TWI528961B - 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 discuses, 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

Amidoxime-substituted carbazole as a poly(ADP-ribose) polymerase (PARP) inhibitor

The present invention relates to a guanamine substituted carbazole which is previously known as poly(ADP-ribose) synthase and poly(ADP-ribosyl)transferase enzyme poly(ADP-ribose) polymerase (PARP) inhibition Agent. The compounds of the present invention are useful as monotherapy for tumors with specific defects in the DNA repair pathway and as enhancers for 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.

Poly(ADP-ribose) polymerase (PARP) constitutes a superfamily of 18 proteins containing PARP catalytic regions ( Bioessays (2004) 26 : 1148). Such proteins include PARP-1, PARP-2, PARP-3, tankyrase-1, tankyrase-2, vaultPARP, and TiPARP. PARP-1 (basal member) consists of three major domains: an amine group (N)-terminal DNA-binding domain (DBD) containing two zinc fingers, a self-modifying domain, and a carboxyl (C)-terminus. 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 a target protein, including topoisomerase, histone, and PARP itself ( Biochem. Biophys. Res. Commun . (1998) 245 : 1-10).

(ADP-ribosyl) polymerization is involved in several biological processes including DNA repair, gene transcription, cell cycle progression, cell death, chromatin function, and genes The group is stable.

Has been confirmed by DNA strand breaks may be rapidly stimulate the catalytic activity of PARP-1 and PARP-2's (see Pharmacological Research (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 compromised, 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, provide a fast signal to stop transcription and complement the enzymes required for DNA repair at the site of damage. Since many chemotherapeutic methods and radiation treatments for cancer treatment play a role in the production of 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).

Most of the biological effects of PARP are related to this (ADP-ribosyl) polymerization process, which affects the nature and function of the target protein; PAR oligomerization that produces different cellular effects upon cleavage from (ADP-ribosyl) polymeric proteins The physical association of PARP and nuclear proteins that form a functional complex; and its NAD, which is reduced in cell levels ( Nature Review (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 intercellular NAD ⁺ , which in turn can cause several NAD ⁺ -dependent metabolic pathways to impair and lead to cell death (see Pharmacological Research ( 2005) 52 : 44-59). As a result of PARP activation, NAD ⁺ levels decreased significantly. Excessive activation of PARP can cause severe DNA damage to cells suffering the severe lack of NAD ^+. The shorter half-life of poly(ADP-ribose) produces a rapid conversion rate, as poly(ADP-ribose), once formed, is rapidly degraded by the constitutively active poly(ADP-ribose) sugar hydrolase (PARG). 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 formation during reperfusion 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 cell 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.

PARP inhibitors have been shown to be useful for specifically killing BRCA-1 and BRCA-2 deficient tumors ( Nature (2005) 434 : 913-916 and 917-921; and Cancer Biology & Therapy (2005) 4 : 934-936).

PARP inhibitors have been shown to enhance the efficacy of anticancer drugs ( Pharmacological Research (2005) 52 : 25-33), which include platinum compounds such as cisplatin and carboplatin ( Cancer Chemother Pharmacol (1993) 33 : 157 -162 and Mol Cancer Ther (2003) 2 :371-382). PARP inhibitors have been shown to increase the antitumor activity of topoisomerase I inhibitors such as irinotecan and topotecan ( Mol Cancer Ther (2003) 2 :371-382; and Clin Cancer Res (2000) 6 : 2860-2867) and this has been demonstrated in an in vivo model ( J Natl Cancer Inst (2004) 96 : 56-67).

PARP inhibitors have been shown to restore sensitivity to temozolomide (TMZ) cytotoxicity and anti-proliferative effects (see Curr Med Chem (2002) 9 : 1285-1301 and Med Chem Rev Online (2004) 1 : 144-150 ). This has been in many in vitro models ( Br J Cancer (1995) 72 : 849-856; Br J Cancer (1996) 74 : 1030-1036; Mol Pharmacol (1997) 52 : 249-258; Leukemia (1999) 13 : 901 - 909; Glia (2002) 40 :44-54; and Clin Cancer Res (2000) 6 :2860-2867 and (2004) 10 :881-889) and in vivo models ( Blood (2002) 99 :2241-2244; Clin Cancer Res (2003) 9 : 5370-5379 and J Natl Cancer Inst (2004) 96 : 56-67). It has also been demonstrated that PAPR inhibitors prevent the occurrence of necrosis caused by selective N3 -adenine methylation reagents such as MeOSO ₂ (CH ₂ )-lexitropsin (Me-Lex) ( Pharmacological Research (2005) 52 :25-33 ).

PARP inhibitors have been shown to be useful as radiosensitizers. It has been reported that PARP inhibitors are effective in radiosensitizing (hypoxia) tumor cells and effectively preventing the potential lethality of tumor cells from DNA after radiation therapy ( Br. J. Cancer (1984) 49 (Supplement VI): 34- 42; and Int. J. Radiat. Bioi. (1999) 75 :91-100) and sublethal death ( Clin. Oncol. (2004) 16 (1): 29-39) damage recovery, presumably by It prevents the ability of DNA strands to break and recombine and is achieved by affecting several DNA damage signaling pathways.

PARP inhibitors have also proved useful in the treatment of acute and chronic myocardial diseases (see, pharmacological Research (2005) 52: 34-43 ). For example, it has been demonstrated that injection of a PARP inhibitor alone in rabbits reduces the infarct size caused by reperfusion and ischemia of the heart or skeletal muscle. In these studies, 3-amino-benzamide (10 mg/kg) was injected alone 1 min before occlusion or 1 min before reperfusion to achieve a similar infarct size reduction (32-42%) in the heart. The other PARP inhibitor 1,5-dihydroxyisoquinoline (1 mg/kg) reduced the infarct size by a considerable extent (38-48%). Based on these results, it is reasonable to set the PARP inhibitor to rescue previous ischemic heart or skeletal muscle tissue reperfusion injury ( PNAS (1997) 94 : 679-683). In pigs ( Eur. J. pharmacol. (1998) 359 : 143-150 and Ann. Thorac. Surg. (2002) 73 : 575-581) and in dogs ( Shock. (2004) 21 : 426-32) Similar findings have also been reported.

PARP inhibitors have been shown to be useful in the treatment of certain vascular diseases, septic shock, ischemic injury and neurotoxicity ( Biochim. Biophys. Acta (1989) 1014 :1-7; J. Clin. Invest. (1997) 100 : 723-735). 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. Neurosci. Res. (1994) 39 : 38-46 and PNAS (1996) 93 : 4688-4692). PARP has also been shown to play an important role in the pathogenesis of hemorrhagic shock ( PNAS (2000) 97 : 10203-10208).

PARP inhibitors have been shown to be useful in the treatment of inflammatory diseases (see Pharmacological Research (2005) 52 : 72-82 and 83-92).

It has also been demonstrated that effective retroviral infection of mammalian cells can be blocked by inhibiting PARP activity. Inhibition of such recombinant retroviral mediator infections has been shown to occur in a variety of different cell classes ( J. Virology, (1996) 70(6) : 3992-4000). 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 I diabetes and diabetic complications ( Pharmacological Research (2005) 52 : 60-71).

It is speculated that PARP inhibition can delay the appearance of senescence characteristics of human fibroblasts ( Biochem. Biophys. Res. Comm. (1994) 201(2) : 665-672 and Pharmacological Research (2005) 52 : 93-99). This may be related to the role of PARP in controlling telomere action ( Nature Gen. , (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 competitive inhibitors of NAD ⁺ ( Expert Opin. Ther. Patents (2004) 14 : 1531-1551). 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 guanamine-substituted phenyl rings fused to a 5-membered heteroaromatic ring; WO 2001/85687 discloses guanidine-substituted oximes; WO 1997/04771, WO 2000/26192, WO 2000/32579, WO 2000/64878, WO 2000/68206, WO 2001/21615, WO 2002/068407, WO 2003/106430 and WO 2004/096793 disclose benzimidazole substituted with 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. Thus, the compounds of the 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.

The present invention provides a compound of formula I: Wherein: R ¹ based hydrogen or fluorine; and R ² system hydrogen or fluorine; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

In one embodiment, R ¹ is hydrogen.

In another embodiment, R ¹ is fluoro.

In one embodiment, R ² is hydrogen.

In another embodiment, R ² is fluoro.

In one embodiment, R ¹ is hydrogen and R ² is hydrogen or fluorine.

In another embodiment, R ¹ is fluoro and R ² is hydrogen or fluoro.

In another embodiment, R ¹ is hydrogen and R ² is hydrogen.

In another embodiment, R ¹ is hydrogen and R ² is fluorine.

In another embodiment, R ¹ is fluoro and R ² is fluoro.

In another embodiment, R ¹ is hydrogen or fluorine and R ² is hydrogen.

In another embodiment, R ¹ is hydrogen or fluorine and R ² is fluorine.

The invention also provides a compound of formula II: Wherein R ¹ and R ² are as defined above; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

The invention also provides a compound of formula III: Wherein R ¹ and R ² are as defined above; or a pharmaceutically acceptable salt or tautomer thereof.

The invention also provides a compound of formula IV: Wherein R ¹ and R ² are as defined above; or a pharmaceutically acceptable salt or tautomer thereof.

The preferred identity of Formulas II, III and IV is as defined above for Formula I (with the 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 available nitrogen atom. The N-oxides can be formed by conventional methods (e.g., by reacting a compound of formula I with an oxone in the presence of moist soil).

The invention encompasses, in its scope, prodrugs of the compounds of formula I above. In general, such prodrugs can be functional derivatives of the compounds of formula I which are readily converted in vivo to the desired compound of formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in 'Design of Prodrugs', H. Bundgaard, Elsevier, 1985.

The prodrug can be a pharmacologically inert derivative of a biologically active substance ("parent drug" or "parent molecule") that needs to be converted in vivo to release the active drug and which has improved delivery properties over the parent drug molecule. In vivo conversion can be the result, for example, of certain metabolic processes (eg, chemical or enzymatic hydrolysis of a carboxylic acid ester, phosphate or sulfate, or reduction or oxidation of a sensitive functional group).

The invention encompasses within its scope solvates of the compounds of the formula I and their salts, for example hydrates.

The compounds of the invention may have asymmetric centers, palmar axes, and palmar planes (as set forth below: EL Eliel and SH Wilen, Stereochemistry of Carbon Compounds , John Wiley & Sons, New York, 1994, 1119- 1190), and as a racemic isomer, a racemic mixture, and as individual diastereomers together with all possible isomers and mixtures thereof (including optical isomers), all such stereoisomers Constructs are encompassed within the invention. Furthermore, the compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be 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, _C1-6 alkyl means a branched, straight-chain, and cyclic saturated aliphatic hydrocarbon group containing one, two, three, four, five or six carbon atoms. For example, "C _1-6 alkyl" specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, iso-butyl, pentyl, hexyl. , cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferred alkyl groups are methyl and ethyl.

The particular compound is within the scope of the present invention: chloride 3- {4- [7- (amine-based yl) -2 H - indazol-2-yl] phenyl} hexahydro-pyridinium; 2- {4- [ (3R)-hexahydropyridin-3-yl]phenyl}-2 H -carbazole-7-formamide; 2-{4-[(3S)-hexahydropyridin-3-yl]phenyl}- 2 H -carbazole-7-formamide; 3-{4-[7-(aminocarbonyl)-5-fluoro- 2H -indazol-2-yl]phenyl}hexahydropyridinium trifluoroacetate ; 5-fluoro-2-(3-fluoro-4-hexahydropyridin-3-ylphenyl)-2 H -carbazole-7-formamide trifluoroacetate; trifluoroacetic acid 3-{4-[ 7-(Aminocarbonyl)-2H-indazol-2-yl]phenyl}hexahydropyridinium; 5-fluoro-2-(4-hexahydropyridin-3-ylphenyl)-2H-carbazole- 7-carbamide; (3S)-3-(4-[7-(aminocarbonyl)-2H-indazol-2-yl]phenyl}hexahydropyridinium chloride; chlorinated (3R)-3 -{4-[7-(Aminocarbonyl)-2Hoxazol-2-yl]phenyl}hexahydropyridinium; (R)-5-fluoro-2-(4-hexahydropyridin-3-ylbenzene (2)-H-carbazole-7-carboxamide; (S)-5-fluoro-2-(4-hexahydropyridin-3-ylphenyl)-2H-indazole-7-carboxamide; R)-5-fluoro-2-{3-fluoro-4-hexahydropyridin-3-ylphenyl}-2H-carbazole-7-carboxamide; (S)-5-fluoro-2-{3 -fluoro-4-hexahydropyridin-3-ylphenyl}-2H-carbazole-7-formamide; and pharmaceutically acceptable , Free base or tautomer thereof. Such compounds may also provide a perspective of isomers.

The present invention specific compounds: chloride, 3- {4- [7- (aminocarbonyl) -2 H - indazol-2-yl] phenyl} hexahydro-pyridinium; or a pharmaceutically acceptable free base Or tautomers. Stereoisomers of this compound are also provided.

Specific compounds of the invention are: 2-{4-[(3R)-hexahydropyridin-3-yl]phenyl}-2 H -indazole-7-carboxamide; or a pharmaceutically acceptable salt thereof, Free base or tautomer. Stereoisomers of this compound are also provided.

Specific compounds of the invention are: 2-{4-[(3S)-hexahydropyridin-3-yl]phenyl}-2 H -indazole-7-formamide; and pharmaceutically acceptable salts thereof, Free base or tautomer. Stereoisomers of this compound are also provided.

The specific compound of the present invention is: 3-{4-[7-(aminocarbonyl)-5-fluoro- 2H -indazol-2-yl]phenyl}hexahydropyridinium trifluoroacetate; or its medicinal Acceptable free base or tautomer. Stereoisomers of this compound are also provided.

The present invention specific compounds: 5-Fluoro-2- (3-fluoro-phenyl-hexahydro-3-yl) -2 H - indazole-7-amine trifluoroacetate acyl; or a pharmaceutically An acceptable free base or tautomer. Stereoisomers of this compound are also provided.

The specific compound of the present invention is: 4-methylbenzenesulfonic acid (3S)-3-{4-[7-(amino-based)-2H-indazol-2-yl]phenyl}hexahydropyridinium; Or a pharmaceutically acceptable free base or tautomer thereof. Stereoisomers of this compound are also provided.

The present invention includes the free base of the compound of formula I, as well as pharmaceutically acceptable salts and stereoisomers thereof. The compounds of the invention may be protonated at the N atom of the amine and/or the N-containing heterocyclic moiety to form a salt. The term "free base" means that the amine compounds are in a non-salt form. The pharmaceutically acceptable salts encompassed include not only the exemplary salts of the specific compounds described herein, but also all of the tours. A typical pharmaceutically acceptable salt of a compound of formula I. The free forms of the particular salt compounds set forth can be separated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous alkaline solution such as a dilute aqueous solution of NaOH, potassium carbonate, ammonia, and sodium bicarbonate. The free forms may differ from their respective salt forms in certain physical properties (e.g., solubility in polar solvents), but for the purposes of the present invention, the acid and base salts are also free. Form of medical equivalent.

The pharmaceutically acceptable salts of the compounds of the invention can be synthesized from the compounds of the invention comprising a basic or acidic moiety by conventional chemical methods. Typically, the salts of the basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric amount or with an inorganic or organic acid which forms the desired salt in a suitable solvent or combination of solvents. . Likewise, salts of such acidic compounds can be formed by reaction with a suitable inorganic or organic base.

Thus, pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention, such as those formed by reacting a basic compound of the invention with a mineral acid, an organic acid or a polymeric acid. For example, conventional non-toxic salts include those derived from inorganic acids (eg, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, aminosulfonic acid, phosphoric acid, phosphorous acid, nitric acid, and the like). And from organic acids (eg, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, balmoic acid, maleic acid, hydroxy maleic acid, phenyl) Acetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, Preparation of isethionethane, palmitic acid, gluconic acid, ascorbic acid, phenylacetic acid, aspartic acid, cinnamic acid, pyruvic acid, ethanesulfonic acid, ethanedisulfonic acid, valeric acid, trifluoroacetic acid, and the like) Salt. Examples of suitable polymeric acid salts include those derived from polymeric acids such as capric acid, carboxymethyl cellulose, and the like. Preferably, the pharmaceutically acceptable salts of the present invention comprise one equivalent of a compound of formula (I) and one, two or three equivalents of a mineral or organic acid. More specifically, the pharmaceutically acceptable salt of the present invention is a trifluoroacetate, chloride or tosylate salt. More specifically, the pharmaceutically acceptable salt of the present invention is a trifluoroacetate or a chloride salt. In one embodiment, the salt is a trifluoroacetate salt. In another embodiment, the salt is a chloride. In another embodiment, the salt is a tosylate salt.

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 bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, divalent, potassium, sodium, zinc, and the like. . Particularly 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 naturally substituted amines), cyclic amines, and salts of basic ion exchange resins, such as spermine. Acid, lysine, betaine, caffeine, choline, N,N ¹ -dibenzylethylenediamine, ethylamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino Ethanol, ethanolamine, diethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylhexahydropyridine, reduced glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine , methyl reduced glucosamine, morpholine, piperazine, hexahydropyridine, polyamine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, tricyclohexyl A salt of an amine, butylamine, benzylamine, phenylbenzylamine, tromethamine or the like.

The preparation of the above pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts is more fully described in Berg et al. (1977), J. pharm. Sci., ' Pharmaceutical Salts ', 66 : 1-19.

It should also be noted that since the deprotonated acidic moiety (e.g., a carboxyl group) of the compound of the invention under physiological conditions can be an anion, and the electronic charge can then be protonated internally or alkylated to a basic moiety ( For example, the cationic charge of the fourth-order nitrogen atom is balanced, so the compound may be an internal salt or a zwitterion.

The compounds of the invention may be employed in a method of treating a human or animal body by therapy.

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, Nature Review Drug Discovery (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 WO 2005/082368 The disease indicated.

The compounds of the present invention are useful for the treatment of inflammatory diseases , including those caused by rejection of organ transplants, for example, chronic inflammatory diseases of the joint including arthritis, rheumatoid arthritis, osteoarthritis and bones associated with enhanced bone resorption. Disease; inflammatory bowel disease, for example, ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung disease, for example, asthma, adult respiratory distress syndrome, and chronic obstruction Sexual airway disease; inflammatory diseases of the eye, including corneal dystrophy, granuloconjunctivitis, onchocerciasis, uveitis, sympathetic ophthalmia and endophthalmitis; chronic inflammatory diseases of the gums, including gingivitis and teeth Zhou Yan; tuberculosis; leprosy; inflammatory diseases of the kidney, including uremic complications, glomerulonephritis and kidney disease; inflammatory diseases of the skin, including sclerosing dermatitis, dryness and eczema; inflammation of the central nervous system Diseases, including chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-related neurodegeneration and Alzheimer's disease (Alzheim) Er's disease), infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and viral or autoimmune encephalitis; diabetic complications , including but not limited to, immune complex vasculitis, systemic lupus erythematosus (SLE); inflammatory diseases of the heart, such as cardiomyopathy, ischemic heart disease, hypercholesterolemia, and atherosclerosis; Other diseases with significant inflammatory components include pre-eclampsia, chronic liver failure, brain and spinal cord trauma, and multiple organ dysfunction syndrome (MODS) (multiple organ failure (MOF)). The inflammatory disease may also be a systemic inflammation of the individual, for example, Gram-positive or Gram-negative shock, hemorrhagic or anaphylactic shock, or shock induced by a chemotactic cytokine reaction by cancer chemotherapy, for example, Shock associated with pro-inflammatory cytokines. This shock may, for example, be triggered by a chemotherapeutic agent administered as a cancer treatment.

Accordingly, the present invention provides 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 treating or preventing an inflammatory 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 reperfusion injury caused by naturally occurring events and during surgical procedures, for example, intestinal reperfusion injury; myocardial reperfusion injury; cardiopulmonary bypass, aortic aneurysm repair, neck Reperfusion injury from arterial endarterectomy or hemorrhagic shock; and reoxidation damage from transplantation of organs such as heart, lung, liver, kidney, pancreas, intestine, and cornea.

Accordingly, 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 for treating or preventing reperfusion injury, 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 in the treatment or prevention of ischemic conditions , including those produced by organ transplants, for example, stable angina, unstable angina, myocardial ischemia, hepatic ischemia, local mesenteric artery Ischemia, intestinal ischemia, severe limb ischemia, chronic severe limb ischemia, cerebral ischemia, acute cardiac ischemia, ischemic nephropathy, ischemic liver disease, ischemic retinopathy , septic shock, and ischemic diseases of the central nervous system, such as stroke or cerebral ischemia.

Accordingly, the present invention 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, 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 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 formula I or a composition comprising a compound of formula I.

The compounds of the invention may also be used to treat or prevent chronic or acute renal failure .

Accordingly, 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 , such as peripheral arterial occlusion, occlusive thromboangiitis, Reynaud's disease and phenomenon, hand and foot cyanosis, erythematous limb pain, Venous thrombosis, varicose veins, arteriovenous fistula, lymphedema, and fatty edema.

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 vascular disease other than cardiovascular disease.

The invention also provides a method for treating or preventing a vascular disease 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 chronic heart failure, atherosclerosis, congestive heart failure, circulatory shock, cardiomyopathy, heart transplantation, myocardial infarction, and arrhythmia, for example, atrium Fibrillation, supraventricular tachycardia, atrial flutter, and paroxysmal atrial tachycardia.

Accordingly, the present invention 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 I or a composition comprising a compound of formula I.

The compounds of the invention may also be used to treat or prevent diabetes , including type I diabetes (insulin dependent diabetes), type II 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 Syndrome, acromegaly, pheochromocytoma, glucagonoma, primary aldosteronism or somatostatin) , type A insulin resistance syndrome, type B insulin resistance syndrome, adipose atrophic diabetes, and diabetes caused by (3-cytotoxin. The compound of the present invention can also be used for treating or preventing diabetic complications, for example, diabetic cataract, glaucoma , retinopathy, nephropathy (eg, microalbuminuria and progressive diabetic nephropathy), polyneuropathy, foot gangrene, atherosclerotic tubular artery disease, peripheral arterial disease, nonketotic hyperglycemia - high Osmotic coma, single neuropathy, autonomic neuropathy, foot ulcer, joint problems, And skin or mucosal complications (eg, infection, axillary spots, candida infection or lipid progressive necrotic diabetic obesity), hyperlipidemia, hypertension, insulin resistance syndrome, coronary artery disease, retinopathy, Diabetic neuropathy, polyneuropathy, idiopathic neuropathy, autonomic neuropathy, foot ulcers, joint problems, fungal infections, bacterial infections, and myocardial disorders.

Accordingly, 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 I.

The compounds of the invention may also be used in the treatment or prevention of cancer , including solid tumors, for example, fibrosarcoma, mucinous sarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphatic vessels Endothelial 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, esophagus Cancer, stomach 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, bronchi Primary cancer, renal cell carcinoma, hepatoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms'tumor, cervical 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 lymphoblastic leukemia ("ALL"), acute lymphoid Cytoplasmic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia ("AML'), acute promyelocytic leukemia ("APL"), acute mononuclear leukemia, acute erythroblasts 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, for example, Hodgkin's disease, non Non-Hodgkin's lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease and polycythemia; CNS and brain cancer, for example, nerve Glioma, fibrocyte astrocytoma, astrocytoma, glioblastoma multiforme, glioblastoma multiforme, medulloblastoma, craniopharyngioma Tumor, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, vestibular schwannomas, adenoma, metastatic brain tumor, meningiomas, myeloma and myeloma Cell tumor.

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 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 are also useful in the treatment of cancers that are defective in homologous recombination (HR)-dependent DNA DSB repair activity (see WO 2006/021801).

The HR-dependent DNA DSB repair pathway repairs DNA double-strand breaks (DSB) by homologous mechanisms to engineer contiguous DNA spirochetes ( Nat. Genet. (2001) 27(3) : 247-254). The components of the HR-dependent DNA DSB repair pathway include, but are not limited to, ATM (NM-000051), RAD51 (NM-002875), RAD51 L1 (NM-002877), RAD51 C (NM-002876), RAD51L3 (NM-002878), DMC1 (NM-007068), XRCC2 (NM7005431), XRCC3 (NM-005432), RAD52 (NM-002879), RAD54L (NM-003579), RAD54B (NM-012415), BRCA-1 (NM-007295), BRCA -2 (NM-000059), RAD5O (NM-005732), MREI 1A (NM-005590), NBSI (NM-002485), ADPRT (PARP-1), ADPRTL2, (PARPO2) 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, RAD1 and RAD9. Other proteins involved in the HR-dependent DNA DSB repair pathway include regulatory factors such as EMSY ( Cell (2003) 115 :523-535).

HR-Dependent DNA DSB Repair of a defective cancer may include or consist of one or more cancer cells whose ability to repair DNA DSB is reduced or eliminated relative to normal cells, ie, HR-dependent DNA The activity of the 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, Science (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 L1 (NM- 002877), RAD51 C (NM-002876), RAD51L3 (NM-002878), DMC1 (NM-007068), XRCC2 (NM7005431), XRCC3 (NM-005432), RAD52 (NM-002879), RAD54L (NM-003579) , RAD54B (NM-012415), BRCA-1 (NM-007295), BRCA-2 (NM-000059), RAD5O (NM-005732), MREI 1A (NM-005590), NBS1 (NM-002485), ADPRT (PARP-1), ADPRTL2, (PARPO2) 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, RAD1 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) ( Cell (2003) 115 : 523-535).

Known in BRCA-1 and BRCA-2 based tumor suppressor genes, which generally lose the wild type allele (Oycogene tumor in the hybrid vector, (2002) 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 ( Exp Clin Cancer Res. , (2002) 21 (3 Suppl) : 9-12). Amplification of the EMSY gene encoding the BRCA-2 binding factor is also known to be associated with breast and ovarian cancer. Vectors of BRCA-1 and/or BRCA-2 mutations are also at high risk for ovarian, prostate and pancreatic cancer. The detection of changes in BRCA-1 and BRCA-2 is well known in the art and is described, for example, in European Patent EP 699 754, European Patent EP 705 903, Genet. Test (1992) 1 : 75-83; Cancer Treat Res ( 2002) 107 :29-59; Neoplasm (2003) 50(4) : 246-50; Ceska Gynekol (2003) 68(1) : 11-16). The assay for BRCA-2 binding factor EMSY amplification is set forth in Cell 115 :523-535. PARP inhibitors have been shown to be useful for specifically killing tumors of BRCA-1 and BRCA-2 deficiency ( Nature (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 of BRCA-1 or BRCA-2 deficiency.

The invention also provides a method for treating or preventing a tumor of 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, Cancer Res. (2005) 65 : 10145).

The compounds of the invention are useful for the treatment or prevention of neurodegenerative diseases , including polyglutamine-expanding-related neurodegeneration, Huntington's disease, Kennedy's disease, spinocerebellar ataxia Dentate nucleus red nucleus globus pallidus hypothalamic nuclear atrophy (DRPLA), protein aggregation-related neurodegeneration, Machado-Joseph's disease, Alzheimer's disease, Parkinson's disease Disease, amyotrophic lateral sclerosis, spongiform encephalopathy, prion-related diseases, and multiple sclerosis (MS).

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 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 formula I or a composition comprising a compound of formula I.

The compounds of the invention may also be used to treat or prevent retroviral infection (US Pat. No. 5,652,260), retinal damage ( Curr. Eye Res. (2004), 29 : 403), skin aging and UV-induced skin damage (US Patent US) 5589483 and Biochem. pharmacol (2002) 63 : 921).

The compounds of the invention are useful for treating or preventing premature aging and delaying the onset of age-related cell dysfunction ( Pharmacological Research (2005) 52 : 93-99).

The compounds of the present invention may be combined in a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, filler, buffer, stabilizer, preservative, or lubricant, in accordance with standard pharmaceutical practice. Investing in mammals, preferably humans.

The compound of the present invention can be administered to a subject by any conventional administration route, whether administered in a systemic/peripheral manner or at a desired point of action, including but Not limited to oral (eg, by ingestion); topical (including, for example, transdermal, intranasal, transocular, transoral, and sublingual); pulmonary (eg, by using, for example, aerosol) (eg) mouth or nose inhalation or insufflation therapy; rectum; vagina; parenteral (eg, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal) , intracapsular, subcapsular, intraocular, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrasternal injection; and by implantation of a reservoir (eg, subcutaneously or intramuscularly).

The subject can be a eukaryote, an animal, a vertebrate, a mammal, a rodent (eg, guinea pig, hamster, rat, mouse), a murine (eg, a mouse), a canine (eg, Dogs, felines (eg, cats), equines (eg, horses), primates, mites (eg, monkeys or baboons), monkeys (eg, marmosets, baboons), 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, for example, lozenges, tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture. Compositions for oral use can be prepared according to any of the methods known in the art for the manufacture of pharmaceutical compositions and such compositions can comprise one or more selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives. The agent is intended to provide a pharmaceutically elegant and palatable preparation. Tablets comprise a mixture of the active ingredient with a non-toxic excipient which is suitable for the manufacture of tablets and is pharmaceutically acceptable. For example, such excipients can be: inert diluent Release agent, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agent and disintegrating agent, for example, microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; Agents, for example, starch, gelatin, polyvinylpyrrolidone or gum arabic; and lubricants, for example, magnesium stearate, 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 (eg, hydroxypropyl-methylcellulose or hydroxypropylcellulose) or a time delay material (eg, 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 paraffin or olive oil) is mixed.

The aqueous suspensions comprise the active material in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, lignan, xanthan gum, and A gum arabic; a dispersing or wetting agent can be a natural phospholipid (eg, lecithin), or a condensation product of an alkylene oxide with a fatty acid (eg, polyoxyethylene stearate), or ethylene oxide with long chain fat a condensation product of a steroid (for example, heptadecyloxy cetyl alcohol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (for example, polyoxyethylene sorbitan monooleate) Ester), or ethylene oxide and derived from A condensation product of a fatty acid with a partial ester of hexitol anhydride (for example, polyoxyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, for example, ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate; one or more coloring agents, one or more flavoring agents, and one or more such as sucrose, saccharin Or sweeteners such as aspartame.

The oily suspension can be formulated by suspending the active ingredient in a vegetable oil (for example, peanut oil, olive oil, sesame oil or coconut oil) or suspended in a mineral oil such as liquid paraffin. These oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents (e.g., those described above) and flavoring agents can be added to provide a palatable oral preparation. Such compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or alpha-tocopherol.

Dispersible powders and granules suitable for the preparation of aqueous dispersions by the addition of water may comprise a mixture of active ingredient and 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, such as sweetening, flavoring, and coloring agents, may also be present. Such compositions can be preserved by the addition of an anti-oxidant (e.g., ascorbic acid).

The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil (eg, olive oil or peanut oil) or a mineral oil (eg, liquid paraffin) or a mixture of such. Suitable emulsifiers can be natural phospholipids (eg, soy lecithin) and esters or partial esters derived from fatty acids and hexitol livers (eg, sorbitan monooleate) and such partial esters and ethylene oxide. The condensation product (for example, polyoxyethylene sorbitan monooleate). The emulsions are also It may contain sweeteners, flavoring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents (for example, glycerol, propylene glycol, sorbitol or sucrose). The formulations may also contain a demulcent, a preservative, a flavoring and coloring agent, and an antioxidant.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.

The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion wherein the active ingredient is dissolved in an oily phase. For example, the active ingredient can be first dissolved in a mixture of soybean oil and lecithin. The oily solution is then introduced into a mixture of water and glycerin and treated to form a microemulsion.

The injectable solutions or microemulsions can be introduced into the bloodstream of the patient by a topical single injection. Alternatively, the solution or microemulsion can be advantageously administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used. Examples of such means of the pump based Deltec CADD-PLUS ^TM 5400 type vein.

Such pharmaceutical compositions may be in the form of a sterile injectable aqueous or oily suspension for intramuscular or subcutaneous administration. The suspensions can be formulated according to known techniques using the appropriate dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. In addition, it is customary to use sterile, fixed oils as a solvent or suspending medium. Any mild, fixed oil, including synthetic mono- or diglycerides, can be used for this purpose. In addition, it can be used in injectable preparations. Such as oleic acid and other fatty acids.

For rectal administration of the drug, the compound of formula I can also be administered in the form of a suppository. The compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and thus melts in the rectum to release the drug. Such materials include cocoa butter, glycerin gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.

For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound of formula I may be employed. (For the purposes of this application, topical applications should include mouthwash and mouthwash.)

The compounds of the present invention can be administered in intranasal form by topical use of suitable intranasal vehicles and delivery devices, or by transdermal routes using such percutaneous dermal patches which are well known to those skilled in the art. Of course, for administration in the form of a transdermal delivery system, the entire dosage regimen should be administered continuously rather than intermittently. The compounds of the present invention can also be delivered as a suppository with a matrix such as cocoa butter, glycerin gelatin, hydrogenated vegetable oil, a mixture of polyethylene glycols of various molecular weights and fatty acid esters 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 end of the action at the point of action. A local concentration that does not cause substantial harm or harmful side effects.

In vivo administration can be carried out in a single dose in a continuous or batch manner (e.g., at appropriate intervals) throughout the treatment period. Methods for determining the most effective administration methods and dosages are well known to those skilled in the art and will vary with the formulation being treated, the purpose of the treatment, the target cell being treated, and the subject being treated. Single or multiple administrations can be performed according to the dosage level and mode selected by the treating physician.

In general, a suitable dosage of the active compound will be between about 100 micrograms to about 250 milligrams per kilogram of subject weight per day. When the active compound is a salt, an ester, a prodrug or the like, the amount administered is calculated from the parent compound and thus the actual weight used should be proportionally increased.

The compounds of the invention may also be used in combination with anticancer or chemotherapeutic agents.

The compounds of the invention are also useful as chemosensitizers and radiosensitizers for the treatment of cancer. It can be used to treat mammals that have previously been or are currently undergoing cancer treatment. Such prior treatments include pre-chemotherapy, radiation therapy, surgery, or immunotherapy (eg, vaccination with a cancer vaccine).

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 chemotherapeutic agent for simultaneous, separate or sequential administration.

The invention also provides a compound of formula I for use in the manufacture of a medicament for use as an adjuvant in the treatment of cancer or in combination with ionizing radiation or a chemotherapeutic agent to enhance tumor cell therapy.

The invention also provides the use of a compound of formula I in the manufacture of a medicament Used as an adjuvant for cancer treatment or by combining with ionizing radiation or other chemotherapeutic agents to enhance tumor cell therapy. These compounds can also be used in combination with ionizing radiation and other chemotherapeutic agents.

The invention also provides a method of chemotherapy or radiation therapy 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 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 compounds of the invention may be administered prior to administration of another anticancer agent (eg, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours) Hour, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before, simultaneously, or after (for example, 5 minutes, 15 minutes) 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 Subjects in need are administered weekly, 8 weeks, or 12 weeks later. In various embodiments, the compound of the present invention and another anticancer agent may be separated by 1 minute, at intervals of 10 minutes, at intervals of 30 minutes, at intervals of less than 1 hour, at intervals of 1 hour to 2 hours, at intervals of 2 hours to 3 hours, Interval 3 hours to 4 hours, interval 4 hours to 5 hours, interval 5 hours to 6 hours, interval 6 hours to 7 hours, interval 7 hours to 8 hours, interval 8 hours to 9 hours, interval 9 hours to 10 hours, interval Administration is carried out from 10 hours to 11 hours, at intervals of 11 hours to 12 hours, at intervals not exceeding 24 hours, or at intervals not exceeding 48 hours.

The compound of the present invention and another anticancer agent may act in an additive manner or in a synergistic manner. A synergistic combination of a compound of the invention and another anticancer agent may be advantageous Administration of one or both of the compounds of the invention and other anticancer agents and/or administration of such agents at a lesser frequency using one or both of such lower doses and/or less frequently, Any toxicity associated with the agent administered to the subject can be reduced without reducing the efficacy of such agents in the treatment of cancer. 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 Cancer Principles and Practice of Oncology by VT Devita and S. Hellman (Editor), 6th Edition (February 15, 2001), 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, antiproliferative agents, and different Pentadienyl protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and survival signaling, apoptosis-inducing agents And agents that interfere with cell cycle checkpoints. The compounds of the invention are especially useful when co-implemented with radiation therapy.

Examples of "HDAC inhibitors" include octanediphenylanilide hydroxamic acid (SAHA), LAQ824, LBH589, PXD101, MS275, FK228, valproic acid, butyric acid, and CI-994.

"Estrogen receptor modulator" refers to a compound that interferes with or inhibits the binding of estrogen to a receptor (independent of the mechanism of action). Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fluorovitamin Fulvestrant, 4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-hexahydropyridyl)) Ethoxy]phenyl]-2 H -1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxydiphenyl ketone-2 , 4-dinitrophenyl-indole and SH646.

"Androgen 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, nilutamide, flutamide, bicalutamide, lia Lolazole and abiraterone acetate.

"Retinoid receptor modulator" refers to a compound that interferes with or inhibits the binding of a retinoid to a receptor (independent of the mechanism of action). Examples of such retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α-difluoromethyl Amino acid, ILX23-7553, trans- N- (4'-hydroxyphenyl) retinamine, and N- 4-carboxyphenyl retinamide.

"Cytotoxicity/cytostatic agent" means a compound which causes cell death or inhibits cell proliferation mainly by directly interfering with the function of the cell or inhibiting or interfering with cell mitosis, and includes an alkylating agent, a tumor necrosis factor, an intercalating agent. , hypoxia-activating compounds, microtubule inhibitors/microtubule stabilizers, inhibitors of mitotic kinesins, inhibitors of kinases involved in mitosis, antimetabolites; biological response modifiers; hormones/antihormones 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 , carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin ), aroplatin liposomes (aroplatin), oxaliplatin, temozolomide, methyl methanesulfonate, procarbazine, dacarbazine, heptaplatin, estramust Estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa ), lobaplatin, satraplatin, profiromycin, cisplatin Irofulven, dexifosfamide, cis-amine dichloro(2-methyl-pyridine)platinum, benzylguanine, glufosfamide, GPX100, IV Chlorinated (reverse, trans, trans)-bis-μ-(hexane-1,6-diamine)-μ-[diamine-platinum(II)] bis[diamine(chloro)platinum(II)], Diaziridinylspermine, arsenic trioxide, 1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin ), idarubicin, daunorubicin (daunorubicin), bisantrene, mitoxantrone, pirarubicin, pinafide, valrubicin, amrubicin, Doxorubicin, epirubicin, pirarubicin, anti-tumor, 3'-desamino-3'-morpholinyl-13-deoxy-10-hydroxyl Erythromycin, liposome annamycin, galarubicin, elinafide, MEN10755, and 4-desmethoxy-3-desamino-3-nitrogen Propidinyl-4-methylsulfonyl-daunorubicin (see WO 00/50032). Other examples include Raf kinase inhibitors (eg, Bay 43-9006) and mTOR inhibitors (eg, Wyeth's CCI-779 and Ariad AP23573). Other examples are PI3K inhibitors (eg, 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; triazene; dacarbazine, procarbazine and temozolomide; Compound: 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/m ² (subject surface area) to about 250 mg/m ² . In another embodiment, it may be between about 5 days to 150 mg / m ² to about 250 mg / m ² dose once daily to the subject and administered intravenously via dacarbazine.

In one embodiment, the alkylating agent is procarbazine. The subject may be administered procarbazine at a dose between about 50 mg/m ² (subject surface area) to about 100 mg/m ² . In another embodiment, the 5 consecutive days may be between about 50 mg / m ² to about 100 mg / m ² doses of a subject intravenously administered daily procarbazine.

In one embodiment, the alkylating agent is temozolomide. The subject can be administered temozolomide at a dose of between about 150 mg/m ² (subject surface area) to about 200 mg/m ² . In another embodiment, it may be between about 5 days to 150 mg / m ² to about 200 mg / m ² dose once daily to the animal orally administered with temozolomide for.

Examples of anti-mitotic agents include: isologue colchicine, halichondrin B, colchicine, colchicine derivatives, dolastatin 10, maytansine ( Maytansine), rhizoxin, thiocolchicine and triphenylmethyl cysteine.

An example of a hypoxic activatable compound is tirapazamine.

Examples of proteasome inhibitors include, but are not limited to, lactacystin, bortezomib, epoxomicin, and peptide aldehydes, for example, MG 132, MG 115, and PSI.

Examples of microtubule inhibitors/microtubule stabilizers include paclitaxel, vindesine sulfate, vincristine, vinblastine, vinorelbine, 3', 4'-didehydro-4'-deoxy-8'-norvinine, docetaxol, rhizoxin, dolastatin, mprebine mesylate (mivobulin isethionate), auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6-five Fluorine- N- (3-fluoro-4-methoxyphenyl)benzenesulfonamide, anhydrovinblastine, N , N -dimethyl-L-dominoamine-L-amidamine Benzyl-N-methyl-L-dominoamine-L-amidoxime-L-proline-tris-butylamine, TDX258, epothilone (see, for example, US 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-aminocamptothecin, camptothecin, cristatol, mitomycin C, 6-ethoxyl Propionyl-3',4',O-exo-benzylidene-chartreusin, 9-methoxy- N , N -dimethyl-5-nitropyrazolo[3, 4,5-kl] acridine-2-(6 H )propylamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1 H , 12 H -benzo[de]pyrano[3',4':b,7]-pyridazino[1,2b]quinoline-10,13(9 H ,15 H )dione, letote Lurtotecan, 7-[2-( N -isopropylamino)ethyl]-(20S) camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide Teniposide, sobuzuxane, 2'-dimethylamino-2'-deoxy-etoposide, GL331, N- [2-(dimethylamino)ethyl]-9- hydroxy-5,6-dimethyl -6 H - pyrido [4,3-b] carbazole-l-carboxylic Amides, asulacrine (5a, 5aB, 8aa, 9b ) -9- [2- [N - [2- ( dimethylamino) ethyl] - N - methylamino] ethyl] -5- [4-hydroxy - 3,5-Dimethoxyphenyl]-5,5a,6,8,8a,9-hexahydrofuro(3',4':6,7)naphtho(2,3-d)-1 , 3-dioxol-6-one, 2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridine Indole, 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione, 5-(3-aminopropylamino)-7, 10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6 H -pyrazolo[4,5,1-de]acridin-6-one, N -[1-[2(2 Ethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxan-4-ylmethyl]carbenamide, N- (2-(dimethylamino) Ethyl) acridine-4-carboxamide, 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7 H -indolo[2,1-c]quinoline -7-ketone, and dimesna; non-camptothecin-type topoisomerase-1 inhibitors, for example, indolocarbazole; and dual topoisomerase-1 and II inhibitors, for example , benzophenazine, XR20 115761MLN 576 and benzopyridinium.

In one embodiment, the topoisomerase inhibitor is irinotecan. The subject may be administered irinotecan at a dose of between about 50 mg/m ² (subject surface area) to about 150 mg/m ² . In another embodiment, the 5 consecutive days (day 1 to day 5) of between about 50 mg / m ² to about 150 mg / m ² dose once daily to the subject intravenously administered Irinotecan, followed by intravenous administration once daily for 5 consecutive days (Day 28 to Day 32) at a dose between about 50 mg/m ² and about 150 mg/m ² , followed by 5 consecutive days From 55 days to 59 days), intravenous administration is again administered once daily at a dose of between about 50 mg/m ² and about 150 mg/m ² .

An example of a mitotic kinesin (and in particular, a human mitotic kinesin KSP) inhibitor is set forth in PCT Publication WO 01/30768, WO 01/98278, WO 02/056880, WO 03/050,064, WO 03/050,122, WO 03/049,527, WO 03/049,679, WO 03/049,678, WO 03/039460, WO 03/079973, WO 03/099211 WO 2004/039774, WO 03/105855, WO 03/106417, WO 2004/087050, WO 2004/058700, WO 2004/058148 and WO 2004/037171, and U.S. Patent Application Nos. US 2004/132830 and US 2004/132719. 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 Mphosph1, and Rab6- Inhibitor of KIFL.

"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), inhibitors of bub-1 And inhibitors of bub-R1.

"Anti-proliferative agents" include antisense RNA and DNA oligonucleotides, for example, G3139, ODN698, RVASKRAS, GEM231, and INX3001; and antimetabolites, for example, enocitabine, carmofur (carmofur) , tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, gallo Galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, thiazofurin (tiazofurin), decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2-methylene cytidine, 2- Fluoromethylene-2'-deoxycytidine, N- [5-(2,3-dihydro-benzofuranyl)sulfonyl] -N '-(3,4-dichlorophenyl)urea, N 6-[4-deoxy-4-[ N 2-[2(E),4(E)-tetradecadienyl]glycolylamino]-L-propane trioxy-BL- Mann-pyrutanosyl] adenine, aplidine, ecteinascidin, troxacitabine (troxac) Itabine), 4-[2-amino-4-oxoyl-4,6,7,8-tetrahydro-3 H -pyrimido[5,4-b][1,4]thiazine-6- Benzyl-( S )-ethyl]-2,5-thienyl-L-glutamic acid, aminopterin, 5-fluorouracil, alanosine, 11-ethenyl-8-(amine A醯oxymethyl)-4-carbamido-6-methoxy-14-oxal-1,11-diazatetracyclo(7.4.1.0.0)-tetradecyl-2,4 , 6-trien-9-yl acetate, swainsonine, lometrexol, dexrazoxane, methionase, 2'-cyano-2' - Deoxy- N 4-palmitiyl-1-BD-furanosylcytosine and 3-aminopyridine-2-carboxamide thiourea.

Examples of monoclonal antibody-targeted therapeutic agents include those having a cytotoxic or radioisotope linked to a cancer cell-specific or target cell-specific monoclonal antibody. Examples include Bexxar.

"HMG-CoA reductase inhibitor" refers to 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 lovastatin (lovastatin) (MEVACOR ^®; see U.S. Patent No. 4,231,938, No. 4,294,926 and No. 4,319,039), simvastatin (simvastatin) (ZOCOR ^®; see U.S. Patent Nos. 4,444,784, No. 4,820,850 and No. 4,916,239), pravastatin (pravastatin) (PRAVACHOL ^®; see U.S. Patent Nos. 4,346,227, No. 4,537,859, No. 4,410,629, No. 5,030,447 and No. 5,180,589 ), fluvastatin ( LESCOL ^® ; see U.S. Patent Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164, 5,118,853, 5,290,946 and 5,356,896) and atorvastatin ) (LIPITOR ^®; see U.S. Patent Nos. 5,273,995, No. 4,681,893, No. 5,489,691 and No. 5,342,952). The structural formulae of these other HMG-CoA reductase inhibitors which can be used in the method of the invention are set forth in M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry , pp. 85-89 (February 5, 1996). U.S. Patent Nos. 4,782,084 and 4,885,314. 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 geranylgeranyl-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, WO 97/23478, WO 97/38665, WO 98 /28980, WO 98/29119, 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, Patent Publication No. 0 618 221, European Patent Publication No. 0 675 112, European Patent Publication No. 0 604 181, European Patent Publication No. 0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612 WO 95/12572, WO 95/10514, 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 96/21456, WO 96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO 96/ 00736, U.S. Patent No. 5,571,792, WO 96/17861, WO 96/33159, WO 96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO 9 6/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO 97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO 97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO 98/02436, and U.S. Patent No. 5,532,359. For an example of the effect of a prenyl-protein transferase inhibitor on angiogenesis, see European J. of Cancer (1999), 35(9) : 1394-1401.

"Angiogenesis inhibitor" refers to a compound that inhibits the formation of novel blood vessels (independent of the mechanism of action). Examples of angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors such as tyrosine kinase receptor Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR2) inhibitors, epidermal sources, fibroblast sources Or inhibitor of platelet-derived growth factor, MMP (matrix metalloproteinase) inhibitor, integrin blocker, interferon-α, interleukin-12, pentosan polysulfate, cyclooxygenase Inhibitors, including non-steroidal anti-inflammatory agents (NSAIDs) (such as aspirin and ibuprofen) and selective cyclooxygenase-2 inhibitors (such as celecoxib and rofecolon) Rofecoxib ) ( PNAS (1992) 89 :7384; JNCI (1982) 69 :475; Arch. Opthalmol. (1990) 108 :573; Anat. Rec. (1994) 238 :68; FEBS Letters (1995) 372 :83; Clin, Orthop. (1995) 313 :76; J. Mol. Endocrinol . (1996) 16 :107; Jpn. J. Pharmacol. (1997) 75 :105; Cancer Res. (1997) 57 :1625 ( 1997); Cell (1998) 93 :705; Intl. J. Mol. Med. (1998) 2 :715; J. Biol. Chem. (1999) 274 :9116)), steroid anti-inflammatory agents (eg, corticosteroids) , mineralocorticoid, dexamethasone (de Xamethasone), prednisone, prednisolone, methylprednisolone, betamethasone, methotrexate, combretastatin A-4 ), squalamine, 6-O-chloroethyl carbonyl-carbonyl) fumagillol, thalidomide, angiostatin, troponin-1, angiotensin II antagonist See J. Lab. Clin. Med. (1985) 105 :141-145), and VEGF antibodies (see Nature Biotechnology (1999) 17 :963-968; Kim et al. (1993) Nature 392 :841-844; WO 00 /44777; and WO 00/61186).

Other therapeutic agents that modulate or inhibit angiogenesis and which may also be used in combination with the compounds of the invention include agents that modulate or inhibit coagulation and fibrinolytic systems (see Clin. Chem. La. Med. (2000) 38 :679-692. ). Examples of such agents that modulate or inhibit the coagulation and fibrinolytic pathways include, but are not limited to, heparin (see Thromb. Haemost. (1998) 80 : 10-23), low molecular weight heparin and carboxypeptidase U inhibitors (also known as Active thrombin activates inhibitors of fibrinolysis inhibitor [TAFIa] (see Thrombosis Res. (2001) 101 : 329-354). The TAFIa inhibitors are described in PCT Publication No. WO 03/013,526, and U.S. Patent No. 60/349, 925, filed on Jan. 18, 2002.

"Agents that interfere with cell cycle checkpoints" refer to compounds that inhibit protein kinases that transduce cell cycle checkpoint signals, thereby rendering cancer cells susceptible to DNA damaging agents. Such agents include inhibitors of ATR, ATM, Chk1 and Chk2 kinases and cdk and cdc kinase inhibitors and specific examples thereof are 7-hydroxysporin, staurosporine, flavopiridol, CYC202 (Cyclacel) and BMS-387032.

"Inhibitors of cell proliferation and survival signaling pathways" refer to pharmaceutical agents that inhibit cell surface receptors and signal transduction pathways downstream of such surface receptors. 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 03/059951), inhibitors of cytokine receptors, inhibitors of MET, inhibitors of PI3K (eg, LY294002), serine/threonine Enzymes (including but not limited to inhibitors of Akt, such as described in WO 03/086404, WO 03/086403, WO 03/086394, WO 03/086279, WO 02/083675, WO 02/083139, WO 02/083140 and WO 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 AP23573). Such agents include small molecule inhibitor compounds and antibody antagonists.

"Apoptosis-inducing agents" include activators of members of the TNF receptor family, including TRAIL receptors.

In one embodiment, the compound of the present invention may be combined with one or more (specifically, one, two or three) agents selected from the group consisting of temozolomide, cisplatin, carboplatin, oxaliplatin, irinotecan, and topotecan. Used to treat 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: aparex (Plenaxis depot ^® ); aldesleukin (Prokine ^® ); Aldesleukin (Aldesleukin) ( Proleukin ^® ); Alemtuzumabb (Campath ^® ); altretinoin (Panretin ^® ); allopurinol (Zyloprim ^® ); altretamine (Hexalen ^® ) ; amifostine (Ethyol ^® ); anastrozole (Arimidek ^® ); arsenic trioxide (Trisenox ^® ); aspartate (Elspar ^® ); azacitidine (Vidaza ^® ) ; bevacuzimab (Avastin ^® ); bexarotene capsule (Targretin ^® ); besaretin ^® (Bargoxin ^® ); bleomycin (Blenoxane ^® ); anti (bortezomib) (Velcade ^®); busulfan (Busulfex ^®) for intravenous use; oral busulfan (Myleran ^®); calusterone (calusterone) (Methosarb ^®); capecitabine (capecitabine) (Xeloda ^® ); Carboplatin (Paraplatin ^® ); Carmustine (BCNU ^® , BiCNU ^® ); Carmustine (Gliadel ^®); carmustine polifeprosan 20 with the implant (Gliadel Wafer ^®); Seli Xi glucosamine (Celebrex ^®); anti-western territories Xidan (cetuximab) (Erbitux ^®); fenbutatin Chlorambucil (Leukeran ^® ); cisplatin (Platinol ^® ); cladribine (Leustatin ^® , 2-CdA ^® ); clofarabine (Clolar ^® ); cyclophosphamide (Cytoxan ^® , Neosar ^® ); Cytoxan Injection ^® ; Cytoxan Tablet ^® ; Cytosar-U ^® ; Cytarabine liposome (DepoCyt ^® ); Dcarb-Dome ^® ; dactinomycin, actinomycin D (Cosmegen ^® ); Darbepoetin alfa (Aranesp ^® ); daunorubicin liposome (DanuoXome ^® ); daunorubicin, daunomycin (Daunorubicin ^® ); daunorubicin, ernomycin (Cerubidine ^® ); denileukin diftitox (Ontak ^® ); right rezzo Health (dexrazoxane) (Zinecard ^®); docetaxel (docetaxel) (Taxotere ^®); doxorubicin (adriamycin PFS ^®); doxorubicin (adriamycin , Rubex ^®); doxorubicin (Adriamycin PFS Injection ^®); doxorubicin liposomal (Doxil ^®); male acid methyl pyrrolidone (Dromostanolone ^®); male acid methyl pyrrolidone (Masterone Injection ^®); Elliott's B Solution ^® ; epirubicin (Ellence ^® ); Epoetin alfa (epogen ^® ); erlotinib (erlotinib) Tarceva ^® ); estramustine (Emcyt ^® ); etoposide phosphate (Etopophos ^® ); etoposide, VP-16 (Vepesid ^® ); exemestane (exemestane) (Aromasin ^®); filgrastim (filgrastim) (Neupogen ^®); floxuridine (intraarterial) (FUDR ^®); fludarabine (fludarabine) (Fludara ^®); fluorouracil, 5-FU (Adrucil ^®) ; fulvestrant (Faslodex ^® ); gefitinib (Iressa ^® ); gemcitabine (Gemzar ^® ); gemtuzumab ozogamicin (Mylotarg ^® ); Goserelin acetate (Zoladex Implant ^® ); koserelin acetate (Zoladex ^® ); histamine leucine acetate Histrelin acetate ^® ); hydroxyurea (Hydrea ^® ); Ibritumomab Tiuxetan (Zevalin ^® ); idarubicin (Idamycin ^® ); ifosfamide (IFEX) ^® ); imatinib mesylate (Gleevec ^® ); interferon alpha 2a (Roferon A ^® ); interferon alpha-2b (Intron A ^® ); irinotecan (Camptosar ^® ); Lenalidomide (Revlimid ^® ); letrozole (Femara ^® ); leucovorin (Wellcovorin ^® , leucovorin ^® ); leuprolide (Eligard ^® ); levotetrazole ( Levamisol) (Ergamisol ^® ); lomustine, CCNU (CeeBU ^® ); meclorethamine, mustard (Mustargen ^® ); megestrol acetate (Megace ^® ); Melphalan, L-PAM (Alkeran ^® ); mercaptopurine, 6-MP (Purinethol ^® ); mesna (Mesnex ^® ); mesnex tabs ^® ; methotrexate ^®); methoxsalen (methoxsalen) (Uvadex ^®); mitomycin C (Mutamycin ^®); mitotane (mitotane) (Lysodren ^®); mitoxantrone (mitoxantrone) (Novantrone ^®); Nandrolone (nandrolone phenpropionate) (Durabolin-50 ®); pull-resistant Bin (nelarabine) (Arranon ^®); Connaught non mAb (Nofetumosab) (Verluma ^®); Aopu Rui Oprelvekin (Neumega ^® ); oxaliplatin (Eloxatin ^® ); paclitaxel (Paxene ^® ); paclitaxel (Taxol ^® ); paclitaxel protein-binding particles (Abraxane ^® ); palifermin (Kepivance ^® ); Palmer diphosphate (pamidronate) (Aredia ^®); Peijia enzyme (pegademase) (Adagen (PegademaseBovine) ®); Peijia Pa enzyme (pegaspargase) (Oncaspar ^®); pegfilgrastim (pegfilgrastim) (Neulasta ^®); Pemetrexeddisodium (Alimta ^® ); pentastatin (Nipent ^® ); pipobroman (Vercyte ^® ); plicamycin, mithramycin (mithramycin) Mithracin ^® ); porfimer sodium (Photofrin ^® ); procarbazone (matulane ^® ); quinacrine (Atabrine ^® ); Rabburicase (Elitek ^® ); rituximab (rituximab) (Rituxan ^®); sargramostim (cargramostim) (Leukine ^®) Sargramostim (Prokine ^®); sorafenib (sorafenib) (Nexavar ^®); streptozotocin (streptozocin) (Zanosar ^®); sunitinib maleate ^{(sunitinib maleate) (Sutent ®)} ; Talc Powder (Sclerosol ^® ); tamoxifen ^® ; Temodar ^® ; teniposide, VM-26 (Vumon ^® ); testosterone (Teslac ^® ); thioguanine, 6 -TG (Thioguanine ^® ); thiotepa (Thioplex ^® ); topotecan (Hycamtin ^® ); toremifene (Fareston ^® ); tositumomab (Bexxar ^® ) Tosimodumab/I-131 tosimozole (Bexxar ^® ); trastuzumab (Herceptin ^® ); retinoic acid, ATRA (Vesanoid ^® ); uracil mustard (Uracil Mustard Capsules) ^® ); valrubicin (Valstar ^® ); vinblastine (Velban ^® ); vincristine (Oncovin ^® ); vinorelbine (Navelbine ^® ); vorinostat (Zolinza ^® ) Zoledronate (Zometa ^® ); nilotinib (Tasigna ^® ) and dasatinib (Sprycel ^® ).

The invention also encompasses combinations with NSAIDs 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 COX-2 compared to COX-1 inhibition specificity. COX-2 IC ₅₀ of the IC and the ratio of the amount of COX-1 as measured by ₅₀ cells or microsome assay assessed. 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. 6,001,843, U.S. Patent No. 6,020,343, U.S. Patent No. 5,409,944, U.S. Patent No. 5,436,265, U.S. Patent No. 5,536,752, U.S. Patent No. 5,550,142, U.S. Patent No. 5,604,260, U.S. Patent No. 5,698,584 , U.S. Patent No. 5,710,140, WO 94/15932, U.S. Patent No. 5,344,991, U.S. Patent No. 5,134,142, U.S. Patent No. 5,380,738, U.S. Patent No. 5,393,790, U.S. Patent No. 5,466,823, U.S. Patent No. 5,633,272, U.S. Patent No. 5,932,598, all incorporated herein by reference. In this article.

A COX-2 inhibitor which is especially useful in the treatment method of the present invention is 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridyl)pyridine or a pharmaceutical thereof can Accept the salt.

As set forth specific inhibitors of COX-2 and are therefore useful in the present invention include but are not limited to: acceptable salt parecoxib (parecoxib), CELEBREX ^® and BEXTRA ^® or a pharmaceutically.

Other examples of angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2) -butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroethenyl)urethane, acetyldinaline, 5- Amino-1-[[3,5-dichloro-4-(4-chlorobenzylidinyl)phenyl]methyl]-1 H -1,2,3-triazole-4-carboxamide, CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannose pentose phosphate, 7,7-(carbonyl-bis[imino- N -methyl-4,2- Pyrrolylcarbonylimino [ N -methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalene disulfonate), and 3-[(2,4-dimethyl) Pyridyl-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 αvβ3 integrin, and selectively antagonizes, inhibits or inhibits the binding of a physiological ligand to αvβ5 integrin. A compound which antagonizes, inhibits or inhibits the binding of a physiological ligand to both αvβ3 integrin and αvβ5 integrin, and a compound which antagonizes, inhibits or counteracts the activity of a particular integrin expressed on capillary endothelial cells. The term also refers to antagonists of αvβ6, αvβ8, α1β1, α2β1, α5β1, α6β1, and α6β4 integrin. The term also refers to antagonists of any combination of αvβ3, αvβ5, αvβ6, αvβ8, α1β1, α2β1, β5α1, α6β1, and α6β4 integrin.

Some specific examples of tyrosine kinase inhibitors include N- (trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide, 3-[(2,4-dimethylpyrrole- 5-yl)methylene)indan-2-one, 17-(allylamino)-17-desmethoxygeldanamycin, 4-(3-chloro-4-fluorobenzene Amino)-7-methoxy-6-[3-(4-morpholinyl)propoxy]quinazoline, N- (3-ethynylphenyl)-6,7-bis(2- Methoxyethoxy)-4-quinazolinamine, BIBX1382, 2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9 ,12-epoxy-1 H -diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzoic azetidin octan-1-one, SH268, genistein (genistein), STI571, CEP2563,4- ( 3- amino-chlorophenyl) -5,6-dimethyl -7 H - pyrrolo [2, 3-d]pyrimidine methanesulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, 4-(4'-hydroxyphenyl)amino group -6,7-Dimethoxyquinazoline, SU6668, STI571A, N- 4-chlorophenyl-4-(4-pyridylmethyl)-1-pyrazinamine, and EMD121974.

In one embodiment, the compounds of the invention are useful for treating or preventing the appearance of necrosis caused by selective N3 -adenine methylation reagents such as MeOSO ₂ (CH ₂ )-lexitropsin (Me-Lex).

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-[gamma] (i.e., PPAR-[gamma]) agonist and a PPAR-[delta] (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 PPAR-γ on endothelial cells and its involvement in angiogenesis has been reported in the literature (see J. Cardiovasc . Pharmacol. (1998) 31 : 909-913; J. Bio1. Chem. (1999) 274 : 9116-9121; Invest. Ophthalmo1 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. ( Arch. Ophthamol. (2001) 119 :709-717). Examples of PPAR-gamma agonists and PPAR-gamma/alpha agonists include, but are not limited to, thiazolidinediones (eg, DRF2725, CS-01, troglitazone, rosiglitazone, and pioglitazone), Fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-HO39242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazole-6-yl)oxy]-2-yl Propionic acid (disclosed in USSN 09/782,856), and 2( R )-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2- Ethylchroman-2-carboxylic acid (disclosed in USSN 60/235,708 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 genetic strategies for treating cancer, see Hall et al. ( Am J Hum Genet (1997) 61 : 785-789) and Kufe et al. ( Cancer Medicine , 5th Ed., pp. 876-889, BC Decker, Hamilton 2000). Gene therapy can be used to deliver any tumor suppressor gene. Examples of such genes include, but are not limited to, p53 which can be delivered by recombinant virus-mediated gene transfer (see, for example, 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, " Gene Therapy, August (1998) 5(8) : 1105-13) and interferon gamma ( J Immunol (2000) 164 : 217-222).

The compounds of the invention may also be administered in combination with inhibitors of intrinsic multidrug resistance (MDR), in particular, MDR is associated with high levels of expression of the transporter. 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 invention may be combined with antiemetic alone or in combination with radiation therapy to treat nausea or vomiting, 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, GABA _B receptor agonists (eg, baclofen), corticosteroids (eg, Decadron) (Misson), Kenalog, Aristocort, Nasallide, Preferid, Benecorten) or others (for example, disclosed in U.S. Patent Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326, and No. 3,749,712), anti-dopamine agents, for example, phenothiazines (eg, prochlorperazine, fluphenazine, thioridazine, and mesoridazine) )), metoclopramide or dronabinol. In one embodiment, an anti-emetic agent selected from the group consisting of a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist, and a corticosteroid is administered as an adjuvant to treat or prevent vomiting caused by administration of a compound of the invention.

The neurokinin-1 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, 5,494,926. No. 5,496,833, 5,637,699, 5,719,147; European Patent Publication No. EP 0 360390, 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, 0 514 274 , 0 514 275, 0 514 276, 0 515 681, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 558 156, 0 577 394, 0 585 913, 0 590 152, 0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0 707 006, 0 708 101 No. 0 709 375, No. 0 709 376, No. 0 714 891, No. 0 723 959, No. 0 733 632 and No. 0 776 893; PCT International Patent Publication No. WO 90/05525, No. 90 /05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661 No. 92/20676, 92/21677, 92/22569, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93 /21155, 93/21181, 93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429 No. 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320 Nos. 94/19323, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95 /06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382 No. 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418 No. 95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96 /29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671 No. 97/17362, No. 97/18206, No. 97/19084, No. 97/19942 and No. 97/21702; and British Patent Publication No. 2266 529, No. 2 268 931, No. 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293 169, and 2 302 689. The preparation of such compounds is fully described in the 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-( R )-(1-( R )-(3, described in U.S. Patent No. 5,719,147. 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxoyl-1 H , 4 H -1 , 2,4-triazolyl)methyl)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 neutropenia treatment agent (for example) can Hematopoietic growth factors that regulate 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 administered with immunopotentiating agents such as levamisole, isoprinosine, and Zadaxin.

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 (incadronate) or smectronate (cimadronate), chlorphosphine Clodronate, EB-1053, minodronate, neridronate, piridronate, and tiludronate, including any and 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 Toxic agents, inhibitors of intrinsic multidrug resistance, antiemetic agents, agents for the treatment of anemia, agents for the treatment of neutropenia, immunopotentiators, inhibitors of cell proliferation and survival signaling, interfering with cell cycle Checkpoint drug, apoptosis inducer and bisphosphonate.

The term "administering" and variants thereof (e.g., "administering" a compound) in connection with a compound of the invention means that the compound or prodrug of the compound is introduced into a system in which the animal is to be treated. When a compound of the invention or a prodrug thereof is provided in combination with one or more other active agents (eg, cytotoxic agents, etc.), "administering" and variants thereof are each understood to include simultaneous and sequential introduction of the compound or prodrug thereof. With other medicines.

The term "composition" as used herein is intended to cover a product comprising a specified quantity of the specified ingredients and any product which may be produced directly or indirectly from a specified combination of the specified ingredients.

The term "therapeutically effective amount" as used herein means an amount of a biological or medical response of an active compound or pharmaceutical agent in a tissue, system, animal or human, which is sought by a researcher, veterinarian, physician or other clinician.

The term "treatment" refers to the treatment of a mammal infected by a pathological condition and refers to the effect of mitigating the condition by killing the cancer cell and also the effect of achieving inhibition of progression of the condition, and including a decrease in the rate of progression and a stop in the rate of progression. The condition is improved and the condition is cured. It also includes treatment as a preventive measure (ie, prevention).

The term "pharmaceutically acceptable" as used herein means suitable for use in contact with a subject (eg, human) tissue within a reasonable pharmaceutical judgment without excessive toxicity, irritation, allergic reaction or other problems or concurrent And reasonable The benefit/risk ratio corresponds to the compound, material, composition and/or dosage form. Each carrier, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

The term "assisted" refers to the use of a compound in conjunction with known methods of treatment. These methods include cytotoxic means and/or ionizing radiation of the drugs used in the treatment of different cancer types. In particular, such active compounds are known to potentiate the effects of many cancer chemotherapeutics, including topoisomerase classes of poisons (eg, topotecan, irinotecan, rubiconcan) Most known alkylating agents (eg, DTIC, temozolomide) and platinum-based drugs (eg, carboplatin, cisplatin) used in the treatment of cancer.

Also included within the scope of the patent application is a method of treating cancer comprising administering a therapeutically effective amount of a compound of formula I in combination with radiation therapy and/or in combination with a compound selected from the group consisting of HDAC inhibitors, estrogen receptor modulators. , androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, angiogenesis Inhibitor, PPAR-γ agonist, PPAR-δ agonist, antiviral agent, intrinsic multi-drug resistance inhibitor, antiemetic agent, agent for treating anemia, agent for treating neutropenia, immunity An agent that enhances drug, cell proliferation, and survival signaling pathways, agents that interfere with cell cycle checkpoints, apoptosis-inducing agents, and bisphosphonates.

These and other aspects of the invention are apparent from the teachings contained herein.

Explain the chemicals and the abbreviations used in the following examples:

AcCl (ethyl chloroformate); (BzO) ₂ (benzamide peroxide); Cbz-Cl (benzyl chloroformate); DCM (dichloromethane); DIPEA (di-iso-propylethylamine) ; DMF (dimethylformamide); DMSO (dimethylammonium); ed. (equivalent); ES (electrospray); EtOAc (ethyl acetate); EtOH (ethanol); mol. sieves (molecular sieve) ;HATU [ O- (7-azabenzotriazol-1-yl) -N,N,N,N '-tetramethyl hexafluorophosphate MeCN (acetonitrile); MeOH (methanol); MS (mass); MW (microwave); NBS (N-bromosuccinimide); NMMO (N-methylmorpholine-N-oxide); NMR ( NMR); Pcol (column pressure); iPrOH (isopropanol); RT (room temperature); sat. aq. (saturated aqueous solution); SiO ₂ (silicone); and THF (tetrahydrofuran). Ac ₂ O (acetic acid); t -BuOH (Third - butanol); DIPEA (two - iso - propyl ethyl amine); KOAc (potassium acetate); MW microwave; IST ISOLUTE ^® SPE column SCX (International Sorbent Technology ISOLUTE ^® Solid Phase Extraction column cation exchange resin; SFC (supercritical fluid chromatography); TBTU tetrafluoroborate O -(1 H -benzotriazol-1-yl)- N,N,N ' ,N '- Tetramethyl And Tcol (column temperature).

Compounds of formula I can be prepared by reacting a compound of formula IA with ammonia:

Wherein R ¹ and R ² are as defined above and R ^x is C _1-6 alkyl, for example, methyl. In carrying out the reaction (cautiously) at 70 deg.] C in a solvent such as THF and the like generally used in an aqueous solution of NH ₃ in the reaction vessel was sealed. Alternatively, a base such as NaOH or KOH may be added to hydrolyze the ester to the corresponding carboxylic acid (R ^x hydrogen), followed by the addition of NH ₃ 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 Boc ₂ O to form a mixed anhydride, and then reacted with ammonium hydrogencarbonate, typically in a solvent such as pyridine. Alternatively, the ester can be converted to a compound of formula IA using, for example, MeOH in a solvent such as MeOH at about 120 ° C in, for example, MW.

The nitrogen atom on the hexahydropyridine ring of the compound of formula IA should be protected by, for example, Boc during the above synthesis.

Compounds of formula IA can be prepared by reacting a compound of formula IB with an azide:

Wherein R ¹ , R ² and R ^x are as defined above. An azide such as NaN ₃ may be used, usually in a solvent such as DMF, at about 90 ° C to 140 ° C. Additives such as 2,6-lutidine can also be used. This reaction can be carried out under a nitrogen atmosphere.

The compound of formula IB can be prepared by the condensation reaction of a compound of formula IC with a compound of formula ID:

Wherein R ¹ , R ² and R ^x are as defined above and the L ¹ is a leaving group, for example, a nitro group or a halogen such as fluorine. The method includes condensation in the presence of a dehydrating agent such as MgSO ₄ or molecular sieve or heating under reflux in an alcohol solvent such as ethanol. This reaction can be carried out under a nitrogen atmosphere.

Compounds of formula IC can be prepared by oxidizing a compound of formula IE using an oxidizing agent such as NMMO:

Wherein R ¹ , R ^x and L ¹ are as defined above and an L ² -based leaving group, for example, a halogen such as bromine, usually in a solvent such as MeCN at about room temperature. This reaction can be carried out under a nitrogen atmosphere.

The compound of the formula IE wherein L ² -based bromine can be prepared by oxidizing a compound of the formula IF using a brominating agent such as NBS in the presence of a radical initiator such as benzamidine peroxide:

Wherein R ¹ , R ^x and L ¹ are as defined above, usually under reflux in a solvent such as CCl ₄ . This reaction can be carried out under a nitrogen atmosphere.

The IF compound of the formula wherein the L ¹ is fluorine can be prepared by diazotization of the compound of the formula IG followed by decomposition of the intermediate diazonium salt:

Wherein R ¹ and R ^x are as defined above. For example, the diazotization reaction can be carried out using a nitrosonium tetrafluoroborate in a solvent such as DCM at about 0 °C. The corresponding diazonium tetrafluoroborate salt can then be separated and subsequently decomposed into the corresponding fluorobenzene derivative (caution) in a solvent such as dichlorobenzene at elevated temperature (for example, by heating to 160 ° C).

The IF compound of the formula wherein the L ¹ -nitro group is prepared by the nitration reaction of the compound of the formula IH, followed by esterification:

Wherein R ¹ is as defined above. The nitration reaction can be carried out at about room temperature in the presence of a nitrate such as potassium nitrate and an acid such as sulfuric acid. The esterification reaction step can be carried out under standard conditions, for example, by using an alkyl halide of the formula R ^x -X (wherein X-based halogen, for example, iodine) in the presence of a base such as cesium carbonate and in a solvent such as DMF The reaction is carried out at about room temperature. The R ^x -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:

Wherein R ¹ and R ² are as defined above. May be used, such as CBz-C1 acyl chloride and the like reducing agent such as NaBH ₄ to the reaction Fuller (Fowler reaction) The reduction embodiment. 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-pyridylboronic acid of formula IL:

Wherein R ¹ , R ² and L ² are as defined above. The reaction is usually carried out under Suzuki coupling conditions (for example, using a catalyst such as Pd ₂ (dba) ₃ and tris(tert-butyl)phosphine and a base such as sodium carbonate and a solvent such as DMF and water at about 90 ° C) Implemented below.

Formula IK compounds can be prepared by condensation of a compound of formula IM with a compound of formula IN:

Wherein R ¹ , R ² and L ² are as defined above and an L ³ -based leaving group, for example, a halogen such as fluorine; is usually present in MW at about 180 ° C in a solvent such as DMF. A base such as K ₂ CO ₃ may also be added.

A compound of the formula IM can be prepared by formulating a compound of the formula IO wherein R ¹ and R ^x are as defined above

Reacting with a base such as KOH or NaOH at about room temperature to hydrolyze the ester to the corresponding carboxylic acid (R ^x hydrogen), followed by the addition of NH ³ in the presence of a coupling agent such as HATU, DIPEA and TBTU, such as DMF In a solvent, the reaction is carried out at about room temperature.

The compound of formula IO can be prepared from a compound of formula IG by acetylating an aniline group with a reagent such as acetamidine chloride in a solvent such as 1,2-DCE at about 55 °C. Cyclization of the desired carbazole can then be accomplished by treatment with sodium nitrite in an acid (e.g., concentrated hydrochloric acid), usually at about 0 ° C in the presence of a cosolvent such as toluene and water.

When the synthesis of the intermediates and starting materials is not elucidated, 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.

The compound of formula I can be converted to other compounds of formula I by known methods or by the methods described above in the synthesis, in the reaction schemes herein and in the examples.

In any of the synthetic sequences described herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved. This can be achieved by conventional protecting groups, for example, as described in Protecting Groups in Organic Synthesis 3rd Edition, Greene, TW and Wuts, PGM; Wiley Interscience, 1999 and Kocienski, PJ Protecting Groups, Thieme, 1994. These protecting groups can be removed at a suitable subsequent stage using methods known in the art. For example, when a Boc (tris-butoxycarbonyl) or benzylcarbonyl 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 (for example, 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 Boc or benzyl carbonyl protecting group at about room temperature.

The compounds of the invention were prepared according to the following reaction schemes. All variables of all types Is 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 procedures (e.g., using SFC, palmitic HPLC or by dissolving the palmitic acid). This separation can be carried out in any step of the process of preparing the compound of formula I. Thus, the separation can be carried out in the last step, or the intermediate can be isolated and then the specific enantiomer can be utilized in subsequent reactions to produce the desired product.

Reaction diagram 1

A procedure for the synthesis of derivatives of the compounds of the invention is shown in Reaction Scheme 1, wherein substituted 2H -carbazoles are 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 benzyl bromide derivative. Oxidation of this benzyl bromide to the corresponding benzaldehyde can be accomplished using, for example, N -methylmorpholine- N -oxide and molecular sieves. After condensation of the aldehyde with the amine, the ring closure can be accomplished by treating the key intermediate at elevated temperatures using sodium azide to introduce the final nitrogen atom and expelling the resulting nitrogen to provide the oxazole ring. A base such as lutidine may also be added to the reaction. Finally, the ester is converted to a primary guanamine to yield the desired derivative. This can be accomplished by heating the ester in an ammonia solution or by converting to the corresponding carboxylic acid followed by guanamine coupling.

Reaction diagram 2

Variation of FIG. 1 shows the type of reaction and may be introduced into such a substituent on the core indazole in Scheme 2 below. When the desired nitrobenzoic acid derivative is not commercially available, it can be prepared, for example, by nitrating the corresponding benzoic acid derivative with potassium nitrate present in concentrated sulfuric acid. The synthesis procedure described above can form the corresponding aniline which can also be cyclized to form the carbazole by first acetylating the aniline and cyclizing it with concentrated sodium nitrite in concentrated HCl acid at 0 °C. Alternatively, the aniline may be diazotized using nitrosonium tetrafluoroborate and the corresponding diazonium tetrafluoroborate may be decomposed at a high temperature to form a corresponding difluorobenzene derivative by a Schiemann reaction (careful). Following the synthesis sequence as described in Reaction Scheme 1 , the benzyl methyl group can be oxidized to the corresponding aldehyde and cyclized with sodium azide by coupling with (hetero) hydrazine instead of the sodium azide to give the desired carbazole derivative.

Reaction Figure 3

Another procedure involves functionalizing the oxazole at a later stage, as shown in the reaction scheme 3 . Here, the carbazole ester is first converted to the corresponding formamide and then the nucleophilic aromatic substitution is carried out with the appropriate fluoro(hetero)aromatic bromide. This makes it possible to prepare a bromide derivative capable of cross-linking coupling under Suzuki coupling conditions (for example, using tris(tert-butyl)phosphine and Pd ₂ (dba) ₃ as a catalyst in the presence of a base such as sodium carbonate. Fuller followed by conversion of the reaction using hexahydro-pyridine moiety is accomplished through a desired acyl chloride and the like CBz-Cl and a reducing agent such as NaBH ₄ and the like. The final hydrogenation reaction produces the corresponding hexahydropyridine derivative.

PARP-1 SPA test

Tested in this assay, the exemplified compounds described herein and found out that the compound has IC ₅₀ values of less than 5 μM (specifically, less than 50 nM) of.

Working reagent

Test buffer : 100 mM Tris pH 8, 4 mM MgCl ₂ , 4 mM spermine, 200 mM KCl, 0.04% Nonidet P-40.

Enzyme mixture : test buffer (12.5 ul), 100 mM DTT (0.5 ul), PARP-1 (5 nM, Trevigen 4668-500-01), H ₂ O (to 35 ul).

Nicotinamide-adenine dinucleotide (NAD)/DNA mixture : [ ³ H-NAD] (250 uCi/ml, 0.4 ul, Perkin-Elmer NET-443H), NAD (1.5 mM, 0.05 ul, SIGMA N -1511), biotinylated NAD (250 uM, 0.03 ul, Trevigen 4670-500-01), activated calf thymus (1 mg/ml, 0.05 ul, Amersham Biosciences 27-4575), H ₂ O (complemented to 10 Ul).

Development mixture : Streptavidin SPA beads (5 mg/ml, Amersham Biosciences RPNQ 0007) dissolved in 500 mM EETA.

experimental design

The reaction was carried out in a 96-well microplate at a final volume of 50 uL/well. Add 5 ul of 5% DMSO/compound solution, add enzyme mixture (35 ul), start the reaction by adding NAD/DNA mixture (10 uL) and incubate for 2 hours at RT. The reaction was stopped by the addition of a developing mixture (25 ul) and incubated for 15 min at RT. Measurements were made using a Packard TOP COUNT instrument.

BRCA-1 silencing HeLa cell proliferation test.

abbreviation:

IMDM (Iscove's modified Dubecca's medium); RPMI (Roswell Park Memorial Institute); MOI (infection diversity); GFP (green fluorescent protein); PBS (phosphate buffered saline); FCS (fetal calf serum); And DMEM (Dubec's Modified Eagle's Medium).

The compounds of the invention can also be tested in matched BRCA1wt and BRCA1-(shRNA) HeLa cells in an anti-proliferation assay. This assay demonstrates that PARP inhibitors can show the growth of cells that selectively inhibit BRCA deficiency. BRCA1 defective cells such compounds in the display below 's selectivity and BRCA richer in the large cells of 10 of 5 μM CC _50.

This test is based on the ability of living cells to convert a redox dye (resazurin) into a fluorescent end product (resofurin). The amount of resorufin produced is proportional to the number of cells.

Cell lines: HeLa shBRCAl-GFP- These are HeLa cells transduced with lentivirus containing shRNA (for BRCA-1) and GFP expression cassette at MOI of 100. The BRCA-1 silencing system is greater than 80% as assessed by Taqman analysis and the cells stably express GFP.

HeLa THM - GFP - These are HeLa cells transduced with a control vector that does not exhibit any shRNA at an MOI of 100.

Test program

- Seeding at 300 cells/well in 90 μl medium in 96-well black plates*: - Incubate at 37 °C for 4 hours, 5% CO ₂ - Add 10X compound at 10 ul/well (5% DMSO is stored in H ₂ O) - incubated at 37 ° C for 168 hours, 5% CO ₂ - Add 10 μl of Celltiter Blue solution (Promega, G8081) pre-diluted in PBS 1x 1:1 - incubate the mixture at 37 ° C 45 ', 5 % CO ₂ - 15' in the dark at RT - read the plate with a fluorometer, ex: 550 nm; em: 590 nm * medium : DMEM (GIBCO, 41966-029), 10% FCS (GIBCO, 10106-169), 0.1 mg/ml penicillin-streptomycin (GIBCO, 15140-114), 2 mM L-glutamine (GIBCO, 3042190)

Proliferation test of a cell line lacking BRCA naturally.

The compounds of this invention also may be less than 5 micromolar display of CC ₅₀ 'inhibition of native BRCA-1 (MDA-MB- 436) and BRCA-2 (CAPAN-1) lines of the cell proliferation defects.

Proliferation test

Cells were seeded at 700 cells/well in 100 ul of the appropriate medium/well in 96-well plates. *

The next day, serial dilutions were added in a final volume of 200 μl/well. Each dilution was tested in triplicate.

After 6 days, cell viability was assessed using the CellTiter-Blue Cell Viability Assay according to the manufacturer's instructions (Promega). Plates were read using a Fusion Alpha microplate reader (Packard Bioscience).

For the low proliferative cell line (ie, CAPAN-1), 14 days after the addition of the compounds (and the medium was changed 1 time on day 7, 170 μl of medium was withdrawn and replaced with 170 μl of fresh medium containing the mixture) Hyperplasia.

*Medium: MDA-MB-436: RPMI (GIBCO), 10% FBS (5% CO ₂ ) CAPAN-1: IMDM (GIBCO), 20 % FBS (5% CO ₂ ) tested in oncology in vivo models The compound showed a significant level of activity.

Preparation example

Example A

2-phenyl- 2H -carbazole-7-formamide (A6)

Step 1: 3-methyl-2-nitrobenzoic acid methyl ester (A1)

To a suspension of 3-methyl-2-nitro-benzoic acid (1.0 eq.) in MeOH (0.4 M) was added dropwise EtOAc (3.0 eq.). The reaction mixture was stirred at reflux for 20 hours. The solvent was reduced in vacuo and the residue was dissolved in EtOAc and washed with saturated aqueous NaHCO _3, washed several times with brine and dried (Na ₂ SO _4). The solvent was evaporated to give a white solid ( EtOAc ). ¹ H NMR (400 MHz, CDCl ₃ , 300K) 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) C 9 H 9} NO 4 predetermined value: 195, ^{Found: 218 (M + Na) +} .

Step 2: Methyl 3-(bromomethyl)-2-nitrobenzoate (A2)

It was refluxed in an atmosphere, N _2, the (A1) (1.0 eq.) , (BzO) 2 (0.06 eq.) And NBS (1.18 eq.) Present in the mixture of CCl ₄ (0.2 M) was heated for 12 h. The mixture was cooled to RT, diluted with DCM, and dried and concentrated simultaneously loaded onto the SiO ₂ under reduced pressure. SiO ₂ by flash column chromatography using a 10: 90EtOAc / petroleum ether, the residue was purified to yield the desired as a white solid (A2). ¹ H NMR (400 MHz, CDCl ₃ , 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) C 9 H 8} BrNO 4 predetermined value: 273: 275, Found: 242: 244 (M-MeO ) +, 227: 229 (M-NO 2) +.

Step 3: Methyl 3-mercapto-2-nitrobenzoate (A3)

NMMO (2.0 eq.) was added to a mixture of ( A2 ) and 4 Å molecular sieves (15 g) in MeCN (0.2M) at RT and the reaction mixture was stirred for 1.5 hours under N ₂ atmosphere. Subsequently, the mixture was diluted with EtOAc, filtered and washed with H ₂ O, 1N HC1, brine, and the filtrate was dried (Na ₂ SO _4). The solvent was evaporated to give a white solid ( 3 ). ¹ H NMR (400 MHz, CDCl ₃ , 300K) δ 9.96 (1H, s), 8.26 (1H, d, J = 7.9 Hz), 8.18 (1H, d, J = 7.9 Hz), 7.77 (1H, t, J = 7.9 Hz), 3.93 ( 3H, s) C 9 H 7 NO 5 predetermined value MS (ES): 209, Found: 208 (MH) ^-..

Step 4: Methyl 2-nitro-3-[(phenylimino)methyl]benzoate (A4)

Under reflux in an atmosphere of N ₂ in the (A3) (1.0 eq.) And aniline (1.05 eq.) Present in the mixture (0.2 M) in EtOH was stirred for 2 hours until the TLC showed completion of the reaction (hexane / EtOAc = 75 :25). The solvent was evaporated to give a white solid ( EtOAc ). ¹ H NMR (400 MHz, CDCl ₃ , 300K) δ 8.51 (1H, d, J = 7.3 Hz), 8.41 (1H, s), 8.11 (1H, d, J = 7.8 Hz), 7.67 (1H, t, J=7.8 Hz), 7.43 (2H, 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-2H-carbazole-7-carboxylic acid methyl ester (A5)

At 90 ℃, in the N ₂ atmosphere in (A4) (1.0 eq) and NaN ₃ (1.05 eq.) In dry DMF (0.3 M) the mixture was stirred overnight. The decrease in vacuo and the crude material by flash column chromatography on silica gel using EtOAc 10:90 to 40:60 from the / petroleum ether gradient to yield the desired residue was purified brown oil (A5). ¹ H NMR (400 MHz, CDCl ₃ , 300K) δ 8.50 (1H, s), 8.12 (1H, d, J = 7.0 Hz), 7.96-7.90 (3H, m), 7.49 (2H, t, J=7.6 Hz), 7.38 (1H, t, J=7.4 Hz), 7.15 (1H, t, J=7.4 Hz), 4.03 (3H, s). MS (ES)C ₁₅ H ₁₂ N ₂ O ₂ specified: 252 , Experimental value: 253 (M+H) ⁺ .

Step 6: 2-Phenyl-2H-carbazole-7-formamide (A6)

At 70 ℃, in a sealed tube, the ester (A5) in a mixture of THF and an aqueous solution of 32% NH ₃ was heated overnight. The solvent was reduced in vacuo and flash column chromatography on silica gel by using EtOAc 30:70 to 50:50 from / petroleum ether gradient to yield the desired residue was purified as a white solid (A6). ¹ H NMR (400 MHz, DMSO, 300K) δ 9.33 (1H, s), 8.56 (1H, bs), 8.16 (2H, d, J = 7.9 Hz), 8.08-8.00 (2H, m), 7.88 (1H , bs), 7.63 (2H, t, J=7.7 Hz), 7.50 (1H, t, 7.4 Hz), 7.27 (1H, t, J=7.9 Hz). _{MS (ES) C 14 H 11} N 3 O predetermined value: 237, ^{Found: 238 (M + H) +} .

Preparation example

Example 1

3-{4-[7-(Aminocarbonyl)-2H-indazol-2-yl]phenyl}hexahydropyridinium chloride (B4)

Step 1: 3-[4-({-[3-(Methoxycarbonyl)-2-nitrophenyl 1 methylene}amino) Phenyl]hexahydropyridine-1-carboxylic acid tert-butyl ester (B1)

( B1 ) was prepared according to the general procedure reported in Step 4 of Preparation Example A using A3 and 3-(4-aminophenyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (until TLC shows the reaction is complete) (Petroleum ether: EtOAc = 4:1)) and used for the next step without further purification.

Step 2: 2-{4-[1-( Thr- Butoxycarbonyl)hexahydropyridin-3-yl]phenyl}-2 H -indazole-7-carboxylic acid methyl ester (B2)

( B2 )) was prepared according to the general procedure for the preparation of Example A, Step 5, and the crude material was purified by silica gel flash column chromatography using 20-40% EtOAc/ pet ether gradient to afford the desired yellow solid ( B2 ). ¹ H NMR (400 MHz, CDCl ₃ , 300K) δ 8.51 (1H, s), 8.13 (1H, d, J = 7.1 Hz), 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 overlaps with H ₂ O signal), 1.48 (9H, s). MS (ES)C ₂₅ H ₂₉ N ₃ O ₄ specified: 435, found: 436 (M+H) ⁺ .

Step 3: 3- {4- [7- (aminocarbonyl) -2 H - indazol-2-yl] phenyl} piperidine-1-carboxylic acid tertiary - butyl ester (B3)

In a sealed tube, at 60 deg.] C to (B2) in the presence of in MeOH (0.1 M) was heated two days of 7N NH _3. The solvent was reduced in vacuo and purified by triturated with Et ₂ O to obtain the desired crude product as a yellow solid (B3). ¹ H NMR (400 MHz, CDCl ₃ , 300K) δ 9.04 (1H, br. s), 8.51 (1H, s), 8.31 (1H, d, J = 6.8 Hz), 7.91 (1H, d, J=8.3 Hz), 7.84 (2H, d, J=8.2 Hz), 7.42 (2H, d, J=8.2 Hz), 7.31-7.22 (1H, m overlaps with CDCl ₃ signal), 5.95 (1H, br. s), 4.40-4.05 (2H, m), 2.90-2.70 (3H, m), 2.15-2.00 (1H, m), 1.85-1.75 (1H, m), 1.75-1.50 (2H, m overlaps with H ₂ O signal) ., 1.48 (9H, s) MS (ES) C 24 H 28 N 4 O 3 predetermined value: 420, ^{Found: 421 (M + H) +} .

Step 4: chloride 3- {4- [7- (aminocarbonyl) -2 H - indazol-2-yl] phenyl} hexahydro-pyridinium (B4)

To (B3) (1.0 eq) was stored in a stirred solution of EtOAc (0.2M) was added 4NHCl / 1,4- dioxane solution (10.0 eq) and the reaction mixture was stirred at RT 3 h. The solvent was evaporated under low pressure and purified by Et ₂ O triturated with to generate a desired crude product as a yellow solid (B4). ¹ H 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 (1H, dd, J=8.4, 7.0 Hz), 3.43-3.27 (2H, m), 3.17-3.03 (2H, m), 3.00-2.85 (1H, m), 2.00-1.70 (4H, . m) MS (ES) C 19 H 21 CIN 4 O prescribed value: 320, ^{Found: 321 (m + H) +} .

Example 2

2-{4-[(3R)-hexahydropyridin-3-yl]phenyl}-2H-indazole-7-carboxamide (C1) and 2-{4-[(3S)-hexahydropyridine- 3-yl]phenyl}-2H-carbazole-7-formamide (C2)

By the palm of the SFC (column: Chiralpak AS-H, 1 × 25 mm, flow rate: 10 ml / min, T _col : 35 ° C, P _col : 100 bar, improver: 55% ( ¹ PrOH + 4%) 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. ¹ H NMR (400 MHz, DMSO-d6, 300K) δ 9.28 (s, 1H), 8.57 (br. s, 1H), 8.06 (d, 2H, J = 7.2 Hz), 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), 1.75-1.47 (m, 4H). MS (ES) C ₁₉ H ₂₀ N ₄ O 320, Experimental value: 321 (M+H) ⁺ . Conversion of the free base to ( 3R )-3-{4-[7-(aminocarbonyl)-2H-indazol-2-yl]phenyl}hexahydropyridinium chloride and measuring the optical rotation: [α ] ²⁰ _D = +133.3 (c 0.15, MeOH).

The second solubilized enantiomer ( C2 ) was obtained as a white powder, and the residence time (SFC): 6.51 min. ¹ H NMR (400 MHz, DMSO-d6, 300K) δ 9.28 (s, 1H), 8.57 (br. s, 1H), 8.06 (d, 2H, J = 7.2 Hz), 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), 1.75-1.47 (m, 4H). _{MS (ES) C 19 H 20} N 4 O a predetermined value: 320, ^{Found; 321 (M + H) +} . The free base was converted to the chloride (3 S) -3- {4- [ 7- ( aminocarbonyl) -2H- indazol-2-yl] phenyl} hexahydro-pyridinium and measuring Optical rotation: [α ] ²⁰ _D = -137.9 (c 0.145, MeOH).

Example 3

3-{4-[7-(Aminocarbonyl)-5-fluoro-2H-indazol-2-yl]phenyl}hexahydropyridinium trifluoroacetate (D4)

Step 1: 5-Fluoro-1H-carbazole-7-carboxylic acid methyl ester (D1)

To a solution of Example 4, E3 (1.0 eq) in 1,2-dichloroethane (0.1 M) was added EtOAc (5 eq). 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., 37%). Subsequently, several portions of NaNO ₂ (10 eq) were slowly added and the mixture was stirred at 0 ° C for 3 h. The organic phase was washed with water (3x), dried over MgSO ₄ and evaporated.

The yellow toluene solution (0.1 M) was then heated at 90 °C for 2 h. The toluene was evaporated to give the desired product as a red solid. ¹ H 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 ⁺ ) C ₉ H ₇ FN ₂ O ₂ specified: 194, 195 (M+H) ⁺ .

Step 2: 5-Fluoro-1H-carbazole-7-formamide (D2)

( D1 ) was dissolved in dioxane/water (1/1, 0.1 M) and KOH (1.5 eq) was added. After stirring at RT for 12 h, the solvent was removed under reduced pressure. The white 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 0 °C. After 15 min, DIPEA (2.0 eq.) and ammonia (3.0 eq., 0.5 M in dioxane) were added and the mixture was stirred at RT for 36 h. EtOAc was added and washed with saturated aqueous NaHCO ₃ (3x) and brine (2x) The organic phase was washed. The organic phase was dried and evaporated under reduced pressure. By flash chromatography using 1-20% MeOH / DCM to yield crude was purified as a white solid (D2). MS (ES ⁺ ) C ₈ H ₆ FN ₃ O: 179, Found: 180 (M+H) ⁺ .

Step 3: 2-(4-Bromophenyl)-5-fluoro-2H-indazole-7-carboxamide (D3)

Add K ₂ CO ₃ (1.3 eq) and 4-bromofluorobenzene (10.0 eq) to a solution of D2 (1.0 eq) in DMF (0.2 M) and heat the reaction mixture at 180 ° C under MW conditions. Min. The reaction mixture was cooled to RT and diluted with EtOAc. The organic phase was washed with brine, dried (Na ₂ SO _4). The solvent was evaporated to give ( D3 ), which was purified eluting eluting eluting ¹ H NMR (400 MHz, DMSO-d ₆ , 300K) 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 +) C 14 H}} 9 BrFN 3 O predetermined value: 334/336, ^{found: 335/337 (M + H) +} .

Step 4: 5-Fluoro-2-(4-pyridin-3-ylphenyl)-2H-indazole-7-carboxamide (D4)

A mixture of ( D3 ) (1.0 eq) and pyridine-3-boronic acid (1.3 eq) in DMF (1.0 M) and 2N Na ₂ CO ₃ solution (2.0 eq) was degassed with a stream of Ar. ^t Bu ₃ PH ⁺ BF ₄ ^- (0.05 eq) and Pd ₂ (dba) ₃ (0.05 eq) were added and the reaction mixture was heated at 90 ° C for 48 h. The mixture was cooled to RT, DCM was added and the organic phase was washed with saturated aqueous NaHCO _3, washed with brine, dried (Na ₂ SO _4). The residue was purified by EtOAc EtOAc (EtOAc) ¹ H NMR (400 MHz, DMSO-d ₆ , 300K) δ 9.40 (1H, s), 9.01 (1H, d, J = 1.6 Hz), 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 (2H, d, J=8.8 Hz ), 7.88-7.82 (2H, m), 7.54 (1H, dd, J=7.8, 4.8 Hz). MS (ES) C ₁₉ H ₁₃ FN ₄ O specified: 332, experimental value; 333 (M+H ⁺ ).

Step 5: 3-{4-[7-(Aminocarbonyl)-5-fluoro-2H-indazol-2-yl]phenyl)hexahydropyridine-1-carboxylic acid benzyl ester (D5)

To (D4) in dry MeOH (0.2 M) was added to the stirred solution NaBH ₄ (1.2 eq) and followed by the dropwise at -65 ℃ was added Cbz-CI (1.2 eq). The reaction was allowed to reach RT O / N and then quenched with H ₂ O. The MeOH was concentrated under reduced pressure and EtOAc was added. The organic phase was washed with saturated _aqueous NaHCO, dried (Na ₂ SO _4). The solvent was evaporated to give ( D5 ) which was used in the next step without further purification. C ₂₇ H ₂₅ FN ₄ O ₃ predetermined value (ES) MS: 472, ^{Found: 473 (M + H +)} .

Step 6: 3-{4-[7-(Aminocarbonyl)-5-fluoro-2H-indazol-2-yl]phenyl}hexahydropyridinium trifluoroacetate (D6)

To (D5) (1.0 eq) was added to deposit Pd / C10% (0.05 eq) and HC1 (1.0 eq) MeOH (0.2 M) of the solution and the reaction mixture was stirred under H ₂ atmosphere (1 atm) 48 h . Subsequently, the mixture was filtered and the solvent was removed in vacuo to give (D6) through diatomaceous earth, which by reverse phase RP-HPLC (column: C18), using H ₂ O (0.1% TFA) and MeCN (0.1% Purification of the title compound ( D6 ) was obtained as a white powder. ¹ H NMR (400 MHz, CD ₃ CN, 300K) δ 9.28 (1H, s), 8.89 (1H, br. s), 8.60-8.50 (2H, m), 8.13 (2H, 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) C 19 H 19 FN 4 O prescribed value: 338, ^{Found: 339 (m + H +)} .

Example 4

5-fluoro-2-(3-fluoro-4-hexahydropyridin-3-ylphenyl)-2H-indazole-7-formamide trifluoroacetate (E6)

Step 1: 5-Fluoro-3-methyl-2-nitrobenzoic acid (E1)

KNO ₃ (1.1 eq) was slowly added to a solution of 3-fluoro-5-methylbenzoic acid (1.0 eq.) in concentrated H ₂ SO ₄ at 0 °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, a white precipitate was filtered, washed with cold water and dried under reduced pressure. The white solid was used in the next step without further purification. ¹ H 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-nitrobenzoic acid methyl ester (E2)

Methyl iodide (1.0 eq.) was added to a solution of ( E1 ) and cesium carbonate (1.5 eq.) in DMF (0.25 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 (Na ₂ SO ₄ ) and concentrated under reduced pressure. The yellow solid was used in the next step without purification. ¹ H NMR (400 MHz, DMSO, 300K) δ 7.63 (2H, m), 3.83 (3H, s), 2.29 (3H, s).

Step 3: 2-Amino-5-fluoro-3-methylbenzoic acid methyl ester (E3)

The mixture of ( E2 ) (1.0 eq.) and Pd/C (10% w/w) in MeOH (0.25 M) was stirred for 3 d under RT, H ₂ atmosphere (1 atm). The mixture was filtered through Celite® and then the solvent was evaporated under pressure. The white solid was used in the next step without further purification. ¹ H 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: Methyl 2,5-difluoro-3-methylbenzoate (E4)

To a solution of ( E3 ) (1.0 eq.) in dry DCM (0.4 M) was added portion of nitrosamine tetrafluoroborate (1.3 eq.) at 0 °C. After 1 h, dry dichlorobenzene (120 eq.) was added at 0 ° C and the reaction was slowly warmed to 160 ° C while DCM was distilled. After 3 hr, the mixture was cooled to rt then EtOAc was added and the organic phase was washed with brine (2x). After drying over MgSO ₄ , the solvent was evaporated under reduced pressure. The crude was purified by flash chromatography using EtOAc EtOAc (EtOAc ) ¹ H NMR (400 MHz, CDCl ₃ , 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-methylindenylbenzoate (E5)

(E5) was prepared from E4 according to the general procedure reported in Preparation Example A, Steps 2 and 3. The crude was purified by flash chromatography (1-20%EtOAcEtOAcEtOAc ¹ H NMR (300 MHz, DMSO, 300K) δ 10.19 (1H, d, J = 2.4 Hz), 7.98 (1H, m), 7.86 (1H, m), 3.89 (3H, s). _{^{MS (ES +) C 9 H}} 6 F 2 O 3 predetermined value: 200, ^{Found: 201 (M + H) +} .

Step 6: 5-Fluoro-2-(3-fluoro-4-hexahydropyridin-3-ylphenyl)-2H-indazole-7-carbenamide trifluoroacetate (E6)

Conversion of (ES) to the corresponding oxime using 3-(4-amino-2-fluorophenyl)hexahydropyridine-1-carboxylic acid tert-butyl ester according to the general procedure reported in Preparation Examples A, Steps 4 and 5. Oxazole.

The resulting 2-{4-[1-(t-butoxycarbonyl) group was treated by a mixture of KOH (1.3 eq.) in dioxane/water (0.1 M) for 12 h at RT. The methyl hexahydropyridin-3-yl]-3-fluorophenyl}-5-fluoro- 2H -indazole-7-carboxylate is further converted to the corresponding formamide. The solvent was removed under reduced pressure. The carboxylic acid was dissolved in DMF (0.1 M) and TBTU (1.5 eq.) was added. After 15 min, DIPEA (2.0 eq.) and ammonia (3.0 eq., 0.5 M in THF) were added and the solution was stirred for 36 h. And the mixture was then washed with saturated aqueous NaHCO ₃ and brine and the organic phase was diluted with EtOAc. After evaporation of the solvent, the residue was used in the next step without purification.

For 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 residue, which (column: C18) was purified by reverse phase HPLC to obtain the title compound (E6). ¹ H NMR (400 MHz, DMSO, 300K) δ 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 +) C 19 H 18 F 2 N 4 O a predetermined value: 356, ^{Found: 357 (m + H) +} .

Example S

4-methylbenzenesulfonic acid (3S)-3-{4-[7-(aminocarbonyl)-2H-indazol-2-yl]phenyl}hexahydropyridinium (F4)

Step 1: (3S)-3-[4-({(IE)-[3-(Methoxycarbonyl)-2-nitrophenyl]methylene}amino)phenyl]hexahydropyridine-1 -carboxylic acid tert-butyl ester (F1)

In accordance with Example 1, B1 and in the self-A3 (3 S) -3- (4- aminophenyl) piperidine-1-carboxylic acid tertiary - butyl ester (2 equivalents by using the in MeOH ( F1 ) is prepared by dissolving 3-(4-aminophenyl)-hexahydropyridine with L-dibenyl tartaric acid and then Boc-protection.

Step 2: 2-{4-[(3S)-1-(Thr-Butoxycarbonyl)hexahydropyridin-3-yl]phenyl}-2H-indazole-7-carboxylic acid (F2)

( F1 ) (1 eq) and sodium azide (1 eq) were slurried in DMF (0.25 M ), inertized and 2,6-lutidine (1.0 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 acid and 2.0 M HC1 and brine and the layers were separated the organic layer was washed further with brine and concentrated to obtain (F2 of), which was used without further purification.

Step 3: (3S)-3-{4-[7-(Aminocarbonyl)-2H-indazol-2-yl]phenyl}hexahydropyridine-1-carboxylic acid tert-butyl ester (F3)

F2 was dissolved in DCM (0.35M) and di-n-butyl carbonate (1.3 eq) and pyridine (1.0 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 and the organic layer was washed twice with water and concentrated to a small volume. The crude compound ( F3 ) was filtered through a pad of diatomaceous earth and subsequently crystallised from methyl-tert-butyl ether.

Step 4: 4-(methyl)benzenesulfonic acid (3S)-3-{4-[7-(aminocarbonyl)-2H-indazol-2-yl]phenyl}hexahydropyridinium (F4)

F3 was dissolved in THF (0.15 M) and water (5% vs. THF) was added. p-Toluenesulfonic acid monohydrate (2.2 eq) was added and the mixture was heated to 66 ° C and stirred overnight. After cooling, the desired solid salt was isolated by filtration and confirmed to be monohydrate ( F4 ). ¹ H NMR (400 MHz, DMSO, 300K) δ 9.34 (1H, s); 9.20 (1H, broad s), 8.58 (1H, s), 8.14 (2H, 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)

The following examples were prepared according to the method of the previous example:

Claims (17)

a compound of formula (I), Wherein: R ¹ based hydrogen or fluorine; and R ² system hydrogen or fluorine; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. The compound of claim 1, which has the formula (II): Wherein R ¹ and R ² are as defined in claim 1; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. The compound of claim 1, which has the formula (III): Wherein R ¹ and R ² are as defined in claim 1; or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 1, which has the formula (IV): Wherein R ¹ and R ² are as defined in claim 1; or a pharmaceutically acceptable salt or tautomer thereof. The compound of any one of claims 1 to 4, wherein R ¹ is hydrogen and R ² is hydrogen or fluorine; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. The compound of claim 1, which is selected from the group consisting of: 2-(4-hexahydropyridin-3-ylphenyl)-2H-indazole-7-carboxamide; 2-{4-[(3R)-hexa Hydropyridin-3-yl]phenyl}-2H-carbazole-7-formamide; 2-{4-[(3S)-hexahydropyridin-3-yl]phenyl}-2H-carbazole-7 -carbamamine; 5-fluoro-2-(4-hexahydropyridin-3-ylphenyl)-2H-indazole-7-carboxamide; 5-fluoro-2-{4-[(3S)- Hexahydropyridin-3-yl]phenyl}-2H-carbazole-7-formamide; 5-fluoro-2-{4-[(3R)-hexahydropyridin-3-yl]phenyl}-2H -carbazole-7-formamide; 5-fluoro-2-(3-fluoro-4-hexahydropyridin-3-ylphenyl)-2H-carbazole-7-carboxamide; 5-fluoro-2 -{3-Fluoro-4-[(3R)-hexahydropyridin-3-yl]phenyl}-2H-indazole-7-carboxamide; 5-fluoro-2-{3-fluoro-4-[(3S)-hexahydropyridin-3-yl]phenyl}-2H-indazole-7-formamide; and pharmaceutically acceptable salts thereof, Tautomers or stereoisomers. a compound, 2-{4-[(3S)-hexahydropyridin-3-yl]phenyl}-2 H -indazole-7-carboxamide; or a pharmaceutically acceptable salt or tautomer thereof . a compound, 2-{4-[(3R)-hexahydropyridin-3-yl]phenyl}-2 H -indazole-7-carboxamide; or a pharmaceutically acceptable salt or tautomer thereof . A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, 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 and 6 to 8, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, which is administered simultaneously, separately or sequentially with an anticancer agent. A compound according to any one of claims 1 to 4 and 6 to 8, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, for use in therapy. Use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, for the manufacture of a treatment for inhibiting poly(ADP- A drug that improves the condition of ribose) polymerase (PARP). A use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, for the manufacture of a medicament for the treatment of cancer, inflammation Sexual disease, reperfusion Injection injury, ischemic condition, stroke, renal failure, cardiovascular disease, vascular disease other than cardiovascular disease, diabetes, neurodegenerative disease, retroviral infection, retinal damage or skin aging and UV-induced skin damage. Use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, for the manufacture of a chemical- and/or radiosensitizing agent for cancer therapy Agent. A pharmaceutical composition, which is a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or tautomer thereof, and temozoloamide. A pharmaceutical composition according to claim 15 which is a compound: 2-{4-[(3S)-hexahydropyridin-3-yl]phenyl}-2 H -indazole-7-carboxamide; or a medicament thereof An acceptable salt, with temozolomide. A pharmaceutical composition according to claim 15 which is a compound: 2-{4-[(3R)-hexahydropyridin-3-yl]phenyl}-2 H -indazole-7-formamide; or a pharmaceutical thereof An acceptable salt, with temozolomide.