base or tautomer thereof. The stereoisomer of this compound is provided. 127700.doc -16- 200836731 The specific compound of the invention is: 2-{4-[(3S)-hexahydropyridin-3-yl]phenylcarbazole-7-formamidine An amine; and a pharmaceutically acceptable salt, free base or tautomer thereof. The stereoisomer of this compound is provided. The specific compound of the present invention is: 3-D4-[7-(aminocarbonyl)-5-fluoro-2//-oxazol-2-yl]phenyl } Hexahydropyridinium; or a pharmaceutically acceptable free base or tautomer thereof. This compound is also provided as a stereoisomer. The specific compound of the present invention is 5_fluoro-2-(3-fluoro-4·hexahydropyridin-3-ylphenyl)-2//-carbazole _7_methantamine trigas acetate; or a pharmaceutically acceptable free base or tautomer thereof. Also provided are stereoisomers of this compound. The specific compounds of the invention are: c; 4·methylbenzene Sulfonic acid (3S)-3-{4-[7-(aminocarbonyl)-2H-indazol-2-yl]phenyl}hexahydrogen ratio sigma; or its pharmaceutically acceptable free base or Tautomers. Stereoisomers of such compounds are also provided. The present invention includes the free bases of the compounds of Formula I, as well as pharmaceutically acceptable | and stereoisomers thereof. The atom and /戋== are protonated to form a salt. The term "free base" means that the substance is in a non-salt form. The pharmaceutically acceptable salts encompassed include not only exemplary salts of the specific compounds described herein. And also includes all the travels of 127700.doc -17- 200836731 from the typical medicinal formula of the compound of formula i and < 盟. W # language type can be good " ". (Iv) of formula 6 using techniques known in the art items Hai For isolated cases, it may be by the free form with a suitable dilute aqueous transcendental (e.g.

The salt is regenerated by treating Na〇H, potassium carbonate, ammonia and a dilute aqueous solution of carbonic acid 14. The free forms 盥J: 久白鵾4 #飞,, /, respective salt forms may differ in certain physical properties (e.g., solubility in polar solvents), but for the purposes of the present invention The acid and test salts are also pharmaceutical equivalents in their free form. The pharmaceutically acceptable salt of the compound of the present invention can be synthesized from a compound of the present invention containing a basic or acidic moiety by a conventional chemical method. In general, the salt of the continuation of the test compound is prepared by ion exchange chromatography or by reacting the free test with a stoichiometric amount or with an inorganic H organic acid which forms a desired salt in a suitable solvent or various solvent combinations. Salts of such acidic compounds can be formed by reaction with a suitable inorganic or organic base. Thus, a pharmaceutically acceptable salt of the compound of the present invention includes a conventional non-salt salt of the compound of the present invention, such as by reacting an inspective compound of the present invention with an inorganic acid, an organic acid or a polymeric acid. For example, conventional non-toxic salts include those derived from inorganic acids (eg, hydrochloric acid, hydrogen acid, hydromolybdic acid, sulfuric acid, sulfurous acid, amino acid, linonic acid, sub-acid, nitric acid, and And such as from organic acids (eg, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, silk acid, tartaric acid, bar acid, ascorbic acid, balmoic acid, maleic acid, By kiramic acid, phenylacetic acid, face amine-formyl hydrazine, salicylic acid, p-aminobenzenesulfonic acid, 2-ethyloxy-benzoic acid, fumaric acid, 曱 曱 酸 acid, 甲烧Acid, Ethylene, Sodium Acid, Oxalic Acid, 127700.doc -18· 200836731 Isethionethane, palmitic acid, gluconic acid, ascorbic acid, phenylacetic acid, aspartic acid, cinnamic acid, pyruvic acid, ethanesulfonate Salts prepared from acids, ethane disulfonic acids, valeric acid, trifluoroacetic acid, and the like. Examples of suitable polymeric acid salts include those derived from polymeric acids such as citric acid, carboxymethyl cellulose. Preferably, the pharmaceutically acceptable salt of the present invention comprises 1 equivalent of the compound of the formula (1) and 1, 2 or 3 equivalents of a mineral or organic acid. More specifically, the pharmaceutically acceptable salt of the present invention is a trifluoroacetate, a vapor or a toluene acid. More specifically, the pharmaceutically acceptable salt of the present invention is a trifluoroacetate or a vapor salt. In one embodiment, the salt is a trifluoroacetate salt. In another embodiment, the salt is a chloride. In another embodiment, the salt is an anthene sulfonate. When the compound of the invention is acidic, suitable "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic tests include aluminum salts. , ammonium salts, strontium salts, copper salts, iron salts, ferrous salts, bell salts, magnesium salts, manganese salts, divalent manganese salts, potassium salts, sodium salts, zinc salts, and the like. Especially preferred are ammonium salts, calcium Salts, magnesium salts, potassium salts, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary amines, secondary amines and tertiary amines, substituted amines (including natural substituted), cyclic amines, and Salts of ion exchange resins, such as arginine, lysine, betaine, caffeine, choline, N, NL dibenzylethylenediamine, ethylamine, monoethylamine, 2-diethylaminoethanol , 2-dimethylaminoethanol, ethanolamine, diethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylhexahydropyridyl, reduced glucosamine, glucosamine, histidine, hexamine Hydrabamine), isopropylamine, lysine, methyl-reducing glucosamine, 127700.doc -19- 200836731 Lynn, tourism, hexahydroquinone Tr, polyamine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, dicyclohexylamine, butylamine, benzylamine, phenylbenzylamine, Salts of tromethamine, etc. The preparation of the above pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts is more fully described in Berg et al. (1977), J. corp./mrm. T/zarmacezzi/ca/ Χα"〆, 66:1 -1 9 It should also be noted that since the deprotonated acidic moiety (for example, a carboxyl group) of the compound of the present invention under physiological conditions can be an anion, and the electronic charge can then be internally The protonated or alkylated basic moiety (eg, a quaternary nitrogen atom) has a cationic charge that is balanced, so the compound may be an internal salt or a zwitterion. It can be used in a method of treating a human or animal body by therapy. A compound of the present invention. The present invention provides a compound for treating or preventing a condition which can be improved by inhibiting poly(ADP-ribose) polymerase (PARP) (see, for example,

Dbcovery (2005) 4:421-440). Accordingly, the present invention provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of a condition which can be ameliorated by inhibition of poly(ADP-ribose) polymerase (PARP). The invention also provides a method for treating or preventing a condition ameliorated by inhibition of poly(ADP-ribose) polymerase (PARP), the method comprising administering to a patient in need thereof an effective amount of a compound of formula I or comprising A composition of a compound of formula I. The PARP inhibitors of the invention are useful in the treatment of the diseases indicated in 127700.doc -20-200836731 in WO 2005/082368. The compounds of the present invention are useful for the treatment of inflammatory diseases, including those caused by rejection of organ transplants, for example; (d) chronic inflammatory diseases including arthritis, rheumatoid arthritis, osteoarthritis and bones associated with enhanced bone resorption Disease; inflammatory bowel disease, %, ileitis, ulcerative colitis, Barrett's syndr〇me and Crohn's disease (ο-, heart (10)); inflammatory lung disease, case ^, asthma, Adult respiratory distress syndrome and chronic obstructive airway disease; inflammatory diseases of the eye, including corneal dystrophy, granular conjunctivitis, onchocerciasis, uveitis, sympathetic ophthalmia and intraocular lens; chronic inflammation of the gums Diseases, including gingivitis and periodontitis; tuberculosis, leprosy; inflammatory diseases of the kidneys, including uremic complications, glomerulonephritis and kidney disease; inflammatory diseases of the skin, including sclerosing dermatitis, cognac and Eczema; inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-related neurodegeneration, and Alzheimer's disease Disease (Alzheimer, s disease), infectious meningitis, encephalomyelitis, Parkinson's disease (Parkins〇n, s(1) Qing (9), Huntington's disease (Huntington, S disease), amyotrophic lateral sclerosis and virus Sexual or autoimmune encephalitis; diabetic complications, including but not limited to immune vasculitis, systemic lupus erythematosus (sle); inflammatory diseases of the heart, for example, cardiomyopathy, ischemic heart disease, high cholesterol Hypertension and atherosclerosis; and various other diseases that may have significant inflammatory components' including pre-eclampsia, chronic liver failure, brain and spinal cord trauma, and cerebral dysfunction syndrome (MODS) (multiple organ failure (m〇f) The inflammatory disease may also be a systemic inflammation of the individual, for example, Gram-positive or 127700.doc 200836731 Gram-negative shock, hemorrhagic or anaphylactic shock, or chemo-inflammatory therapy by cancer chemotherapy Shock induced by a factoric reaction, for example, shock associated with proinflammatory fines. This shock may be caused, for example, by treatment as a cancer: a chemotherapeutic agent. "> A compound of formula I for use in the manufacture of a medicament for the treatment or prevention of an inflammatory disease. The invention also provides a method for the treatment or prevention of an inflammatory disease, the method comprising administering an effective amount to a patient in need thereof A compound of the formula or a composition comprising a compound of formula I. The compounds of the invention may also be used to treat or prevent reperfusion injury caused by naturally occurring events and during surgical procedures, for example, intestinal reperfusion injury; myocardial reperfusion injury; Reperfusion injury from cardiopulmonary bypass, aortic aneurysm repair, carotid endarterectomy or hemorrhagic shock; and transplantation from organs such as heart, lung, liver, kidney, pancreas, intestine, and cornea Reoxidation damage. 〇 Therefore, the present invention provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of reperfusion injury. ▲ The invention also provides a method of treating or preventing reperfusion injury with & 4 methods comprising administering to a patient in need thereof an effective amount of a compound of formula or a composition comprising a compound of formula I. / The compounds of the invention may also be used for the treatment or prevention of ischemic conditions, including those produced by organ transplants, for example, stable angina, unstable narrow blood vessels, ischemia, liver ischemia, local mesenteric artery Missing.卩 Ischemia, severe limb ischemia, chronic severe limbs 127700.doc -22- 200836731 ischemia, cerebral ischemia, a ^ heart, ischemic heart disease, local disease, ischemic liver disease, sex Months /, ischemic retinal disorders, septic gram, and central nervous system filaments + p sputum sputum ..., ischemic disease, for example, stroke $ cerebral ischemia. A wind or a broad formula provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of an ischemic condition. The invention also provides a method for treating or preventing an ischemic condition,

ϋ The method comprises administering to a patient in need thereof an effective amount of a compound of the formula or a composition comprising a compound of formula I. The present invention provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of stroke. The invention also provides a method for treating or preventing stroke, the method comprising administering to a patient in need thereof an effective amount of a compound of the formula or a composition comprising the compound. The compounds of the present invention are also useful for treating or preventing chronic or acute renal failure. Thus, the present invention provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of renal failure. The invention also provides a method for treating or preventing renal failure, the method comprising administering to a patient in need thereof an effective amount of a compound of formula I or a composition comprising a compound of formula I. The compounds of the present invention are also useful for treating or preventing vascular diseases other than cardiovascular diseases, for example, peripheral arterial occlusion, occlusive thromboangiitis, Reynaud's disease and phenomenon, hand and foot rash, erythema limb 127700 .doc -23- 200836731 Pain, venous thrombosis, varicose veins, arteriovenous fistula, lymphedema and fat edema. Accordingly, the present invention provides a formula for the manufacture of a medicament for treating or preventing a vascular disease other than a cardiovascular disease. The invention also provides a method for treating or preventing a blood disorder other than a cardiovascular disease, the method comprising administering to a patient in need thereof an effective amount of a compound of formula I or a composition comprising a compound of formula I. The compounds of the present invention are also useful for treating or preventing cardiovascular diseases such as spastic heart failure, atherosclerosis, congestive heart failure, circulatory shock, cardiomyopathy, heart transplantation, myocardial infarction, and arrhythmia, for example, Atrial fibrillation, supraventricular tachycardia, atrial flutter, and paroxysmal atrial tachycardia. Thus, the present invention k provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of cardiovascular diseases. The invention also provides a method for treating or preventing a cardiovascular disease, the method comprising administering to a patient in need thereof an effective amount of a compound of formula or a composition comprising a compound of formula I. The compounds of the present invention are also useful for treating or preventing diabetes, including work type diabetes (insulin dependent diabetes), „type diabetes (non-insulin dependent diabetes), gestational diabetes, autoimmune diabetes, insulin disease, caused by pancreatic diseases Diabetes, diabetes associated with other endocrine diseases (eg, Cushing, s Syndr〇me, acromegaly, pheochromocytoma, glucagonoma, primary hyperplasia) Or somatostatin), type A insulin resistance syndrome, type b insulin to 127700.doc -24- 200836731 anti-symptomatic group, adipose atrophic diabetes, urinary disease. The compound of the present invention can also be used for ...:; For example, diabetic cataract, blue # " (for example, microalbuminuria and two: =: see omental disease, kidney disease, degenerative diabetic nephropathy), multiple minerals, ampoules, atherosclerosis Sclerosing tubular: disease: non-four blood sugar coma, single-shot god:: Second, autonomic nerve money, foot ulcers, _ section problems, and skin or mucous membrane

: = infection, ankle spot, candida infection or lipid-induced obesity obesity), hyperlipidemia, hypertension, pancreas = resistance syndrome, coronary artery disease, retinopathy, diabetic lesions, multiple Neuropathy, single neuropathy, autonomic neuropathy, foot ulceration, joint problems, fungal infections, bacterial infections, and: muscle disorders. Thus, the present invention provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of diabetes. The invention also provides a method for treating or preventing diabetes comprising administering to a patient in need thereof an effective amount of a compound of formula i or a composition comprising a compound of formula 1. The compounds of the invention may also be used in the treatment or prevention of cancer, including solid tumors 'eg, fibrosarcoma, mucinous sarcoma, liposarcoma, chondrosarcoma, protozoa sarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphatic vessels Sarcoma, synovial tumor, mesothelioma, Ewing, s tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer 127700.doc -25- 200836731 Tuberculosis, gastric cancer, oral cancer, nasal cancer, laryngeal cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, papillary carcinoma, papillary cystadenoma , cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, hepatoma, biliary cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wilms'tumor, cervix Cancer, uterine cancer, testicular cancer, small cell lung cancer, bladder cancer, lung cancer, epithelial cancer, skin cancer, melanoma, neuroblastoma and retinoblastoma; blood-borne cancer, for example, acute drenching Cellular leukemia ("ALL"), acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia ('AML''), acute promyelocytic leukemia (" Apl"), acute mononuclear leukemia, acute erythroblastic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute non-lymphocytic leukemia, undifferentiated acute leukemia, chronic myeloid leukemia "CML"), chronic lymphocytic leukemia ("CLL"), hairy cell leukemia and multiple myeloma; acute and chronic leukemia, for example, lymphoblastic, myeloid, lymphocytic, myeloid leukemia; Lymphoma, such as 'Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma' Waldenstrom's macroglobulinemia, Heavy chain disease and polycythemia vera; CNS and brain cancer, for example, glioma, fibrillar cell Astrocytoma, astrocytoma, glioblastoma multiforme, glioblastoma multiforme, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, Acoustic neuroma, oligodendroglioma, meningioma, vestibular neuroma, adenoma, metastatic brain tumor, meninges 127700.doc -26- 200836731 Tumor, myeloma and medulloblastoma. Accordingly, the present invention provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of cancer. The invention also provides a method for treating or preventing cancer, the method comprising administering to a patient in need thereof an effective amount of a compound of formula I or a composition comprising a compound of formula I.

• The compounds of the invention may also be used to treat cancers that are defective in homologous recombination (HR)-dependent DNA DSB repair activity (see WO 2006/021801). ^ HR-dependent DNA DSB repair pathways can repair DNA double-strand breaks (DSBs) by homologous mechanisms to engineer continuous DNA spirochetes (#ai. Genet. (2001) 27(3): 247-254). The components of the HR-dependent DNA DSB repair pathway include, but are not limited to, ATM (NM_000051), RAD51 (NM-002875), RAD51 LI (NM-002877) > RAD51 C (NM-002876), RAD51L3 (NM-002878), DMC1 (NM-007068), XRCC2 (NM700543 1), XRCC3 (NM-005432), RAD52 (NM-002879), RAD54L (NM-003579), RAD54B (NM-012415), BRCA-1 (NM-007295), BRCA -2 (NM-000059), RAD50 (NM-005732), MREI ΙΑ (NM-005590), NBS1 (NM-002485), ADPRT (PARP-1), ADPRTL2, (PARP02) CTPS, RPA, RPA1, RPA2 RPA3, XPD, ERCC1, XPF, MMS19, RAD51, RAD51p, RAD51C, RAD51D, DMC1, XRCCR, XRCC3, BRCA1, BRCA2, RAD52, RAD54, RAD50, MRE11, NB51, WRN, BLMKU70, RU80, ATM, ATRCHK1, CHK2 FANCA, FANCB, 127700.doc -27- 200836731 FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, RADI and RAD9. Other proteins involved in the HR-dependent DNA DSB repair pathway include regulatory factors such as EMSY (Ce// (2003) 115:523-535) ° HR-dependent DNA DSB repair defective cancer may include one or more cancer cells or One or more cancer cells constitute a reduced or absent ability of the cancer cells to repair DNA DSB relative to normal cells, i.e., the activity of the HR dependent DNA DSB repair pathway is reduced or eliminated in the one or more cancer cells. The activity of one or more of the HR-dependent DNA DSB repair pathways may be lost in one or more cancer cells of an individual having a HR-dependent DNA DSB repair defective cancer. The composition of the HR dependent DNA DSB repair pathway is well characterized in the art (see, for example, (2001) 291:1284-1289) and includes the compositions listed above. The present invention provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of a cancer which is defective in HR-dependent DNA DSB repair activity. The invention also provides a method for treating or preventing a cancer which is defective in HR-dependent DNA DSB repair activity, the method comprising administering to a patient in need thereof an effective amount of a compound of formula I or a composition comprising a compound of formula I. In one embodiment, one or more of the cancer cells have one or more HR-dependent DNA DSB repair activities selected from the group consisting of: ATM (NM-000051), RAD51 (NM-002875), RAD51 LI (NM- 127700.doc -28- 200836731 002877) , RAD51 C (NM-002876), RAD51L3 (NM- 002878), DMC1 (NM-007068), XRCC2 (NM7005431) > XRCC3 (NM-005432), RAD52 (NM-002879 ), RAD54L (NM-003579), RAD54B (NM-012415), BRCA-1 (NM-007295), BRCA-2 (NM-000059), RAD50 (NM-005732), MREI ΙΑ (NM-005590), NBS1 (NM-002485) ), ADPRT (PARP-1), ADPRTL2, (PARP02) CTPS, RPA, RPA1, RPA2, RPA3, XPD, ERCC1, XPF, MMS19, RAD51, RAD51p, RAD51C, RAD51D, DMC1, XRCCR, XRCC3 , BRCA1, BRCA2, RAD52, RAD54, RAD50, MRE11, NB51, WRN, BLMKU70, RU80, ATM, ATRCHK1, CHK2, FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCC, FANCD1, FANCD2, FANCE , FANCF, FANCG, RADI and RAD9. In another embodiment, the cancer cells have a phenotype of BRCA1 and/or BRCA2 deficiency. Cancer cells of this phenotype may be defective in BRCA1 and/or BRCA2, ie, the expression and/or activity of BRCA1 and/or BRCA2 in such cancer cells may be reduced or eliminated, for example, by means of a mutation or polypeptide encoding a nucleic acid Amplification or amplification, mutation or polypeptide phenomenon by means of a gene encoding a regulatory factor (eg, an EMSY gene encoding a BRCA2 regulatory factor) (Ce// (2003) 115: 523-535). The BRCA-1 and BRCA-2 tumor suppressor genes are known, and their wild-type alleles are usually lost in tumors of hybrid vectors (2002) 127700.doc -29- 200836731 21(58):8981-93; Trends Mol Med., (2002) 8(12):571-6). The relationship between BRCA-1 and/or BRCA-2 mutants and breast cancer has been well characterized (five xp C///7 (2002) 21 5 noisy/;/): 9-12). Amplification of the EMSY gene encoding the BRCA-2 binding factor is also known to be associated with breast and ovarian cancer. The vector of BRCA-1 and/or BRCA-2 mutations is also at high risk for ovarian cancer, prostate cancer and pancreatic cancer. The detection of BRC A-1 and BRC Α·2 changes is well known in the art and is described, for example, in European Patent 699 699 754, European Patent 705 705 903, GeM,. Γαί (1992) 1:75-83; Treat Res (2002) 107:29-59; Neoplasm (2003) 50(4): 246-50; CeAa (2003) 68(1): 1 1 -16). The assay for BRCA-2 binding factor EMSY amplification is set forth in Ce// 115:523-535. PARP inhibitors have been shown to be useful for specifically killing BRCA-1 and BRCA-2 deficient tumors (2005) 434: 913-916 and 917-920). Accordingly, the present invention provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of a tumor deficient in BRC A-1 or BRC A-2. The invention also provides a method for treating or preventing a tumor of a BRCA-1 or BRCA-2 deficiency, the method comprising administering to a patient in need thereof an effective amount of a compound of formula I or a composition comprising a compound of formula I. In one embodiment, the PARP inhibitors of the invention are useful for prophylactic treatment to eliminate BRCA2-deficient cells (see, (2005) 65: 10145). The compounds of the present invention are useful for the treatment or prevention of neurodegenerative diseases, including polyglutamine-expanding-related neurodegeneration, Huntington's disease 127700.doc -30-200836731 (Huntington s disease), Kennedy's disease (Kennedy's disease) Disease), spinal cord cerebellar ataxia, dentate nucleus red nucleus globus pallidus hypothalamic nuclear atrophy (DRPLA), protein aggregation-related neurodegeneration, Machado-Joseph's disease, Alzheimer's disease (Alzheimer, s disease), Parkinson's disease, amyotrophic lateral sclerosis, spongiform encephalopathy, prion-related diseases, and multiple sclerosis (MS). Accordingly, the present invention provides a compound of the formula for use in the manufacture of a medicament for the treatment or prevention of a neurodegenerative disease.

The invention also provides a method for treating or preventing a neurodegenerative disease, the method comprising administering to a patient in need thereof an effective amount of a compound of the formula or a composition comprising a compound of formula I. The compounds of the present invention are also useful for treating or preventing retroviral infection (US Pat. No. 5,652,260), retinal damage (CMrr and recognition (20〇4) '29·403), skin aging and uv-induced skin damage (US Patent US) 5589483 and (2〇〇2). The compounds of the present invention are useful for treating or preventing premature aging and delaying the onset of age-related cell dysfunction (/>waki (4)-fine (4) (2005) 52:93-99) Very standard medical practice, this hair ^ dry judgments on the music:! _, excipients, thinners, adjuvants, fillers, buffers, ignorant drug delivery _ _, body / peripheral way is still in anticipation The point of action is administered, including but 127700.doc • 31· 200836731 in , two (eg 'by ingestion'); local (including, for example, percutaneous, intranasal/transocular, transoral and sublingual) The lungs (for example, by using (eg,) urinary gels through, for example, mouth or nose inhalation or insufflation therapy; rectum; vaginal, non-, and second intestines (eg, by injection, including subcutaneous, Intradermal, intramuscular, intravascular, intracardiac, intrathecal, intraspinal The capsule, subcapsular intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, and intrasternal injection); and by depot implantation (e.g., subcutaneously or intramuscularly).

Civil and military personnel can be eukaryotes, animals, vertebrates, mammals, hairy animals (eg 'scorpine hamsters, hamsters, rats, mice), murines (such as, stingy), canines (eg , dog), feline (eg, Shutian) equine (eg, horse), primate, scorpion (eg, monkey or lynx), simian (eg, marmoset, lynx), mites (for example, gorillas, chimpanzees, orangutans, gibbons) or humans. The invention also provides a pharmaceutical composition comprising one or more of a compound comprising a compound of the invention and a pharmaceutically acceptable carrier. The pharmaceutical composition comprising the active ingredient may be in a form suitable for oral use such as a tablet, tablet, lozenge, aqueous or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule, or syrup or Tincture. The composition to be used orally can be prepared according to any method known in the art for the manufacture of a pharmaceutical composition and the same: and the person may comprise one or more selected from the group consisting of a sweetener, a flavoring agent, and : Reagents consisting of a mixture of agents to provide a medically pleasing and palatable trend. Tablets comprise a mixture of the active ingredient with a pharmaceutically acceptable excipient which is suitable for the manufacture of a tablet. For example, such excipients may be: diquat 127700.doc -32 - 200836731 release agents, for example, calcium carbonate, sodium carbonate, lactose, calcium sulphate or sodium sulphate; granulating agents and disintegrants , for example, microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; a binder such as starch, gelatin, polyethylene σ-pirone or gum arabic; and a lubricant, for example, a hard Magnesium citrate, stearic acid or talc. The lozenges may be uncoated or they may be enveloped by known techniques to mask unpleasant taste or delay disintegration and absorption in the gastrointestinal tract and thereby provide a long lasting effect. For example, a water-soluble taste masking material (e.g., hydroxypropyl-methylcellulose or hydroxypropylcellulose) or a time delay material (e.g., ethylcellulose, cellulose acetate butyrate) can be used. Formulations for oral use may also be presented as a hard gelatin capsule, wherein the active ingredient is mixed with an inert solid diluent (for example, calcium carbonate, calcium phosphate or kaolin); or it may be a soft gelatin capsule, wherein the active ingredient A water-soluble carrier (for example, polyethylene glycol) or an oily vehicle (for example, peanut oil, liquid stone or olive oil) is mixed. The aqueous suspension comprises the active material in admixture with an excipient suitable for preparing an aqueous t-liquid. Such excipients are suspending agents', for example, sodium carboxymethylcellulose, methylcellulose, propylmethyl-cellulose, sodium alginate, polyethylene: pyridinium, xanthan gum, xanthan Gum and gum arabic; dispersant or wetting:: natural phospholipids (such as 'lecithin), or alkylene oxide and fatty acid (such as & oxyethylene stearic acid s), or epoxy a condensation product (for example, ethene monooleate) with a long-chain fat== product (for example, hepta-exetyloxy) or an epoxy such as TL from a fatty acid and a hexitol Or a condensation product of ethylene oxide with a portion of the vinegar derived from 127700.doc -33-200836731 fatty acid and hexitol (for example, polyoxyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, for example, p-hydroxyphenyl f-ethyl or p-hydroxybenzoic acid; one or more coloring agents, one or more flavoring agents, and one or more such as A sweetener such as sucrose, saccharin or aspartame. The oily suspension can be formulated by suspending the active ingredient in a vegetable oil (for example, peanut oil, eucalyptus oil, sesame oil or coconut oil) or suspended in a mineral oil such as liquid sarcophagus. These oily suspensions may contain a thickening agent, such as bee, hard stone or hexadecanol. Sweetening agents (e.g., as described above) and flavoring agents can be added to provide a palatable oral preparation. These groups of substances can be preserved by the addition of an antioxidant (for example, butylated benzomethazine or = broth). Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water may contain the active ingredient in admixture with dispersing or wetting agents, suspending agents and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Other excipients may also be present, such as a coloring agent. Such compositions can be preserved by the addition of anti-sclerosing sputum (e.g., ascorbic acid). The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. For example, a mixture of plants such as eucalyptus oil or peanut oil or mineral oil (for example, qingqing, etc.) The suitable emulsifier can be a natural dish fat (for example: large: India = and vinegar or partial derivative derived from fatty acid and hexitol liver) (for example, wood alcohol anhydride monooleate) and the partial ester and epoxy ethylene product (9), such as polyoxyethylene sorbitol Xuan oleic acid cool. The money is also 127700.doc • 34- 200836731 can include Sweeteners, bridges, preservatives and antioxidants. Sweeteners (for example, glycerin, propylene glycol, sorbitol: alcohol or recommended sugar) can be used for syrups and granules. (4) These formulations may also contain a demulcent and antiseptic. d, flavoring agents and coloring agents and antioxidants. These pharmaceutical compositions can be injected into the form of Helmets, 囷, 囷, 王射水洛液. The available media and solvents are water, enchanting夂· a RS Grignard (Rlnger, s) solution and isotonic sodium chloride solution. The sterile injectable preparation may also be an injection of an oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. For example, The active ingredient can be first cut: in a mixture of large oil and _phospholipid. Then The oily solution is introduced into a mixture of water and glycerin and treated to form a microemulsion. The injectable solutions or microemulsions can be introduced into the patient by topical single injection or can be advantageously used to maintain the compounds of the invention. The IV fluid or microemulsion is administered in the form of a circulating concentration. To maintain this concentration, a continuous intravenous delivery device can be used. An example of this device is the "CADD-PLUSTM 5400 intravenous pump." The poultry muscles are administered subcutaneously in the form of an aqueous or oily suspension. The suspensions may be formulated according to the known techniques using such suitable dispersing or wetting agents and suspending agents as mentioned above. Injectable (d) may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution dissolved in hydrazine or 3-butane diol. Use volatile oil as solvent or suspension medium. Any mild fixed oil (including synthetic monoglycerides or diglycerides) can be used for this purpose. In addition, '127700.doc can be used in injectable preparations - 35- 200836731 For example, fatty acids such as oleic acid. For rectal administration of the drug ^" and s, the compound of formula 1 can also be used as a suppository. It can be used as a suitable and non-irritating excipient. Mixing to prepare a two composition' The excipient is solid at ambient temperature but liquid at rectal temperature and thus thaws in the rectum to release the drug. These materials include cocoa butter, oil gelatin, chlorinated vegetable oil, each a mixture of a molecular weight polyethylene glycol and a fatty acid ester of ethoxyethyl alcohol. For topical use, a cream, soft lean, gel, solution or suspension containing the compound of formula I may be employed. For topical application, mouthwashes and mouthwashes should be included.) The compounds of the present invention can be administered intranasally in a form suitable for intranasal training and delivery by topical application and or by transdermal routes. Transdermal skin patch forms well known to those skilled in the art are administered. Of course, for administration in the form of a transdermal delivery system, the dose administered throughout the dosage regimen should be continuous rather than intermittent. The compound of the present invention can also be used as a test mixture using a mixture of a glycol such as the following 2 matrix delivery cocoa butter, glycerin gelatin, hydrogenated vegetable oil, various molecular oximes, and a fatty acid ester of polyethylene glycol. When a subject is administered a compound of the invention, the selected dosage level will depend on various factors including, but not limited to, the activity of the particular compound, the severity of the individual's symptoms, the route of administration, and the administration. Time, rate of excretion of the compound, duration of treatment, other drugs, compounds and/or materials used in the combination, and age, sex, weight, condition, general health and prior medical history of the patient. The amount of the compound and the route of administration should ultimately be determined by the physician, but usually the dose should reach the target concentration at the point of action. 127700.doc •36·200836731 The local concentration that does not cause substantial harm or harmful side effects. In vivo administration can be carried out in a single dose, either continuously or intermittently (e.g., at a suitable interval) throughout the treatment period. Methods for determining the most effective administration methods and agents are well known to those skilled in the art and will vary with the formulation being used for the treatment, the purpose of the treatment, the target cells being treated, and the subject being treated. Single or multiple doses can be administered depending on the dosage level and mode selected by the treating physician.

适宜 The general dose of "Hai/tongue compound is between about 1 〇〇 microgram to , , , spoon 250 mg / kg and the tester weight / day. When the active compound is a salt, a known, a drug or the like, the S is administered in accordance with the parent compound and thus the actual weight used should be proportionally increased. This & month sigma can also be used in combination with an anticancer or chemotherapeutic agent. This I month can also be used as a chemical sensitizer and radiosensitizer for cancer treatment. It can be used in mammals that have been or are currently undergoing cancer treatment. Such prior treatments include pre-chemotherapy, radiation therapy, surgery or immunotherapy (e.g., vaccination against cancer). Accordingly, the present invention provides a combination of a compound of formula I and an anticancer agent for simultaneous, separate or sequential administration.

The present invention provides a combination of a compound of formula I, radiation therapy and another chemical chemotherapeutic agent for ρη # X , time, separate or sequential administration. The invention also provides a compound of formula I for use in the manufacture of a medicament for use as a medicament for the treatment of cancer or for the combination of ionizing radiation or a chemotherapeutic agent to enhance tumor cell therapy. The invention also provides the use of a compound of formula 1 for the manufacture of a medicament for use as an adjuvant for cancer therapy or for enhancing tumor cell therapy by combination with ionizing radiation or other chemotherapeutic agents. These compounds can also be used in combination with ionizing light radiation and other chemotherapeutic agents. The invention also provides a method of chemotherapy or radiation therapy comprising administering to a patient having 11 an effective compound of formula 4 or a composition comprising a compound of formula I and an ionizing radiation or chemotherapeutic agent. These compounds can also be administered in combination with ionizing radiation and other chemotherapeutic agents. In combination therapy, the compound of the invention may be administered prior to administration of another anti-cancer agent (eg, 5 minutes, 15 minutes, 3 minutes, 45 minutes, } hours, hours, 4 hours, 6 hours, 12 hours, 24 hours) Hours, 48 hours, hours, ^ hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks), simultaneously, or after (for example, 5 minutes, 15 minutes, 3 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, μ ^ hour, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, Subjects in need were administered 6 =, 8 weeks, or 12 weeks later. In each of the second embodiment: the compound of Ming can be separated from another anticancer agent! Minutes, interval (7) knife main clock, interval 30 minutes, interval less than 1 hour, interval i hour to 2 hours, interval 2 hours to 3 hours, interval 3 hours to call, to 5 hours, interval 5 hours to 6 hours, interval 6 hours to next day; door every other day 7 [interval 8 hours to 9 hours, interval 9 hours: interval to u hour, interval 1H, hour to 12 24 hours, or no more than 48 hours. The compound of the present invention and the other anticancer agent may act in combination. The synergistic combination of the compound of the invention in the form of a compound or a combination of another anticancer agent may be advantageous for 127700.doc •38·200836731 using a lower dose of one or both of these drugs and/or Or a lesser frequency fork to one or both of the compounds of the invention and other anticancer agents and/or to administer the agents at a lesser frequency, without reducing the efficacy of such agents in the treatment of cancer Any toxicity associated with administration of the agent to the subject is reduced. In addition, synergistic effects may improve the efficacy of such agents in the treatment of cancer and/or reduce any undesirable or undesirable side effects associated with the use of either agent alone. Examples of anticancer or chemotherapeutic agents for use in combination with the compounds of the present invention can be found in the Cancer Principles and Practice 〇f 〇nc〇l〇gy ^ VT Devita and S. Heilman (editor), 6th edition (2〇〇1) February 15 曰), Lippincott Williams & Wilkins Publishers. The ordinarily skilled artisan should be able to discern which combination of agents can be used based on the specific characteristics of the drugs and the cancer involved. Such anticancer agents include, but are not limited to, HDAC inhibitors, estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, anti-proliferative agents, Isoprenyl-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 An agent that interferes with cell cycle checkpoints. The compounds of the invention are especially useful when implemented in conjunction with light radiation therapy. Examples of "HDAC inhibitors" include octanediamine aniline isocyanate (SAHA), LAQ824, LBH589, PXD1G1, MS275, FK228, valproic acid, butyric acid, and CI-994. "π-estrogen receptor modulator" refers to a compound that interferes with or inhibits the binding of estrogen to a receptor 127700.doc • 39- 200836731 (independent of the mechanism of action). Examples of estrogen receptor modulators include, but are not limited to, tamoxifen Tamoxifen, raloxifene, idoxifene, LY35338 1, LY1 17081, toremifene, fuivestrant, 4-[7-(2 , 2_Dimethyl_ι_ oxopropoxy-4-methyl-2-[4-[2-(1-hexahydroacridinyl)ethoxy]phenyl]-2仏1·benzene And pyran_3_ylphenyl-2,2-dimethylpropionate, 4,4,di-diphenyldiphenyl ketone-2,4-dinitrophenyl-anthracene and SH646. A hormone receptor modulator refers to a compound that interferes with or inhibits the binding of androgen to a receptor (independent of the mechanism of action). Examples of androgen receptor modulators include finasteride and other 5α-reductase inhibitors. , mlutamide, flutamide, bicalutainide, liar〇z〇le, and abiraterone acetate (. plus (10) plus acetate). Receptor modulator" means dry Or a compound that inhibits retinoid binding to a receptor (independent of the mechanism of action). Examples of such retinoid receptor modulators include bexarrotene, tretin〇in, oc- - gas methyl ornithine, 13-cis-retinoic acid, 9-cis retinoic acid, ILX23-7553, trans | (4, m phenyl) retinol, and ^4 side groups Phenyl retinoin.

Inhibitors, antimetabolites; include an alkylating agent, a tumor necrosis factor, a microtubule inhibitor/microtubule stabilizer, a preparation, a kinase biological response modifier involved in the process of mitosis; a hormone/antihormone 127700.doc -40- 200836731 Therapeutic agents, hematopoietic growth factors, monoclonal antibody targeted therapeutics, topoisomerase inhibitors, proteasome inhibitors and ubiquitin ligase inhibitors. Examples of cytotoxic agents include, but are not limited to, cyclophosphamide, chlorambucil, carmustine (BCNU), lomustine (CCNU), white. Busulfan, treosulfan, sertenef, cachectin, ifosfamide, tasonermin, lonidamine , card initial, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, neda Ne dap 1 at in), aroplatin, oxaliplatin, temoguanamine, methicillin, procarbazine, dacarbazine ), heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibromospiro Dibrospidium chloride, pumitepa, music (lobaplatin), satraplatin, profiromycin, cis, irofulven, dexifosfamide, cis-amine dioxin (2- Methyl-° ratio precipitation, benzyl bird σ 呤 呤, glufosfamide, GPX100, four gasification (reverse, anti, trans)-bis-μ-(hexane-1,6-two Amine)-μ-[diamine-platinum(II)] bis [diamine (gas) platinum (II)], diaziridinylspermine, arsenic trioxide, 1-(11-dodecylamine) Alkyl-10-hydroxyundecyl)·3,7-dimercaptopurine, zorubicin, idarubicin, daunorubicin 127700.doc -41 - 200836731 (daunorubicin ), bisantrene, mitoxantrone, pirarubicin, σpinafide, valrubicin, amrubicin , doxorubicin, epirubicin, pirarubicin, anti-tumor, 3 '-deamino-31 - morphine-13 - de-emulsion-10 -Controlled erythropoietin, lipid Anthocyanin, galarubicin, elinafide, MEN10755, and 4-demethoxy-3-desamino-3-aziridine Mercaptosulfonyl-daunorubicin (see WO 00/50032). Other examples include Raf kinase inhibitors (e.g., Bay 43-9006) and mTOR inhibitors (e.g., Wyethfs CCI-779 and Ariad AP23573). Other examples are PI3K inhibitors (e.g., LY294002). In one embodiment, the compounds of the invention can be used in combination with an alkylating agent. Examples of alkylating agents include, but are not limited to, nitrogen mustards: cyclophosphamide, ifosfamide, tromethamine, and chlorambucil; nitrosoureas: carmustine (BCNU) and Lo Mostin (CCNU); alkyl sulfonates: busulfan and treosulfan; triazenes: dacarbazine, procarbazine and temoride; Inclusion complexes: cisplatin, carboplatin, orlibolite liposomes and oxaliplatin. In one embodiment, the alkylating agent is dacarbazine. The subject may be administered dacarbazine at a dose of between about 150 mg/m2 (subject surface area) to about 250 mg/m2. In another embodiment, the subject can be intravenously administered dacarbazine once daily for 5 consecutive days at a dose between about 1 50 mg/m2 to about 25 mg/m2. 127700.doc -42- 200836731 In one embodiment, the alkylating agent is procarbazine. The subject may be administered procarbazine at a dose of between about 50 mg/m2 (subject surface area) to about 1 mg/m2. In another embodiment, the subject can be administered intravenously with procarbazine once daily for 5 consecutive days at a dose between about 50 mg/m2 to about 1 mg/m2. In one embodiment, the alkylating agent is temozolomide. The subject may be administered temozolomide at a dose of between about 150 mg/m2 (subject surface area) to about 2 mg/m2. In another embodiment, the animal can be orally administered temozolomide once daily for 5 consecutive days at a dose of between about 1 50 mg/m2 to about 200 mg/m2. Examples of anti-mitotic agents include: allocolchicine, halichondrin B, colchicine, colchicine derivatives, dolastatin (d〇lstatin) 10, beauty Maytansine, rhizoxin, thiocolchicine, and triphenyl decyl cysteate. An example of a hypoxic activatable compound is tirapazamine (1) rapazarnine). Examples of proteasome inhibitors include, but are not limited to, lactacystin, börtezomib, epoxomicin, and peptides, eg, MG 132, MG 115, and PSI. Examples of tube inhibitor/microtubule stabilizers include paclitaxel, vindesine sulfate, vincristine, vinblastine, vin〇relbine, 3, , 4, · didehydro-4'-deoxy-8'-norvinine, docetaxel (d〇cetax〇1), rhizoxin (rhizoxin), dolastatin (d〇lastatin), hydroxy Metbuterin sulfonate 127700.doc -43· 200836731 (mivobulin isethionate), auristatin, cemadotin, RPR109881, BMS184476, vinflunine, clitfecine Cryptophycin), 2,3,4,5,6-pentafluoro·#-(3-fluoro-4-decyloxyphenyl)benzenesulfonamide, anhydrovinblastine, #,#_ --L-Amidoxime-L-proline-N-methyl-L-line amine thiol-L-cholamine aryl-L-cholinic acid-third " butylamine, T DX258, ep〇thilone (see, for example, U.S. Patent Nos. 6,284,781 and 6,288,237) and BMS188797. Some examples of topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubiconcan, exatecan, gimetecan, diflupremox (diflomotecan), silyl-camptothecin, 9-amino-based eucalyptus, euphorbia, cristatol, mitomycin C, 6-ethoxy Propionyl-3'/-Ο·Exo-benzylidene-chartreusin, 9-methoxydimethyl-5-nitropyrazolo[3,4,5-kl] Acridine-2-(6//)propylamine, 1·amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4_methyl-1//, 12 ft. benzene And [de]pyrano[3',4|:1),7-disoxazin[1,2b]喧琳_ 1 〇, 13(9丹,1 5/ί)dione, letoticon (lurtotecan), 7-[2-(7V·isopropylamino)ethyl]-(20S) camptothecin, BNP1350, BNPI1100, ΒΝ80915, ΒΝ80942, etoposide phosphate, teniposide Teniposide, sobuzuxane, 2'-dimethylamino-2f-deoxy-etoposide, GL331, 7V_[2_(dimethylamino)ethyl]-9-carbyl- 5,6-.-methyl- 6//· ° ratio of yttrium [4, 唆-1 - amide, asulacrine, (5a, 5aB, 8aa, 9b)-9-[2-[iV-[2-(dimethylamino)) 127700.doc -44- 200836731 】] methylamino] ethyl b 5 [[hydroxy_3,5-dimethoxyphenyl]-cyclopentadiene-6,2,3- (Asia Methyldioxy) _methyl-winter hydroxy j-methoxybenzo[C] phenanthrene, 6,9-bis[(2-aminoethyl)amino]benzo(4)isoindene- 5,l〇-一_,5-(3-aminopropylamino)_7,1〇_dipyridylethylaminomethyl)_6/^biszolo[^丨士]吖pyridine _6 ketone, like oxime [2 (monoethylamino) ethylaminophenyl 7-methoxy-9-oxo-9H-thioxylmethyl]carbamamine, hydrazine (2-(two) Methylamino)ethyl)acridine_4_formamide, 6-[[2-(dimethylamino)ethyl]amino]_3_hydroxy_77/-茚[2,Kc] Quinoline-7-one, and dimesna; non-camptothecin-type topoisomerase inhibitors, for example, indolocarbazole; and dual topoisomerases 1 and 11 inhibitors, For example, benzophenazine, XR2〇1 15761MLN 576, and benzopyrazine are deuterated. In one embodiment, the topoisomerase inhibitor is irinotecan. The irinotecan can be administered to the subject at a dose of between about 50 mg/m2 (subject surface area) to about 15 Torr. In another embodiment, the subject can be administered intravenously once daily for 5 consecutive days (Day 1 to Day 5) at a dose between about 5 〇 mg/m2 to about 15 〇 mg/m2. Irinotecan, followed by intravenous administration for once every 5 days (Day 28 to Day 32) at a dose between about 5 〇 mg/m 2 and about 15 〇 mg/m 2 , followed by 5 consecutive days From 55 days to 59 days), intravenous administration once again at a dose of between about 50 mg/m2 and about 150 mg/m2. Examples of inhibitors of mitotic kinesins (and in particular, human mitotic kinesin KSP) are described in PCT Publication WO 01/30768, 127700.doc -45-200836731

WO 01/98278 &gt; 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 &gt; WO 03/079973 &gt; WO 03 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> WO 2004/058700, WO 2004/058148 and WO 2004/037171 /132719. In one embodiment, the inhibitor of mitotic kinesin includes, but is not limited to, an inhibitor of KSP, an inhibitor of MKLP1, an inhibitor of CENP-E, an inhibitor of MCAK, an inhibitor of Kifl4, an inhibitor of Mphosphl, and a Rab6_KIFL Inhibitors ''Inhibitors of kinases involved in mitotic processes'' include, but are not limited to, inhibitors of aurora kinase, inhibitors of Polo-like kinase (PLK) (specifically, inhibitors of PLK-1), bub -1 inhibitor and inhibitor of bub-Rl. π anti-proliferative agents include antisense RNA and DNA oligonucleotides, for example, G3139, ODN698, RVASKRAS, GEM231, and ΙΝΧ3001; and antimetabolites, for example, enocitabine, carmofur (carmofur) , tegafur, pentostatin, dexifluridine, trimetrexate, fludarabine, capecitabine, gallo Calocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, (paltitrexid), emitefur, 嗟σ Sitting on tiazofurin, decitabine, nola cexi 127700.doc •46- 200836731 (nolatrexed), pemetrexed, nelzarabine, 2'-deoxy- 2,_methylenecytidine, 2,_fluoromethylene-2, deoxycytopent, #-[5-(2,3-ILO·benzopyranyl) 醯 ]]]_τν^(3 ,4-dichlorophenyl)urea, genus-[4-deoxy-4-[#2-[2], 4 kg)-tetradecadienyl]glycine]aminoamine]_L-propyl Trioxy- BL-mannose-heptanopyranosyl] adenine, aplidine, ecteinascidin, troxacitabine, 4-[2-amino-4-oxo-4,6,7, 8-tetrahydro-3//-pyrimido[5,4-13][1,4]thiazin-6-yl-(phanyl-ethyl)-2,5-thienyl-L-glutamic acid, Aminopterin, 5-fluorourine' sigma, alanosine, 11-acetamido-8-(aminomethoxymethyl)-4-carboxyl-6-methoxy-14 -oxal-1,11-diazatetracyclo(7·4·1·0·0)-tetradecyl-2,4,6-trien-9-yl acetate, hummus Swainsonine, lometrexol, dexrazoxane, methionine, cyano-2, _deoxypalmitosylfuranosylcytosine and arginylpyridine_2_ Formaldehyde Aminothiol. Examples of monoclonal antibody dry therapeutic agents include those having a cytotoxic or radioisotope linked to a cancer cell-specific or stem cell-specific monoclonal antibody. Examples include Bexxar. ''HMG-CoA reductase inhibitor') means an inhibitor of 3-hydroxy-3-methylpentadienyl-CoA reductase. Examples of hmG-CoA reductase inhibitors that may be used include, but are not limited to, lovar Lavastatin (MEVAC® R8; see U.S. Patent Nos. 4,231,938, 4,294,926 and 4,319,039), simvastatin (ZOCOR8; see U.S. Patent Nos. 4,444,784, 4,820,850 and 4,916,239 'Pravastatin 127700.doc -47-200836731 (pravastatin) (PRAVACHOL8; see U.S. Patent Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL®; see U.S. Patent Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164, 5,1 18,853, 5,290,946 and 5,356,896) and atorvastatin ( Atorvastatin) (LIPITOR®; see U.S. Patent Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952). Other HMG-CoA reductase inhibitors which can be used in the methods of the present invention. Structure set forth in formula M · Yalpani, "Cholesterol Lowering Drugs '', Chemistry &amp; Industry, 8 pages 5-89 (5 February 1996), page 87 of U.S. Patent No. 4,782,084 and No. 4,885,314 second. The term HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and ring opening acid forms of a compound having HMG-CoA reductase inhibitory activity (ie, wherein the lactone ring is opened to form a free acid) and a salt And ester forms, and thus the use of such salts, esters, ring opening acids and lactone forms are within the scope of the invention. "Prenyl-protein transferase inhibitor" means a compound which inhibits any one or any combination of isoprenyl-protein transferase enzymes, such isoprenyl-protein transferase enzymes Including farnesyl-protein transferase (FPTase), type I geranyl-based geranyl-protein transferase (GGPTase-I), and type II geranyl-based geranyl-protein transferase (GGPTase-II) Also known as Rab GGPTase). Examples of isoprenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, 127700.doc -48-200836731 WO 97/23478, WO 97/38665, WO 98/28980, WO 98/291 19, WO 95/32987, U.S. Patent No. 5,420,245, U.S. Patent No. 5,523,430, U.S. Patent No. 5,532,359, U.S. Patent No. 5,510,510, U.S. Patent No. 5,589,485 U.S. Patent No. 5,602,098, European Patent Publication No. 0 618 221, European Patent Publication No. 0 675 1 12, European Patent Publication No. 0 604 181, European Patent

开 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO 95/12572, WO 95/105 14 (U.S. Patent No. 5,661,152, WO 95/) 10515, WO 95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/ 21,456, WO 96/22278, WO 96/2461 1, WO 96/24612, WO 96/05168, WO 96/05169, WO 96/00736, US Patent No. 5,571,792, WO 96/17861, WO 96/33 159, WO 96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO 96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96 /3 1501, WO 97/00252, WO 97/03047 &gt; WO 97/03050, WO 97/04785, WO 97/02920, WO 97/17070, WO 97/23478, WO 97/26246 &gt; WO 97/30053 WO 97/44350, WO 98/02436, and U.S. Patent No. 5,532,359. For examples of the effects of prenyl-protein transferase inhibitors on angiogenesis, see JJ o/Cancer (1999), 35 (9): 1394-1401. π angiogenesis inhibitor means a form of inhibiting novel blood vessel formation 127700.doc -49- 200836731 Mechanism-independent compounds. Examples of angiogenesis inhibitors include, but are not limited to, tyrosine kinase receptor Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR2) inhibitors Amino acid kinase inhibitor, epidermal source, fibroblast source or inhibitor of platelet-derived growth factor, MMP (matrix metalloproteinase) inhibitor, integrin blocker, interferon-α, interleukin-12, polysulfate Pentosan polysulfate, cyclooxygenase inhibitors, including non-steroidal anti-inflammatory agents (NSAIDs) (such as aspirin and ibuprofen) and selective cyclooxygenase-2 inhibitors (eg celecoxib and rofecoxit^KPA^S (1992) 89:7384; JNCI (1982) 69:475; Arch. Opthalmol. (1990) 108:573; Anat. Rec· (1994) 238:68; FEES Letters (1995) 372:83; Clin, Orthop. (1995) 313:76; J. MoL Endocrinol. (1996) 16:107; Jpn. J. Pharmacol. (1997) 75: 105; Cancer Res. (1997) 57:1625 (1997); Cell (1998) 93:705; Inti J. Mol. Med. (1998) 2:715; J. Biol. Chem. (1999) 274:9116) ),Steroid Inflammatory agents (eg, corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylprednisolone, betamethasone, guanamine) °Sit, combretatatin A-4 (combretastatin A-4), squalamine, 6-0-ephthyl-carbonyl) fumagillol (thalidomide), thalidomide, Angiostatin, myoma protein-1, angiotensin II antagonist (see /· C/M. MeA (1985) 105:14 145), and VEGF antibody (see (10) (1999) 17: 963-968;

Kim et al. (1993) 362:841-844; WO 00/44777; and WO 127700.doc-50-200836731 00/61186) other therapeutic agents that modulate or inhibit angiogenesis and which may also be used in combination with the compounds of the invention Includes agents that modulate or inhibit coagulation and fibrinolytic systems (see C7k. Ζα· Med. (2000) 38:679-692). Examples of such agents that modulate or inhibit coagulation and fibrinolytic pathways include, but are not limited to, heparin (see TTzrowZ® (1998) 80:10-23), low molecular weight heparin and carboxypeptidase U inhibitors ( Also known as active thrombin can activate the inhibitor of fibrinolysis inhibitor [TAFIa] (see (: and (2001) 101: 329-354). TAFIa inhibitors have been described in 卩 (: Ding public case 0 03/013, 526 and U.S. Patent No. 60/349, 925, filed Jan. 18, 2002, the disclosure of which is incorporated herein by reference. A compound that causes cancer cells to be sensitive to DNA damaging agents. These agents include inhibitors of ATR, ATM, Chkl, and Chk2 kinases, and cdk and cdc kinase inhibitors, and specific examples thereof are 7-synthesis staurosporin, star Sporomycin, flavopirid〇l, 〇CYC202 (Cyclacel) and BMS_387032. Inhibitors of π cell proliferation and survival signaling pathways, f, can inhibit fine cell surface receptors and these surface receptors. A pharmaceutical agent for downstream signal transduction pathways. Such agents include inhibitors of EGFR (eg, gefitinib and erlotinib), inhibitors of ERB-2 (eg, 'trastuzumab'), inhibition of IGFR Agents (for example, those disclosed in WO 03/05995 1), inhibitors of cytokine receptors, inhibitors of MET, inhibitors of PI3K (eg, LY294002), serine/threonine 127700. Doc • 51 - 200836731 Enzymes (including but not limited to inhibitors of Akt, as described, for example, in WO 03/086404, WO 03/086403, WO 03/086394, WO 03/086279, WO 02/083675, WO 02/083139, WO Inhibitors of Raf kinase (eg, BAY-43-9006), inhibitors of MEK (eg, CI-1040 and PD-098059), and inhibitors of mTOR (eg, Wyeth CCI-779 and Ariad AP23 5 73). These agents include small molecule inhibitor compounds and antibody antagonists. ''Apoptosis inducers' include activators of TNF receptor family members, including TRAIL receptors. In one embodiment, the compounds of the invention may be combined with one or more (specifically, one, two or Species) is selected from temozolomide, cisplatin, carboplatin, oxaliplatin, irinotecan and topotecan Kang medicament for the treatment of cancer. The compounds of the invention may also be used in combination with any one or more of the following therapeutic agents for the treatment of cancer: abarelix (Plenaxis depot®); aldesleukin MProkine^; Aldesleukin (Proleukin); Alemtuzumabb (Campath); altretinoin (KPanretin^); allopurinol (Zyloprim®); altretamine XHexalen®; amifostine (amifostine) Ethyol®); anastrozole XArimidex®; Trisenox®; aspartate (Elspar®); azacitidine (Vidaza@); bevacizimab XAvastin® ); bexarotene capsule (Targretin®); borarotin® (Bargoxin®); bleomycin (Blenoxane®); poltidan 127700.doc •52- 200836731 anti-bortezomib (Velcade®); Busulfex® for intravenous use; Myleran® for oral administration; caluterone XMethosarb®; capecitabine (Xeloda@); Carboplatin (Paraplatin) ®); Carmustine (BCNU®, BiCNU@); Carmustine (Gliadel®); Carmustine and Polyphenylene 20 implants (Gliadel Wafer®); Celebex®; cetuximab (Erbitux@); chlorambucil ( chlorambucilXLeukeran®); Platinol®; cladribine (Leustatin®, 2-CdA@); clofarabine (Clolar@); Cytoxan®, Neosar® Cytoxan Injection8; Cytoxan Tablet®; Cytosar-U®; DepoCyt®; Dcarb-Dome® ); dactinomycin, actinomycin DXCosmegen®; Darbepoetin alfa (Aranesp8); daunorubicin liposome (DanuoXome®); daunorubicin, daunro Daunomycin (Daunorubicin®); daunorubicin, Cerubidine®, Denileukin diftitox (Ontak®); dexrazoxane (Zinecard@); Dorsey Docetaxel (Taxotere8); Adriamycin PFS®; Adriamycin® (Rulex®); Doxorubicin (Adriamycin PFS Inj) Scope®); Doxil®; Dromostanolone®; Masterone Injection®; Elliott's B solution (Elliott's B) Solution®); epirubicin (Ellence®); Epoetin alfa (epogen8); erlotinib (Tarceva8); 127700.doc -53- 200836731 espresso Ester (estramustine KEmcyt®); etoposide phosphate (Etopophos@); etoposide, VP-^ (Vepesid®); exemestane (exemestane KAromasin®); filgrastim (FilgrastimXNeupogen) ®); fluorouridine (intra-arterial KFUDR0); fludarabine (Fludara8); fluorourine, bite, 5-FU (Adrucil@); vesistan (fulvestrantXFaslodex®); gefitinib ( Gefltinib) (Iressa8); gemcitabine (Gemzar8); gemtuzumab ozogamicin (Mylotarg8); goserelin acetate (Zoladex Implant®); goserelin acetate ( Zoladex®); histrelin acetate (Histreli) n implant®); ureua (Hydrea@); tiltanebezumab (Ibritumomab Tiuxetan MZevalin®); idarubicin (Idamycin,; ifosfamide (IFEX®); mesylate Imatinib mesylate KGleevec®; interferon a 2a (Roferon A@); interferon a-2b (Intron A®); irinotecan (Camptosar®); lenalidomide (Revlimid®); Letrozole XFemara®; leucovorin (Wellcovorin®, leucovorin®); leuprolide acetate (Eligard®); levamisole (Ergamisol®); lomustine (lomustine), CCNU (CeeBU®); meclorethamine, Mustargen®; megace® acetate; melphalan, L-PAN^Alkeran® ); 嗓呤基嗓呤,ό-ΜΡΡιιιίι^ΙιοΙ®); mesna (Mesnex®); Mesnex tabs®; Methotrexate®; methoxalin (Uvadex®); mitomycin (^(Mutamycin®); mitto 127700.doc -54- 200836731

Mitotane (Lysodren@); mitoxantrone (Novantrone0); nandrolone phenpropionate (Durabolin-50®); nelarabine (Arranon8); Nofetumomab (Verluma9); Oprelvekin (Neumega®); Oxali@ (Eloxatin@); Paclitaxel (Paxene8); Paclitaxel (Taxol®); Paclitaxel Protein Binding Particles (Abraxane®); paliferminXKepivance®; pamidronate (Aredia®); pegademase (Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar8); pefibrate ( Pegnigrastim) (Neulasta®); pemetrexed disodium XAlimta®; pentastatin (Nipent®); pipobroman (Vercyte@); plicamycin, radiance Mithracin (Mithracin®); porfimer sodium (Photofrin®); procalaquinone (Matulane®); quinacrine (Atabrine@); Rabrizyme (RasburicaseKElitek) ®); Rituximab (Rituxan0) Shags Sargramostim (Leukinec§)); sagstatin (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar0); sunitinib maleate ( Sunitinib maleate) (Sutent®); stalrosol®; tamoxifen®; Temodar®; teniposide, VM-26 (Vumonc§); Testosterone (Teslac®); thioguanine, 6-TG (Thioguanine@); σ thiotepa (Thioplex@); topotecan (Hycamtin®); toremifene (Fareston®) ); Tosi 127700.doc -55- 200836731 Tositumomab (Bexxar®); tosimozumab/1-13 1 tositumomab (Bexxar8); trastuzumab (Trastuzumab) Herceptin®); Atra (Vesanoid®); Uracil Mustard Capsules®; valrubicin (Valstar@); vinblastine (Velban®); vincristine ( Oncovin®); Navelbine 8; vorinostat (Zolinza@), zoledronate (Zometa@); nii〇tinib (Tasigna8) and Dasatini bRSprycel®).

U The present invention also encompasses combinations with NS AIDs as selective COX-2 inhibitors. For the purposes of this specification, an NSAID that is a COX-2 selective inhibitor is defined as a substance that has at least 100-fold inhibition specificity for c〇X-2 compared to cox-! The ratio of C0X-22 to c〇x_丨 IC~ was measured by cell or microsomal assay. Such compounds include, but are not limited to, those disclosed in U.S. Patent No. 5,474,995, U.S. Patent No. 5,861,419, U.S. Patent No. 5, 063, U.S. Patent No. 6,020,343, U.S. Patent No. 5,4,9,944, U.S. Patent No. 5,436,265, U.S. Patent No. 5,536,752, U.S. Patent 5,55(), 142, U.S. Patent 5,6,4,26, U.S. Patent 5,69 M84, U.S. Patent 5,71,14,14,94,932, U.S. Patent 5,344,991, U.S. Patent 5,134 </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; In particular, the salt 2 inhibitor which can be used in the treatment method of the present invention is % gas-methylsulfonyl)phenyl-2·(2-methylpyrazine ^ &amp; pot, (methyl-5-pyridyl)pyridine Or a pharmaceutically acceptable salt thereof 127700.doc -56·200836731. Compounds which are described as COX-2 specific inhibitors and are therefore useful in the present invention include, but are not limited to, parecoxib (celecbrex), celebrex0 And BEXTRA or a pharmaceutically acceptable salt thereof. Other examples of angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy_4-[2_ • Mercapto-3-(3-mercapto-2-butenyl)oxiranyloxaspiro[2,5]octyl-6-yl (gasacetic acid) urethane, acetamidine (acetyldinaline), 5-amino-1—[[3,5-dichloro-4-(4-carbobenzyl)phenyl]methyl]-1 han-1,2,3-triazole-4- Formamide, CM101, squalamine, combretastatin, RPI4610, NX3 1 838, sulfated mannose pentose phosphate, 7,7-(carbonyl-bis[imino-7V-A Base-4,2-pyrrolylcarbonylimino[7V-methyl-4,2-pyrrole]-carbonylimino] -bis-(1,3-naphthalene disulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indanone (SU5416) As used herein, an "integrin blocker" refers to a compound that selectively antagonizes, inhibits or counteracts the binding of a physiological ligand to ay beta 3 integrin, and optionally inhibits, inhibits or counteracts the binding of a physiological ligand to an ανβ5 integrin. a compound, a compound that antagonizes, inhibits or inhibits the binding of a physiological ligand to ανβ3 integrin and ανβ5 integrin, and a compound that antagonizes, inhibits or counteracts the activity of a particular integrin expressed on capillary jk endothelial cells The term also refers to antagonists of ανβ6, ανβ8, αΐβι, 〇〇2βΐ, α5βΐ, α6βΐ and α6β4 integrin. The term also refers to ανβ3, ανβ5, ανβ6, ανβ8, αιβι, α2βΐ, β5〇Π, α6βΐ and α6β4 integration. Antagonists of any combination of the compounds. 127700.doc -57- 200836731 Some specific examples of tyrosine kinase inhibitors include TV-(trifluoromethylphenyl)-5-methyl chewing salicylamine, 3_[(2,4_Dimethylpyrrole-5-yl)methylene)哚 哚 | ketone, η · (dilylpropyl) _n_ demethoxy aldostermycin, 4- (3- gas-4-fluorophenylamino)_7_methoxy _6- [3-('morpholinyl)propoxy]quinazoline, Y-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, ΒΙΒΧ1382,^^仏 hexahydro^^hydroxymethyl)-10-hydroxy-9·methyl_9,12-epoxy-1/^diindole π,2,3_fg:3',2', L'_kl]. Prodoxobenzodiazepine ketone, SH268, genistein, STI571, CEp2563, 4 chlorophenylamino)-5,6-dimethyl-7fpyrrolo[2,3- d] pyrimidine methane sulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, 4_(4,_ via basic)amino-6, 7-Dimethoxy phthalocyanine, SU6668, STI571A, phenylphenyl-4(4-pyridylmethyl)pyridazinamine, and EMD121974 〇 In one embodiment, the compounds of the invention are useful for the treatment or prevention Necrosis induced by a selective #3-adenine methylation reagent such as MeOS02(CH2)-lexitropsin (Me-Lex) occurs. Combinations of compounds other than anti-cancer compounds are also contemplated by the methods of the invention. For example, a combination of a compound of the invention and a PPAR-y (i.e., ΡΡΑκ_γ) agonist and a PPAR-δ (i.e., PPAR-delta) agonist can be used to treat certain malignancies. PPAR-γ and PPAR-δ are nuclear peroxisome proliferator-activated receptors γ and δ. The expression of AR-γ on endothelial cells and its involvement in angiogenesis has been reported in the literature (see 乂Car Pharmacol. (1998) 31:909-913; J. Biol. Chem (1999) 127700.doc • 58 - 200836731 274:9116-9121; Invest, Ophthalmol Vis · Sci, (2000) 41:2309-2317). Recently, it has been confirmed that PPAR-γ agonists can inhibit the angiogenic response of VEGF in vivo; both troglitazone and rosiglitazone maleate can inhibit retinal neoplasia in mice. The development of angiogenesis. (drc/2.0p/^/mmo/. (2001) 119:709-7 1 7). Examples of PPAR-gamma agonists and PPAR-gamma/alpha agonists include, but are not limited to, thiazolidinediones (eg, DRF2725, CS-011, troglitazone, rosiglitazone, and sigma-glitazone ( Pioglitazone)), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyltrifluoromethyl-1,2-benzisoxazole-6-yl)oxy]-2- Methylpropionic acid (disclosed in USSN 09/782,856), and 2(7?)·7·(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)- 2-ethylchroman-2 -carboxylic acid (disclosed in USSN 60/23 5,708 and 60/244,697). Another embodiment of the invention is the use of a compound of the invention in combination with an antiviral agent for cancer therapy (e.g., a nucleoside analog, including ganciclovir). See WO 98/04290. Another embodiment of the invention is the use of a compound of the invention in combination with gene therapy for cancer therapy. For a genetic strategy for treating cancer, see Hall et al. (dm Ge (10) ί (1997) 61:785-789) and

Kufe et al. (C(10)cer ΜΜζϋβ, 5th edition, pp. 876-889, BC 127700.doc -59- 200836731

Decker, Hamilton 2000). Gene therapy can be used to deliver any tumor suppressor gene. Examples of such genes include, but are not limited to, p53 which can be delivered by recombinant virus-mediated gene transfer (for example, see U.S. Patent No. 6,069,134), uPA/uPAR antagonists (''Adenovirus-Mediated Delivery of a uPA) /uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in Mice, 11 Gene Therapy, August (1998) 5(8): 1105-13) and Interferon Gamma Plus / (2000) 164:217- 222) ° The present invention Compounds can also be administered in combination with inhibitors of intrinsic multidrug resistance (MDR), in particular, MDR is associated with high levels of transporter expression. Such MDR inhibitors include p-glycoprotein (P-gp) inhibitors, for example, LY335979, XR9576, OC144-093, R101922, VX853, verapamil, and PSC833 (valspodar) . The compounds of the present invention may be combined with an antiemetic agent, alone or in combination with radiation therapy, to treat sigma nausea or ovulation, including acute, delayed, late, and expectant vomiting that may result from the use of a compound of the invention. For the prevention or treatment of vomiting, the compounds of the invention may be used in combination with other antiemetic agents, especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists (eg, ondansetron, gera) Granisetron, tropisetron, and zatisetron, GABAB receptor agonists (eg, baclofen), corticosteroids (eg, Decadron (dexamethasone) ), Kenalog, Aristocort, Nasalide, Preferid, Benecorten) or others (for example, disclosed in U.S. Patent Nos. 2,789,118, 2,990,401, 3,048,581, 127700.doc-60-200836731 3'126'375, Nos. 3, 929, 768, 3, 996, 359, 3, 92 8, 326 and 3 749 71? (in the case of ^, 5, 712), anti-dopamines, for example, phenothiazines (eg, propyl chloride) Prochlorperazine, flUphenaZlne, thioridazine and mesoridazine, met〇ci〇pramide or dronabinol . In one embodiment, an anti-emetic agent selected from the group consisting of a neurokinin-丨 receptor antagonist, a 5HT3 receptor antagonist, and a corticosteroid is administered as an adjuvant to treat or prevent vomiting caused by administration of the compound of the present invention. The neurokinin-i receptor antagonists used in connection with the compounds of the present invention are described in, for example, U.S. Patent Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, No. 5, 494, 926, No. 5, 496, 833, No. 5, 637, 699, No. 5, 719, 147; European Patent Publication No. EP 0 360 390, No. 0 394 989, No. 0 428 434, No. 0 429 366, No. 0 430 771 No. 0 436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0 512 902, 0 514 273, 〇 514 274, 0 514 275, 0 514 276, 〇 515 681, 0 517 589, 0 520 555, 522 808, 528 495, 〇 532 45 、, 0 533 280, 〇 536 817, 0 545 478, 0 558 156, 〇 577 394, 〇 585 913, 〇 590 152, 0 599 538 No. 610 793, No. 0 634 402, No. 0 086 629, No. 693 489, 0 694 535, 〇 699 655, 0 099 074, 〇7〇7 〇〇 6, 〇 708 1〇1, -61 - 127700.doc 200836731 No. 0 709 375, No. 0 709 376, 0 714 891, 0 723 959, 0 733 632 and 0 776 893; PCT International Patent Publication Nos. WO 90/05525, 90/05729, 91/09844 No. 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, Nos. 92/21677, 92/22569, 93/00330, 93/00331, 93/01 159, 93/01 165, 93/01 169, 93/01 170 No. 93/06099, 93/091 16 , 93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21 155 No. 93/21181, 93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429, Nos. 94/03445, 94/04494, 94/〇4496, 94 /05625, 94/07843, 94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/1 1368, 94/ No. 13639, Nos. 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740 , Nos. 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/1 1880, 95/14017, 95/153 1 1 , 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, Nos. 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418 127700.doc-62-200836731, 95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/ No. 16939, No. 96/18643, No. 96/20197, No. 96/21661 , Nos. 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084, 97/19942 and 97/ No. 21702; and British Patent Publication Nos. 2 266 529, 2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, Nos. 2,293,169 and 2,302,689. The preparation of such compounds is fully described in the above-identified patents and publications, which are incorporated herein by reference. In one embodiment, the neurokinin-1 receptor antagonist used in conjunction with a compound of the invention is selected from the group consisting of: 2_(Bu(7?)·(3,5-double) as described in U.S. Patent No. 5,719,147 (trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxoyl-1//,4 open-1,2 , cardiac triazolyl) indenyl) morpholine or a pharmaceutically acceptable salt thereof. The compounds of the invention may also be administered with an agent for the treatment of anemia. This anemia therapeutic agent is, for example, a continuous erythropoietin receptor activator (e.g., Alfa Iberetine). The compounds of the invention may also be administered with an agent for the treatment of neutropenia. This neutropenic therapeutic agent (for example) can be 127700.doc • 63 - 200836731 A hematopoietic growth factor that regulates neutrophil production and function, for example, human granulocyte colony stimulating factor (G-CSF). Examples of G-CSF include filgrastim. The compounds of the invention may also be associated with, for example, levofloxacin. Immune-enhancing drugs such as levamisole, isoprinosine, and Zadaxin are administered together. The compounds of the invention may also be combined with bisphosphonates (which are understood to include bisphosphonates, bisphosphonates, bisphosphonates, and bisphosphonates) for the treatment or prevention of cancer, including bone cancer. Examples of bisphosphonates include, but are not limited to, etidronate (didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (riseronate) (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, chlorine Clodronate, EB-1053, minodronate, neridronate, piridronate, and tiludronate, including any All pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof. Accordingly, the scope of the present invention encompasses the use of the claimed compounds in combination with ionizing radiation and/or in combination with a second compound selected from the group consisting of HDAC inhibitors, estrogen receptor modulators, androgen receptor modulators, and the like. Retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, angiogenesis inhibitors, PPAR-gamma agonists, PPAR-δ agonist, disease resistance 127700.doc -64- 200836731 Tincture, inhibitor of intrinsic multidrug resistance, antiemetic, agent for anemia treatment, agent for treatment of neutropenia, immunity An agent that enhances drug, cell proliferation, and survival signaling, an agent that interferes with cell cycle checkpoints, an apoptosis inducing agent, and a bisphosphonate. A term associated with a compound of the invention, "administering" and variants thereof (eg, administration of a ''compound) means that the compound or prodrug of the compound is introduced into a system in need of treatment of the animal. Where a prodrug is provided in combination with one or more other active agents (e.g., cytotoxic agents, etc.), "administered" and variants are each understood to include both the simultaneous and sequential introduction of the compound or its prodrugs and other agents. As used herein, it is intended to cover a product comprising a specified amount of the specified ingredient X and any combination of specified ingredients in a specified amount, directly or indirectly. The term "therapeutically effective amount" as used herein means the active compound or A pharmaceutical agent that produces a biological or medical response in a tissue, system, animal, or human, ', is sought by a researcher, veterinarian, physician, or other clinician. Surgery::/σ therapy system, refers to the treatment of mammals infected by pathological conditions and aims to alleviate the condition by killing cancer cells and also means that the progress of inhibition of the progress of the brothers is reduced, The rate of progression is stopped, the condition is improved, and the condition is cured. Also included as a precautionary measure (ie, prevention). "Apply acceptable" means a reasonable pharmaceutical judgment: Sex 2 is used in contact with a subject (eg, human) without excessive, allergic reactions or other problems or complications. Reasonable 127700.doc -65- 200836731 Benefits / Wind Harmony &amp; L + 剞.帛 帛 The corresponding compound, material #, composition and/or agent 1 (four) agent and the like are compatible with the other components of the formulation, and must also be, acceptable,,. : A helper, refers to the use of a compound in combination with known treatments. These include the cytotoxic regimen and/or ionizing radiation of the drugs used in the treatment of different cancer types.牿 ^, 5, it is known that the active compound of sputum can strengthen many cancer chemotherapeutic treatments from ^_ ^, the specific active compounds include topoisomerases (eg ^^, Shi

• Topotecan, irinotecan, Rubiconkine (4) 1 (4), most known alkylating agents (eg, DTIC, temozolomide), and drug-based drugs used in the treatment of cancer (eg, Kashun, Shun A method for treating cancer comprising administering a therapeutically effective amount of a compound of Formula 1 in combination with Light Shot # and/or in combination with a compound selected from the group consisting of: HDAC inhibitors, Estrogen receptor regulation of sputum, androgen style regulators, retinoid receptor modulators, cytotoxicity/cytostatic agents, antiproliferative agents, isoprenyl-protein transferase inhibition y hmg-c〇a reduction Enzyme inhibitors, angiogenesis inhibitors, gamma agonists, PPAR-delta agonists, antiviral agents, intrinsic multidrug resistance inhibitors, antiemetic agents, agents for the treatment of anemia, for the treatment of neutropenia The agent, the immunopotentiator, the inhibitor of cell proliferation and survival signal scale, the agent that interferes with the cell cycle detection point, the apoptosis-inducing agent, and the bisphosphonate. These and other aspects of the invention can be readily ascertained from the teachings herein. 0 127700.doc -66-200836731 The chemicals used and the abbreviations used in the following examples:

AcCl (acetamethylene); (Bz〇) 2 (benzaldehyde peroxide); Cbz_cl (benzyl chloroformate); DCM (dichlorodecane); DIPEA (di-iso-propylethylamine) ;DMF (dimethylformamide); DMSO (dimethyl sulfoxide); eq·(equivalent); ES (electrospray); EtOAc (ethyl acetate); EtOH (ethanol); mol·Sieves (molecular sieve) ;HATU [hexafluorophosphoric acid 0-(7-azabenzotrien-1-yl), #: tetramethylhydrazine]; MeCN (acetonitrile); MeOH (methanol); MS (mass); Microwave); NBS (沁 bromide succinimide); NMMO (W_methylmorpholine-ΛΓ·oxide); NMR (nuclear magnetic resonance); Pcol (column pressure); iPrOH (isopropanol); RT (room Temperature); sat· aq·(saturated aqueous solution); SiO 2 (silicone); and THF (tetrahydrofuran). aC2〇 (acetic acid); BuBuOH (third-butanol); mPEA (di-iso-propylethylamine) K;Ac (potassium acetate); MW microwave; 1ST ISOLUTE8 SPE column SCX (International Sorbent Technology ISOLUTE® Solid Phase Extraction column cation exchange resin); Sfc (supercritical fluid chromatography); TBTU bismuth tetrafluoroborate-(1 Helium, benzene And triazol-1-yltetramethylguanidine and Tcol (column temperature). The compound of formula I can be prepared by reacting a compound of formula IA with ammonia:

Wherein R1 and R2 are as defined above and Rx is C&quot; alkyl, for example, methyl. The reaction is usually carried out in a sealed reaction vessel using an aqueous solution of NH3 in a solvent such as 127700.doc-67-200836731 THF at 70 ° C (prudent). Alternatively, a base such as NaOH or KOH may be added to hydrolyze the ester to the corresponding carboxylic acid (RX-based hydrogen), followed by the addition of NH3, in the presence of a coupling agent such as HATU or TBTU and DIPEA, in a solvent such as DMF. The reaction is carried out at about room temperature. Alternatively, the carboxylic acid can be activated, for example, with boC2 oxime to form a mixed acid anhydride&apos; and subsequently reacted with ammonium bicarbonate, typically in a solvent such as a bite. Alternatively, the ester can be converted to a compound of the formula in, for example, MW at about 12 (TC) in a solvent such as MeOH. The above compound should be protected by, for example, Boc. A nitrogen atom on a hexahydropyridinium ring. A compound of formula 1A can be prepared by reacting a compound of formula 1B with an azide:

"R, R and RX are as defined above. Can be used such as NaN3, etc.

And the nitride is usually in a solvent such as DMF at about 90. Additives such as 2,6-lutidine can also be used at temperatures up to 140 °C. This reaction can be carried out under a nitrogen atmosphere. The compound of the formula IB can be prepared by a condensation reaction of a compound of the formula with a compound of the formula ι: 127700.doc -68 - 200836731

(ic) R2

Wherein R1, R2 and Rx are as defined above and the L1 is a leaving group such as a nitro group or a halogen such as fluorine. The method includes condensation in the presence of a dehydrating agent such as MgS 4 or a molecular sieve or heating under reflux in an alcohol solvent such as ethanol. This reaction can be carried out under a nitrogen atmosphere.

The compound of formula 1C can be prepared by oxidizing a oxime compound using an oxidizing agent such as NMMO: C〇2Rx

R (IE) wherein R1, Rx and L1 are as defined above and a l2 leaving group, for example, a halogen such as bromine is usually present in a solvent such as MeCN at about room temperature. This reaction can be carried out under a nitrogen atmosphere. The IE compound of the formula L2 bromine can be prepared by oxidizing an IF compound using a brominating agent such as NBS in the presence of a radical initiator such as peroxybenzate: co2rx (IF) 127700.doc -69- 200836731 Wherein R1, Rx and L1 are as defined above, usually under reflux in a solvent such as cci4. This reaction can be carried out under a nitrogen atmosphere. The L1-based fluorine-type if compound can be prepared by decomposing the intermediate diazonium salt by the diazotization reaction of the compound:

(IG), , R and R are as defined above. For example, the diazotization reaction can be carried out in a solvent such as DCM at about 〇t:T using nitrosonium tetrafluoroborate. The corresponding tetrafluoro(tetra) diazonium salt can then be separated and subsequently decomposed to the corresponding fluorobenzene derivative (caution) in a solvent such as dichlorobenzene by heating to 160. The L1 system The formula of the nitro group can be prepared by the oximation reaction of the formula, followed by the esterification reaction.

Wherein R1 is as defined above. The nitrate and the presence of an acid such as sulfuric acid may be carried out under standard conditions under a standard condition such as potassium citrate or the like. The esterification is reversed by, for example, by reacting an alkyl group 127700.doc-70-200836731 with a halogen (wherein x-based halogen, for example, moth) in the presence of, for example, cesium carbonate and in a solvent such as DMF at about room temperature The next reaction. The Rx-OH alcohol of the formula may also be used together with an acid catalyst such as HCl which is produced in situ from AcCl/MeOH under reflux. The desired IF compound can then be obtained by hydrogenation of a nitro compound using hydrogen and a catalyst such as palladium on carbon (usually in an alcohol solvent such as MeOH) to form the corresponding aniline. Alternatively, a compound of formula I can be prepared by reduction of a compound of formula IJ: CONH.

(IJ)

Wherein R1 and R2 are as defined above. The reduction can be carried out in a Fowler reaction using ruthenium chloride such as CBz-Cl and a reducing agent such as NaBH4. Hydrogenation on carbon-supported palladium completes the reaction and removes the CBz-protecting group. The compound of formula IJ can be prepared by crosslinking a IK compound with 3-pyridyl boronic acid of formula IL:

(IK) (IL) wherein R1, R2 and L2 are as defined above. The reaction is usually at 127700.doc -71 - 200836731

The Suzuki coupling conditions are carried out, for example, using a catalyst such as Pd2(dba)3 and tris(t-butyl)phosphine, and a base such as sodium carbonate and a solvent such as DMF and water at about 90 °C. Formula IK compounds can be prepared by condensation of a compound of formula IM with a compound of formula IN:

(IM)

(IN) wherein R1, R2 and L2 are as defined above and the L3 is a leaving group, for example, a halogen such as fluorine; usually in a solvent such as DMF at about 180 ° C in MW. A base such as K2C03 may also be added. Compounds of formula IM can be prepared by formulating compounds of formula IO wherein R1 and Rx are as defined above

(10) reacting with a base such as KOH or NaOH at about room temperature to hydrolyze the ester to the corresponding carboxylic acid (Rx-based hydrogen), followed by the addition of NH3 in the presence of a coupling agent such as HATU, DIPEA and TBTU, such as in In a solvent such as DMF, the reaction is carried out at about room temperature. 127700.doc •72- 200836731 r^r In a solvent such as coffee (3), use a compound such as B to brew an aniline group from a compound of formula ig to prepare a formula: 来: =: two uses: acid ^ The % of the bow squat is usually at about 〇 ° C in the presence of a co-solvent such as toluene and water. When the synthesis of the intermediate and starting materials is not known, such compounds are commercially available or can be prepared by standard methods or by extending the above synthesis, the reaction schemes herein and the examples from commercially available compounds. • Compounds of formula j can be converted to other formulas by known methods or by the methods described above in the synthesis, in the reaction schemes and in the examples. In the course of any-synthesis sequence described herein, it may be necessary and/or useful to protect any of the sensitive or reactive groups on the molecule involved. This can be achieved with the help of the white-protected group, for example, they are stated at the price of h... sigh, __ 3rd edition, Gr_, τ w and Wuts,

Wiley Interscience, 1999 and Kocienski, P. j

Pro(10)仏(10)..., Thieme, 1994. These protecting groups can be removed at a suitable subsequent stage using methods known in the art. For example, when a Boc (dibutyloxycarbonyl) or benzylcarboxy protecting group is present, the protecting group can be removed by adding a solvent such as TFA, DCM and/or MeCN at about room temperature. . The compound can also be hydrogenated using standard methods (e.g., using a catalyst such as pd/c in a solvent such as methanol under a hydrogen atmosphere). EtOAc can also be added in the presence of HCl and 1,4-dioxane to remove the B〇c or benzylcarbonyl protecting group at about room temperature. The compounds of the invention were prepared according to the following reaction schemes. All variables of the formula 127700.doc -73- 200836731 are as defined above. When the compound of the invention has a palmitic center, the individual enantiomers can be separated from the racemic mixture by standard separation methods (e.g., using SFC, palmitic HPLC or by dissolving the palmitic acid). This separation can be carried out in any step of the process for preparing the compound of formula I. Thus, the separation can be carried out in the final step, or the intermediate can be isolated and subsequently utilized in a subsequent reaction to produce the desired product. Reaction Scheme 1 A procedure for the synthesis of derivatives of the compounds of the present invention is shown in Reaction Scheme 1 wherein a substituted 2//-carbazole is prepared using a synthetic route similar to that described in WO 2005/066136. After the initial conversion of the 2-nitro-3-methyl-benzoic acid derivative to the corresponding ester, group bromination of the methyl group using reagents such as N-bromosuccinimide and benzamidine peroxide , producing a key benzyl bromide derivative. Oxidation of the benzyl bromide to the corresponding benzaldehyde can be accomplished using, for example, methylmorpholine-onium oxide and molecular sieves. After condensation of the aldehyde with the amine, the critical intermediate can be treated by using sodium azide at elevated temperatures. The body is introduced by introducing a final nitrogen atom and the resulting nitrogen to provide a carbazole ring to complete the ring closure. A base such as lutidine may also be added to the reaction. Finally, the S is converted to a -grade guanamine. Producing the desired material. This can be accomplished by heating the ester in an ammonia solution or by converting to the corresponding carboxylic acid and subsequently performing a guanamine coupling 127700.doc -74 - 200836731

For example, AcCI, RxOH reflux co2rx

Bromination such as NBS, (BzO)2, CCI4) Δ C02Rxj^Yn〇2 Ri^^-CH2Br oxidation For example, NMMO, molecular sieve

Rx = C^alkyl

i) _3, DMF, 90oC H) amide formation NH3, THF or MeOH, 70 ° C sealed test tube, or

NaOH or KOH, NH3, HATU

Or TBTU, DIPEA, DMF, RT Reaction Figure 1 Reaction Figure 2 Variations of Reaction 圊 1 are shown below in Reaction Scheme 2 and substituents can be introduced on the oxazole core. When the desired nitrobenzoic acid derivative is not commercially available, it can be prepared, for example, by nitrating a corresponding benzoic acid derivative with potassium nitrate present in concentrated sulfuric acid. The synthesis operation as described above forms the corresponding aniline which can also be cyclized to form the carbazole by first acetylating the aniline and cyclizing it with sodium nitrite at 〇 ° C in concentrated HCl. Alternatively, the aniline may be diazotized using nitrosonium tetrafluoroborate and the corresponding diazonium tetrafluoroborate may be decomposed at a high temperature to produce a corresponding diphenyl derivative by Schiemann reaction (care). According to the synthesis sequence as described in the reaction scheme 1, the benzylmethyl group can be oxidized to the corresponding aldehyde and the ring is formed by sodium azide by combining with the (hetero) quinone 127700.doc-75-200836731 amine couple. To produce the desired α-zolyl derivative R1 CO# such as KN〇jconc h2S〇4 9°2Η

CH3 R1

CH, bioesterification N〇2 eg .AcCI, MeOH, Δ

Restore H2&gt; Pd/C

CHO C〇2Rx

i) NOBF4, DCM C〇2Rx ϋ) gas benzene, △

R1', CH3 cyclization

For example i) AcCI, 55〇C ii) NaN02l cone HCI, 0°C

See reaction diagram 3

Reaction Figure 2 Reaction Figure 3

Another procedure involves functionalizing the oxazole at a later stage, as shown in Figure 3 of the reaction. Here, the carbazole ester is first converted to the corresponding formamide and then subjected to nucleophilic aromatic substitution with an appropriate fluorine (hetero) aromatic bromide. This can prepare a bromide derivative capable of cross-linking coupling under Suzuki coupling conditions (e.g., using tris(t-butyl)phosphine and Pd2(dba)3 as a catalyst in the presence of a base such as sodium carbonate. Subsequent conversion to the desired hexahydropyridine moiety is accomplished by a Fuller reaction using ruthenium chloride such as CBz_cl and a reducing agent such as NaBH4. The final hydrogenation reaction produces the corresponding hexahydropyridine derivative. 127700.doc -76- 200836731

CO〇RX

Amide formation, for example, NH3, ΔN or K〇g, followed by ΤΒΊ^υ NH - C0NH〇

S&gt;jAr reaction ^ , MW, 180 ° C

Suzuki coupling

Reaction Scheme 3 PARP-1 SPA Assay The exemplary compounds described herein were tested in this assay and found to have an IC5 enthalpy of less than 5 μΜ, specifically less than 50 nM. Working Reagents Test buffer: 100 mM Tris pH 8, 4 mM MgCl2, 4 mM spermine, 200 mM KC1, 0.04% Nonidet P-40.

U Enzyme mixture: test buffer (12.5 ul), 100 mM DTT (0.5 ul), PARP-1 (5 nM, Trevigen 4668-5 00-01), H20 (to 35 ul) o nicotinic amine-gland嘌呤 dinucleotide (NAD) / DNA mixture · [3H-NAD] (250 uCi / ml, 0.4 ul, Perkin-Elmer NET-443H), NAD (1.5 mM, 0.05 ul, SIGMA N-1511), biological The NAD (250 uM, 0.03 ul, Trevigen 4670-500-01) was activated to activate the calf thymus (1 mg/ml, 0.05 ul, Amersham Biosciences 27-4575) and H20 (to 10 ul). 127700.doc -77- 200836731 Development mixture: Streptavidin SPA beads (5 mg/ml, Amersham Biosciences RPNQ 0007) dissolved in 500 mM EDTA. Experimental Design The reaction was carried out in a 96-well microplate at a final volume of 50 uL/well. 5 ul of 5% DMSO/compound solution was added, and the enzyme mixture (35 ul) was added. The reaction was started by adding a NAD/DNA mixture (10 uL) and incubated at RT for 2 hours. The reaction was stopped by the addition of a developing mixture (25 ul) and incubated for 15 min at RT. Measurements were performed using a Packard TOP COUNT instrument. BRCA_1 Silencing HeLa Cell Proliferation Assay Abbreviation: IMDM (Iscovei Modified Dubecca Medium); MM (Roswell Park Memorial Institute); MOI (infection); GFP (green fluorescent protein); PBS (phosphoric acid) Flushing salt solution; FC: S (fetal calf serum); and DMEM (Dubec's modified eagle medium) °

It can also match BRCAlwt and BRCAlJshl^W ^ t in anti-proliferation test.

The compounds of the invention were tested in HeLa cells. This test demonstrates that PARP inhibition can show the growth of cells that selectively inhibit BRCA deficiency. These compounds showed less than 5 μΜ of CC5〇's in BRCA1-deficient cells and a selectivity of 20 cells of BRCA-containing cells in the plant. The test is based on the fact that living cells can convert the redox dye (resazurin) into the final product of glory (resofurin). The amount of the test is proportional to the number of cells. Cell lines are HeLa cells transduced with lentiviral transduction of shRNA (for BRCA-1) and GFP expression cassette at MOI of 1〇0 &amp; 127700.doc -78 - 200836731. The BRCA-1 silencing system is greater than 80% as assessed by Taqman analysis and the cells stably express GFP. Ugly/ΓΜ-GT^P- These are HeLa cells transduced with a control vector that does not exhibit any shRNA at an MOI of 100. Test protocol* Seeding at 300 cells/well in 90 μM medium in 96-well black plates*: “4 hours incubation at 37°C, 5% C02 - 10X compound (5 % DMSO) at 10 ul/well Stored in H20) - Incubate at 37 ° C for 168 hours, 5% C02 - Add 10 μM of Cell titer Blue solution (Promega, G8081) pre-diluted in PBSlx at 1:1 - Mix the mixture at 37 °C Incubate 45', 5% C02 - 15 in the dark at RT,

- Reading the plate with a light meter, ex: 550 nm; em: 590 nm ' * Medium: DMEM (GIBCO, 41966-029), 10% FCS (GIBCO, 10106-169), 0.1 mg/ml penicillin-chain Protease (GIBCO, 15140-114), 2 mM L-glutamine (GIBCO, 3042190) Proliferation assay of cell lines naturally lacking BRC A · The compounds of the invention may also be less than 5 micromoles of CC 5 〇1 inhibits proliferation of cell lines deficient in native BRCA-1 (MDA-MB-436) and BRCA-2 (CAPAN-1). Proliferation assay 127700.doc -79- 200836731 Cells were seeded at 700 cells/well in 100 ul of the appropriate medium/well in 96-well plates. * Secondary enthalpy, adding serial dilutions in a final volume of 200 μΐ/well. Each dilution was tested in triplicate. After 6 days, cell viability was assessed using CellTiter-Blue Cell Viability Assay according to the manufacturer's instructions (Promega). Plates were read using a Fusi(R) I1 Alpha microplate reader (Packard Bioscience). For the low proliferative cell line (ie 'CAPAN-1), 14 days after the addition of the compounds (and on the 7th day, the medium was changed once, 17 〇μ1 medium was withdrawn and 170 μ 新鲜 fresh medium containing the mixture was used instead) Test proliferation. *Medium: MDA-MB-436: RPMI (GIBCO), 10% FBS (5% C02) CAPAN-1: IMDM (GIBCO), 20% FBS (5% C02) Compounds tested in oncology in vivo models Significant activity levels.

PREPARATION EXAMPLE EXAMPLE A 2 -Phenyl-2 ugly-0 丨嗤-7-carbamimid (a 6) Step 1: 3-methyl-2-nitrobenzoic acid methyl ester (A1) at 〇 ° C To a suspension of 3-methyl-2-nitro-benzoic acid (ΐ·〇eq·) in MeOH (0.4 Μ) was added dropwise EtCl (3.0 eq.). The reaction mixture was stirred under reflux for 20 hours. The solvent was reduced in vacuo and the residue was taken from EtOAc EtOAc EtOAc EtOAc The solvent was evaporated to give a white solid (Ai), which was used in the next step without further purification. 1H NMR (400 MHz, CDC13, 300K) 127700.doc -80 - 200836731 δ 7.86 (1H,d,J=7.5 Hz), 7.53-7.42 (2H,m),3·89 (3H,s) 2.36 (3H , s). MS (ES) C9H9N04 specified: 195, calcd.: 218 (M+Na), step 2 · 3-(Ximethyl)-2-succinylbenzoic acid methyl acetonate (A 2 ) under reflux, N 2 atmosphere, The mixture of (A1) (1.0 eq.), (BzO)2 (〇〇6 eq) and NBS (1.18 eq·) in CC14 (0.2 Μ) was heated for 12 hours. The mixture was cooled to RT, diluted with DCM, concentrated under reduced pressure and dried and then applied to Si. The residue was purified by flash chromatography eluting with EtOAc EtOAc (EtOAc) 'Η NMR (400 MHz5 CDC13, 300K) δ 7.93 (1H? d? J = 7.7 Hz), 7.72 (1H, d, J = 7.7 Hz), 7·57 (1H, t, J = 7.7 Hz), 4 · 43 (2H, s), 3.88 (3H, s). MS (ES) C9H8BrN04: 273: 275, calc.: 242: 244 (M-MeO)+, 227: 229 (Μ-Ν02) +. Step 3: Methyl 3-mercapto-2-nitrobenzoate (A3) Add NMMO (2.0) to a mixture of (A2) and 4A molecular sieves (15 g) in MeCN (0.2M) at RT. Eq.) and the reaction mixture was stirred under N2 atmosphere for 1.5 hours. Subsequently, the mixture was diluted with EtOAc, filtered and washed with EtOAc EtOAc EtOAc The solvent was evaporated to give a white solid (A3). b NMR (400 MHz, CDC13, 300K) δ 9.96 (1H, s), 8·26 (1Η, d, J=7.9 Ηζ), 8.18 (1Η, d, J=7.9 Hz), 7·77 (1Η, t, J = 7.9 Hz), 3·93 (3H, s). MS (ES) C9H7N05 specified: 209, found: 208 (MH)-. Step 4: Methyl 2-nitro-3-[(phenylimino)methyl]benzoate (A4) 127700.doc -81 - 200836731 (Α3) in a N2 atmosphere under reflux (1· The mixture of 〇eq·) and aniline (1〇5 ··) in EtOH (〇·2 Μ) was stirred for 2 hours until τιχ showed the reaction was completed (H.sub.1/EtOAc = 75:25). The solvent was evaporated to give a white solid (A4), which was used in the next step without further purification. iH NMR (4(9) MHz5 CDC13,300K) δ 8.51 (1Η5 d, J=7.3 Ηζ)5 8.41 (1Η5 s)5 8·11 (1Η,d,J=7.8 Ηζ), 7.67 (1Η,t,J=7.8 Ηζ), 7.43 (2Η, t, J 7.8 Hz), 7.31 (1H, t, J = 7.3 Hz), 7.16 (2H, d, J = 7.8 Hz), 3.94 (3H, s). Step 5: 2-Phenyl-2-H-indazole-7-formic acid methyl ester (A5) is stored in (in the &amp; atmosphere, (α4) (1·〇eq) and NaN3 〇〇5 eq.) at 90C The mixture in dry DMF (0.3 M) was stirred overnight. The crude material was reduced in vacuo and the residue was purified eluting with EtOAc EtOAc (EtOAc) H NMR (400 MHz, CDC13, 300K) δ 8.50 (1H, s), 8"2 (1Η, d, J=7.0 Ηζ), 7·96-7·90 (3Η, m), 7.49 (2Η, t , J = 7.6 Hz), 7·38 (1H, t, J = 7.4 Hz), 7·15 (1H, t, J = 7.4 Hz), 4·〇3 (3H, s)· MS (ES) C15H12N202 Specified value: 252, Experimental value: 253 (M+H) + 〇Step 6 · 2_Phenyl-2H_carbazole_7_Mercaptoamine (A6) At 70 C, in an sealed tube, the ester ( A5) Heating in a mixture of thf and 32% NH3 in water overnight. The solvent was reduced in vacuo and the residue was purified by flash chromatography eluting with EtOAc (EtOAc) eluting lH NMR (4〇〇MHz, DMSO, 300K) δ 9.33 (1H, s), 8.56 (1H, bs), 8.16 (2H, 127700.doc -82- 200836731 d5 J=7.9 Hz)5 8.08 -8 00 ,” • U0 (2H, m), 7.88 (1H, bs), 7.63 (2H, t, J = 7.7 Hz), 7.50 (1H, t, 7.4 Hz), 7.27 (1H, t, J= 7.9 Hz) 〇MS (4) Cl4HllN3 〇 Specified value: 237, Experimental value: 238 (m+h)+. Example of preparation Example 1 Gasification 3-{4-[7·(Amino M group)_2Hn2_yl]phenyl }六氮吨 bite town (B4) Step 1 · 3-[4-({-[3-(Methoxy)-2- sureylphenyl]methylene}amino) phenyl] Hydropyridine-1,3-carboxylic acid tert-butyl ester (B1) (B1) is prepared according to the general procedure reported in Step 4 of Preparation Example a and 3-(4-Amino-phenyl)hexahydropyridine 4•carboxylic acid Tri-butyl ester was prepared (until TLC showed the reaction was completed (petroleum ether: Et EtOAc: 4: 1)) and was used in the next step without further purification. Step 2: 2-{4_[1· (cold triylcarbonyl)hexa-argon 0-pyridin-3-yl]phenyl bromide 2 uglyoxazole-7-formic acid methyl ester (Β2) (Β2)) was prepared according to the general procedure reported in Preparation Example 5, Step 5. And use 2 〇 by gel column chromatography The crude material was purified by EtOAc/EtOAc (EtOAc) (EtOAc) (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ), 7·95 (1H, d, J=8.3 Hz), 7.91 (2H, d, J=8.4 Hz), 7·39 (2H, d, J = 8.4 Hz), 7.18 (1H, t, J= 7.2 Hz), 4.30-4.10 (2H, m), 4.00 (3H, s), 2·85, 2·70 (3H, m), 2.11-2.03 (1H, m), 1.83-1.75 (1H, m) , 1.73-1.53 (2H, m is superimposed on H20 signal), 1.48 (9H, s). MS (ES) C25H29N304 specified value: 435, experimental value: 436 (M+H)+. 127700.doc -83 - 200836731 3 · 3-{4-[7_(Aminocarbonyl)_2carbazole•yl]phenylphosphonium hexahydropyridine_1-carboxylic acid tert-butyl ester (B3)

(B2) was heated in a sealed tube at 60 ° C for 2 days in 7 Torr 3 in MeOH (0.1 M). The solvent was reduced in vacuo and the crude product was purified by trituration with Et2 to afford the desired yellow solid (B3). lH NMR (400 MHz, CDC13, 300K) δ 9.04 (1H, br. s), 8·51 (1H, s), 8.31 (1Η, d, J = 6.8 Ηζ), 7.91 (1Η, d, J=8.3 Ηζ), 7.84 (2Η, d, J - 8·2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.31-7.22 (1H, m overlaps with CDC13 signal), 5.95 (1^1, |^) 3), 4 4〇_4 〇5(211,111), 2 9〇_ 2·7〇(3H,m), 2.15-2.00 (1H,m),1.85-1.75 (1H,m)5 1.75- 1·5〇(2H,m overlaps with H20 signal), ι ·48 (9H,s)_ MS (ES) C24H28N4〇3 specified value: 420, experimental value: 421 (m+H)+. Step 4: Gasification 3_{4-[7-(Aminomethyl)-2 oxazol-2-yl]phenyl}hexahydropyridinium (B4) to (B3) (1.0 eq) in EtOAc A 4N HC1/1,4-oxohedo-sinter solution (1 〇·〇eq) was added to the stirred solution (0.2 M) and the reaction mixture was stirred at RT for 3 h. The solvent was evaporated under reduced pressure and the crude product was purified by trituration with Et20 to yield the desired yellow solid (B4). 4 NMR (400 MHz, DMSO-d6, 300K) δ 9·32 (1H, s), 9.12 (1H, br·s), 8.87 (1H, br·s), 8.55 (1H, br. s), 8.13 (2H, d, J = 8.6 Hz), 8.06 (1H, J = 7.0 Hz), 8.02 (1H, d, J = 8.4 Hz), 7.89 (1H, br. s), 7.55 (2H, d, J = 8.6 Hz), 7.27 (lH, dd, J = 8.4, 7.0 Hz), 3.43 - 3.27 (2H, m), 3.17 - 3.03 (2H, m), 3.00 - 2.85 (lH, m), 2.00 · 1.70 (4H , m)· MS (ES) C19H21C1N40 specified value: 320, experiment 127700.doc -84- 200836731 Value: 321 (M+H)+. Example 2 2-{4_[(3R)-Hexahydropyridine-3-yl]phenyl}-2H-indazole-7-carboxamide (C1) and 2-{4-[(3S)-hexahydropyridine -3-yl]phenyl}-2H-carbazole-7-carboxamide (C2) by palmitic SFC (column: Chiralpak AS-H, 1 X 25 mm, flow rate: 10 ml/min, Tcol : 35 ° C, Pc〇i : 100 bar, improver: 55% (iprOH + 4 ° / 〇 Et 2 NH)) Separation of Example 1, B4 using CO 2 as a supercritical solvent to obtain two pure enantiomers . The first eluted enantiomer (C1) was obtained as a white powder, and the residence time (SFC): 4.80 min. 4 NMR (400 MHz, DMSO-d6, 300K) δ 9.28 (s, 1 Η), 8.57 (br· s, 1 Η), 8.06 (d, 2 Η, J = 7.2 Ηζ), 8·04 (d, 2H, J =8.4 Hz), 7.88 (br. s, 1H), 7.49 (d, 2H, J = 8.4 Hz), 7.27 (dd, 1H, J=8.4, 7.2 Hz), 3.08-2.94 (m, 2H), 2.77 -2.67 (m,1H), 2.64-2.52 (m,1H), 1.98=1.90 (m,1H), 1.75] 47 (m,4H). MS (ES) C19H2〇N40 Specified value: 320, Experimental value: 321 (M+H)+. Conversion of the free base to gasified (3 and)-3-{4-[7-(aminobenzyl)-2H-indazol-2-yl]phenyl}hexahydro-pyridinium oxime and measuring the optical rotation : [ol]20d=+133.3 ( c 〇·15, MeOH). The second eluted enantiomer (C2) was obtained as a white powder, and the residence time (SFC): 6.51 min. 4 NMR (400 MHz, DMSO-d6, 3 〇〇Κ) δ 9·28 (s, 1 Η), 8·57 (br· s, 1 Η), 8·06 (d, 2 Η, J = 7.2 Ηζ), 8 〇4 (d, 2H, J=8.4 Hz), 7·88 (br· s, 1H), 7.49 (d, 2H, J = 8 4 Hz) 7.27 (dd, 1H, J=8.4, 7.2 Hz) ,3.08-2.94 (m,2H),2·77·2 67 (m,1H),2.64-2.52 (m,1H),1.98-1.90 (m,1H),〇127700.doc -85 - 200836731 (m , 4H). MS (ES) C19H2 〇 N40: 320, found: 321 (M + H) +. The free assay was converted to (35)-3-{4_[7-(aminocarbonyl)-2H-indazol-2-yl]phenyl}hexahydropyridinium chloride and the optical rotation was measured: = -137.9 ( c 0.145, MeOH). Example 3 Trifluoroacetic acid 3_{4-[7-(aminocarbonyl)-5-fluoro-2H-indazol-2-yl]phenyl} hexahydro 11 ratio bite (D4) Step 1: 5-Fluoro- 1H-carbazole_7-methyl formate (D1) To a solution of Example 4, E3 (1_0 eq) in 1,2-dioxaethane (〇.1 μ) was added AcCl (5 eq) at 55 C Heat down for 2 h. Thereafter, the solvent was removed under reduced pressure. The white solid was dissolved in toluene/water (5/1, 0.1 M). The solution was cooled to 0 ° C and HCl (10 eq·, 3 7%) was added. Subsequently, several portions of NaN02 (10 eq) were slowly added and the mixture was spoiled at 〇 ° C for 3 h. The organic phase was washed with water (3x), dried over MgSCU and solvent was removed under pressure. The yellow benzene solution (〇·ΐ M) was then heated at 90 ° C for 2 h. The toluene was evaporated to give the desired product as a red solid. 1H NMR (400 MHz, DMSO, 300K) δ 13·37 (1H, s), 8.23 (1H, s), 7.63 (1H, dd, J = 8.6 Hz, J = 2.5 Hz), 7.48 (1H, dd, J=8.6 Hz, J=2.5 Hz), 3·66 (3H, s)· MS (ES+) C9H7FN2〇2 specified value·· m, experimental value·· 195 (M+H), step 2: 5-fluorine -1H_carbazole·7-formamide (D2) (Dl)/valid in monooxane/hydroquinone/}, 〇· im) was added (1·5 eq). After stirring for 12 h at RT, the solvent was removed under reduced pressure. White 127700.doc -86 - 200836731 The solid was used for subsequent coupling without purification. The carboxylic acid was dissolved in DMF (0.1 M) and TBTU (1.5 eq) was added at EtOAc. After 15 min, DIPEA (2.0 eq.) and ammonia (3.0 eq., 0.5 Μ' in dioxane) were added and the mixture was stirred at rt. EtOAc was added and the organic phase was washed with saturated aq. NaH.sub.3 (3x) and brine (2x). The organic phase was dried and evaporated under reduced pressure. The crude was purified by flash chromatography using EtOAc (EtOAc) elute MS (ES+) C8H6FN30: 179, found: 180 (M+H)+. Step 3: 2-(4-Bromophenyl)-5-fluoro-2H-indazole-7•carboxamide (D3) Add K2C〇3 to D2 (1.0 eq) in DMF (0.2 Μ) 1 3 eq) and 4-bromofluorobenzene (ι〇·〇eq) and the reaction mixture was heated at i80 ° C for 20 min under Mw conditions. The reaction mixture was cooled to RT and diluted with EtOAc. The organic phase was washed with brine and dried (NaeCU). The solvent was evaporated to give (D3), which was purified eluting eluting eluting 1H NMR (400 ΜΗι DMS〇-d6, 3G〇K) δ 9.34 (1H, s), 8.50 (1H, br·s), 8.17 (2H, d, J 9.0 Hz), 8.03 (1H, br. s), 7.90-7.80 (4H, m). MS (ES+) C14H9BrFN30 Specified value: 334/336, Experimental value: 335/337 (M+H) + 〇 Step 4 ··S-Fluoro-2-(4-pyridin-3-ylphenyl)·2Η-吲Oxazole. _Metformamide (D4) Degassed with a mixture of (D3) (1.0 eq) and pyridine-3_boric acid (13 in dmf (1·〇M) and 2N Na2CCMe (2〇eq) with Ar gas stream , 30 minutes. Add BV (〇〇5 eq) m (d called (〇·〇5 eq) and the reaction mixture is at 9 〇.(;; heating for 48 h. Make the mixture 127700.doc -87-200836731 After cooling to RT, DCM was added and EtOAc (EtOAc m.). /DCM </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> <RTIgt; , 8.63 (1H, dd, J = 4.8, 1.6 Hz), 8.57 (1H, br. s), 8.32 (2H, d, J = 8.8 Hz), 8.20 (1H, d, J = 7.8 Hz), 8.10 ( 1H, br · s), 8.01 (2 H,d,J - 8 · 8 H z),7 · 8 8 - 7 · 8 2 (2 H,m),7 · 5 4 (1H dd, J=7.8 , 4.8 Hz). MS (ES) C19H13FN40: 332, 303 (M+H+). Step 5: 3-{4-[7-(aminocarbonyl)-5-fluoro-2H-carbazole -2-yl]phenyl} Benzyl hexahydropyridine-1-decanoate (D5) was added to a stirred solution of (D4) in dry MeOH (0.2 Μ).

NaBH4 (1.2 eq) and then Cbz-Cl (1.2 eq) was added dropwise at _65 °C. The reaction was allowed to reach RT O/N and then quenched with HA. The MeOH was concentrated under EtOAc (EtOAc)EtOAcEtOAcEtOAc. C27H25FN403 specified: 472, found: 473 (M+H+). Step 6: trifluoroacetic acid 3-{4-[7-(aminocarbonyl)_5-fluoro-2H-indazole-2-yl]phenyl To the solution of (D5) (1.0 eq) in MeOH (0.2 M), add pd/c 10% (0.05 eq) and HCl (1.0 eq) and the reaction mixture in h2 The mixture was stirred for 48 h under atmosphere (1 atm). Subsequently, the mixture was filtered through celite and the solvent was removed in vacuo at 127700.doc -88 - 200836731 to obtain (D6) by reversed phase RP-HPLC (tube Column: C18), Purified using H20 (0.1% TFA) and MeCN (0.1% TFA) as solvent. The desired portion was lyophilized to give the title compound (D6) as white powder. 4 NMR (400 MHz, CD3CN, 300K) δ 9·28 (1H, s), 8.89 (1Η, br. s) 5 8·60_8·50 (2Η, m), 8·13 (2Η, d, J=8_6 Hz), 8.09 (1H, Br. s), 7.90-7.70 (2H,m), 7·54 (2H,d,J=8.6 Hz), 3.40-3.30 (2H m), 3.20-2.80 (3H, m), 2.00-1.90 (2H, m), 1.80-1.70 (2H, m), MS (ES) C19H19FN40: 338, 355 (M+H+). Example 4 5-Fluoro-2-(3- gas_4·hexahydropyridin-3-ylphenyloxazole-7-formamide trifluoroacetate (E6) Step 1: 5-fluoro-3-methyl -2-Nitrobenzoic acid (E1) slowly added KNO3 (1.1 eq) to a solution of 3·fluoro-5-methylbenzoic acid (ι·0 eq.) in concentrated H2S04 at 〇 °C The mixture was stirred at rt for 1 h and then slowly poured into ice water. After stirring until the ice was completely melted, filtered, white precipitated, washed with cold water and dried under reduced pressure. Used in the next step. iH NMR (400 MHz, DMSO, 300K) δ 14.08 (1H, br. s), 7.65 (2H, m), 2.30 (3H, s). Step 2: 5-fluoro-3- Methyl 2-nitrobenzoate (E2) Add methyl iodide (1.0 eq·) to a solution of (El) and cesium carbonate (1_5 eq·) in DMF (〇·25 M) at RT . After the mixture was stirred for 18 h, brine was added and the mixture was extracted with EtOAc. The organic phase was dried (Na2S EtOAc (EtOAc m.) m), 3.83 (3H, s), 2.29 (3H, s) Step 3: 2-Amino-5-fluoro-3-methylbenzoic acid methyl ester (E3) under RT, H2 atmosphere (1 atm) The mixture of (E2) (1.〇eq·) and pd/C (10% w/w) in MeOH (0·25 Μ) was stirred for 3 d. The mixture was passed through Celite® and then pressurized. The solvent was evaporated. The white solid was used in the next step without further purification. 1H NMR (400 MHz, DMSO, 300K) δ 7·29 (1H, dd, J=9.5 Hz, J=3.0 Hz), 7.12 (1H , dd, J = 9.5 Hz, J = 3.0 Hz), 6.36 (2H, br · s), 3.78 (3H, s), 2.11 (3H, s) Step 4: 2,5·Difluoro-3 Methyl-mercaptobenzoate (E4) To a solution of (Ε3) (1.0 eq·) in dry DCM (0.4 Μ), nitroxonium tetrafluoroborate (1·3 eq) was added at 〇°C. ·) After 1 h, dry monofluorobenzene (12 0 eq ·) was added at 0 ° C and the reaction was slowly heated to 16 ° C while distilling off DCM. After hr, the mixture was cooled to EtOAc, EtOAc (EtOAc)EtOAc.EtOAc. To produce a yellow oil (E4). iH NMR (400 MHz, CDC 135 300K) δ 7·42 (1H, m), 7·06 (1H, m), 3.92 (3H, s), 2.30 (3H, d, J = 2.3 Hz). Step 5: Methyl 2,5-difluoro-3-indolylbenzoate (E5) Prepared from E4 according to the general procedure reported in Preparation Example A, Steps 2 and 3. (E5) The crude was purified by flash chromatography (1-20%EtOAcEtOAcEtOAc) elute (1Η,m),7·86 (1Η,m),3·89 (3Η, 127700.doc -90- 200836731 S).MS (ES+) C9H6F203 specified value: 200, experimental value: 201 (M+H) +. Step 6 · 5-Fluoro-2(3-fluoro-4-hexahydropyridin-3-ylphenyl)-2H-indazole-7-carbenamide trifluoroacetate (E6) according to Step 4 in Preparation Example A And the general procedure reported in 5 uses 3_('amino-2-fluorophenyl)hexahydroacridine_;^carboxylic acid tert-butyl ester to convert (E5) to the corresponding σ?| The resulting 2-{4-[1-(third-butoxy) was obtained by treatment in a mixture of dioxane/water (mixed (0.1 M) for 12 h at RT). The carbonyl group) hexahydropyridine-3· kib 3-fluorophenyl b 5-fluoro 1-2 lb-carbazole-7-carboxylic acid methyl ester is further converted into the corresponding formamide. The solvent is removed under reduced pressure. Soluble in DMF (〇·ΐ M) and add TBTU (1 5 ··). After 15 (five) ,, add DIPEA (2.0 eq·) and ammonia (3.0 eq·, 〇·5 Μ, stored in THF) and The solution was stirred for 36 h. The mixture was diluted with EtOAc and EtOAc EtOAc EtOAc.

To carry out deprotection, the crude material was dissolved in TFA/DCM (0.1 M) and stirred at RT for 3 h. The solvent was evaporated to give a crystal crystal crystal crystal crystal crystal crystal crystal crystal NMR ' (4〇〇MHz, DMS0, 300K) 5 9.34 (1H, s), 8.90 (1H, m), 8.61 (1H, m), 8.49 (1H, s), 8.18 (1H, dd , J=11.6 Hz, 2.0 Hz), 8.05 (2H, m), 7.81 (2H, m), 7.63 (1H, m), 3.34 (3H, m), 3.13 (1H, m), 2.94 (1H, m ), 1.95-1.76 (4H, m). MS (ES + )

Ci9H18F2N40 specified value: 356, experimental value: 357 (M+H)+. Example 5 127700.doc -91 - 200836731 4-Mercaptobenzenesulfonic acid (3S)-3-{4-丨7_(aminocarbonyl)_2H•carbazole_2•ylphenyl”hexahydroindole (F4) Step 1: (3S)_3-[4-({(IE)_[3-(Methoxycarbonyl)- small nitrophenyl]methylene}amino)amino]hexahydropyrene _ 1 - formic acid tert-butyl ester (F1) as described in Example 1, B1, from Oct. 3 and Magic-3-(4-aminophenyl)hexahydropyridinium 1-carboxylic acid tert-butyl ester ( (F1) was prepared by splitting 3-(4-aminophenyl)-hexahydroacridine with 2 equivalents of L-dibenyl tartaric acid in Me〇H and then Boc-protection. Step 2 ···{{[[3S)-M-t-butoxycarbonyl)hexahydroacridine_3_yl]phenyl}-211-carbazole_7_carboxylic acid (F2) (1 eq) and sodium azide u eq) were slurried in dmF (0.25 M), inertized and 2,6-lutidine (1·〇eq) was added. The mixture was heated to an internal temperature of 110 ° C for 20 hours. The resulting brown solution was cooled to 20 ° C and THF and a 25 wt% aqueous solution of LiCl were added. The phases were separated and the organic portion was washed three more times with a 25 wt% aqueous solution of LiCl. 2.0 M NaOH (10 eq) was added to the above organic solution and the mixture was heated to 35 ° C for 20 hours, then cooled to 20 ° C and the phases were separated. The organic layer was washed with a mixture of 2.0M EtOAc and brine and the layers were partitioned. Step 3: (3S)-3-{4-[7-(Aminocarbonyl)-2H-indazol-2-yl]phenyl}hexahydropyridine-1-carboxylic acid tert-butyl ester (F3) F2 was dissolved in DC Μ (0.3 5 M) and di-tert-butyl carbonate (1.3 eq) and pyridine (1·〇eq) were added at RT. After 30 minutes, ammonium bicarbonate (1.3 eq) was added and stirring was continued for 20 hours. 1 M HCl (5 mL/g) was added and the phases were separated 127700.doc • 92-200836731. The organic layer was washed twice with water and concentrated to a smaller volume. The crude compound (F3) was filtered through a pad of diatomaceous earth and subsequently crystallized from methyl third-butyl ether. Step 4: 4-methylbenzenesulfonic acid (3S)_3_{4_[7-(aminocarbonyl&gt;211_carbazole-2-yl)phenyl}hexahydrofluorene (F4) F3 is dissolved in THF ( Water (5%, relative to THF) was added to 0.15 M). p-Toluenesulfonic acid monohydrate (2·2 eq) was added and the mixture was heated to % C and stirred overnight. The desired solid salt was isolated by filtration and confirmed to be monohydrate (F4). iH NMR (4 〇〇mHz, DMSO, 300K) δ 9.34 (1 Η, s); 9·20 (1 Η, broad s), 8.58 (1 Η, s), 8.14 (2Η, d, J—8.8 Hz), 8.05 (2H, ddd, J=1.2, 7.2, 16.8 Hz), 7.93 (1H, s), 7.52 (4H, dd, J=8.8, 16.8 Hz), 7.27 (1H, dd, J=6.8, 8.0 Hz), 7.13 (2H, d, J=8 Hz), 3.48 (3H, m), 3·10 (2H, m), 2.90 (1H, m); 2.30 (3H, s), 1.89 (2H, m), 1.75 (2H, m). Poor name MW M+H+ Example procedure 6 Difluoroacetic acid 3_{4_[7_(aminocarbonyl)_2Η· Carbazolyl]phenyl} hexahydropyridinium rust 320 321 1 7 5-fluoro·2·(4-hexahydropyridin-3-ylphenyl)-2H-carbazole-7-formamide 338 339 3 8 Gasification (3S)-3_{4_[7_(Amino-based)_2Η-σ引σ基基]Phenyl} Hexahydropurine rust 3 20 321 2 9 fluorinated (3R)_3-{4-[7-(amino aryl)-2Η-called sylylene]phenyl} hexahydroacridinium 320 321 2 10 (R)-5-fluoro- 2-(4-hexahydroindole-3-ylphenyl)-2Η-σ 弓 坐-7-carbamimid 338 339 2 11 (8)-5-fluoro-2-(4-hexahydrogen ratio Bite-3-basic)-2Η-σ 嗤-7-nonylamine _ 338 339 ------ 2 12 (R)-5-gas-2-{3-fluoro-4-hexafluorene Than -3-ylphenyl}-2Η-α-induced salivary 7-carbamimid 356 357 2 13 7-carbamamine _ 356 357 2 127700.doc -93-

Claims (1)

200836731 X. Patent application scope: 1. A compound of formula I: (I) wherein: R1 is hydrogen or fluorine; and R2 is hydrogen or fluorine; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. 2. The compound of claim 1 which has the formula II: (Π) wherein R1 and R2 are as defined in claim 1; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. 3. The compound of claim 1 which has the formula III: Wherein R1 and R2 are as defined in claim 1; 127700.doc 200836731 or a pharmaceutically acceptable substance thereof 4. A compound, salt or tautomer of claim 1, which has the formula IV: Where R1 and R2 are as defined in the request; Or a pharmaceutically acceptable salt or tautomer thereof. 5. A compound according to any one of items 1 to 4, wherein R1 is hydrogen and r2 is nitrogen or fluorine. 6. The compound of claim 1, which is selected from the group consisting of: 2-(4-hexahydrozepin-3-ylphenyl)_2H•, oxazolamide; 2-{4-[(3R)-hexahydro Pyridinyl]phenyl bromide 2H-carbazole-7-formamide; 2-{4_[(3 8)-hexahydropyridine-3-yl]phenyl}-211-carbazole-7-formamide ; 5_fluoro-2-(4-hexahydropyridin-3-ylphenyl)-2H-carbazole-7-formamide; 5-fluoro-2-{4-[(3S)-hexahydropyridine- 3-yl]phenyl azole-7-carbamamine; 5-fluoro-2-{4-[(3R)·hexahydroσ ratio π定-3 -yl]phenyl}-2Η_ϋ引啥-7- Brewing amine; 5-fluoro-2-(3-fluoro-4-hexahydropyridin-3-ylphenyl)-2indole-carbazole-7-formamide; 5-deficient_2-{3_ gas-4 -[(3R)-hexaazinium quinone-3-yl]phenyl}-2Η-σ5|σ sit-7_carbamamine; 5-fluoro-2-{3_fluoro-4-[(3S) _ Hexahydroacridin-3-yl]phenyl}_2Η-carbazole-7-methyl 127700.doc 200836731 Indoleamine; and pharmaceutically acceptable salts, tautomers or stereoisomers thereof. 7. A compound according to claim 6 which is selected from the group consisting of: 2_{4-[(3R)-hexahydro. Bispin-3-yl]phenyl}-2-oxazol-7-nonylamine; 2-{4-[(38)-hexahydropyridin-3-yl]phenyl}-2//-吲Zol-7-carbamamine; and pharmaceutically acceptable salts or tautomers thereof. A pharmaceutical composition comprising the combination of any one of claims 1 to 7 Or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and a pharmaceutically acceptable carrier. A compound according to any one of claims 1 to 4, 6 and 7 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, which is administered simultaneously, separately or sequentially with an anticancer agent. 10. A compound according to any one of claims 4, 6 and 7 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, for use in the treatment of 11. Use of a compound according to any one of the items 7 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof for the manufacture of a = treatment or prevention by inhibition of poly(A-ribose) A drug that improves the condition of the enzyme (PARP). The use of a compound of any one of items 1 to 7 or a pharmaceutically acceptable compound thereof or a tautomer thereof, for use in the treatment of priests, π „ ^ disease, reperfusion , the main two Jiafang drugs for the following diseases · cancer, inflammatory disease / main scallops, ischemic, sputum, mouth. Disease, except cardiovascular disease, kidney failure, cardiovascular disease, reversal铮, ▲, blood disease, diabetes, neurodegenerative ^ propyl infection, retinal damage or skin aging and UV 127700.doc 200836731 caused by skin damage 13. A compound of any one of claims 1 to 7 Or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof for use as a chemical-and/or radiosensitizer for cancer treatment. 127700.doc 200836731 VII. Designation of representative drawings: (1) The representative representative of this case is: (none) (2) The symbolic symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 127700.doc