MX2007002318A - 4-heteroarylmethyl substituted phthalazinone derivatives. - Google Patents

Abstract

A compound of formula (I): for use in treating cancer or other diseases ameliorated by the inhibition of PARP, wherein: A and B together represent an optionally substituted, fused aromatic ring; X can be NRx or CRxRy; if X=NRx then n is 1 or 2 and if X=CRxRy then n is 1; Rx is selected from the group consisting of H, optionally substituted C1-20 alkyl, C5-20 aryl, C3-20 heterocyclyl, amido, thioamido, ester, acyl, and sulfonyl groups; Ry is selected from H, hydroxy, amino; or Rx and Ry may together form a spiro-C3-7 cycloalkyl or heterocyclyl group; RC1 and RC2 are independently selected from the group consisting of hydrogen and C1-4 alkyl, or when X is CRxRy, RC1, RC2, Rx and Ry, together with the carbon atoms to which they are attached, may form an optionally substituted fused aromatic ring; R1 is selected from H and halo; and Het is selected from: (i) formula (i), where Y1 is selected from CH and N, Y2 is selected from CH and N, Y3 is selected from CH, CF and N, where only one or t wo of Y1, Y2 and Y3 can be N; and (ii) formula (ii), where Q is O or S.

Description

DERIVATIVES OF FTALAZINONE SUBSTITUTED WITH 4-HETEROARILMETI O FIELD OF THE INVENTION The present invention relates to phthalazinone derivatives, and their use as pharmaceuticals, in particular, the present invention relates to the use of these compounds to inhibit the activity of the enzyme poly (ADP-ribose) polymerase-1, also known as poly (ADP-ribose) synthase and poly ADP-ribosyltransferase, and commonly referred to as PARP-1. BACKGROUND OF THE INVENTION The mammalian enzyme PARP-1 (a 113-kDa multidomain protein) has been implicated in the signaling of DNA damage through its ability to rapidly recognize and bind single or double stranded DNA. it is broken (D'Amours, et al., Biochem. J., 342, 249-268 (1999)). The family of poly (ADP-ribose) polymerases now includes about 18 proteins, all of which play a certain level homology in their catalytic domain but differ in their cellular functions (Ame et al., Bioessays, 26 (8), 882- 893 (2004)). Of this family PARP-1 (the discovered member) and PARP-2 are until now the only enzymes whose catalytic activity is stimulated by the occurrence of DNA chain breaks, making them unique in the family. REF .: 179834 PARP-1 is known to participate in a variety of DNA-related functions including gene amplification, cell division, differentiation, apoptosis, excision repair of DNA base as well as effects on telomere length and chromosomal stability (Adda di Fagagna, et al., Nature Gen., 23 (1), 76-80. (1999) ) . Studies on the mechanism by which PARP-1 modulates DNA repair and other processes have identified its importance in the formation of poly (ADP-ribose) chains within the cell nucleus (Althaus, F.R. and Richter, C, ADP-Ribosylation of Proteins: Enzymology and Biological Significance, Springer-Verlag, Berlin (1987)). Activated PARP-1, linked to DNA uses NAD + to synthesize poly (ADP-ribose) in a variety of nuclear target proteins, including topoisomerases, histones and PARP by itself (Rhun, et al., Biochem. Biophys. ., 245, 1-10 (1998)). Poly (ADP-ribosylation) has also been associated with malignant transformation. For example, the activity of PARP-1 is higher in the isolated nuclei of fibroblasts transformed with SV40, while both leukemic cells and colon cancer cells show higher enzymatic activity than equivalent normal leukocytes and colonic mucosa (Miwa, et al. , Arch. Biochem. Biophys, 181, 313-321 (1977), Burzio, et al., Proc. Soc. Exp. Bio. Med., 149, 933-938 (1975); and Hirai, et al., Cancer Res., 43, 3441-3446 (1983)). More recently in malignant prostate tumors compared to benign prostate cells, significantly increased levels of active PARP (predominantly PARP-1) associated with higher levels of genetic instability have been identified (Mcnealy, et al., Anticancer Res., 23, 1473- 1478 (2003)). A number of low molecular weight inhibitors of PARP-1 have been used to elucidate the functional role of poly (ADP-ribosylation) in DNA repair. In cells treated with alkylating agents, inhibition of PARP leads to a marked increase in DNA strand break and cell death (Durkacz, et al., Nature, 283, 593-596 (1980); Berger, NA, Radiation Research , 101, 4-14 (1985)). Subsequently, such inhibitors have been shown to increase the effects of radiation response by suppressing the lethal damage repair potentially (Ben-Hur, et al., British Journal of Cancer, 49 (Suppl VI), 34-42 (1984) Schlicker, et al., Int. J. Radiat, Biol., 75, 91-100 (1999)). PARP inhibitors have been reported to be effective in radio-sensitive hypoxic tumor cells (U.S. Patent 5,032,617; U.S. Patent 5,215,738 and U.S. Patent 5,041,653). In certain tumor cell lines, the chemical inhibition of PARP-1 (and PARP-2) activation is also associated with marked sensitization to small doses of radiation (Chalmers, Clin. Oncol., 16 (1), 29-39 (2004 )). Additionally, animals with gene suppression with PARP-1 (PARP - / -) exhibit genomic instability in response to alkylating agents and irradiation and (Wang, et al., Genes Dev., 9, 509-520 (1995).

; Menissier de Murcia, et al., Proc. Nati Acad. Sic. Usa, 94, 7303-7307 (1997)). More recent data indicate that PARP-1 and PARP-2 have both overlapping and non-redundant functions in maintaining genomic stability, making them both interesting targets (Menissier de Murcia, et al., EMBO, J. 22 (9) , 2255-2263 (2003)). A role for PARP-1 has also been demonstrated in certain vascular diseases, septic shock, ischemic injury and neurotoxicity (Canton, et al., Biochim, Biophys, Acta, 1014, 1-17 (1989); Szabo, et al. , J. Clin. Invest., 100, 723-735 (1997)). Damage to DNA by radical oxygen that leads to strand breaks in DNA, which are subsequently recognized by PARP-1, is a major contributor to such disease states as shown by studies of PARP-1 inhibitors (Cosi, et al., J. Neurosci. Res., 39, 38-46 (1994); Said, et al., Proc.

Nati Acad. Sci. U.s.A., 93, 4688-4692 (1996)). More recently, PARP has been shown to play a role in the pathogenesis of hemorrhagic shock (Liaudet, et al., Proc.

Nati Acad. Sci. U.S.A., 97 (3), 10203-10208 (2000)). It has also been shown that efficient retroviral infection of mammalian cells is blocked by the inhibition of PARP-1 activity. Such inhibition of recombinant retroviral vector infections is shown to occur in several different cell types (Gaken, et al., J. Virology, 70 (6), 3992-4000 (1996)). The PARP-1 inhibitors have thus been developed for use in antiviral therapies and cancer treatment (application WO 91/18591). On the other hand, I know that the inhibition of PARP-1 delays the onset of aging characteristics in human fibroblasts (Rattan and Clark, Biochem, Biophys, Res. Co m., 201 (2), 665-672 (1994)). ). This can be related to the role that PARP plays in controlling telomere function (d'Adda di Fagagna, et al., Nature Gen., 23 (1), 76-80 (1999)). It is also thought that PARP-1 inhibitors are relevant for the treatment of irritable bowel disease (Szabo C, Role of Poly (ADP-Ribose) Polymerase Activation in the Pathogenesis of Shock and Inflammation, in PARP as a Therapeutic Target; Ed. J. Zhang, 2002 by CRC Press; 169-204), ulcerative colitis (Zingarelli, B, et al., Immunology, 113 (4), 509-517 (2004)) and Crohn's disease (Jijón, HB, et al., Am. J. Physiol. Gastrointest. Liver Physiol., 279, G641-G651 (2000) Some of the present inventors have previously described (application WO 02/36576) a class of 1 (2H) -phthalazinone compounds which act as inhibitors of PARP. They have the general formula: wherein A and B together represent a fused aromatic ring, optionally substituted and where Rc is represented by -L-RL. A large number of examples are of the formula: wherein R represents one or more optional substituents. In the present invention it has now been discovered that compounds wherein R is of a certain nature and the phenyl group is replaced exhibit surprising levels of inhibition of PARP activity, and / or enhancement of tumor cells to radiotherapy and various chemotherapies. BRIEF DESCRIPTION OF THE INVENTION Accordingly, the first aspect of the present invention provides a compound of the formula (I): and isomers, salts, solvates, chemically protected forms, and prodrugs thereof wherein: A and B together represent a fused aromatic ring, optionally substituted: X may be NR * or CRXRY; If X = NRX then n is 1 or 2 and if X = CRXRY then n is 1; R * is selected from the group consisting of H, optionally substituted C2-20 alkyl, Cs-o aryl, C3-20 heterocyclyl, amido, thioamido, ester, acyl, and sulfonyl groups; R? is selected from H, hydroxy, amino; or Rx and R? they can together form a C3-7 spiro-cycloalkyl or heterocyclyl group; R01 and R02 are independently selected from the group consisting of hydrogen and C? -4 alkyl, or when X is CSTR "', Ra, R02, R * and R ?, together with the carbon atoms to which they are attached may forming an optionally substituted fused aromatic ring: R1 is selected from H and halo, and Het is selected from: (i) where Y1 is selected from CH and N, Y2 is selected from CH and N, Y3 is selected from CH, CF and N, where only one or two of Y1, Y2 and Y3 can be N; and (ü) W // Q- - where Q is O or S. Therefore, if X is CRXRY, then n is 1 and the compound is of the formula (la): If X is NRX, and n is 1, the compound is of the formula (Ib) If X is NRX, and n is 2, the compound is of the formula (le): The possibilities for Het are: A second aspect of the present invention provides a pharmaceutical composition which comprises a compound of the first aspect and a pharmaceutically acceptable carrier or diluent. A third aspect of the present invention provides the use of a compound of the first aspect in a method of treating the human or animal body. A fourth aspect of the present invention provides the use of a compound as defined in the first aspect of the invention in the preparation of a medicament for: (a) preventing the formation of poly (ADP-ribose) chain by inhibiting the activity of cellular PARP (PARP-1 and / or PARP-2); (b) the treatment of: vascular disease; septic shock; Ischemic damage, both cerebral and cardiovascular; reperfusion damage, both cerebral and cardiovascular; neurotoxicity, including acute and chronic treatments for infarction and Parkinson's disease, hemorrhagic shock; inflammatory diseases, such as arthritis, irritable bowel disease, ulcerative colitis and Crohn's disease, multiple sclerosis; side effects of diabetes; as well as the acute treatment of cytoxicity that follows cardiovascular surgery or diseases improved by the inhibition of PARP activity; (c) use as an adjunct in cancer therapy or to enhance tumor cells for treatment with ionizing radiation or chemotherapeutic agents. In particular, the compounds as defined in the first aspect of the invention can be used in anti-cancer combination therapies (or as adjuncts) together with alkylating agents, such as methyl methanesulfonate (MMS), temozolomide and dacarbazine (DTIC for its acronym in English), also with topoisomerase-1 inhibitors such as Topotecan, Irinotecan, Rubitecan, Exatecan, Lurtotecan, Gimetecan, Diflomotecan (homocamptothecin); as well as also 7-substituted silatecanes; the 7-silylcamptothecins, BNP 1350; and non-camptothecin topoisomerase inhibitors such as indolecarbazoles and also inhibitors of topoisomerase I and II dual such as benzophenazines, XR 11576 / MLN 576 and benzopyridoindoles. Such combinations may be given, for example, as intravenous preparations or by oral administration as dependents in the preferred method of administration for the particular agent.

Still other aspects of the invention provide improved disease treatment by the inhibition of PARP, which comprises administering to a subject in need of treatment a therapeutically effective amount of a compound as defined in the first aspect, preferably in the form of a Pharmaceutical composition and cancer treatment, which comprises administering to a subject in need of treatment a therapeutically effective amount of a compound as defined in the first aspect in combination, preferably in the form of a pharmaceutical composition, simultaneously or sequentially with radiotherapy (ionizing radiation) or chemotherapeutic agents. In a further aspect of the present invention, the compounds can be used in the preparation of a medicament for the treatment of cancer which is deficient in reparative activity of double-stranded DNA (DSB) breakdown dependent upon recombination homologous (HR), or in the treatment of a patient with a cancer which is deficient in HRB-dependent DNA DSB repair activity, which comprises administering to the patient a therapeutically effective amount of the compound. The HRB-dependent DNA DSB repair pathway repairs double-strand breaks (DSB) in DNA through homologous mechanisms to reform a continuous DNA helix (KK Khanna and SP Jackson, Nat. Genet 27 (3): 247 -254 (2001)). Components of the HRB-dependent DNA DSB repair pathway include, but are not limited to, ATM (NM 000051), RAD51 (NM_002875), RAD51L1 (NM_002877), RAD51C (NM_002876), RAD51L3 (NM_002878) DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432) RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415) BRCAl (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732) MRE11A (NM_005590) and NBSl (NM_002485). Other proteins involved in the HRB-dependent DNA DSB repair pathway include regulatory factors such as EMSY (Hughes-Davies, et al., Cell., 115, pp. 523-535). The HR components are also described in Wood, et al., Science, 291, 1284-1289 (2001). A cancer which is deficient in repair of DSB of HR-dependent DNA may comprise or consist of one or more cancer cells which have a reduced or abrogated capacity to repair DSB of DNA through the path, relative to normal cells, that is, the activity of the HRB-dependent DNA DSB repair pathway can be reduced or abolished in one or more cancer cells. The activity of one or more components of the HRB-dependent DNA DSB repair pathway can be abolished in the one or more cancer cells of an individual having a cancer which is deficient in HRB-dependent DNA DSB repair. The components of the HRB-dependent DNA DSB repair pathway are well characterized in the art (see for example, Wood, et al., Science, 291, 1284-1289 (2001)) and include the components listed above. In some preferred embodiments, the cancer cells may have a deficient phenotype to BRCA1 and / or BRCA2 ie the BRCA1 activity and / or BRCA2 is reduced or abolished in the cancer cell. Cancer cells with this phenotype can be deficient in BRCA1 and / or BRCA2, ie the expression and / or activity of BRCA1 and BRCA2 can be reduced or abolished in cancer cells, for example by means of a mutation or polymorphism in the acid encoding nucleic acid, or by means of amplification, mutation or polymorphism in a gene encoding a regulatory factor, for example the EMSY gene which encodes a regulatory factor of BRCA2 (Hughes-Davies, et al., Cell, 115, 523-535 ) or by an epigenetic mechanism such as methylation of gene promoter. BRCA1 and BRCA2 are known tumor suppressors whose wild-type alleles are frequently lost in tumors of heterozygous carriers (Jasin M., Oncogene, 21 (58), 8981-93 (2002); Tutt, et al., Trends Mol Med., 8 (12), 571-6, (2002)). The association of BRCA1 and / or BRCA2 mutations with breast cancer is well characterized in the art (Radice, P.J., Exp. Clin Cancer Res., 21 (3 Suppl.), 9-12 (2002)). The amplification of the EMSY gene, which encodes a BRCA2 binding factor, is also known to be associated with mammary and ovarian cancer. Carriers of mutations in BRCA1 and / or BRCA2 are also at high risk of ovarian, prostate and pancreatic cancer. In some preferred embodiments, the individual is heterozygous for one or more variations, such as mutations and polymorphisms, in BRCA1 and / or BRCA2 or a regulator thereof. The detection of variation in BRCA1 and BRCA2 is well known in the art and is described, for example in European Patents EP 699 754, EP 705 903, Neuhausen, S.L. and Ostrander, E.A., Genet. Test. 1, 75-83 (1992); Janatova M., et al., Neoplama, 50 (4), 246-50 (2003). The amplification determination of the BRCA2 EMSY binding factor is described in Hughes-Davies, et al., Cell, 115, 523-535). Mutations and polymorphisms associated with cancer can be detected at the nucleic acid level by detecting the presence of a variant nucleic acid sequence or at the protein level by detecting the presence of a variant polypeptide (i.e., a mutant or allelic variant). ).

Definitions The term "aromatic ring" is used herein in the conventional sense to refer to cyclic aromatic structure, that is, a cyclic structure which has delocalized p-electron orbitals. The aromatic ring fused to the main core, ie that formed by -A-B, can also carry fused aromatic rings (resulting in, for example, naphthyl or anthracenyl groups). The aromatic rings may comprise single carbon atoms, or may comprise carbon atoms and one or more heteroatoms, which include but are not limited to, nitrogen, oxygen and sulfur atoms. The aromatic rings preferably have five or six ring atoms. The aromatic rings can optionally be substituted. If a substituent itself comprises an aryl group, this aryl group is not considered to be a part of the aryl group to which it is attached. For example, the biphenyl group is considered herein to be a phenyl group (an aryl group which comprises a single aromatic ring) substituted with a phenyl group. Similarly, the benzylphenyl group is considered to be a phenyl group (an aryl group which comprises a single aromatic ring) substituted with a benzyl group.

In a group of preferred embodiments, the aromatic group comprises a single aromatic ring, which has five or six ring atoms, the ring atoms are selected from carbon, nitrogen, oxygen and sulfur, and the ring is optionally substituted. Examples of these groups include, but are not limited to, benzene, pyrazine, pyrrole, thiazole, isoxazole and oxazole. 2-Pyrone can also be considered to be an aromatic ring but is less preferred. If the aromatic ring has six atoms, then preferably at least four, or even five or all, the ring atoms are carbon. The other ring atoms are selected from nitrogen, oxygen and sulfur, with nitrogen and oxygen being preferred. Suitable groups include a ring with: non-heteroatoms (benzene); a nitrogen ring atom (pyridine); two nitrogen ring atoms (pyrazine, pyrimidine and pyridazine); an oxygen ring atom (pyrone); and an oxygen and nitrogen ring atom (oxazine). If the aromatic ring has five ring atoms, then preferably at least three of the ring atoms are carbon. The remaining ring atoms are selected from nitrogen, oxygen and sulfur. Suitable rings include a ring with: a nitrogen ring atom (pyrrole); two nitrogen ring atoms (imidazole, pyrazole); an oxygen ring atom (furan); a sulfur ring atom (thiophene); a ring atom of nitrogen and sulfur (isothiazole, thiazole); and a nitrogen and oxygen ring atom (isoxazole or oxazole). The aromatic ring can carry one or more substituent groups in any available ring position. These substituents are selected from halo, nitro, hydroxy, ether, thiol, thioether, amino, C? _7 alkyl, C3-20 heterocyclyl and C5_2o aryl. The aromatic ring may also carry one or more substituent groups which together form a ring. In particular these can be of the formula - (CH2) m- or -0- (CH2) p-0- where m is 2, 3, 4 or 5 and p is 1, 2 or 3. Alkyl: the term "alkyl" as used herein, it pertains to a monovalent portion obtained by removing the hydrogen atom from a carbon atom of a hydrocarbon compound having 1 to 20 carbon atoms (unless otherwise specified), the which can be aliphatic or alicyclic, and which can be saturated or unsaturated (for example, partially unsaturated, totally unsaturated). Thus, the term "alkyl" includes the subclasses alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, etc., discussed below. In the context of alkyl groups, the prefixes (eg, C? _, C? -7, C? -20, C2-, C3_7, etc.) denote the number of carbon atoms, or number of atoms range of carbon. For example, the term "C?-Alkyl", as used herein, pertains to an alkyl group which has 1 to 4 carbon atoms. Examples of alkyl groups include C? ~ 4 alkyl ("lower alkyl"), C alquilo-alkyl and C?-0 alkyl. Note that the first prefix may vary according to other limitations; for example, for unsaturated alkyl groups, the first prefix must be at least 2; for the cyclic alkyl groups, the first prefix must be at least 3; etc. Examples of saturated (unsubstituted) alkyl groups include, but are not limited to, methyl (Ci), ethyl (C2), propyl (C3), butyl (C4), pentyl (C5), hexyl (C6), heptyl (C7) ), octyl (Cs), nonyl (Cg), decyl (Cio) -undecyl (Cu), dodecyl (C? 2), tridecyl (C? 3), tetradecyl (d4), pentadecyl (C15) and eicodecyl (C20) . Examples of saturated (unsubstituted) linear alkyl groups include, but are not limited to, methyl (Ci), ethyl (C2), n-propyl (C3), n-butyl (C4), n-pentyl (amyl) (C5) ), n-hexyl (C6), and n-heptyl (C7). Examples of saturated (unsubstituted) branched alkyl groups include, but are not limited to, iso-propyl (C3), isobutyl (C4), sec-butyl (C), tert-butyl (C), isopentyl (C5) and neopentyl ( C5). Alkenyl: the term "alkenyl", as used herein, belongs to an alkyl group which has one or more carbon-carbon double bonds. Examples of alkenyl groups include C2-4 alkenyl, C2-7 alkenyl, C2-2 alkenyl- Examples of unsaturated (unsubstituted) alkenyl groups include, but are not limited to, ethenyl (vinyl, -CH = CH2), 1-propenyl (-CH = CH-CH3), 2-propenyl (allyl, -CH-CH = CH2), isopropenyl (1-methylvinyl-, C (CH3) = CH2), butenyl (C), pentenyl (C5) , and hexenyl (C6). Alkynyl: The term "alkynyl", as used herein, belongs to an alkyl group which has one or more triple carbon-carbon bonds. Examples of alkynyl groups include C2-4 alkynyl, C2- alkynyl, C2-20 alkynyl. Examples of unsaturated (unsubstituted) alkynyl groups include, but are not limited to, ethynyl (ethynyl, -C = CH) and 2-propynyl (propargyl, -CH2-C = CH). Cycloalkyl: The term "cycloalkyl", as used herein, pertains to an alkyl group which is also a cyclyl group: that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a ring carbocyclic of a carbocyclic compound, the carbocyclic ring may be saturated or unsaturated (eg, partially unsaturated, fully unsaturated), the portion having from 3 to 20 carbon atoms (unless otherwise specified), including from 3 to 20 ring atoms. Thus, the term "cycloalkyl" includes the subclasses of cycloalkenyl and cycloalkynyl. Preferably, each ring has from 3 to 7 ring atoms. Examples of groups of cycloalkyl groups include C3-20 cycloalkyl, C3-? 5 cycloalkyl, C3-? Cycloalkyl, or C3-7 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, those derived from: Saturated monocyclic hydrocarbon compounds: cyclopropane (C3), cyclobutane (C4), cyclopentane (C5), cyclohexane (C6), cycloheptane (C7), methylcyclopropane (C4) ), dimethylcyclopropane (C5), methylcyclobutane (C5), dimethylcyclobutane (Ce), methylcyclopentane (Ce), dimethylcyclopentane (C7), methylcyclohexane (C7), dimethylcyclohexane (C8), menthane (Cio); Unsaturated monocyclic hydrocarbon compounds: Cyclopropene (C3), cyclobutene (C4), cyclopentene (C5), cyclohexene (Ce), methylcyclopropene (C), dimethylcyclopropene (C5), methylcyclobutene (C5), dimethylcyclobutene (Ce), methylcyclopentene (Ce) , dimethylcyclopentene (C7), methylcyclohexene (C7), dimethylcyclohexene (Cs); Saturated polycyclic hydrocarbon compounds: Tujano (Cío), carano (Cío) pinano (Cío) bornano (Cío) < norcarane (C7), norpinano (C7), norbornane (C7), adamantane (C? 0), decalin (decahydronaphthalene) (Cío); Unsaturated polycyclic hydrocarbon compounds: Canfeno (Cio) limonene (Cio) pinene (Cio); Polycyclic hydrocarbon compounds having an aromatic ring: Indene (Cg), indane (for example, 2, 3-dihydro-lH-indene) (Cg), tetralin (1, 2, 3, 4-tetrahydronaphthalene) (Cio), acenaphthene (C? 2), fluorene (C? 3), phenalene (C? 3), acefenanthrene (C? 5), aceanthrene (C? 6), colantrene (C20). Heterocyclyl: The term "heterocyclyl", as used herein, pertains to a monovalent portion obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, the portion having from 3 to 20 ring atoms (unless otherwise specified), of which 1 to 10 are ring heteroatoms. Preferably, each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms. In this context, the prefixes (for example C3_20, C3.7, C5-6, etc.) denote the number of ring atoms, or range of number of ring atoms, whether they are carbon atoms or heteroatoms. For example, the term "C5-6 heterocyclyl", as used herein, pertains to a heterocyclyl group which has 5 or 6 ring atoms. Examples of heterocyclyl groups include heterocyclyl of C3.2o, heterocyclyl of Cs-2o, heterocyclyl of C3-i5, heterocyclyl of C5-15, heterocyclyl of C3-? 2, heterocyclyl of Cs-? 2, heterocyclyl of C3-? or, C5-10 heterocyclyl, C3.7 heterocyclyl, C5-7 heterocyclyl, and C5-6 heterocyclyl. Examples of monocyclic heterocyclyl groups include, but are not limited to, those derived from: i; aziridine (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (for example, 3-pyrroline, 2,5-dihydropyrrole) (C5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C5), piperidine (C6), dihydropyridine (Ce ), tetrahydropyridine (Ce), azepine (C7); I heard: oxirane (C3), oxetane (C4), oxolane (tetrahydrofuran) (C5), oxol (dihydrofuran) (C5), oxano (tetrahydropyran) (Ce), dihydropyran (Ce), pyran (Ce), oxepin (C7); Si: thirano (C3), thietane (C), thiolane (tetrahydrothiophene) (C5), thiano (tetrahydrothiopyran) (Ce), tiepane (C7); 02: dioxolane (C5), dioxane (Ce), and dioxepane (C); 03: trioxane (Ce); N2: imidazolidine (C5), pyrazolidine (diazolidine) (C5), imidazoline (C5), pyrazoline (dihydropyrazole) (C5), piperazine (C6); NiOi: tetrahydrooxazole (C5), dihydrooxazole (C5), tetrahydroisoxazole (C5), dihydroisoxazole (C5), morpholine (Ce), tetrahydrooxazine (Ce), dihydrooxazine (Ce), oxazine (Ce); N1S1: thiazoline (C5), thiazolidine (C5), thiomorpholine (C6); N2O? : oxadiazine (C6); O1S1: oxathiol (C5) and oxathia (thioxane) (Ce); and, N1O1S1: oxathiazine (Ce). Examples of substituted monocyclic (non-aromatic) heterocyclyl groups include those derived from saccharides, in cyclic form, for example, furanoses (C5), such as arabinofuranose, lixofuranose, ribofuranose, and xylofuranose, and pyranose (C5), such as alipyranose, altropyranose, glucopyranose, mannopyranose, gulopyranose, idopyranose, galactopyranose and talopiranose. Spiro-cycloalkyl or C3- heterocyclyl: The term "spiro-cycloalkyl or C-7 heterocyclyl" as used herein refers to a cycloalkyl ring of C3.7 or C3.7 heterocyclyl ring attached to another ring for a single common atom for both rings. C5-10 aryl: the term "C5-2o aryl" as used herein, pertains to a monovalent portion obtained by removing a hydrogen atom from an aromatic ring atom of a C5-2 aromatic compound , the compound which has a ring, or two or more rings (e.g., fused), and having 5 to 20 ring atoms, and wherein at least one of the rings is an aromatic ring. Preferably, each ring has from 5 to 7 ring atoms. The ring atoms can be all carbon atoms, as in "carbaryl groups" case in which the group can conveniently be referred to as the "carboaryl group".

C5-2o "• Examples of aryl groups of C5_2o which do not have ring heteroatoms (ie, C5-20 carboaryl groups) include, but are not limited to, those benzene derivatives (ie phenyl) (C6), naphthalene (Cio) / anthracene (C? 4), phenanthrene (C? 4), and pyrene (C? 6) Alternatively, the ring atoms may include one or more heteroatoms, which include but are not limited to oxygen, nitrogen , and sulfur, as in "heteroaryl groups." In this case, the group can conveniently be referred to as the "C5_2o heteroaryl" group, where "C5-2o" denotes ring atoms, whether they are carbon atoms or heteroatoms Preferably, each ring has from 5 to 7 ring atoms, of which 0 to 4 are ring heteroatoms Examples of Cs-2o heteroaryl groups include, but are not limited to, C5 heteroaryl groups derived from furan ( oxol), thiophene (thiol), pyrrole (azole), imidazole (1,3-diazole), pyrazole (1,2-diazole), triazole, oxazole, isox azole, thiazole, isothiazole, oxadiazole, tetraxol and oxatriazole; and heteroaryl groups of Ce derivatives of isoxazine, pyridine (azine), pyridazine (1,2-diazine), pyrimidine (1,3-diazine, eg, cytosine, thymine, uracil), pyrazine (1,4-diazine) and triazine. The heteroaryl group can be linked by means of a carbon ring atom or heteroatom. Examples of C5-20 heteroaryl groups which comprise fused rings, include, but are not limited to, Cg heteroaryl groups derived from benzofuran, isobenzofuran, benzothiophene, indole, isoindole; Cyan heteroaryl groups derived from quinoline, isoquinoline, benzodiazine, pyridopyridine; heteroaryl groups of C? 4 derived from acridine and xanthene. The above alkyl, heterocyclyl, and aryl groups, either alone or part of another substituent, may themselves optionally be substituted with one or more groups selected from them and the additional substituents listed below. Halo: -F, -Cl, -Br and -I. Hydroxy: -OH. Ether: -OR, wherein R is an ether substituent, for example, an alkyl group of C? -7 (also referred to as an alkoxy group of C? -7), a heterocyclyl group of C3-2o (also referred to as an C3-2o heterocyclyloxy group), or an aryl group of C5-2o (also referred to as a C5-20 aryloxy group) / preferably an alkyl group of C? _. Nitro: -N02. Cyan (nitrile, carbonitrile): -CN. Acyl (keto): -C (= 0) R, wherein R is an acyl substituent, for example, H, an alkyl group of C? - (also referred to as a C? _ Alkanoyl or C? -7 alkanoyl) ), a C3-2o heterocyclyl group (also referred to as a C3_20 heterocyclycyl), or an aryl group of Cs-2o (also referred to as an arylacil of Cs-2o), preferably an alkyl group of C? -7. Examples of acyl groups include, but are not limited to, -C (= 0) CH 3 (acetyl), -C (= 0) CH 2 CH 3 (propionyl), -C (= 0) C (CH 3) 3 (butyryl), and -C (= 0) Ph (benzoyl, phenone). Carboxy (carboxylic acid): -COOH. Ester (carboxylate, carboxylic acid ester, oxycarbonyl): -C (= 0) 0R, wherein R is an ester substituent, for example, an alkyl group of C7-7, a heterocyclyl group of C3-20, or a group C5-20 aryl preferably an alkyl group of C? -7. Examples of the ester groups include, but are not limited to, -C (= 0) OCH3, C (= 0) OCH2CH3, -C (= 0) OC (CH3) 3, and -C (= 0) 0Ph. Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide); -C (= 0) NR1R2, wherein R1 and R2 are independently amino substituents, as defined for amino groups. Examples of amido groups include, but are not limited to, -C (= 0) NH2, -C (= 0) NHCH3, C (= 0) N (CH3) 2, C (= 0) NHCH2CH3, and -C ( = 0) N (CH2CH3) 2, as well as also amido groups in which R1 and R2, together with the nitrogen atom to which they are attached, form a heterocyclic structure as in, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinylcarbonyl . Amino: -NR ^ -R2, wherein R1 and R2 are independently amino substituents, for example, hydrogen, an alkyl group of C? _7 (also referred to as C? -7 alkylamino or di? alkylamino of C? -7), a heterocyclyl group of C3-2o, an aryl group of C5-2o, preferaH or an alkyl group of C? _7, or in the case of a "cyclic" amino group, R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring which has from 4 to 8 ring atoms . Examples of amino groups include, but are not limited to, -NH2, -NHCH3, -NHCH (CH3) 2, -N (CH3) 2, -N (CH2CH3) 2, and -NHPh. Examples of cyclic amino groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, perhydrodiazepinyl, morpholino and thiomorpholino. In particular, the cyclic amino groups can be substituted on their ring by any of the substituents defined herein, for example, carboxy, carboxylated and amido. Acylamido (acylamino): -NR1C (= 0) R2, wherein R1 is an amide substituent, eg, hydrogen, an alkyl group of C? -7, a heterocyclyl group of C.2o, or an aryl group of C5- PreferaH or an alkyl group of C? -7, more preferaH, and R2 is an acyl substituent, for example, an alkyl group of C? -7, a heterocyclyl group of C-2o- or an aryl group of C5 -20, preferaan alkyl group of C? -. Examples of acylamide groups include, but are not limited to, -NHC (= 0) CH3, -NHC (= 0) CH2CH3 and -NHC (= 0) Ph. R1 and R2 can together form a cyclic structure, as in, for example, succinimidyl, maleimidyl and phthalimidyl: Succinimidyl maleimidyl phthalimidyl Ureido: -N (RX) CONR2R3 wherein R2 and R3 are independently amino substituents, as defined by amino groups, and R1 is a ureido substituent, eg, hydrogen, an alkyl group of C? -7, a heterocyclyl group of C3-2o, or an aryl group of Cs-2o, preferably hydrogen or an alkyl group of C? -. Examples of ureido groups include, but are not limited to, -NHCONH2, -NHCONHMe, -NHCONHEt, -NHCONMe2, -NHCONEt2, -NMeCONH2, NMeCONHMe, -NMeCONHEt, -NMeCONMe2, -NMeCONEt2 and -NHCONHPh.

Acyloxy (reverse ester): -OC (= 0) R, wherein R is an acyloxy substituent, for example, an alkyl group of C? -, a heterocyclyl group of C3-2o or an aryl group of C5-2C preferably a alkyl group of C? -7. Examples of acyloxy groups include, but are not limited to, -0C (= 0) CH3 (acetoxy), -OC (= 0) CH2CH3, -OC (= 0) C (CH3) 3, -OC (= 0) Ph , -OC (= 0) C6H4F, and -0C (= 0) CH2Ph. Tiol: -SH. Thioether (sulphide): -SR, wherein R is a thioether substituent, for example, an alkyl group of C? _ (Also referred to as an alkylthio group of C? -7), a heterocyclyl group of C3-2o, or a aryl group of C5-2o, preferably an alkyl group of C? _7. Examples of alkylthio groups include, but are not limited to, -SCH 3 and -SCH 2 CH 3. Sulfoxide (sulfinyl): -S (= 0) R, wherein R is a sulfoxide substituent, for example, an alkyl group of C? _? , a heterocyclyl group of C3-2o, or an aryl group of C5-20 / preferably an alkyl group of C? -. Examples of sulfoxide groups include, but are not limited to, -S (= 0) CH and -S (= 0) CH2CH3. Sulfonyl (sulfone): -S (= 0) 2R, wherein R is a sulfone substituent, for example, an alkyl group of C7-7, a heterocyclyl group of C3-2o, or an aryl group of C5-20 / preferably an alkyl group of C? -. Examples of sulfone groups include, but are not limited to, -S (= 0) 2CH3 (methanesulfonyl, mesyl), -S (= 0) 2CF3, -S (= 0) 2CH2CH3, and 4-methylphenylsulfonyl (tosyl). Thioamido (thiocarbamyl): -C (= S) NR1R2, where R1 and R 2 are independently amino substituents, as defined by the amino groups. Examples of amido groups include, but are not limited to, -C (= S) NH2, -C (= S) NHCH3, C (= S) N (CH3) 2 and -C (= S) NHCH2CH3. Sulfonamino: -NR1S (= 0) 2R / wherein R1 is an amino substituent, as defined for the amino groups, and R is a sulfonamino substituent, for example, an alkyl group of C? _7 / a heterocyclyl group of C3_2o, or an aryl group of C5-20 preferably an alkyl group of C? _7.

Examples of sulfonamino groups include, but are not limited to, -NHS (= 0) 2CH3, -NHS (= 0) 2Ph and -N (CH3) S (= 0) 2C6H5. As mentioned above, the groups forming the substituted groups listed above, for example C alquilo -7 alkyl, C3-2 heter heter heterocyclyl and C5-20 ar ar aryl, can themselves be substituted. In this way, the above definitions cover the substituent groups which are substituted. DETAILED DESCRIPTION OF THE INVENTION Additional Preferences The following preferences may apply to each aspect of the present invention, where applicable. In the present invention, the fused aromatic rings represented by -A-B- preferably consist of carbon ring atoms only, and thus may be benzene, naphthalene, and is more preferably benzene. As described above, these rings can be substituted, but in some embodiments they are preferably not substituted. If the fused aromatic ring represented by -A-B, carries a substituent group, it is preferably attached to the atom which by itself is attached to the central ring β at the carbon atom in the central ring. In this way, if the fused aromatic ring is a benzene ring, the preferred place of substitution is shown in the following formula by *: which is usually named position five of the phthalazinone moiety. The substituent is preferably an alkoxy, amino, halo (eg, fluorine) or hydroxy group, and more preferably a C 1 - alkoxy group (eg, -OMe). If the substituent is a halo, it can be in position 8 of the phthalazinone moiety. Preferably, Het is selected from pyridylene, fluoro-pyridylene, furanylene and thiophenylene. More preferably Het is selected from: More preferably Het is selected from: It is preferred that R cl and R c 2 are independently selected from hydrogen and C 1 - alkyl, and more preferably H and methyl. It is more preferred that at least one of Rcl and Rc2 is hydrogen, with the most preferred option being that both are hydrogen. When n is 2, X is NRX. In these embodiments, Rx is preferably selected from the group consisting of: H; optionally substituted C de _2o alkyl (eg, optionally substituted C 5-20 arylmethyl); optionally substituted C5-20 aryl; optionally substituted ester groups, wherein the ester substituent is preferably a C? -2 alquilo alkyl; optionally substituted acyl groups; optionally substituted amido groups; optionally substituted thioamido groups; and optionally substituted sulfonyl groups. Rx is more preferably selected from the group consisting of: H; optionally substituted C 1-20 alkyl (more preferably optionally substituted C 7 -7 alkyl, for example methyl); and optionally substituted ester groups, wherein the ester substituent is preferably C 1-20 alkyl (more preferably optionally substituted C 1 -7 alkyl, eg, t-butyl). When n is 1, X can be NRX or CRxCR ?. In embodiments wherein X is NRX, Rx is preferably selected from the group consisting of: H: optionally substituted C? -2 alquilooalkyl (eg, optionally substituted Cs-2o arylmethyl); optionally substituted C5-20 aryl; optionally substituted acyl; optionally substituted sulfonyl; optionally substituted amido; and optionally substituted thioamido groups. In these embodiments, it is preferred that Het is pyridylene. When Het is pyridylene, Rx is more preferably selected from the group consisting of: optionally substituted acyl; optionally substituted sulfonyl; and optionally substituted amido. When Het is furanylene or thiophenylene, R x is more preferably selected from the group consisting of: optionally substituted C 1-20 alkyl (for example, optionally substituted C 5-20 arylmethyl); optionally substituted C5-20 aryl; optionally substituted acyl; optionally substituted sulfonyl; and optionally substituted amido. In modalities where X is CRXRY, R? is preferably H. Rx is preferably selected from the group consisting of: H; optionally substituted C1-20 alkyl (for example, optionally substituted C5-20 arylmethyl); optionally substituted C5-20 aryl; optionally substituted C-2o heterocyclyl; optionally substituted acyl, wherein the acyl substituent is preferably selected from the C5-20 aryl group and C3-2o heterocyclyl (eg, piperazinyl); optionally substituted amino, wherein the amino groups are preferably selected from H and C? -20 alkyl or together with the nitrogen atom, form a heterocyclic group of C5_2o; optionally substituted amido, wherein the amino groups are preferably selected from H and Ci-20 alkyl or together with the nitrogen atom, form a heterocyclic group of C5-20; and optionally substituted ester groups, wherein the ester substituent is preferably selected from C? -20 alkyl groups. In these embodiments, when Het is furanylene or thiophenylene, Rx is more preferably selected from optionally substituted amino, wherein the amino groups are preferably selected from H and C 1-20 alkyl or together with the nitrogen atom, form a heterocyclic group of C5-20, for example morpholino.

Particularly preferred compounds include: 2, 3, 5, 6, 9, 10, 12, 13, 56, 57, 58, 62, 65, 66, 67, 74 and 75. Where appropriate, the above preferences can be taken in combination with each other. Other forms included Included in the above are the well-known ionic, salt, solvate and protected forms of these substituents. For example, a reference to carboxylic acid (-COOH) also includes the anionic form (carboxylate) (-COO "), a salt or solvate thereof, as well as also conventional protected forms Similarly, a reference to an amino group includes the protonated form (-N + HR1R2), a salt or solvate of the amino group , for example, a hydrochloride salt, as well as conventionally protected forms of an amino group Similarly, a reference to a hydroxyl group also includes the anionic form (-0"), a salt or solvate thereof, as well as forms conventional protections of a hydroxyl group. Isomers, Salts, Solvates, Protected Forms, and Prodrugs Certain compounds may exist in a geometric, optical, enantiomeric, diastereoisomeric, epimeric, stereoisomeric, tautomeric, conformational, or more particular anomeric form, including but not limited to, cis- and trans forms; E- and Z- forms; c-, t- forms and endo and exo reforms; R-, S- and meso forms; Forms D- and L-; forms D and 1; forms (+) and (-); keto-, enol and enolate forms; Synonyms and anti-forms; synclinal and anticlinal forms; forms a and ß; axial and equatorial forms; boat, chair, turn, card and half-chair shapes; and combinations thereof, hereinafter referred to as "isomers" (or "isomeric forms"). If the compound is in the crystalline form, it can exist in a number of different polymorphic forms. Note that, except as discussed below for tautomeric forms, specifically excluded from the term "isomers", as used herein, are structural (or constitutional) isomers (ie, isomers which differ in the connections between more atoms). that simply by the position of atoms in space). For example, a reference to a methoxy group, -OCH3, is not to be constructed, as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chlorophenyl is not constructed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include isomeric forms structurally within this class (eg, C?-7 alkyl includes n-propyl and iso-propyl, butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl). The above exclusion does not belong to tautomeric forms, for example, forms, keto-, enol-, and enolate, as in, for example, the following tautomeric pairs; keto / enol, imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enetiol, N-nitroso / hiroxiazo, and nitro / aci-nitro. Particularly relevant to the present invention is the tautomeric pair illustrated below: Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in the isotopic form, including 1H, 2H (D), and 3H (T); C can be in any isotopic form, including 12C, 13C and 1C; Or it can be in any isotopic form, including 160 and 180; and similar. Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including (in whole or in part) racemic mixtures and others thereof. The methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallization and chromatographic medium) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or methods known, in a known manner. Unless otherwise specified, a reference to a particular compound also includes ionic forms, salts, solvates and protected therefrom, for example, as discussed below, as well as their different polymorphic forms. It may be convenient or desirable to prepare, purify and / or handle a corresponding salt of the active compound, for example, a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge, et al., "Pharmaceutically Acceptable Salts," J. Pharm. Sci., 66, 1-19 (1977). For example, if the compound is anionic, or has a functional group which can be anionic (for example, -COOH can be -COO "), then a salt with a suitable cation can be formed. Examples of suitable inorganic cations include, but they are not limited to alkali metal ions such as Na + and K + cations, alkaline tories such as Ca2 + and Mg2 +, and other cations such as Al3 + Examples of suitable organic cations include, but are not limited to, ammonium ion (ie, NH +) and substituted ammonium ions (eg NH3R +, NHR2 +, NHR3 +, NR +) Examples of some of the suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine , ethanolamine, diethanolamine, piperazine, benzylamine, enilbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.An example of a common quaternary ammonium ion is N (CH3) 4+. compound is cationic, or has a functional group which can be cationic (for example, -NH2 can be -NH3 +), then a salt can be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, iodohydric, sulfuric, sulfuric, nitric, nitroso, phosphoric, and phosphorous. Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: acetic, propionic, succinic, glycolic, stearic, palmitic, lactic, malic, pamoic, tartaric, citric, gluconic, ascorbic, maleic, hydroximic, phenylacetic, glutamic, aspartic, benzoic, cinnamic, pyruvic, salicyclic, sulphanilic, 2-acetioxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, ethanedisulfonic, oxalic, isethionic, valeric and gluconic. Examples of suitable polymeric anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethylcellulose. It may be convenient or desirable to prepare, purify and / or handle a corresponding solvate of the active compound. The term "solvate" is used herein in the conventional sense to refer to a solute complex (e.g., active compound, salt of active compound) and solvent. If the solvent is water, the solvate can conveniently be referred to as a hydrate, for example, a monohydrate, a dihydrate, a tri-hydrate, etc. It may be convenient or desirable to prepare, purify, and / or handle the active compound in a chemically protected form. The term "chemically protected form", as used herein, pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions, ie, they are in the form of a protected group or protector (also known as a masked or masking group or a blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group can be removed, usually in a subsequent step, without substantially affecting the rest of the molecule. See, for example, "Protective Groups in Organic Synthesis" (T. Green and P. Wuts: 3rd Edition: John Wiley and Sons, 1999). For example, a hydroxy group can be protected as an ether (-0R) or an ester (-OC (= 0) R), for example, as: a t-butyl ether, a benzyl, a benzhydryl (diphenylmethyl), or trifly (triphenylmethyl) ether, a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester of (-0C (= 0) CH3, -OAc). For example, an aldehyde or ketone group can be protected as an acetal or ketal respectively, in which the carbonyl group (> C = 0) is converted to a diether (> C (OR) 2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is easily regenerated by hydrolysis using a large excess of water in the presence of acid. For example, an amine group can be protected, for example, as an amide or a urethane, for example, as: a methylamide (-NHCO-CH 3); a benzyloxyamide (-NHCO-OCH2C8H5, -NH-Cbz); as a t-butoxy amide (-NHCO-OC (CH 3) 3, -NH-Boc); a 2-biphenyl-2-propoxyamide (-NHCO-OC (CH3) 2C6HC6H5, -NH-Bpoc), such as a 9-fluorenylmethoxy amide (-NH-Fmoc), such as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), such as a 2,2,2-trichloroethyloxy amide (-NH-Troc), such as an allyloxy amide (-NH-Alloc), such as a 2- (phenylsulfonyl) ethyloxy amide (-NH-Psec); or in appropriate cases, such as an N-oxide (> N0.). For example, a carboxylic acid group can be protected as an ester for example, such as: an alkyl ester of C? -7 (for example, a methyl ester, a t-butyl ester); a haloalkyl ester of C? _7 (for example, a trihaloalkyl ester of C? -7); an alkylsilyl ester of C? -7-C? -7 alkyl (eg, a benzyl ester, a nitrobenzyl ester); or as an amide, for example, as a methylamide. For example, a thiol group can be protected as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC (= 0) CH3). It may be convenient or desirable to prepare, purify and / or handle the active compound in the form of a prodrug. The term "prodrug" as used herein, pertains to a compound which, when metabolized (e.g. in vivo), produces the desired active compound. Typically, the prodrug is inactive, or less active than the active compound, but may provide advantageous handling, administration, or metabolic properties. For example, some prodrugs are esters of the active compound (eg, a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C (= 0) OR) is cleaved to produce the active drug. Such esters can be formed by esterification, for example, of any of the carboxylic acid groups (-C = 0) OH) in the parent compound, with, where appropriate, prior protection of any of the other reactive groups present in the parent compound, followed by deprotection if required. Examples of such metabolically labile esters include, but are not limited to, those wherein R is C? -20 alkyl (for example -Me, -Et); aminoalkyl of C? -7 (for example, aminoethyl; 2- (N, N-diethylamino) ethyl; 2- (4-morpholino) ethyl; and acyloxy-C? -7 alkyl (for example acyloxymethyl; acyloxyethyl; , pivaloyloxymethyl, acetoxymethyl, 1-acetoxyethyl, 1- (1-methoxy-1-methyl) ethylcarbonyloxyethyl, 1- (benzoyloxy) ethyl isopropoxycarbonyloxymethyl, 1-isopropoxycarbonyloxyethyl cyclohexylcarbonyloxymethyl, 1-cyclohexylcarbonyloxyethyl cyclohexyloxy- carbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl, (4-tetrahydropyranyloxy) carbonyloxymethyl, 1- (4-tetrahydropyranyloxy) carbonyloxyethyl, (4-tetrahydropyranyl) carbonyloxymethyl, and 1- (4-tetrahydropyranyl) carbonyloxyethyl.) Additional suitable prodrug forms include salts of phosphonate and glycolate., hydroxy groups (-OH), can be made in phosphonate prodrugs by reaction with chlorodibenzylphosphite, followed by hydrogenation, to form a phosphonate group -OP (= 0) (OH) 2. Such a group can be cleaved by phosphatases enzymes during metabolism to produce the active drug with the hydroxy group. Also, some prodrugs are activated enzymatically to produce the active compound, or a compound which, upon further chemical reaction, produces the active compound. For example, the prodrug can be a sugar derivative or another glycoside conjugate, or it can be an amino acid ester derivative. Acronyms For convenience, many chemical portions are represented using well-known abbreviations, including but not limited to, methyl (Me), ethyl (Et), n-propyl (nPr), iso-propyl (Ipr), n-butyl (nBu) , tert-butyl (tBu), n-hexyl (nHex), cyclohexyl (cHex), phenyl (Ph), biphenyl (biPh), benzyl (Bn), naphthyl (naph), methoxy (MeO), ethoxy (EtO), benzoyl (Bz), and acetyl (Ac). For convenience, many chemical compounds are represented using well-known abbreviations, including but not limited to, methanol (MeOH), ethanol (EtOH), isopropanol (i-PrOH), methyl ethyl ketone (MEK), ether or diethyl ether (Et20), acid acetic acid (AcOH), dichloromethane (methylene chloride, DCM), trifluoroacetic acid (TFA), dimethylformamide (DMF), tetrahydrofuran (THF) and dimethylsulfoxide (DMSO). Synthesis In the synthesis routes given below, the fused ring A-B is shown as a benzene ring fused for convenience. Compounds in which ring A-B is different from benzene can be synthesized using analogous methodologies to those described later by the use of appropriate alternative starting materials. The compounds of the present invention can be synthesized by reaction of a compound of Formula 1: Formula 1 in which Het is as previously defined, with a compound of Formula 2: Formula 2 in which, n, Rcl, Rc2 and X are as previously defined, in the presence of a coupling reagent system, for example 2- (lH-benzotriazol-1-yl) tetrafluoroborate -1,1,3 , 3-tetramethyluronium, 2- (lH-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate or hydrochloride (dimethylaminopropyl) ethylcarbodiimide / hydroxybenzotriazole, in the presence of a base, for example diisopropylethylamine, in a solvent, for example dimethylacetamide or dichloromethane, at a temperature in the range of 0 ° C to the boiling point of the solvent used. Alternatively, compounds of the present invention can be synthesized by conversion of a compound of Formula 1 into an activated species, for example an acid chloride or an activated ester such as N-hydroxysuccinimide ester, using well-known methodologies, and reaction of the species activated with a compound of Formula 2. Compounds of Formula 1 can be synthesized by reaction of a compound of Formula 3: Formula 3 in which R1 is as previously defined, or a compound of Formula 4: Formula 4 wherein R1 is as previously defined, or a mixture of a compound of Formula 3 and a compound of Formula 4, with a hydrazine source, for example hydrazine hydrate or hydrazine monohydrate, optionally in the presence of a base, for example triethylamine, optionally in the presence of a solvent, for example industrial methylated spirit, at a temperature in the range of 0 ° C to the boiling point of the solvent used. The compounds of Formula 3 or Formula 4, or mixtures thereof, can be synthesized by reaction of a compound of Formula 5: Formula 5 in which R1 is as previously defined, with a reagent capable of hydrolysing a nitrile portion, for example sodium hydroxide, in the presence of a solvent, for example water, at a temperature in the range of 0 ° C to boiling point of the solvent used. The compounds of Formula 5 can be synthesized by reaction of a compound of Formula 6 Formula 6 in which R1 is as previously defined, with a compound of Formula 7: Formula 7 in which Ra is an alkyl group of C? -4, in the presence of a base, for example triethylamine or lithium hexamethyldisilazide, in a solvent, for example tetrahydrofuran, at a temperature in the range of -80 ° C to the boiling point of the solvent used. The compounds of Formula 7 can be synthesized by analogous methods for those described in the application WO 02/26576. The compounds of Formula 4 can also be synthesized directly from the compounds of Formula 7, by reacting them with a compound of Formula 8: in the presence of a base, for example triethylamine or lithium hexamethyldisilazide, in a solvent , for example tetrahydrofuran, at a temperature in the range of -80 ° C to the boiling point of the solvent used. The compounds of Formula 6, where Het is: they can be synthesized from the compounds of Formula 9: Formula 9 by oxidation of the hydroxy group with, for example, DMSO, dicyclohexylcarbodiimide (DCC) and anhydrous phosphoric acid. The compounds of Formula 9 can be synthesized from the compounds of Formula 10: Formula 10 by removal of the acetyl group using an acid, such as dilute sulfuric acid, in an organic solvent, for example, THF.

The compounds of Formula 10 can be synthesized from the respective compounds of the formulas Formula Ia Formula 11b By addition to a preheated solution of acetic anhydride. The compounds of Formulas lia and 11b can be synthesized from the compounds of Formulas 12a and 12b respectively: Formula 12a Formula 12b by oxidation, for example by m-chloroperoxybenzoic acid (m-CPBA) in an organic solvent, such as DCM. The compound of Formula 12a can be synthesized from a compound of Formula 13: Formula 13 by first reacting with iodomethane, followed by addition in drops of potassium cyanide, to an ethanol-water solution of the first stage product. The compound of Formula 12b can be synthesized from a compound of Formula 13 by first reacting with iodoethane, followed by dropwise addition of aqueous potassium cyanide to an ethanol-water solution of the first stage product. The compounds of Formula 8: Formula 8 where Het is selected from: can be synthesized from compounds of the Formula Formula 14 by oxidation of the alkene, for example, using ozone in a solution of the compound of Formula 14 in methanol and DCM (1: 1) at -78 ° C. The compounds of Formula 14 where Het is: can be synthesized from compounds of Formula 15: Formula 15 by Suzuki copulation with a compound of, for example, Formula 16: Formula 16 under the usual conditions Compounds of Formula 15 can be synthesized from compounds of Formula 17: Formula 17 by oxidation, for example, using potassium permanganate in aqueous solution. Compounds of Formula 14.

Formula 14 where Het is can be synthesized from compounds of the Formula 18: Formula 18 by hydrolysis of the cyano group, by, for example, sodium hydroxide in methanol. The compound of Formula 18 where Het: it can be synthesized from the compound of Formula 19: Formula 19 by Suzuki coupling with a compound of, for example, Formula 16.

Formula 16 under the usual conditions.

The compound of Formula 19 can be synthesized from the compound of Formula 20: Formula 20 by reaction with sodium cyanide in an organic solvent, for example, DMF. The compound of Formula 18 where Het is: it can be synthesized from a compound of Formula 21: Formula 21 by reaction with sodium cyanide in an organic solvent, for example, DMF. The compound of Formula 21 can be synthesized from a compound of Formula 20 Formula 20 by Suzuki coupling with a compound of, for example, Formula 16: Formula 16 under the usual conditions, The compounds of Formula 8 Formula 8 where Het is s1" they can be synthesized from a compound of Formula 22: Formula 22 by deprotection of the aldehyde group using, for example, a mixture of acetone and water with a catalytic amount of pyridinium paratoluensulfonate. The compound of Formula 22 can be synthesized from a compound of Formula 23: Formula 23 by reaction with a strong base, for example lithium diisopropylamide (LDA), followed by the addition of C02. This reaction can, for example, be carried out at -78 ° C in THF, where C02 is added as dry ice. The compound of Formula 23 can be synthesized from the compound of Formula 24: or H I Formula 24 for protection of the aldehyde group, for example, by reaction with ethylene glycol (for example, 1.5 equivalents) in the presence of a catalytic amount of paratoluenesulfonic acid in toluene, under reflux in an apparatus Dean-stark The compound of Formula 24 can be synthesized from the compound of Formula 25: Formula 25 by reaction with a strong base, for example, butylthio, followed by addition of DMF. This reaction can, for example, be carried out at -78 ° C. The compounds of Formula 8: Formula 8 HX where Het is selected from: < T '"\\ // They are commercially available or easily synthesized. The compounds of Formula 1 can also be synthesized by methods analogous to those described above in which the nitrile portion in all Formulas is replaced by other portions capable of generating a carboxylic acid, for example ester or carboxamide moieties. The compounds of the present invention in which X is NH can be represented by Formula 26: Formula 26 in which n, Rcl, Rc2 and R1 are as previously defined. These compounds can be used to generate libraries of compounds of the invention as described below. The compounds of the present invention in which X is NRX, in which Rx is an acyl moiety, and which can therefore be represented by Formula 27: Formula 27 in which n, Rcl, Rc2 and R1 are as previously defined and Rc3 is selected from the group which consists of optionally substituted C? _2o alkyl, C5-2o aryl and C3-2o heterocyclyl / can be synthesized by the reaction of a compound of Formula 26 with a compound of Formula Rc3COX, in which Rc3 is a previously defined group and X is a suitable leaving group, for example a halogen such as chlorine, optionally in the presence of a solvent , for example dichloromethane, at a temperature in the range of 0 ° C to the boiling point of the solvent used. The compounds of the Formula Rc3COX are commercially available or can be synthesized by methods reported in the chemical literature.

The compounds of Formula 27 can also be synthesized by reaction of a compound of Formula 26 with a compound of Formula Rc 3 CO 2 H, in which R c 3 is as previously defined, in the presence of a coupling reagent system, for example 2- (lH-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate, 2- (lH-benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate or (hydrochloride) of dimethylaminopropyl) ethylcarodiimide / hydroxybenzotriazole, in the presence of a base, for example diisopropylethylamine, in a solvent, for example dimethylacetamide or dichloromethane, at a temperature in the range of 0 ° C to the boiling point of the solvent used. The compounds of the Formula Rc3C02H are commercially available or can be synthesized by methods reported in the chemical literature. The compounds of the present invention in which X is NRX, in which RX is an amido or thioamido portion, and which can therefore be represented by Formula 28: Formula 28 in which n, Rcl, Rc2 and R1 are as previously defined, Y is 0 or S and RN3 is selected from the group consisting of optionally substituted C1-20 alkyl, C5-2o aryl and C3- heterocyclyl 2, can be synthesized by reaction of a compound of Formula 26 with a compound of Formula RN3NCY, in which Y and RN3 are as previously defined, in the presence of a solvent, for example dichloromethane, at a temperature in the range from 0 ° C to the boiling point of the solvent used. The compounds of the formula RN3NCY are commercially available or can be synthesized by methods reported in the chemical literature. The compounds of the present invention in which X is NRX, in which Rx is a sulfonyl moiety, and the. which can therefore be represented by Formula 29: Formula 29 in which n, Rcl, Rc2 and R1 are as previously defined and Rsl is selected from the group consisting of optionally substituted C ?_2o alkyl, Ce-2o aryl and C3-20 heterocyclyl, can be synthesized by reaction of a compound of Formula 26 with a compound of Formula RS1S02C1, in which RsI is as previously defined, optionally in the presence of a base, for example pyridine, triethylamine or diisopropylethylamine, in the presence of a solvent, example dichloromethane, at a temperature in the range of 0 ° C to the boiling point of the solvent used. The compounds of the Formula RS1S02C1 are commercially available or can be synthesized by methods reported in the chemical literature. The compounds of the present invention in which X is NRX, in which Rx is selected from the group which consists of optionally substituted C1-20 alkyl or C3-20 heterocyclyl, and which may therefore be represented by the Formula 30: Formula 30 in which n, Rcl, Rc2 and R1 are as previously defined and Rc4 and Rc5 are each individually selected from the group which consists of H, optionally substituted Ci-20 alkyl, Cs-2o aryl, heterocyclyl C-20 or can together form an optionally substituted C3-7 cycloalkyl or heterocyclyl group, can be synthesized by reaction of a compound of Formula 26 with a compound of Formula Rc4CORc5, in which Rc4 and Rc5 are as previously defined , in the presence of a reducing agent, for example sodium cyanoborohydride or sodium triacetoxyborohydride, in the presence of a solvent, for example methanol, optionally in the presence of an acid catalyst, for example acetic acid, at a temperature in the range from 0 ° C to the boiling point of the solvent used. The compounds of the formula Rc4CORc5 are commercially available or can be synthesized by methods reported in the chemical literature. Use The present invention provides active compounds, specifically, active to inhibit the activity of PARP. The term "active" as used herein, pertains to compounds which are capable of inhibiting PARP activity, and specifically includes both compounds with intrinsic activity (drugs) as well as prodrugs of such compounds, prodrugs which by they exhibit little or no intrinsic activity. An assay which can be conveniently used in order to evaluate the inhibition of PARP offered by a particular compound is described in the following examples. The present invention further provides a method for inhibiting the activity of PARP in a cell, which comprises contacting the cell with an effective amount of an active compound, preferably in the form of a pharmaceutically acceptable composition. Such a method can be practiced in vitro or in vivo. For example, a sample of cells can be grown in vitro and an active compound can be contacted with the cells, and the effect of the compound on those cells is observed. As examples of "effect", the amount of DNA repair performed in a certain time can be determined. Where the active compound is found to exert an influence on the cells, this can be used as a prognostic marker or diagnostic of the efficacy of the compound in methods of treating a patient which carries the cells of the same cell type. The term "treatment", as used herein in the context of treating a condition, generally pertains to treatment and therapy, either of a human or an animal (e.g. in veterinary applications), in which some of the desired therapeutic effect, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a stop in the rate of progress, improvement of the condition and cure of the condition. Treatment as a prophylactic measurement (ie, prophylaxis) is also included. The term "adjunct" as used herein relates to the use of active compounds together with known therapeutic means. Such means include cytotoxic drug regimens and / or ionizing radiation as used in the treatment of different types of cancer. In particular, the active compounds are known to enhance the actions of a number of cancer chemotherapy treatments, which include the class of poisome topoisomerase and most of the known alkylating agents used in treating cancer. The active compounds can also be used as cell culture additives to inhibit PARP, for example, in order to sensitize the cells to known chemotherapeutic agents or ionize ionization radiation treatments in vitro. The active compounds can also be used as part of an in vitro assay, for example, in order to determine whether a candidate candidate is similar to benefit from treatment with the compound in question. Administration The active compound or pharmaceutical composition which comprises the active compound can be administered to a subject by any convenient route of administration, either systematically / peripherally or at the site of the desired action, including but not limited to, oral administration (by example by ingestion); topical (including for example transdermal, intranasal, ocular, buccal and sublingual); pulmonary (for example by inhalation or insufflation therapy using, for example, an aerosol, for example through the mouth or nose); rectal; vaginal; parental, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrastérnica; by implanting a reservoir, for example, subcutaneously or intramuscularly. The subject can be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent (for example a guinea pig, a hamster, a rat, a mouse), murine (for example a mouse), canine (for example a dog) , feline (for example a cat), equine (for example a horse), a primate, ape (for example a monkey or monkey), a monkey (for example marmoset, baboon), a monkey (for example a gorilla, a chimpanzee , orangutan, gibbon) or a human. Formulations While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (eg, formulation) which comprises at least one active compound, as defined above, together with one or more carriers, adjuvants, excipients pharmaceutically acceptable lubricants, diluents, fillers, buffers, stabilizers, preservatives, lubricants or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents. Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods for making a pharmaceutical composition which comprise mixing at least one active compound, as defined above, together with one or more carriers, excipients, buffers. , adjuvants, stabilizers, or other pharmaceutically acceptable materials as described herein. The term "pharmaceutically acceptable" as used herein pertains to compounds, materials, compositions and / or dosage forms which are, within the scope of the medical judgment served, suitable for use in contact with the tissues of a subject ( for example human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation. Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts. See, for example, "Handbook of Pharmaceutical Additives" 2nd Edition (Eds M. Ash and I. Ash), 2001 (Synapse Information Resources, Inc., Endicott, New York, USA), "Remington's Pharmaceutical Sciences", 20th edition, publ. Lippincott, Williams "Wilkins, 2000; and" Handbook of Pharmaceuticals Excipients ", 2nd edition, 1994. The formulations may conveniently be presented in dosage unit form and may be prepared by any methods well known in the pharmacy art. they include the step of bringing into association the active compound with the carrier which constitutes one or more accessory ingredients In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then if it is necessary to shape the product Formulations can be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, pills, granules, powders, capsules, sachets, pills, ampoules, suppositories, pessaries, ointments , gels, pastes, creams, sprays, mists, foams, lotions, oils, bowls, electuarios or ae The formulations suitable for oral administration (eg, by ingestion) can be presented as discrete units such as capsules, sachets or tablets, each containing a predetermined amount of the active compound.; as well as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquids; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; like a bolus; as an electuary; or as a pasta. A tablet can be made by a conventional means; for example compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound in a fluid-free form such as powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethylcellulose); fillers or diluents (for example lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (for example magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surfactants or dispersants or humectants (for example, lauryl sulfate and sodium); and preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid). The molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Tablets can optionally be coated or sorted and can be formulated so as to provide slow or controlled release of the active compound therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide the desired release profile. The tablets may optionally be provided with an enteric coating, to provide release in parts of the intestine rather than in the stomach. Formulations suitable for topical administration (eg, transdermal, intranasal, ocular, buccal, and sublingual) can be formulated as an ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol, or oil. Alternatively, a formulation may comprise a patch or a band such as a bandage or adhesive tape impregnated with active compounds and optionally one or more excipients or diluents. Formulations suitable for topical administration in the mouth include lozenges which comprise the active compound in a flavored base, usually sucrose and acacia or tragacanth; pills which comprise the active compound in an inert base such as gelatin and glycerin, or sucrose and acacia; and buccal washes which comprise the active compound in a suitable liquid carrier. Formulations suitable for topical administration to the eye also include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound. Formulations suitable for nasal administration, wherein the carrier is a solid, include a coarse powder which has a particle size, for example, in the range of about 20 to about 500 microns which is administered in the form in which a breath is taken, that is by rapid inhalation through the nasal passage from the powder container is kept closed to the nose. Suitable formulations wherein the carrier is a liquid for administration such as, for example, nasal dispersion, nasal drops, or by nasal administration by nebulizer, include aqueous or oily solutions of the active compound. Formulations suitable for administration by inhalation include those presented as an aerosol dispersion from the pressurized package, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide, or other suitable gases. Formulations suitable for topical administration by means of the skin include ointments, creams and emulsions. When formulated in an ointment, the active compound can optionally be employed with either a paraffinic or water-miscible ointment base. Alternatively, the active compounds can be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% w / w of a polyhydric alcohol, ie, an alcohol which has two or more hydroxyl groups such as propylene glycol, butane -1, 3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. Topical formulations may desirably include a compound which increases the absorption or penetration of the active compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethisulfoxide and related analogs. When formulated as a topical emulsion, the oily phase may optionally simply comprise an emulsifier (otherwise known as an emulsifier), or may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.

Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier with or without stabilizer forms the so-called emulsifying wax, and the wax together with the oil and / or grease forms the so-called emulsifying ointment base which forms the oil-dispersed phase of the cream formulations. Suitable emulsifiers and emulsion stabilizers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The choice of oil or fats suitable for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations can be very low. In this way the cream should preferably be a non-greasy product, without staining and washable with adequate consistency to avoid filtration from the tubes or other containers. Mono or dibasic straight or branched chain alkyl esters, such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, palmitate 2 -ethylhexyl or a mixture of branched chain esters known as Crodamol CAP can be used, the last three being preferred esters. These can be used alone or in combination depending on the required properties. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used. Formulations suitable for rectal administration can be presented as a suppository with a suitable base which comprises, for example, cocoa butter or a salicylate. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations which contain in addition to the active compound, such carriers as are known in the art to be appropriate. Formulations suitable for parental administration (eg, by injection, including skin, subcutaneous, intramuscular, intravenous and intradermal), include sterile, pyrogen-free, aqueous and non-aqueous isotonic injection solutions which may contain antioxidants, buffers, preservatives, stabilizers, bacteriostats, and solutes which lead to the isotonic formulation with the blood of the proposed recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to objectify the compound for blood components or one or more organs. Examples of isotonic vehicles suitable for use in such formulations include sodium chloride injection, Ringer's solution, or lactated Ringer's injection. Typically, the concentration of the active compound in the solution is from about 1 ng / ml to about 10 μg / ml, for example from about 10 ng / ml to about 1 μg / ml. The formulations can be presented in sealed unit dose or multi-dose containers, for example, ampoules and vials, and can be stored in a freeze-dried condition (lyophilized) which requires only the addition of the sterile liquid carrier, for example water for injections, immediately before use. The extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets. The formulations may be in the form of liposomes or other microparticulate systems which are designed to objectify the active compound for blood components or one or more organs. Dosage It will be appreciated that the appropriate doses of the active compounds, and compositions which comprise the active compounds, may vary from patient to patient. Determining the optimum dose will generally involve balancing the level of therapeutic benefit against any risk or damaging side effects of the treatments of the present invention. The level of dose selected will depend on a variety of factors which include, but are not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and / or materials used in combination, and the patient's age, sex, weight, condition, general health, and medical history. The amount of the compound and the route of administration will ultimately be at the discretion of the physician, although generally the dose will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial damage or damaging side effects. In vivo administration can be effected in one dose, continuous or intermittent (eg, in divided doses at appropriate intervals) throughout the course of treatment. Methods for determining the most effective medium and administration dose are well known to those skilled in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell to be treated, and the subject to be treated. . Simple or multiple administrations can be performed with the dose level and the pattern that is selected by the attending physician. In general, a suitable dose of the active compound is in the range of about 100 μg to about 250 mg per kilogram of body weight of the subject per day. Where the active compound is a salt, an ester, prodrug or the like, the amount administered is calculated on the basis of the parent compound and thus the actual weight to be used is proportionally increased. EXAMPLES General Experimental Methods Preparative HPLC Samples are purified with a Waters mass directed purification system which uses a Waters 600 LC pump, Waters Xterra C18 Column (5 μm 19 mm x 50 mm) and Micromass ZQ mass spectrometer, which operates in a positive ion electrospray ionization mode.

Mobile phases A (0.1% formic acid in water) and B (0.1% formic acid in acetonitrile) are used in a gradient; 5% from B to 100% over 7 minutes, maintained for 3 minutes, at a flow rate of 20 ml / minutes.

Analytical HPLC-MS Analytical HPLC is typically performed with a Spectra System P400 pump and Jones Genesis C18 column (4 μm, 50 mm x 4.6 mm). Mobile phases A (0. 1% formic acid in water) and B (acetonitrile) are used in a 5% B gradient for 1 minute which increases to 98% B after 5 minutes, maintained for 3 minutes at a flow rate of 2 ml / minute. Detection is by a TSP UV 6000 LP detector at 254 nm UV and 210-600 nm PDA range. The mass spectrometer is a Finnigan LCQ which operates in a positive ion electrospray mode. NMR Typically 1 H NMR and 13 C NMR are recorded using a Bruker DPX 300 spectrometer at 300 MHz and 75 MHz respectively. The chemical changes are reported in parts per million (ppn) on the scale d in relation to the internal tetramethylsilane standard. Unless otherwise stated all samples are dissolved in DMSO-de. Synthesis of key intermediates (i) Synthesis of (3-oxo-l, 3-dihydro-isobenzofuran-1-yl) -phosphonic acid dimethyl ester O Dimethyl phosphite (22.0 g, 0.2 mol) is added dropwise to a solution of sodium methoxide (43.0 g) in methanol (100 ml) at 0 ° C. The 2-carboxybenzaldehyde (21.0 g, 0.1 mole) is then added in portions to the reaction mixture as a suspension in methanol (40 ml), with the temperature being kept below 5 ° C. The resulting pale yellow solution is heated to 20 ° C in 1 hour. The methanesulfonic acid (21.2 g, 0.22 mol) is added to the reaction in droplets and the resulting white suspension is evaporated in vacuo. The white residue is stopped with water, extracted with chloroform (3 x 100 ml). Wash the combined organic extracts with water (2 x 100 ml), dry in MgSO 4, and evaporate in vacuo to yield (i) as a white solid (32.0 g, 95%, 95% purity). This is then used without further purification in the next step. (ii) Synthesis of the aldehyde intermediates 6-formyl-pyridine-2-carboxylic acid (lia) (a) 1 equivalent of potassium permanganate is added to 6-bromo-2-methyl-pyridine in water. The solution is heated leading to reflux for 2 hours. The reaction is followed and potassium permanganate is added until no starting material remains. After it is cooled, the solution is filtered and the solution is acidified to pH = 3. The precipitate is filtered and dried. (b) A solution of 6-bromo-2-pyridinecarboxylic acid, 1. 5 equivalents of dibutyl ester of vinylboronic acid, 1. 2 equivalents of potassium carbonate in DMA / water 9/1 the gas is removed for twenty minutes, then 0.06 equivalents of palladium tetrakis are added, the gas is removed from the suspension for an additional thirty seconds and the suspension is heated in the Microwave oven at 170 ° C for twenty-five minutes. The resulting suspension is filtered through a pad of silica gel and the filtrate is concentrated. (c) A solution of 6-vinyl pyridine-2-carboxylic acid in methanol / DCM 1/1 is cooled to -78 ° C and ozone is bubbled through it until the solution becomes blue. A stream of nitrogen is then passed through to remove the excess ozone and 1.5 equivalents of methyl sulfide are added. The solution is allowed to warm to room temperature and concentrated. The product (iia) is then purified by flash silica chromatography. 6-formyl-pyridine-2-carbonitrile (iib) (iib) (a) iodomethane (204 ml, 3.1 moles) is added in drops to 2-picoline-N-oxide (100 g, 0.9 moles) over 1 hour at 25 ° C. The reaction is left to stand for 12 hours. The reaction mixture is filtered, washed with Et20 and dried in a vacuum oven for 3 hours to produce the product which is then directed to the next step without purification. (b) A solution of aqueous KCN (112.0 g) is added dropwise., 1.7 moles in 250 ml of H20) to a solution of ethanol-H20 of the product from the previous step (7: 3) at 0 ° C over 180 minutes. The reaction is allowed to stir for an additional 30 minutes. The reaction is then heated to 25 ° C, extracted in 200 ml and an additional 4 x 100 ml of dichloromethane are added. The combined organic layers are washed with 200 ml of saturated brine, dried with MgSO 4, filtered and evaporated to yield a dark red liquid (51.0 g) which is allowed to crystallize at rest for 12 hours. The solid is filtered, washed with cold hexane (2 x 50 ml) and air dried. The solid is then purified by column chromatography (70 g of silica, hexane, ethyl acetate) to yield the product as a white solid (7.0 g, 7%). M / z [M + 1] + 119 (98% purity). (c) Add m-CPBA (16.2 g, 0.14 mol) to a solution of the product from the previous step (52.0 g, 0.15 mmole) in DCM (50 ml) and let the reaction stir for 12 hours. Na 2 S 2 3 3 (21.5 g) is added and the reaction mixture is allowed to stir for an additional 30 minutes. The reaction is then filtered, washed with saturated NaHCO3 (2 x 30 ml), brine (2 x 30 ml), dried with MgSO4, filtered and evaporated to yield the product as a white solid (13.6 g, 73.8% ) which is taken to the next stage without purification. (d) The product from the previous step (13.5 g, 101.3 mmol) is added to a preheated solution of acetic anhydride (60 ml) at 120 ° C and the reaction is refluxed for 90 minutes, then 60 ml of Ethanol is cautiously added to the reaction mixture, refluxed for an additional 10 minutes and cooled to 25 ° C. The reaction is added to water (100 ml) and neutralized with NaHCO 3 (50 g). The reaction is extracted into diethyl ether (2 x 30 ml). The combined organic layers are washed with water (2 x 20 ml) and dried with MgSO, filtered and evaporated to yield a brown oil which is purified by column chromatography (hexane: ethyl acetate) to produce the product as a yellow oil (5.4 g, 30%). m / z [M + 1] + 177 (30% purity). (e) NH 2 SO 4 (6 ml) is added to a solution of the product from the previous step (5.4 g, 30.6 mmol) in tetrahydrofuran (15 ml) and the reaction is refluxed for 18 hours. The reaction is cooled, poured into water (150 ml), neutralized with NaHCO 3 and extracted into DCM (3 x 50 ml). The combined organic layers are washed with 100 ml of saturated brine, dried with MgSO, filtered and evaporated to yield the product as a brown solid which is taken to the next step without purification, m / z [M + l] + 134 (71% purity), (f) The product of the previous step and N, N'-dodohexylcarbodiimide (19.3 g, 93.0 mmol) are added to a mixture of DMSO (22 ml) and anhydrous H3P04 (1.4 g) and the reaction is allowed to stir for 1.5 hours. The reaction is filtered and washed with diethyl ether (2 x 30 ml) and water (2 x 30 ml). The reaction layers are separated and the organic layer is washed with saturated brine (2 x 30 ml), dried with MgSO 4, filtered and evaporated to produce (iib) as a yellow solid which is taken to the next step without purification. 2-formyl-isonicotinic acid (ii) (a) 1 equivalent of potassium permanganate is added to 2-bromo-4-methyl-pyridine in water. The solution is heated under reflux for 2 hours. The reaction is followed and the potassium permanganate is added until no starting material remains. After cooling, the solution is filtered and the solution is acidified, until pH = 3. The precipitate is filtered and dried. (b) A solution of 2-bromo-isonicotinic acid, 1.5 equivalents of dibutyl ester of vinylboronic acid, 1.2 equivalents of potassium carbonate in DMA / water 9/1 the gas is removed for twenty minutes, then 0.06 equivalents of tetrakis are added of palladium, the gas is removed from the suspension for an additional thirty seconds and the suspension is heated in the microwave at 170 ° C for twenty-five minutes. The resulting suspension is filtered through a pad of silica gel and the filtrate is concentrated. (c) A solution of 2-vinyl isonicotinic acid in methanol / DCM 1/1 is cooled to -78 ° C and the ozone is bubbled through it until the solution becomes blue. A stream of nitrogen is then passed through to remove the excess ozone and 1.5 equivalents of methyl sulfide are added. The solution is allowed to warm to room temperature and concentrated. The product is then purified (iic) by flash chromatography on silica. -formyl-isonicotinonitrile (iid) (a) iodoethane (265 ml, 3.3 moles) is added dropwise to 2-picoline-N-oxide (100 g, 0.9 moles) over 1 hour at 25 ° C. The reaction is allowed to stand for 12 hours. The reaction mixture is filtered, washed with Et20 and dried in a vacuum oven for 3 hours to produce the product which is taken to the next step without purification. (b) A solution of aqueous KCN (52.0 g, 0.8 mole in 100 ml of H20) is added dropwise to an ethanol-H20 solution of the product from the previous step (7: 3) at 50 ° C over 110 minutes. The reaction is allowed to stir for an additional 30 minutes. The reaction is then heated to 25 ° C, extracted in 200 ml and an additional 4 x 100 ml of dichloromethane. The combined organic layers are washed with 200 ml of saturated brine, dried with MgSO 4, filtered and evaporated to yield a dark red liquid (51.0 g). This procedure is repeated and combined to yield a total of 102.0 g of the reaction mixture which is purified by column chromatography (360 g of silica, hexane, ethyl acetate) to yield the product as a white solid (10.6 g. , 10%). m / z [M + 1] + 119 (98% purity). (c) m-CPBA (27.7 g, 80.2 mmol) is added to a solution of the product from the previous step (8.6 g, 72.8 mmol) in DCM (30 ml) and the reaction is allowed to stir for 12 hours. Na2S203 (10.0 g, 16.0 mmol) is added and the reaction mixture is allowed to stir for an additional 30 minutes. The reaction is then filtered, washed with saturated NaHCO 3 (2 x 30 ml), brine (2 x 30 ml), dried with MgSO 4, filtered and evaporated in vacuo to yield the product as a white solid (6.5 g, 67%) which is taken to the next stage without purification. (d) The product of the previous step (8.0 g, 60.00 mmol) is added to a preheated solution of acetic anhydride (30 ml) at 120 ° C and the reaction is refluxed for 90 minutes. 30 ml of ethanol is then added cautiously to the reaction mixture, refluxed for an additional 10 minutes and cooled to 25 ° C. The reaction is added to water (100 ml) and neutralized with NaHCO 3 (50 g). The reaction is extracted into diethyl ether (2 x 30 ml). Wash the combined organic layers with water (2 x 20 ml) and dry with MgSO 4, filter and evaporate in vacuo to yield a brown oil which is purified by column chromatography (hexane, ethyl acetate) to produce the product as a yellow solid (4.0 g, 38%). m / z [M + 1] + 177 (96% purity). (e) NH 2 SO 4 (16 ml) is added to a solution of the product from the previous step (2.7 g, 15.6 mmol) in tetrahydrofuran (25 ml) and the reaction is refluxed for 18 hours. The reaction is cooled, poured into water (150 ml), neutralized with NaHCO 3 and extracted into DCM (3 x 50 ml). The combined organic layers are washed with 100 mL of saturated brine, dried with MgSO 4, filtered and evaporated in vacuo to yield the product as a yellow solid. (1.4 g, 67%) which is taken to the next stage without purification. (f) The product of the previous stage (1.4 g, 10.2 mmol) and N, N'-dicyclohexylcarbodiimide (6.2 g, 30.0 mmol) is added to a mixture of DMSO (22 ml) and anhydrous H3P04 (0.45 g) and the reaction is allowed to stir for 1.5 hours.

The reaction is filtered and washed with diethyl ether (2 x 30 ml) and water (2 x 30 ml). The reaction layers are separated and the organic layer is washed with saturated brine (2 x 30 ml), dried with MgSO 4, filtered and evaporated in vacuo to yield (iid) as a yellow solid which is taken to the next stage without purification. (iii) Copulation of aldehyde intermediates (ii) to dimethyl ester of (3-oxo-l, 3-dihydro-isobenzofuran-1-yl) -phosphonic acid (i) (a) Synthesis of 2- (3-oxo) acid -3H-isobenzofuran-l-ylidenemethyl) -isonicotinic (iiia) (i) (fc) (Hia) It is added to a mixture of acid dimethyl ester (3-oxo-l, 3-dihydro-isobenzofuran-1-yl) -phosphonic acid (i) (0.18 g, 0. 77 mmoles) and 2-formyl-isonicotinic acid (iic) (0.12 g, 0. 77 mmole) in tetrahydrofuran (10 ml) triethylamine (0.32 ml, 2.8 mmol). The reaction mixture is stirred at 50 ° C for 4 hours, then allowed to cool to room temperature. The tetrahydrofuran is evaporated to half its volume, then a solution of IN HCl is added until pH 3. The water is added until no more solid is separated from the solution. The white solid is filtered, washed with water, then hexane and recrystallized from acetonitrile. Quantity: 0.9 g, m / z [M + l] + 268 (90% purity). All aldehydes which contain a carboxylic acid function are coupled with the dimethyl ester of (3-oxo-l, 3-dihydro-isobenzofuran-1-yl) -phosphonic acid using the conditions described above, except that the reaction is carried out at room temperature for 16 hours instead of 50 ° C for 4 hours. The compounds synthesized following the above protocol are: 6-formyl-pyridine-2-carboxylic acid (iia), 6- [3-oxo-3H-isobenzofuran-1-ylidenemethyl] -pyridine-2-carboxylic acid (iiib) 5-formyl-furan-2-carboxylic acid, 5- [3-oxo-3H-isobenzofuran-1-ylidenemethyl] -thiophene-2-carboxylic acid (iüc): m / z [M + 1] + 287 (92%) purity) 5-formyl-thiophene-2-carboxylic acid, 5- [3-oxo-3H-isobenzofuran-1-ylidene-1-yl] -furan-2-carboxylic acid (iiid): m / z [M + l] + 257 (90% purity). (b) Alternative synthesis of 2- (3-oxo-3H-isobenzofuran-1-ylidenemethyl) -isonicotinic acid (iiia) (i) is O) (iw) O8 - '"1) <" la) add triethylamine (2.2 ml, 15 mmol) to a mixture of dimethyl ester of (3-oxo-l, 3-dihydro-isobenzofuran- 1-yl) -phosphonic (i) (2.4 g, 10.2 mmol) and (iid) (10.2 mmol) in tetrahydrofuran (10 mL). The reaction mixture is stirred for more than 12 hours at 25 ° C and concentrated in vacuo to yield 2- [3-oxo-3H-isobenzofuran- (1, Z) -ylidenemethyl] -isonicotinonitrile (iii-int) as a red solid which is taken to the next stage without purification, (ii) A mixture of 2- [3-oxo-3H-isobenzofuran- (1E, Z) -ylidenemethyl] -isonicotinonitrile (iii-int) (10.2 mmoles), Water (50 ml) and potassium hydroxide granules (1.7 g, 30.7 mmol) are brought to reflux for 16 hours. The reaction is cooled to 25 ° C and washed with dichloromethane (2 x 30 ml). The aqueous layer is then concentrated in vacuo and the obtained solid (iiia) is taken in the next step without further purification. All the aldehydes which contain a group are subjected to coupling with dimethyl ester of (3-o? O- 1, 3-dihydro-isobenzofuran-1-yl) -phosphonic acid, then hydrolyzed to the carboxylic acid using the conditions described above . The compounds synthesized following the above protocol are: Of 6-formyl-pyridine-2-carbonitrile acid (iib), 6- [3-oxo-3H-isobenzofuran-1-ylidenemethyl] -pyridine-2-carboxylic acid (iiib): step (a) gives a yellow solid: m / z [M + 1] + 249 (98% purity); step (b) gives a dark yellow oil: m / z [M + 1] + 286 (83% purity). (c) 4- (3-oxo-3H-isobenzofuran-1-ylidenemethyl) -pyridine-2-carbonitrile (iii'e) To a solution of 4-formyl-pyridine-2-carbonitrile (4.89 g, 37.0 mmol) in anhydrous THF (200 ml) is added [dimethyl ester of (3-oxo-l, 3-dihydro-isobenzofuran-1-yl) ) -phosphonic] phosphonate (9.2 g, 37.0 mmol), triethylamine (5.1 ml, 37.0 mmol) and the reaction is stirred for 18 hours at room temperature. The reaction mixture is then filtered and the solid isolate is washed with dry THF (2 x 25 ml) and dried in vacuo. Two peaks by LC-MS analysis (geometric isomers), (7.0 g, 76%); m / z (LC-MS, ESP), rt = 4.19 minutes, (M + H) = 249 and rt = 4.36 minutes, (M + H) = 249. This material is taken through without the need for purification. (iv) Conversion of isobenzofuran compounds to phthalazinone compounds (a) synthesis of 5- (4-oxo-3,4-dihydro-phthalazin-1-ylmethyl) -furan-2-carboxylic acid (ila) (Tila) ( iva) It is added to a suspension of 2- [3-oxo-3H-isobenzofuran-ylidenmethyl] isonicotinic acid (iiia) (87 mg, 0.32 mmol) in water (2 ml), hydrazine monohydrate (33 mg, 0.64 mmol) and heat the mixture to reflux for 5 hours. The solution is concentrated to half its volume and acidified with a 1 N HCl solution to pH 3. The white solid is filtered, washed with water and dried. Amount: 32 mg. m / z [M + 1] + 282 (42% purity) The phthalazinone nucleus is formed in all the compounds according to the protocol described above. The compounds synthesized following the above protocol are: 6- [3-Oxo-3H-isobenzofuran-1-ylidenemethyl] -pyridine-2-carboxylic acid (iiib), 6- (4-oxo-3,4-dihydro) acid phthalazin-1-ylmethyl) -pidirin-2-carboxylic acid (ivb): m / z [M + 1] + 282 (48% purity); 5- [3-Oxo-3H-isobenzofuran-1-ylidenemethyl] -thiophene-2-carboxylic acid (iiic), 5- (4-oxo-3,4-dihydro-phthalazin-1-ylmethyl) -thiophenic acid 2-carboxylic acid (ivc): m / z [M + 1] + 287 (60% purity); - (3-Oxo-3H-isobenzofuran-1-ylidenemethyl) -furan-2-carboxylic acid (iiid), 5- (4-oxo-3,4-dihydro-phthalazin-1-ylmethyl) -furan- acid 2-carboxylic acid (ivd): m / z [M + 1] + 271 (94% purity); (b) Synthesis of 4- (4-oxo-3,4-dihydro-phthalazin-1-ylmethyl) pyridine-2-carboxylic acid (ive) It is added to a 4- (3-oxo-3H-isobenzofuran-1-ylidenemethyl) pyridine-2-carbonitrile (iii'e) (3.72 g, 15.0 mmol) water (100 ml) and hydrazine monohydrate (1.5 g, 30.0 mmoles). The reaction is then heated at 100 ° C for 6 hours and then cooled to room temperature. The white suspension is filtered and washed with diethyl ether (2 x 20 ml). The material is then dried in vacuo. Main peak by LC-MS analysis (7.0 g, 76%): m / z (LC-MS, ESN), rt = 3.54 minutes, (M + H) = 261. To a solution of the resulting material (2.36 g, 9.0 mmol) in ethanol (10 ml) concentrated hydrochloric acid (5 ml) is added. A reaction mixture is then heated at 70 ° C for 18 hours and then cooled to 5 ° C, the resulting white suspension is filtered and washed with water (2 x 5 ml) followed by diethyl ether (2 x 20 ml). . The beige solid was isolated with a main peak in LC-MS analysis (2.40 g, 94%); m / z (LC-Ms, ESP), RT = 3.49 minutes, (M + H) = 282; and (2M + H) = 563. The material is taken through without need for purification. (v) addition of the piperazine group (a) Synthesis of 4- [6- (piperazin-1-carbonyl) -pyridin-2-ylmethyl] -2H-phthalazin-1-one (vb) b) (vb) A mixture of 6- (4-oxo-3,4-dihydro-phthalazin-1-ylmethyl) -pyridine-2-carboxylic acid (ivb) (0.3 g, 1.1 mmol), triethylamine (0.3 ml, 2.1 mmol), tert-butyl-1-piperazine carboxylate (0.23 g, 1.3 mmol) and 2 (1 H-benzotriazol-1-yl) -l, 1,3-tetramethyluronium hexafluorophosphate (0.5 g, 1.3 mmoles) in dimethylformamide (10 ml) for 18 hours. The reaction mixture is precipitated in the addition of water (50 ml) and dried in air. Dissolve the white precipitate in ethanol (3 ml) and 12 M hydrochloric acid (6 ml) to the solution and stir the reaction for 30 minutes. The reaction is then concentrated in vacuo, redissolved in water (10 ml) and washed with dichloromethane (2 x 10 ml). The aqueous layer is basified with ammonium hydroxide and extracted with dichloromethane (2 x 10 ml). Dry the combined organic layers with MgSO4, filtered and evaporated to yield the expected product (va) as a pink solid (0.23 g, 73%). m / z [M + 1] + 250 (96% purity). All the compounds are coupled to tert-butyl ester of piperazine-1-carboxylic acid and have their protective group removed according to the protocol described above. The compounds are synthesized following the above protocol are: 5- (4-Oxo-3,4-dihydro-f talazin-1-ylmethyl) furan-2-carboxylic acid (iva), 4- [4- (piperazin -l-carbonyl) -pyridin-2-ylmethyl] -2H-phthalazin-l-one (va); m / z [M + 1] + 250 (96% purity); 5- (4-Oxo-3,4-dihydro-phthalazin-1-ylmethyl) -thiophene-2-carboxylic acid (ivc), 4- [5- (piperazin-1-carbonyl) -thiophen-2-ylmethyl acid ] -2H-phthalazin-1-one (vc): m / z [M + 1] + 339 (80% purity); 5- (4-Oxo-3,4-dihydro-f talazin-1-ylmethyl) furan-2-carboxylic acid (ivd), 4- [5- (piperazin-1-carbonyl) -furan-2-ylmethyl acid ] -2H-phthalazin-1-one (vd): m / z [M + 1] + 355 (84% purity). (b) Synthesis of 4- [2- (piperazin-1-carbonyl) -pyridin-4-ylmethyl] -2H-f talazin-1-one (ve) (Go) (Vß) To a solution of 4- (4-oxo-3,4-dihydro-phthalazin-1-ylmethyl) -pyridine-2-carboxylic acid (ive) (0.563 g, 2.0 / 0 mmol) in anhydrous DCM (30 mL) was added. add tert-butyl 1-piperazinecarboxylate (0.45 g, 2.4 mmol) and 0-benzotriazole-N, N, N ', N' -tetramethyluronium-hexaf luorophosphorylate (0.91 g, 2.4 mmol). The mixture is stirred for 5 minutes before N ', N'-diisopropylethylamine (0.42 ml, 2.4 mmol) is added. After 30 minutes of stirring at room temperature, the reaction mixture is filtered and concentrated in vacuo. The resulting oil is subjected to chromatography using EtOAc: MeOH 9: 1 (with reference to 0.23), a white solid is isolated. The single peak in LCMS analysis, (0.71 g, 79%) and does not require additional purification, m / z (LC-Ms, ESP), RT = 3.75 min. (M + H) = 450. 4M Hydrogen chloride (3.25 mL, 13.0 mmol) is added to the resulting compound (0.60 g, 1.35 mmol) and dioxane). After 15 minutes the solvent is removed in vacuo and 7N ammonia in methanol (3 mL, 15.0 mmol). The resulting cream precipitate is filtered. The filtrate is concentrated in vacuo to yield a sticky gum (0.31 g, 89% yield). 93% purity DC-MS analysis, without further purification attempt. m / z (LC-Ms, ESP), RT = 2.86 minutes. (M + H) = 350. Example 1 The appropriate acid chloride or sulfonyl chloride (0.24 mmol) is added to a solution of 4- [4- (piperazin-1-carbonyl) -pyridin-2-ylmethyl] -2H-f-talazin-1-one (goes ) in dichloromethane (2 ml). The Hunigs base (0.4 mmol) is then added and the reaction is stirred at room temperature for 16 hours. The reaction mixtures are then purified by preparative HPLC. The synthesized compounds are indicated below.

Example 2 (a) The appropriate acid chloride or sulfonyl chloride (0.24 mmol) is added to a solution of 4- [4- (piperazin-1-carbonyl) -pyridin-2-ylmethyl] -2H-phthalazin-1-one. (vb) in dichloromethane (2 ml). The Hunigs base (0.4 mmol) is then added and the reaction is stirred at room temperature for 16 hours. The reaction mixtures are then purified by preparative HPLC. The synthesized compounds are indicated below. (b) The appropriate isocyanate (0.24 mmol) is added to a solution of 4- [4- (piperazin-1-carbonyl) -pyridin-2-ylmethyl] -2H-phthalazin-1-one (vb) in dichloromethane (2). ml). The reaction is stirred at room temperature for 16 hours. The reaction mixtures are then purified by preparative HPLC. The synthesized compounds are indicated later (c) A mixture of 6- (4-oxo-3,4-dihydrophthalazin-1-ylmethyl) -pyridine-2-carboxylic acid (iva) (0.3 g, 1.1 mmol), triethylamine (0.3 ml, 2.1 mmol), the appropriate amine (1.3 mmol) and 2- (lH-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate (0.5 g, 1.3 mmol) in dimethylformamide (10 mL) for 18 hours. The reaction mixtures are then purified by preparative HPLC. The synthesized compounds are indicated below.

Example 3 (a) The appropriate acid chloride (0.24 mmol) is added to a solution of 4- [5- (piperazine-1-carbonyl) -furan-2-ylmethyl] -2H-phthalazin-1-one (vd) in dichloromethane (2 ml). The Hunig base (0.4 mmol) is then added and the reaction is stirred at room temperature for 16 hours. The reaction mixtures are then purified by preparative HPLC. The synthesized compounds are indicated below. (b) The appropriate isocyanate (0.24 mmol) is added to a solution of 4- [5- (piperazain-1-carbonyl) -furan-2-ylmethyl] -2H-phthalazin-1-one (vd) in dichloromethane (2). ml). The reaction is stirred at room temperature for 16 hours. The reaction mixtures are then purified by preparative HPLC. The synthesized compounds are indicated below. (c) A mixture of 5- (4-oxo-3,4-dihydrophthalazin-1-ylmethyl) furan-2-carboxylic acid (ivd) (1.1 mmol), triethylamine (0.3 ml, 2.1 mmol) is stirred. the appropriate amine (1.3 mmol) and 2- (lH-benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate (0.5 g, 1. 3 mmol) in dimethylformamide (10 ml) for 18 hours. The reaction mixtures are then purified by preparative HPLC. The synthesized compounds are indicated below.

Example 4 (a) The appropriate acid chloride (0.24 mmol) is added to a solution of 4- [5- (piperazin-1-carbonyl) -thiophen-2-ylmethyl] -2H-phthalazin-1-one (vc) ) in dichloromethane (2 ml). The Hunig base (0.4 mmol) is then added and the reaction is stirred at room temperature for 16 hours. The reaction mixtures are then purified by preparative HPLC. The synthesized compounds are indicated below: (b) The appropriate isocyanate (0.24 mmol) is added to a solution of 4- [5- (piperazin-1-carbonyl) -thiophen-2-ylmethyl] -2H-phthalazin-1-one (vc) in dichloromethane (2). ml). The reaction is stirred at room temperature for 16 hours. The reaction mixtures are then purified by preparative HPLC. The synthesized compounds are indicated below: c) A mixture of 5- (4-oxo-3,4-dihydro-phthalazin-1-ylmethyl) -thiophene-2-carboxylic acid (ivc) (1.1 mmol), triethylamine (0.3 ml, 2.1 mmol) is stirred, the appropriate amine (1.3 mmol) and 2- (lH-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (0.5 g, 1.3 mmol) in dimethylformamide (10 ml) for 18 hours. The reaction mixtures are then purified by preparative HPLC. The synthesized compounds are indicated below.

Compound Rt (min) M + l 55 3.53 383 Example 5 (a) An appropriate acid chloride (0.13 mmol) is added to a solution of 4- [2- (piperazin-1-carbonyl) -pyridin-4-ylmethyl] -2H-phthalazin-1-one (ve) ( 0.045 g, 0.13 mmol) in anhydrous DCM (1.0 ml). Then add N'N'-diisopropylethylamine (47 μl, 0.26 mmol) and stir at room temperature for 18 hours. The reaction mixtures are then purified by preparative HPLC.

The synthesized compounds are indicated below: (b) Add to a solution of 4- (4-oxo-3,4-dihydro-phthalazin-1-ylmethyl) -pyridine-2-carboxylic acid (ive) (0.037 g, 0.13 mmol) in anhydrous dimethylacetamide (1) ml) appropriate secondary amine (0.14 mmoles) and 0-benzotriazole-N, N, N ', N'-tetramethyl-uronium-hexafluoro-phosphate (0.060 g, 0.16 mmoles). The mixture is stirred for 5 minutes before N ', N'-diisopropylethylamine (0.47 μl, 0.26 mmol) is added and stirred at room temperature overnight. The reaction mixtures are then purified by preparative HPLC. The synthesized compounds are indicated below. 64 63 Compound 64 is deprotected using concentrated HCl in an organic solvent, to yield compound 63. Rt 3.21 minutes, M + l 364.

Example 6: Alternative synthesis of 5 (a) 2-hydroxymethyl-isonicotinonitrile To a stirred solution of 4-cyanopyridine (10.4 g, 100. OOmmoles) in methanol (100 ml) and water (50 ml) at room temperature is added concentrated sulfuric acid (5 ml), a slight exothermic is noted. After 10 minutes, sulfate heptahydrate and iron (910 mg, 3.0 mmol) are added and the reaction is immediately returned to a dark yellow / orange. After sonification of the reaction mixture under nitrogen for 20 minutes, the hydroxylamine-O-sulfuric acid (11.3 g, 100. OOmmoles) is added in one portion. A slight exothermic is observed after 10 minutes, the reaction is maintained under a nitrogen atmosphere. After 2 hours the additional hydroxylamine-O-sulfuric acid (11.3 g, 100.0 mmol) is added together with concentrated sulfuric acid (5 ml) and iron (II) sulfate heptahydrate (910 mg, 3.0 mmol). After an additional 3 hours of stirring the reaction is neutralized by the addition of sodium carbonate (18.0 g 200 mmol). The mixture is then diluted with water (100 ml) and filtered to remove a dark red / brown precipitate, the filtrate is concentrated to dryness and the resulting solid is dissolved in water (50 ml) and extracted with EtOAc (5 x 100). ml). The combined organics are dried in MgSO, and concentrated in vacuo to yield a gray solid of 6.1 g. The material is then subjected to flash chromatography, eluent 8: 1 Hex: EtOAc to remove the unreacted 4-cyanopyridine and then increase the polarity to 2: 1, Hex: EtOAc to isolate the desired product as a fluffy white solid (rf 0.5, 2: 1 Hex / EtOAc). Single peak in LC-Ms analysis (3.3 g, 24.6%), m / z (LC-MS, ESP), RT = 1.70 minutes, (M + H) = 135.0. 1 H NMr (30 MHz) 8.72 (OH, dd, J 0.9, 6.0 Hz), 7.78 (lH, m), 7.71 (OH, dt, J 0.9, 6.0 Hz), 5.65 (OH, t, J 6.9 Hz-OH ), 4.61 (lH, d, J 6.9 Hz); 13 C NMR (100 MHz), 163.72, 149.85, 123.60, 121.69, 119.77, 116.99, 63.70; (b) 2-formyl-isonicotinone trile (iid) To a cooled solution of oxalyl chloride (13.2 ml, 150 mmol) in anhydrous DCM (86 ml) under nitrogen aphere at -78 ° C DMSO (21.2 ml in drops for 20 minutes The mixture is stirred for 15 minutes at (-78 ° C) before 2-hydroxymethyl-isonicotinonitrile (4.0 g, 30 mmol) dissolved in anhydrous DCM (60 ml) drops to the reaction mixture for 5 minutes The reaction is stirred for 2 hours at -78 ° C while maintaining a nitrogen aphere.A solid white precipitate is formed and the temperature is increased (-55 ° C) and triethylamine is added in drops. (6.15 ml, 450 mmol) for more than 15 minutes, the cooling bath is removed allowing the mixture to warm to room temperature for 2 hours. The aqueous phase is extracted with DCM (3x 50 ml). Combine the combined organic layers and concentrate in vacuo. The white buff solid that is used is isolated without any additional purification. the single peak in LC-MS analysis (yield taken to be quantitative), m / z (LC-MS, ESP), RT = 2.53 minutes, (M + H) = 133.0. (c) 2- (3-oxo-3H-isobenzofuran-1-ylidenemethyl) -isonicotinonitrile (iii-int) To a cooled (about 0 ° C) solution of [3-oxo-1] dimethyl ester phosphonate , 3-dihydro-isobenzofuran-1-yl) -phosphoric acid] (i) (8.0 g, 33.0 mmol) in THF (400 ml) is added 2-formyl-isonicotinonitrile without purification (iid) (30.0 mmol) followed by triethylamine ( 6.2 ml, 33.0 mmol). The mixture is stirred for 30 minutes at 0 ° C and then allowed to stand overnight under hot conditions.

The reaction mixture is then evaporated in vacuo, then the resulting solid is washed with ethyl acetate (2 x 50 ml), methanol (1 x 15 ml) and then diethyl ether (2 x 20 ml). Two peaks are detected in LC-MS analysis, the desired product; m / z (LC-MS, ESP), RT = 4.27 minutes, (M + H) = 249.0, and an impurity peak (approximately 40%) RT = 4.47 minutes M + H 194). This material is used without need for any purification. (d) 2- (4-oxo-3,4-dihydro-phthalazin-1-ylmethyl) -isonicotinonitrile Suspending 2- (3-oxo-3H-isobenzofuran-1-ylidenemethyl) -isonicotinonitrile without purification (iii-int) (approximately 4.0 mmol) in water (40 ml) and hydrazine monohydrate (2 ml). The reaction mixture is then heated at 90 ° C for 90 minutes and then cooled to room temperature. Filter and wash the resulting suspension with methanol (5 ml), water (10 ml), and then ethyl ether (2 x 30 ml). Rugged solid is isolated with a single peak in LC-MS analysis. (0.61 g, 26.7% in more than 3 stages): m / z (LC-MS, ESP), RT = 3.48 minutes, (M + H) = 263.0. (e) 2- (4-Oxo-3,4-dihydro-phthalazin-1-ylmethyl) -isonicotinic acid (iva) It is added to a suspension of 2- (4-oxo-3,4-dihydro-phthalazine-1) -ylmethyl) -isonicotinonitrile (0.54 g, 2.06 mmol) in absolute ethanol (2.5 ml) concentrated hydrochloric acid (1.3 ml). The reaction mixture is then heated at 70 ° C overnight. The reaction is then cooled to 5 ° C and then the white suspension is filtered and washed with water (2 x 5 ml), then diethyl ether (2 x 20 ml). The bright yellow solid was isolated with single peak in LC-MS analysis (0.49 g, 88%); m / z (LC-MS, ESP), RT = 3.08 minutes, (M + H) = 282 and (2M + H) = 563. (f) 4- [4- (4-cyclohexanecarbonyl-piperazine-1-carbonyl) -pyridin-2-ylmethyl-2H-phthalazin-1-one] (5) It is added to a stirred solution of 2- (4-) acid. o? o- 3, 4-dihydro-phthalazin-1-ylmethyl) -isonicotinic acid (iva) (0.25 g, 0. 89 moles) in dimethylacetamide (2 ml) cyclohexyl-piperazin-1-yl-methanone (0.20 g, 1.0 mmol) followed by HBTU (0.38 g, 1.0 mmol) and diisopropylethylamine (0.35 mL, 20.0 mmol) and stirred. The reaction mixture is then concentrated in vacuo and the resulting oil subjected to eluent of flash chromatography 9: 1 EtOAc / MeOH. (rf of 0.3). The title compound is isolated as a white solid. Single peak in LC-MS analysis, (0.18 g, 56%); m / z (LC-MS, ESP), RT = 4.07 minutes, (M + H) = 460; XH NMr (300 MHz) 12.57 (HH, S-NH), 8.56 (HH, d, J = 5.1 Hz), 8.26 (HH, dd, J 1.5, 8.1 Hz), 7.95-7.80 (3H, m), 7.38 (HH, S), 7.25 (HH, d, J 5.7 Hz), 4.51 (2H, S), 3.56-3.17 (8H, m), 2.58 (lH, m), 1.71-1.61 (5H, m), 1.38 -1.22 (5H, m).

Example 7 In order to evaluate the inhibitory action of the compounds, the following assay is used to determine IC 50 values (Dillon, et al., JBS., 8 (3), 347-352 (2003)). Mammalian PARP is incubated, isolated from Hela cell nuclear extract with Z buffer (25 mM Hepes (Sigma), 12.5 mM MgCl2 (Sigma): 50 mM KCl (Sigma); 1 mM DTT (Sigma); glycerol 10% (Sigma) NP-40 at 0.001% (Sigma); pH 7.4) in 96 well FlashPlates (Registered Trade Mark) (NEN, UK) and varying concentrations of the aggregated inhibitors. All compounds are diluted in DMSO and give final assay concentrations of between 10 and 0.01 μM, with DMSO being in the final concentration of 1% per well. The total assay volume per well is 40 μl. After 10 minutes of incubation at 30 ° C the reactions are initiated by the addition of 10 μl of reaction mixture, containing NAD (5 μM), 3H-NAD and 30mer double-stranded DNA oligonucleotides. The designated positive and negative reaction wells are made in combination with (unknown) compound wells in order to calculate the percent of enzyme activities. The plates are then shaken for 2 minutes and incubated at 30 ° C for 45 minutes.

After incubation, the reactions are stopped by the addition of 50 μl of 30% acetic acid to each well. The plates are then stirred for 1 hour at room temperature. The plates are transferred to TopCount NXT (registered trademark) (Packard, UK) for scintillation counting. Registered values are counted by minutes (cpm) after a 30-second count for each well. The% of enzyme activity for each compound is then calculated using the following equation:% incubation = 100- [100x (cpm of unknown-average negative cpm) / (average positive cpm-average negative cpm)]. The IC50 values (the concentration at which 50% of the enzymatic activity is inhibited) are calculated, which are determined over a range of different concentrations, usually from 10 μM to 0.001 μM. Such IC5o values are used as comparative values to identify potencies of increased compounds. All tested compounds have an IC 50 of less than 1 μM. The following compounds have an IC 50 less than O.lμM: 1-7, 9-14, 17-18, 21-24, 26-29, 35, 50-52, 56-75. The potentiation factor (PF50) for compounds is calculated as a ratio of the IC50 of control cell growth divided by the IC50 of cell growth + PARP inhibitor. The growth inhibition curves for both control and cells treated with compounds are in the presence of the methyl alkylating agent methanesulfonate (MMS). The test compounds are used in a fixed concentration of 0.2 micromolar. The MMS concentrations are in a range of 0 to 10 μg / ml. Cell growth is evaluated using the sulfonyl-orhodamine B (SRB) assay (Skehan, P., et al., (1990) New colorimetric cytotoxicity assaz for anticancer-drug screening, J. Nati. Cancer Inst. 82, 1107-1112). The 2,000 HeLa cells are seeded in each well of a 96 well flat bottom microtiter plate in a volume of 100 μl and incubated for 6 hours at 37 ° C. Cells are replaced either with the medium alone or with media containing PARP inhibitor at a final concentration of 0.5, 1 or 5 μM. Cell growth is allowed for an additional hour before the addition of MMS in a range of concentrations (typically 0, 1, 2, 3, 5, 7 and 10 μg / ml) to either untreated cells or treated cells by the PARP inhibitor. Cells treated with PARP inhibitor alone are used to evaluate the inhibition of growth by the PARP inhibitor. The cells are left for an additional 16 hours before replacing the medium and allowing the cells to grow for an additional 72 hours at 37 ° C. The medium is then removed and the cells are fixed with 100 μl of cold ice with 10% trichloroacetic acid (w / v). The plates are incubated at 4 ° C for 20 minutes and then washed four times with water. Each cell well is then stained with 100 μl of 0.4% (w / v) of SRB in 1% acetic acid for 20 minutes prior to washing four times with 1% acetic acid. The plates are then dried for 2 hours at room temperature. The dye from the stained cells is solubilized by the addition of 100 μl of 10 mM Tris Base in each well. The plates are gently shaken and left at room temperature for 30 minutes before measuring the optical density at 564 nM in a Microquant microtiter plate reader. All tested compounds have a PF50 at 200 nM of at least 1. The following compounds have a PF50 at 200 nM of at least 2: 2, 3, 5, 8, 9, 10, 12, 13, 56, 57 , 58, 62, 65, 66, 67, 74, 75.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (23)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of the formula (I): and isomers, salts, solvates, chemically protected forms, and prodrugs thereof characterized in that: A and B together represent a fused aromatic ring, optionally substituted: X may be NRX or CRXRY; If X = NRX then n is 1 or 2 and if X = CRXRY then n is 1; R x is selected from the group consisting of H, optionally substituted C 1-20 alkyl, C 5-20 aryl C 3-20 heterocyclyl / amido, thioamido, ester, acyl and sulfonyl groups; R? is selected from H, hydroxy, amino; or Rx and R? they can together form a C3-7 spiro-cycloalkyl or heterocyclyl group; Rcl and Rc2 are independently selected from the group consisting of hydrogen and C? -4 alkyl, or when X is CRXRY, Rcl, Rc2, Rx and R ?,, together with the carbon atoms to which they are attached can form a ring optionally substituted fused aromatic; R1 is selected from H and halo; and Het is selected from: 0) where Y1 is selected from CH and N, Y2 is selected from CH and N, Y3 is selected from CH, CF and N, where only one or two of Y1, Y2 and Y3 can be N; Y (») where Q is O or S.
2. 2. The compound according to claim 1, characterized in that the fused aromatic ring represented by A-B- consists of carbon ring atoms only.
3. 3. The compound according to claim 2, characterized in that the fused aromatic ring represented by -A-B- is benzene.
4. 4. The compound according to any of claims 1 to 3, characterized in that Rcl and Rc2 are hydrogen.
5. 5. The compound according to any of claims 1 to 4, characterized in that n is 2, X is NRX, and RX is selected from the group which consists of: H; optionally substituted C1-20 alkyl; optionally substituted Cs-2o aryl; ester groups optionally substituted; optionally substituted acyl groups; optionally substituted amido groups; optionally substituted thioamido groups; and optionally optionally substituted sulfonyl groups.
6. 6. The compound according to any of claims 1 to 4, characterized in that n is 1, X is NRX, and RX is selected from the group consisting of: H, optionally substituted C? -20 alkyl; optionally substituted C5-20 aryl; optionally substituted acyl; optionally substituted sulfonyl; optionally substituted amido; and optionally substituted thioamido groups. The compound according to claim 6, characterized in that Het is pyridylene and Rx is selected from the group consisting of: optionally substituted acyl; optionally substituted sulfonyl; and optionally substituted amido. 8. The compound according to claim 6, characterized in that Het is furanylene or thiophenylene and Rx is selected from the group consisting of: optionally substituted C1-20 alkyl; optionally substituted C5-20 aryl; optionally substituted acyl; optionally substituted sulfonyl; and optionally substituted amido. 9. The compound according to any of claims 1 to 4, characterized in that n is 1, X is CRXRY, R? is H and Rx is selected from the group consisting of: H; optionally substituted C1-20 alkyl; C5-2o aryl optionally substituted; optionally substituted C3-20 heterocyclyl; optionally substituted acyl; optionally substituted amino; optionally substituted amido and optionally substituted ester groups. The compound according to claim 9, characterized in that Het is furanylene or thiophenylene, and R x is selected from optionally substituted amino, wherein the amino groups are selected from H and C 1-20 alkyl or together with the nitrogen atom , form a heterocyclic group Cs-2o- 11. A A pharmaceutical composition characterized in that it comprises a compound according to any of claims 1 to 10 and a pharmaceutically acceptable carrier or diluent. The compound according to any of claims 1 to 10 characterized in that it is used in a method of treating the human or animal body. 13. The use of a compound according to any of claims 1 to 10 in the preparation of a medicament for preventing the formation of poly (ADP-ribose) chain by inhibiting the activity of cellular PARP (PARP-1 and / or PARP-2). The use of a compound according to any of claims 1 to 10 in the preparation of a medicament for the treatment of: vascular disease; septic shock; ischemic damage; reperfusion damage; neurotoxicity; hemorrhagic shock; inflammatory diseases; multiple sclerosis; side effects of diabetes; acute treatment of cytoxicity after cardiovascular surgery or diseases improved by the inhibition of PARP activity. 15. The use of a compound according to any of claims 1 to 10 in the preparation of a medicament for use as an adjunct in cancer therapy or for enhancing tumor cells for treatment with ionizing radiation or chemotherapeutic agents. The use of a compound according to claims 1 to 10 in the manufacture of a medicament for use in the treatment of cancer in an individual, wherein the cancer is deficient in the HRB-dependent DNA DSB repair pathway. 17 The use in accordance with the claim 16, wherein the cancer comprises one or more cancer cells which have a reduced or abrogated capacity to repair DNA DSB by HR in relation to normal cells. 18. Use in accordance with the claim 17, wherein the cancer cells have a deficient phenotype to BRCA1 and BRCA2. 19. The use according to claim 18, wherein the cancer cells are deficient in BRCA1 or BRCA2. 20. The use according to any of claims 16 to 19, wherein the individual is heterozygous for mutation in a gene which encodes a component of the HRB-dependent DNA DSB repair pathway. twenty-one . The use according to claim 20, wherein the individual is heterozygous for a mutation in BRCA1 and / or BRCA2. 22 The use according to any of claims 16 to 21, wherein the cancer is breast, ovarian, pancreatic or prostate cancer. 2. 3 . The use according to any of claims 16 to 22, wherein the treatment further comprises the administration of ionizing radiation or a chemotherapeutic agent.