OA17331A - Substituted phthalazin-1 (2H)-one derivatives as selective inhibitors of poly (ADPribose) polymerase-1. - Google Patents

Abstract

The present invention relates to novel compounds of general formula (I), their stereoisomers, regioisomers, tautomeric forms and novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them. The present invention also relates to a process of preparing novel compounds of general formula (I), their stereoisomers, regioisomers, their tautomeric forms, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutical compositions containing them, and novel intermediates involved in their synthesis.

Description

The présent invention relates to novel compounds of general formula (1), their stereoisomers, regioisomers, tautomeric forms and novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, pharmaceutically acceptable solvatés and pharmaceutical compositions containing them. The présent invention also relates to processes for preparing the novel compounds of general formula (I), their stereoisomers, regioisomers, their tautomeric forms, their pharmaceutically acceptable salts, pharmaceutically acceptable solvatés, pharmaceutical compositions containing them, and novel intermediates involved in their synthesis.

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The présent invention is further directed to compounds which cause sélective inhibition of the poly (ADP-ribose) polymerase-1.

BACKGROUND & PRIOR ART

Exploitation of synthetic léthal rclationship is a trustworthy therapeutic strategy to target genetic différences between tumor and normal cells which eventually provide large therapeutic window for the treatment of cancer. Poly (ADP-ribose) polymerase1(PARP-1, 113 kDa) is a prototype member of the 17 member PARP protein superfamily. PARP-1 is a nuclear protein whose zinc finger DNA binding domain localizes PARP-1 to the site of DNA damage. This NAD dépendent enzyme catalyzcs poly (ADP-ribosylatîon) of proteins, involved in the détection and repair of DNA damage. It plays a frontal rôle in the decision of a cell to live or to die in a stress situation [Senthil kumar B., Rajmohan, et al.. Mol. Cell. Biol. 2009, 29(/5), 41164129). The primary structure of the enzyme is highly conservcd in cukaryotes with

X human enzyme having 92% homology with mouse enzyme at the level of amino acid sequence and a 50 amino acid block showing 100% homology between vertebrates [Virag Laszlo and Szabo Csaba, Pharmacol. Reviews 2002, 54(3), 375-429]. Studies on the molecular mechanism of PARP-1 suggests that, it is involved in various DNA related fonctions including gene amplifications, cell division, différentiation, apoptosis, DNA base excision repair and also effects on telomere length and chromosome stability [d’Add di Fagogna et al., Nature Gen. 1999,23(70), 76-80].

It has been reported that PARP-1 modulâtes DNA repair and other processes and can produce long chains of poly (ADP-ribose) within the cell nucléus which is central to its activity [Althaus, F. R.; Richter, C. Mol. Biol., Biochem. Biophys. 1987, 37, 1237]. Different studies on knock out mouse models, report that the délétion of PARP1 impairs DNA repair but is not embryonically léthal. Double knock out PARP-1 and PARP-2 mice die during early embryogenesis, which shows that PARP-2 as the closest homolog of PARP-1 (62% identical in its catalytic domain to PARP-1) &

plays a major rôle in the DNA repair during the absence of PARP-1 enzyme [Ratnam Kapil and Law Jenifer A. Clin. Cancer Res. 2007, 17(5), 1383-1388]. A group of scientists from Newcastle University and University of Konstanz, in British Journal of Cancer 2009, 101(2), 256 - 26, daims to be the first to directly compare PARP-1 polymorphisme, cellular levels of PARP-1 protein and PARP activity in a systematic way and reveals that PARP activity dépends on other factors beside the level of protein and the active site SNP.

In a recent review from Free Radical Biology & Medicine 2009, 47, 13-26 suggests that PARP inhibitors could be used not only as chemo/radiotherapy sensitizers, but also as single agents to selectively kill cancers which are due to defect in DNA repair, spedfically cancers with mutations in the breast cancer-associated gene (BRCA1 and BRCA2). PARP becomes activated in response to oxidative DNA damage and depletes cellular energy pools, thus leadîng to cellular dysfonction in various tissues. The activation of PARP may also induce various cell death processes and promûtes an inflammatory response associated with multiple organ failure.

Recently some of the investigators hâve demonstrated in Biochem. Pharmacol. 2009,

77,1348-1357 that PARP inhibitors combined with DNA-damage inducing cytostatic ^y^-

I agents like taxol can lead to effective tumor therapy through activation of PI-3-kinaseAkt pathway.

The American Society of Clinical Oncology held its Annua! Meeting in Orlando, Florida (May 29-June 2, 2009) and as reported in Eur. J. Cancer 2009, 45, 1897 5 1901 that two drugs Olaparib and BSI-201 from a new class of targeted agents called poly (ADP-ribose) polymerase (PARP) inhibitors hâve demonstrated significant activity against hard-to treat breast cancers, according to findings from two separate phase II trials.

Several small molécules that specifîcally target PARP-1 enzyme as an inhibitor are 10 being investigated and among them BSI 201 (BiPar) is in Phase III clinical trial and

AG 14699 (Cancer Res. UK), AZD 2281 (KuDOS), ABT 888 (Abbott) are in Phase II clinical trial, with promising initial results. However, spécial attention must be paid to the possibility that enhanced therapeutic efïïcacy might be accompanied by increased off-target effects because of effect on DNA-repair mechanism in normal tïssues.

Recent findings hâve thrust poïy(ADP-ribose) polymerases (PARPs) into the limelight as potential chemotherapeutic targets as described in Nature Reviews Cancer 4 March 2010, 1-9. Crystal Structure of the Catalytic Domain of Human PARP2 in Complex with PARP Inhibitor ABT-888 repoted by [Herwig Schuler et al., Pharmacol. Biochemistry 2010,49,1056-1058]

Novel compounds which are sélective PARP-1 inhibitors, their préparation and their use in medicine hâve also been reported in WO 2002036576, WO 2006039545, WO

2007062413, WO	2004080976,	WO	2009093032,	WO	2008047082,	WO
2001042219, WO	2005066163,	WO	2006106326,	WO	2008146035,	WO
2006021801, US	20090192156,	WO	2012019427,	WO	2012071684,	WO

2012019426, WO 2012072033, which are incorporated as references in their entirety.

Synthesis of pthalazinone dérivatives of the following general formula and having the potential to inhibit PARP for the treatment of cancer or for potentiating tumor cells for the treatment with ionizing radiation or chemotherapeutic agents has been disclosed in US 2009/0192156 Al and WO 2009/093032 Al. uz—

Synthesis of thiophene carboxamide class of compounds as the combination of CHK and PARP inhibitors for the treatment of cancer is disclosed in WO 2008146035 Al and WO 2005066163 A2. Représentative compounds hâve the following general 5 formula,

R²

Wherein X is selected from NH, S and O. Y is selected from CH or N.

Crystalline form and improved method for the synthesis of particular pthalazinone dérivatives and use of the crystalline form as PARP-1 inhibitor has been reported in 10 WO 2008047082. Représentative compounds hâve the following structure:

o

Synthesis of 4-heteroarylmethyl substituted pthalazinone dérivatives has been disclosed in WO 2006021801 Al and WO 2004080976 Al 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 NR^X or CR^XR^Y; If X= NR^X then n is 1 or 2 and if X= CR^XR^Y then n is 1 ; R^x is selected from the group consisting of H, optionally substituted C1.20 alkyl, C1.20 aryl, C(3-20} heterocyclyl, thioamido, ester, acyl, and sulfonyl groups; R^Y is selected from H, hydroxyl, amino; R^x and R^Y may together form a spiro C3.7 cycloalkyl or heterocyclyl group; R^C1 and R⁰² are independently selected from the group consisting of H and ϋμ alkyl; R¹ is selected from H and halo; And Het is selected from where Y¹ is selected from CH and N, Y² is selected from CH and N, Y³ is selected from CH, CF and N, where one or two of Y¹, Y², and Y³ can be N; and wherein Q is O or S.

Optimization of Phenyl-Substituted Benzimidazole Carboxamide Poly(ADP-Ribose) 5-Benzamidoisoquinolin-l-ones and 5-(œ-Caiboxyalkyl)isoquinolin-l-ones as Isoform-Selective Inhibitors of Poly(ADP-ribose) Polymerase 2 (PARP-2) has been described in J. Med. Chem. 2011,54,2049-2059 by Peter T. Sunderland et. al.

Tumor Growth Inhibition by Olaparib in BRCA2 Germline-Mutated Patient-Derived Ovarian Cancer Tissue Xenografts has been recently published in Clin Cancer Res 2011,17,783-791.

Sîmultaneous détermination of ABT-888, a poly (ADP-ribose) polymerase inhibitor, and its métabolite in human plasma by liquîd chromatography/tandem mass spectrometry has been described in Journal of Chromatography B, 2011, 878, 333339.

“Evolution of Poly(ADP-ribose)Polymerase-l(PARP-l) inhibitors, From Concept to Clinic” a review article by Dana V. Ferraris has been published in J. Med. Chem. 2010, 53, 4561-4584, which describes in details of the efforts by different

V pharmaceutical industries and academie institutions in the development of the PARP inhibitors.«z' “Development of substituted6-[4-fiuoro-3-(piperazin-l -ylcarbonyl)benzyl]-4,5dimethylpyridazin-3-(2H)-ones as potent poly(ADP-ribose)polymerase -l(PARP-l) înhibitors active in BRCA déficient cells “ artcle has been published by Federica Ferrigno et al. in Bioorg. Med. Chem. Lett. 2010,20. 1100-1105.

‘Polymerase Inhibitors: Identification of (S)-2-(2-Fluoro-4-(pyrrolidin-2-yl)phenyl)lH-benzimidazole-4-carboxamide (A-966492), a ighly Potent and Efficacious Inhibitor’ has been described in J. Med. Chem., 2010,53, 3142-3153.

Design, synthesis of Quinoline-8-carboxamides, a new class of Poly (adenosinediphosphate-ribose) polymerase-1 (PARP-1) Inhibitor has been described in J. Med. Chem. 2009, 52. 868-877. Synthesis of 2-[(R)-2-methylpyrrolidin-2-yl]-l/Zbenzimida2ole-4-carboxamide as a Poly (ADP-ribose) Polymerase (PARP) Inhibitor has been disclosed in J. Med. Chem. 2009,52. 514-523.

Synthesis of aminoethyl pyrrolo dihydroisoquinolinones as novel poly (ADP-ribose) polymerase-1 inhibitors has been described in Bioorg. Med. Chem. Lett. 2009, 19, 4042-4045. Représentative compounds hâve the following general formula.

Synthesis of isoquinolinone-based tetracycles as poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors inhibitors has been described in Bioorg. Med. Chem. Lett. 2009, 19,7537-7541. Représentative compounds hâve the following general formula.

Identification of substituted pyrazolo[I,5-a]quinazolin-5(4H)-one as potent poly(ADP-ribose)poIymerase-l (PARP-1) inhibitors has been described in Bioorg.

Med. Chem. Lett. 2009, 19, 4196-4200. Représentative compounds hâve the following general formula

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Synthesis of novel tricydic quinoxalinone as the inhibitors of poly (ADP-ribose) polymerase-1 (PARP-1) has been stated in Bioorg. Med. Chem. Lett. 2009,19,40504054. Représentative compounds hâve the following general formula.

R²

Identification of ring-fused pyrazolo pyridin-2-ones as novel poly (ADP-ribose) polymerase-1 inhibitors has been published in Bioorg. Med. Chem. Lett. 2008, 18, 5126-5129. This describes compounds of the following general formula.

Discovery of Orally Active and Brain-Penetrable Quinoxalinone Inhibitors of Poly (ADP-ribose) polymerase has been disclosed in J. Med. Chem. 2004, 47, 4151-4154 and describes compounds of the following general formula.

Discovery of potent Poly(ADP-ribose) Polymerase-1 Inhibitors from the modification of Indeno[l,2-c]isoquinolinone and the described compounds of the following general 10 formula I has been reported in J. Med. Chem. 2005,48, 5100-5103.

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(1)

WO 2012 019426 discloses PARP inhibitors of the following general formula (I)

wherein: A and B are connected together to the carbon atoms to form a cycloalkyl group, heterocyclic group, aryl or heteroaryl group, Each of the ring atoms D or E is independently selected from C or N atoms; when n is 1, D and E are connected to one another to accomplish 6 ~ 10-membered ring X; This spécification is incorporated as reference in its entirety.

WO 2012 072033 discloses compounds of formula I or II, their isomers, salts, solvatés, chemically protected form, and prodrugs:

wherein the substituents are as defined in the spécification which is incorporated in 10 entirety as reference.

New Gen Therapeutics, Inc has published a patent WO 2012166983 and disclosed tricyclic inhibitors of poly(ADP-ribose)poIymerase.

Substituted 4-(4-fluoro-3-(piperazine-1 -carbonyl)benzyl)phthalazin-1 (2H)-one dérivatives as Poly (ADP-ribose) polymerase-1 inhibitors has been published in WO 15 2012014221 by Cadila Healthcare Ltd. and discloses the following general structure

Shanghai Institute of Materia Medica, Chinese Academy of Science disclosed 220 AryIbenzofuran-7-formamide compounds préparation method and use thereof in patent WO 2013117120 and mentions the following formula:

(I)

Merck disclosed tetrahydro-quinazolinone dérivatives as tankyrase and PARP inhîbitors in patent WO 2013/117288 and mentions the following general structure

O

Novel compounds having PARP inhibitory activity has been disclosed by Santen Pharmaceutical Co. Ltd. in a patent WO 2013/008872 and the following formula has been disclosed.

O

(I)

Fused tetra or penta- cyclic pyridophthalazinones as PARP inhîbitors hâve been reported by Belgena, Ltd. in a patent WO 2013097226.

AstraZeneca AB has published a patent US 8475842 for immédiate release pharmaceutical formation of 4-[3-4(cyclopropanecarbonyl-piperazine-l-carbonyl)-415 fluoro-benzyl]-2H-phthalazin-l-one.

BioMarin recently published a patent US 2013/0053365 and disclosed the formula (M)

-B Z

Y

R₃ formula (M)

Though several compounds hâve been reported in the literature as PARP-I inhibitors, very few hâve actually shown actual clinical benefits and none hâve been approved so far. Looking at the large unmet medical needs, there appears a need for developing 5 further compounds which hâve better safety and efïicacy profile. We herein disclose a new sériés of compounds which shows potential as PARP-I inhibitors.

SUMMARY OFTHE INVENTION

The présent invention describes novel compounds useful as poly (ADP-ribose) 10 polymerase-1 inhibitors. The compounds are defined by the general formula (I) below.

O

(I)

The compounds of the présent invention acts by inhibiting PARP1 enzyme to prevent the process of DNA repair and induce cell mediated apoptosis. As a resuit of 15 compromised repair, PARP-1 déficient or inhibited cells are more sensitive to DNA damaging agents (γ radiation, topoisomerase inhibitors, and alkylating agents).The compounds of the présent invention are sélective inhibitors of the poly (ADP-ribose) polymerase-1.

OBJECTS OFTHE INVENTION

The main object of the présent invention is to provide novel compounds of general formula (I), their stereoisomers, tautomeric forms, their regioisomers, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvatés and pharmaceutical compositions containing them or their mixtures and their use in medicine.

O

(I)

Another object of the présent invention is provided a process for the préparation of novel compounds of general formula (I), their stereoisomers, regioisomers and their tautomeric forms, novel intermediates involved in their synthesis, pharmaceutically acceptable salts, pharmaceutically acceptable solvatés and pharmaceutical compositions containing them.

Another object of the présent invention is to provide a method of treatment of diseases which can be treated or whose symptoms can be reversed with by adminîstering a therapeutically effective & non-toxic amount of the compound of formula (I) or their pharmaceutically acceptable compositions to the mammals.

DETAILED DESCRIPTION OFTHE INVENTION

The compounds of the présent invention are defined by the general formula (I) below:

O

(I) wherein ‘A’ and ‘B’ may be independently selected from hydrogen, alkyl or connected together to the carbon atoms to form a cycloalkyl, heterocyclyl , aryl or heteroaryl groups, wherein each of the said cycloalkyl, heterocyclyl, aryl or heteroaryl groups are further substituted independently by one or more substituent groups selected from alkyl, halogen, hydroxyl , alkoxy , cycloalkyl, heterocyclyl , aryl, heteroaryl, -C(O)OR^S, -OC(O)R^S, -O(CH₂)_PC(O)OR⁵, -C(O)R^S, -NHC(O)R⁵, NR⁶R⁷, -OC(O)NR⁶R⁷ or-C(O)NR⁶R⁷ groups.

R¹ at each occurrence is independently selected from H, halogen, or the groups selected from (Ci-Ci₂)alkyl, haloalkyl, cycloalkyl, alkylthio or the group (OSO2) alkyl, wherein each of these groups may be further substituted by suitable substituents selected from those disclosed hereinafter below; m = 1-4;

L=-O,-S,-NH;

R² is selected from substituent groups consisting of hydrogen atom, hydroxyl, alkyl, cycloalkyl, oxo, C(O)OR^S, -C(O)R^S, or -C(O)NR⁶R⁷, wherein said alkyl or cycloalkyl group may be further substituted by one or more substituents groups selected from halogen, hydroxyl, alkyl or alkoxy.

R³ and R⁴ are each independently selected from the groups such as hydrogen atom, alkyl , hydroxyl, alkoxy, cycloalkyl, - C(O)OR⁵, -OC(O)R^S, -O(CH2)pC(0)0R⁵, C(O)R⁵, -NHC(O)R^S, -NR⁶R⁷, -OC(O)NR⁶R⁷ or -C(O)NR⁶R⁷; altematively, R³ and R⁴ together form an oxo group;

Each of ring atoms ‘D’ and Έ* is independently selected from C or N atoms;

‘D’ and Έ’ are connected to one another to form 5 membered ring ‘X*, wherein ‘X’ is selected from the groups such as cycloalkyl, heterocyclyl, heteroaryl, wherein the cycloalkyl, heterocyclyl or heteroaryl groups is further substituted with one or more substituents selected from alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, benzyl, oxo, OR^S, -C(O)OR⁵, -OC(O)R⁵, -O(CH2)PC(O)OR^S, C(O)R⁵, S(O)nR^s, -NHC(O)R^S, NR⁶R⁷, -OC(O)NR⁶R⁷ or -C(ONR⁶R⁷, wherein the alkyl , cycloalkyl, heterocyclyl, aryl, heteroaryl or benzyl are each independently substituted further with one or more substituents selected from alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo,- C(O)OR⁵, OC(0)R⁵, O(CH₂)_pC(O)OR⁵, -C(O)R⁵, -S(O)nR^s„ -NHC(O)R⁵, NR⁶R⁷, OC(O)NR⁶R⁷ or-C(O)NR⁶R⁷ substituents;

R⁵ at each occurrence is independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups; wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each independently substituted by one or more substituents selected from alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid ester substituents. Each of R or R at each occurrence are independently selected from the groups consisting of hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups; wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each independently further substituted by one or more substituents selected from alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid ester substituents;

Altematively, R⁶ and R⁷ are joined together with nitrogen atom to form a heterocyclic ring; wherein said heterocyclic ring contains one or more heteroatoms selected from N, O, S(O)_n, furthermore the stated heterocyclic ring is further substituted with one or more substituents selected from alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid ester substituted substituents;

n is 0,1 or 2 and p is 0,1 or 2.

Suitable substituents wherever applicable and where substituents are not specifically mentioned includes, but are not limited to the following radicals, alone or in combination with other radicals, hydroxyl, oxo, halo, thio, nitro, amino, alkyl, alkoxy, haloalkyl or haloalkoxy groups.

The preferred heterocycles representing

may be selected from the following bicyclîc rings mentioned below

In another preferred embodiment, the groups representing the above may further be selected from those described hereinafter.

The “aryl” may be selected from phenyl, naphthyl, tetrahydronaphthyl, indenyl, 5 dihydroindenyl, biphenyl groups and each of these groups may be optionally substituted with one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, hydroxyl, haloalkyl, haloalkoxy, cyano, thioalkyl, cycloalkyl groups;

“Heteroaryl” or “hetero aromatic” is selected from suitable single or fused mono, bi or tricyclic aromatic heterocyclic radicals contai ni ng one or more hetero atoms selected 10 from O, N or S, more preferably the groups are selected from pyridyl, thienyl, furyl, pyrrolyl, indolinyl, indolyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, purinyl groups, each of these groups may be further optionally substituted with one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, hydroxyl, haloalkyl, haloalkoxy, aryl, aralkyl, 15 cyano, alkylthio, thioalkyl groups;

“Heterocyclyl” may be selected from suitable saturated, partially saturated or unsaturated aromatic or non-aromatic mono, bi or tricyclic radicals, containîng one or more heteroatoms selected from nitrogen, sulfur and oxygen, more preferably selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 220 oxopiperidinyl, 4-oxopiperidiny), 2-oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl, azepinyl, diazepinyl, oxapînyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thienopiperidinyl groups, each of these groups may be optionally substituted with one or more substituents selected from hydrogen, halogen, alkyl, aîkoxy, hydroxyl, haloalkyl, haloalkoxy, aryl, aralkyl, cyano, alkylthio, thioalkyl 5 groups;

In a further embodiment the groups, radicals described above may be selected from:

- the term“alkyl” used either alone or in combination with other radicals, dénotés a linear or branched radical contaîning one to six carbons, selected from methyl, ethyl, n-propyl, iso-propyl, π-butyl, sec-butyl, rerr-butyl, amyl, t-amyl, zi-pcntyl, n-hexyl, and the like;

- the term“alkoxy” used either alone or in combination with other radicals, is selected from groups contaîning an alkyl radical, as defîned above, attached directly to an oxygen atom, more preferably groups selected from methoxy, ethoxy, π-propoxy, iso-propoxy, n-butoxy, r-butoxy, ùo-butoxy, pentyloxy, hexyloxy, and the like;

- the term“haloalkyl” is selected from an alkyl radical, as defîned above, suitably substituted with one or more halogens; such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, buty), pentyl or hexyl groups;

- “Haloalkoxy” is selected from suitable haloalkyl, as defîned above, directly attached to an oxygen atom, more preferably groups selected from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy and the like;

- the term“a!kylthio” used either alone or in combination with other radicals, dénotés a straight or branched or cyclic monovalent substituent comprising an alkyl group as defîned above, linked through a divalent sulfur atom having a free valence bond from the sulfùr atom, more preferably the groups may be selected from methylthio, ethylthio, propylthio;

- the term “aralkyl” represents an aryl group as defîned above attached to an alkyl group as described above;

- “Heteroaralkyl” and “heterocyclyclakyl” represents heteroaryl and heterocyclyl groups respectively as defîned above attached to an alkyl group as defîned above.

The compounds of formula (I) may optionally be converted to their suitable pharmaceutically acceptable salts by processes as are known in the art. The novel compounds of the présent invention can further be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by 5 techniques and processes and concentrations as are well known.

The compounds of the présent invention modulate PARP-1 receptor and are usefùl as a therapeutic target for many diseases and especially for the treatment of cancer.

The compounds prepared according to présent invention include, but are not limited to:

Example 1:4’(3-(5-benzyloctahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-4fluorobenzyl)phthalazin-1 (2H)-one;

Example 2:2-benzyl-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l -yl)methyl) benzoyl)tetrahydropyrrolo[3,4-c]pyrrole-l,3(2H,3aH)-dione;

Example 3:4-(4-fluorO’3-(l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carbonyl) benzyl)phthalazin-l(2H)-one;

Example 4:4-(3-(5-(cyclopropanecarbonyl)octahydropyrrolo[3,4-c]pynOle-2carbonyI)-4-fl uorobenzyl)phthalazin-1 (2 H)-one;

Example 5:4-(3-(l-(cyclopropylmethyI)-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5carbonyl)-4-fl uorobenzyl)phthal azin-1 (2H )-one;

Example 6:4-(3-(5-(cyclopropylmethy!)octahydropynOlo[3,4-c]pyrrole-2-carbonyl)4-fluorobenzyl)phthalazin-l(2H)-one;

Example 7:4-(4-fl uoro-3 -(5-(2,2,2-tri fl uoroethyl)octahydropyrrolo [3,4-c] pyrrol e-2carbonyl)benzyl)phthalazin-1 (2H)-one;

Example 8:4-(3-(5-(cyclopropylmethyl)-l ,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole25 2-caibonyl)-4-fluorobenzyl)phthalazin-l (2H)-one;

Example 9:4-(3-(5-benzyloctahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-4fluorobenzyl)phthalazin-l (2H)-one hydrochloride;

Examplel 0:4-(4-fluoro-3-(5-(2-((3-fluorophenyl)thio)-2-methylpropanoyl) octahydropyrrolo[3,4-c]pyrrole-2-caibonyl)benzyl)phthalazin-l(2H)-one;

Example 11:2-benzyl-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazm-l-yl)methyl) benzoyl)tetrahydropyrrolo[3,4-c]pyrrole-l ,3(2H,3aH)-dione;

Example 12:4-(3-(l-(cyclopropanecarbonyl)-l,4,5,6-tetrahydropyrrolo[3,4-c] pyrazole-5-carbonyl)-4-fluorobenzyl)phthalazin-l(2H)-one;

Example 13: tert-butyl 5-(2-fluoro-5-((4-oxo-3,4-dihydrophthaIazin-l-yl)methyl) benzoyl) hexahydropyrrolo[3,4-c]pyrrole-2(l H)-carboxylate;

Example 14:4-(4-fluoro-3-(hexahydro-lH-ftiro[3,4-c]pynOle-5-carbonyl) benzyl)phthalazin-1 (2H )-one;

Example 15:4-(4-fluoro-3-(octahydropyrro1o[3,4-c]pyrrole-2-caibonyl) benzyî) phthalazin-1 (2H)-one;

Example 16:4-(4-fluoro-3-(5-(methyIsulfbnyl)octahydropyrrolo[3,4-c]pyrrole-2carbonyl)benzyl) phthalazin-l(2H)-one;

Example 17:4-(4-fluoro-3-(l-(rnethylsulfonyl)-l,4,5,6-tetrahydropyTTolo[3,4-c] pyrazole-5-carbonyl)benzyl)phthalazin-l(2H)-one;

Example 18:4-(3-(5-benzoyloctahydropynOlo[3,4-c]pyrrole-2-carbonyl)-4fluorobenzyl)phthalazin-1 (2H)-one;

Exampl e 19:4-(3-(5 -(2,4-di fluorobenzyl)octahydropynOlo[3,4-c] pyrrole-2-carbonyl )4-fluorobenzyl) phthalazin-1 (2H)-one;

Example 20:4-(3-(5,6-dihydro-4H-furo[3,4-c]pyrrole-5-carbonyl)-4-fluorobenzyl) phthalazin-1 (2H)-one;

Example 21:4-(4-fluoro-3-(5-methyloctahydropynOlo[3,4-c]pyrrole-2-carbonyl) benzyl)phthalazin-1 (2H)-one;

Example 22: 5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l-yl)methyl)benzoyl) tetrahydropyrrolo[3,4-c]pyrrole-1,3 (2H,3 aH)-dione;

Example 23:4-(4-fluoro-3-(octahydrocyclopenta[c]pyrrole-2-carbonyl)benzyl) phthalazin-1 (2H)-one;

Example 24:4-(4-fluoro-3-(5-(4-fluorobenzyl)octahydropyiTOlo[3,4-c]pynOle-2carbonyl)benzyl) phthalazin-l(2H)-one;

Example 25:4-(4-fluoro-3-(5-(2-fluorobenzyl)octahydropyrrolo[3,4-c]pyrrole-2carbonyl)benzyl) phthalazin-1 (2 H)-one;

Example 26:4-(4-fluoro-3-(5-(2-4-(4-fluoro-3-(5-((6-methoxypyridin-2-yl)methyl) octahydropyrrolo [3,4-c]pyrrole-2-caibonyl)benzyl)phthalazin-l(2H)-one;

Example 27: 5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l-yl)methyl)benzoyl)-2methyl tetrahydropyrrolo[3,4-c]pyrrole-l,3(2H,3aH)-dione;

Example 28:4-(4-fluoro-3-(l-methyl-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5carbonyl)benzyl)phthalazin-l(2H)-one compound with 4-(4-fluoro-3-(2-methyl2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carbonyl)benzyl)phthalazin-l(2H)-one (1:3);

Example 29:4-(3-(2,2-dioxido-3,4,5,6-tetrahydro-lH-thieno[3,4-c]pyrrole-5carbonyl)-4-fluorobenzyl) phthalazin-1 (2 H)-one;

Example 30:4-(3-(5,6-dihydro-4H-thieno[3,4-c]pyrrole-5-caibonyl)-4-fluorobenzyl) phthalazin-1 (2H)-one;

Example 31:4-(4-fluoro-3-(l,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole-2-carbonyl) benzyljphthalazin-1 (2H)-one;

Example 32:4-(4-fluoro-3-(5-phenyloctahydropyrrolo[3,4-c]pyrrole-2-carbonyl) benzyl)phthalazin-l (2H)-one;

Example 33:4-(4-fluoro-3-(5-methyl-l ,2,3,4,5,6-hexahydropyrrolo[3,4-c]pynOle-2carbonyl)benzyl) phthalazin-1 (2 H)-one;

Example 34:4-(3-((3aR,8bR)-decahydropyrrolo[3,4-a]pyrrolizine-2-carbonyl)-4fluorobenzyl)phthalazin-1 (2H)-one;

Example 35:4-(4-fluoro-3-(2-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5carbonyl)benzyl)phthal azi η-1 (2 H)-one;

Example 36:4-(4-fluoro-3-(l -methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5carbonyl)benzyl) phthalazin-1 (2H)-one;

Example 37:2-((5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l-yl)methyl) benzoyl) hexahydropyrrolo [3,4-c]pyrrol-2(l H)-yl)methyl)-6-methoxypyridine-l -oxide;

Exampl e 3 8:4-(3-(5-(d i fluoromethyl)octahydropyrrolo [3,4-c] pyrrol e-2-carbonyl)-4fluorobenzyl) phthalazin-l(2H)-one;

Example 39:4-(4-fluoro-3-((3aR,baS)-5-oxooctahydrocydopenta[c]pyrrole-2carbonyl)benzyl) phthalazin-1 (2H)-one;

Example 40: Mixture of 1 & 2 Ethyl 4-(3-(2,4,5,6-tetrahydropynOlo[3,4-c]pyrazole-5 carbonyl)-4-fl uorobenzyl)phthalazin-1 (2 H)-one;

Example 41:4-(3-(2-ethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carbonyl)-4fluorobenzyl)phthalazin-l (2H)-one;

Example 42:4-(3-( 1 -ethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carbonyl)-4fluorobenzyl)phthal azin-1 (2 H)-one;

Example 43:4-(4-fluoro-3-(l-isopropyl-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5carbonyl)benzyl) phtha!azin-l(2H)-one;

Example 44: Mixture of (1 & 2 isopropyl ) 4-(4-fluoro-3-( 1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol e-5-carbonyl)benzyl)phthalazin-1 (2H)-one;

Example 45:4-(4-fluoro-3-(2-isopropyl-2,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol e-5carbonyl)benzyl) phthalazin-l(2H)-one;

Example 46:4-(3-((3aÆ,6aS)-5,5-difluorooctahydrocyclopenta[c]pyrrole-2-carbonyl)4-fluorobenzyl)phthalazin-1 (2H)-one;

Example 47:4-(4-fluoro-3-(5-(2-methoxyethyl)octahydropyrTolo[3,4-c]pyrrole-210 carbonyl)benzyl) phthalazin-1 (2H)-one;

Example 48: N-((3a/?,6aS)-2-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l -yl)methyl) benzoyl)octahydrocyclopenta[c]pyrrol-5-yl)cyclopropanecarboxamide;

Example 50:4-(4-fluoro-3-(l-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5carbonyl)benzyl) phthalazin-1 (2 H)-one hydrobromide;

Example 51:4-(4-fluoro-3-(l-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5carbonyl)benzyl) phthalazin-1 (2 H)-one hydrochloride;

Example 52:4-(4-fluoro-3-(l-methyl-l,4,5,6-tetrahydropynOlo[3,4-c]pyrazole-5carbonyl)benzyl) phthalazin-l(2H)-one sulfate;

Example 53:4-(4-fluoro-3-(l-methyl-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-520 carbonyljbenzyl) phthalazin-1 (2H)-one 4-methylbenzenesulfonate;

Example 53:4-(4-fluoro-3-(l-methyl-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5caibonyl)benzyl) phthalazin-1 (2H)-one benzenesulfonate;

Example 54: 5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l-yl)methyl)benzoyl)-2îsopropyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-2-ium hydrogensulfate;

Example 55:4-(3-( 1 -cyclopropyl-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazo!e-5carbonyl)-4-fluorobenzyl) phthalazin-1 (2H)-one;

Suitable groups and substituents on the groups may be selected from those described anywhere in the spécification.

The compounds of the présent invention may be prepared using the methods 30 described below, together with conventional techniques known to those skilled in the art of organic synthesis, or variations thereon as appreciated by those skilled in the art.

Referred methods include, but are not limited to those described below, where ail symbols are as defined earlier.

The compounds of the présent invention can be prepared according to the following schemes 1

Scheme 1:

Reagents and conditions:, DMF, TBTU, triethylamine, 0-27 °C. 2-6 h

Synthesis of compound of general formula (I)

General process of préparation:

The Compounds of the general formula (II) can be synthesized by processes reported for e.g. în J. Med. Chem. 2008,51, 6581-6591 with suitable modifications/alterations as required which are within the skills of a skilled person.

Compounds of the general formula (I) can be synthesized by coupling the compounds of the general formula (III) with the compounds of the general formula (II), using suitable coupling agents such as O-(Benzotriazol-l-yl)-N,N,N*,N’tetramethyluronium-tetrafluoroborate(TBTU),dimethylaminopyridine(DMAP), dicyclohexylcatbodiimide (DCC), hydroxybenzotriazole (HOBt.HîO), and l-EthyI-3(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl) & the like in the presence of organic bases such as DIPEA, TEA, pyridine, & the like in the solvents such as tetrahydrofiiran, dimethyl formamide, dichloromethane, chloroform & the like or their suitable mixtures at ambient température.

The invention is further exemplified by the following non-limiting examples which are provided for exemplifying the invention and should not be construed as lîmiting the scope of the invention in any ways. It will be appreciated that the other embodiments which are not exemplified can be easily practiced by a skilled person using his routine skills after reading the spécifie examples provided below. Such changes/alterations/modifications etc. which may be required to practice the full scope of the invention as described and claimed in the présent invention are well within the scope of a person skilled in the art.

Unless otherwise specified, 1H NMR spectral data given in the examples are recorded using a 400 MHz spectrometer (Broker Topspin 2.0) and reported in 6 scale. Tetra methyl silane is used as the internai standard.

Example 1

Synthesis of 4-(3-(5-benzyloctahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-4fluorobenzyl)phthalazin-l (2H)-one.

o

To a solution of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l-yl)methyl)benzoic acid (1 g, 3.35 mmol) in dry DMF (15 mL) was added TBTU (1.292 g, 4.02 mmol) at room température under atmosphère of nitrogen. To this 2benzyloctahydropyrrolo[3,4-c]pyrrole (0.678 g, 3.35 mmol) and DIPEA (1.32 mL, 6.71 mmol) were added. The reaction mixture was stirred at room température for 2 h. The progress of reaction was checked by TLC by using mobile phase 5 % methanol in chloroform. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous NaiSCU and solvents were evaporated on a rotatory evaporator under reduced pressure to crode solid which was purified by the flash column chromatography using eluent chloroform : methanol (97 : 3) to afford 4-(3-(5-benzyloctahydropyrrolo[3,4-c]pyrro!e-2-carbonyl)-4-fluorobenzyl) phthalazin-l(2H)-one as white solid (1.19 g, 74 %).

'H-NMR (400 MHz, DMSO-d₆)5 12.59 (s, 1H), 8.25 (dd, J= 7.6 Hz & 0.6 Hz, 1H), 7.94 (d, J= 7.6 Hz, 1H), 7.86 - 7.80 (m, 2H), 7.35 (m, 1H), 7.32 (dd, 1H), 5.29 - 7.24 (m, 4H), 7.23 - 7.20 (m, 2H), 4.32 (s, 2H ), 3.63 (m, 1H), 3.47 (m, 1H), 3.46 (m, 2H), 3.36 (m, 1H),2.9(dd, 1H),2.60-2.8(m,3H),2.51 -2.49(m,2H),2.1 (m, 1H).

Example 2 &—

2-benzyl-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l-yl)methyl)benzoyl) tetrahydropyrrolo[3,4-c]pyrrole-l,3(2H,3aH)-dione.

’H-NMR (400 MHz, DMSO-4s) δ 12.59 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.807.89(m, 3H), 7.41 - 7.43 (m, 1 H), 7.13 - 7.40 (m, 7H), 4.55 (s, 2H ), 4.26 (s, 2H), 4.15-4.17 (brd, 1H), 3.50-3.62 (m, 4H), 3.37-3.40 (brd, 1H).

Example 3

4-(4-fluoro-3-(l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoIe-5-carbonyl)benzyl) phthalazin-1 (2H)-one.

’H-NMR (400 MHz, DMSO-</₆)8 12.74 (s, 1H), 12.58 (s, 1H), 8.25 (d, J= 7.6 Hz, 1H), 7.97 (dd, J = 8 & 3.6 Hz, 1H), 7.80 - 7.90 (m, 2H), 7.42-7.59 (m, 3H), 7.25 (t, J = 9 Hz, 1H), 4.56 (s, 2H ), 4.35 (s, 2H ), 4.25-4.29 (brd, 2H ).

Example 4

4-(3-(5-(cyclopropanecarbonyl) octahydropyrrolo [3,4-c]pyrrole-2-carbonyl)-4fluorobenzy!)phthalazin-l (2H)-one.

’H-NMR (400 MHz, DMSO-J₀)8 12.59 (s, 1H), 8.24 (d, J = 1.2 Hz, 1H), 7.96 (dd, J = 8 & 4.8 Hz, IH), 7.82 - 7.90 (m, 2H), 7.40 (dd, J= 6.8 & 5.2 Hz, 2H), 7.23 (dd, J= 9.6 & 3.6 Hz, 2H), 4.32 (s, 2H ), 3.89-3.90 (brt, 1H), 3.70-3.80 (m, 1H), 3.50-3.60 (m,

1H), 3.40-3.49 (m, 2H), 3.22-3.26 (m, 2H), 3.11 - 3.16 (m, 2H), 2.90-3.0 (m, 1H),

1.17-1.25 (m, 1H), 0.69-0.72 (brt, 4H).

Example 5

4-(3-(l-(cyclopropylmethyl)-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carbonyl)-45 fluorobenzyljphthalazin-1 (2H)-one

1H NMR (400 MHz, DMSO-d6): 6 12.77 (brs, 1H), 8.30 (d, J= 7.6 Hz, 1H), 8.03 (dd, J= 7.6 & 4.8 Hz, 1H), 7.83-7.91 (m, 2H), 7.46-7.58 (m, 3H), 7.24-7.29 (brt, 1H), 4.57 (s, 2H), 4.37 (s, 2H), 4.25-4.29 (brd, 2H), 4.0 (d, J= 7.2 Hz, 2H), 1.12-1.19 (m, 1H), 10 0.35-0.47 (m,4H).

Example 6

4-(3-(5-(cyclopropylmethyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-4fluorobenzyl)phthalazin-1 (2H)-one

1H NMR (400 MHz, CDC13): δ 10.30 (s, 1H), 8.44-8.47 (m, 1H), 7.70-7.79 (m, 3H),

7.35 (dd, J= 6.4 & 2.4 Hz, 1H), 7.26-7.31 (m, 1H), 7.0-7.05 (brt, 1H), 4.27 (s, 2H ), 3.75-3.76 (brd, 2H), 3.45-3.47 (m, 1H), 2.88-3.24 (m, 4H), 2.36-2.52 (m, 5H), 0.98 (brs, 1H), 0.56-0.58 (brd, 2H), 0.19-0.58 (brd, 2H).

Example 7

4-(4-fl uoro-3-(5 -(2,2,2-trifluoroethyl)octahydropyrrol o [3,4-c] pyrrol e-2-carbonyl) benzyl)phthalazin-1 (2H)-one

CF,

1H NMR (400 MHz, In CDC13): δ 10.28 (s, 1H), 8.45-8.47 (m, 1H), 7.70-7.77 (m,

3H), 7.36 (dd, J=6.4 & 2.4, 1H), 7.26-729 (m, 1H), 6.99-7.04 (m, 1H), 4.27 (s, 2H ),

3.86-3.91 (m, 1H), 3.61-3.65 (m, 1H), 3.48-3.53 (m, 1H), 3.15-3.19 (m, 1H), 3.0-3.07 (m, 1H), 2.86-2.99 (m, 1H), 2.69-2.82 (m, 3H), 2.50-2.53 (m, 1H)

Exemple 8

4-(3-(5-(cyclopropylmethyl)-123»4,5,6-hexahydropyrrolo[3,4-c]pynOle-2-caibonyl)4-fluorobenzyl)phthal azin-1 (2H)-one

1H NMR (400 MHz, DMSO-d6): δ 12.59 (s, 1H), 8.27 - 8.25 (m, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.91 - 7.87 (m, 1H), 7.83 (dd, J = 7.6 Hz & 1.2 Hz, 1H), 7.42 (dd, J = 10.4 Hz & 52 Hz, 2H), 7.26 - 7.22 (m, 1H), 4.32 (s, 2H ), 4.23 (s, 2H), 3.92 (s, 2H), 3.78 - 3.46 (m, 3H), 3.42 (s, 1H), 2.69 - 2.66 (m, 1H), 1.0 - 0.7 (m, 1H), 0.5 - 0.035 (m, 2H), 02 (m, 2H).

Example 9

4-(3-(5-benzyloctahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-4-fluorobenzyl)phthalazin1 (2H)-one hydrochloride

1H NMR (400 MHz, DMSO-d6): δ 12.62 (s, 1H), 10.81 (s, 1H), 8.26 (m, 1H), 8.32

- 7.98 (m, 1H), 7.87 - 7.61 (m, 1H), 7.59 (dd, 1H), 7.53 (dd, 1H), 7.44 (m, 4H), 7.38

- 7.35 (m, 1H ), 7.27 - 7.19 (m, 1H), 4.39 - 4.31 (m, 4H), 3.72 (d, 1H), 3.28 (m, 1H), 3.16 (m, 2H), 2.99 - 2.89 (m, 2H), 2.73 - 2.49 (m, 2H).

ExamplelO

4-(4-fIuoro-3-(5-(2-((3-fluorophenyl)thio)-2-methylpropanoyl)octahydropyrTolo[3,4c]pyrrole-2-carbonyl)benzyl)phthalazin-l(2H)-one ,λ/'

Ο

1Η NMR (400 MHz, DMSO-d6): δ 12.58 (s, 1H), 8.25 (d, J = 6.4 Hz, 1H), 7.90 (d,

1H), 7.88 (ζ 1H), 7.82 (t, 1H), 7.37 (d, J = 6.4 Hz, 1H), 7.34 (m, 2H), 7.19 (t, 2H),

7.1 (m, 2H), 4.45 (d, 2H), 4.39 (t, 4H ), 4.30 (s, 2H), 3.43 - 3.36 (m, 3H), 3.17 (d,

2H), 1.4 (s, 6H).

Example 11

2-benzyl-5-(2-fIuoro-5-((4-oxo-3,4-dihydrophthaIazin-1 -yl)methy))benzoyl) tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione o

o ‘H NMR (400 MHz, DMSO-dé): δ 12.59 (s, 1H), 8.25 (dd, J = 7.6 Hz & 0.6 Hz, 1H),

7.94 (d, J = 7.6 Hz, 1H), 7.86 - 7.80 (m, 2H), 7.35 (m, 1H), 7.32 (dd, 1H), 5.29 - 7.24 (m, 4H), 7.23 - 7.20 (m, 2H), 4.32 (s, 2H ), 3.63 (m, 1H), 3.47 (m, 1H), 3.46 (m, 2H),

3.36 (m, 1H),2.9(dd, 1H),2.60-2.8(m,3H),2.51 -2.49(m,2H),2.1 (m, 1H)

Example 12

4-(3-(l-(cyclopropanecaTbonyl)-l,4,5,6-tetrahydropynOlo[3,4-c]pyrazo!e-5-carbonyl)

-4-fluorobenzyl)phthalazin-l (2H)-one

1H NMR (400 MHz, DMSO-d6): δ 12.57-12.60 (brd, 1H), 8.26 (d, J= 7.6 Hz, 1H), 7.97 (d, J= 7.6 Hz, 1H), 7.69-7.92 (m, 3H), 7.45-7.49 (m, 2H), 7.25-7.30(brt, 1H), 4.80(brs, 2H), 4.37 (brs, 2H), 4.34 (s, 2H), 4.28(brs,lH), 2.97-3.0 (m, 1H), 1.07-1.23 (m,4H).

Example 13 tert-butyl 5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l-yl)methyl)benzoyl) hexahydropyrTolo[3,4-c]pyrrole-2(lH)-carboxylate o

1H NMR (400 MHz, DMSO-d6): δ 12.59 (s, 1 H), 8.25 (t, J = 8 Hz, 1 H), 7.97 (d, J = 8

Hz, 1H), 7.82-7.88 (m, 2H), 7.39-7.41 (m, 2H), 7.21-7.23 (brt, 1H), 4.32 (s, 2H ), 3.68 (brs, 1H), 3.50 (brd, 2H), 3.39-3.41 (brd, 2H), 3.00-3.03 (brt, 2H), 2.81-2.89 (brd, 2H), 1.39 (s, 9H).

Example 14

4-(4-fluoro-3-(hexahydro-lH-furo[3,4-c]pyrrole-5-carbonyl)benzyl)phthalazin-l(2H)one

1H NMR (400 MHz, DMSO-d6): δ 12.59 (s, 1H), 8.26 (dd, J= 7.6 & 0.8 Hz, 1H),

7.97 (d, J= 8 Hz, 1H), 7.80-7.89 (m, 2H), 7.39-7.43 (m, 1H), 8.35 (dd, J= 6.4& 2 Hz, 15 1H), 7.19-7.23 (brt, 1H), 4.32 (s, 2H), 3.74-3.78 (m, 1H), 3.64-3.69 (m, 2H), 3.333.55 (m, 4H), 3.01-3.02 (m, 2H), 2.91-3.07 (m, 2H).

Example 15

4-(4-fluoro-3-(octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzyl)phthalazin-l(2H)20 one

NH

1H NMR (400 MHz, DMSO-d6): δ 12.60 (s, 1H), 8.26 (dd, J = 7.6& 0.8 Hz, 1H),

7.96 (d, J = 7.6 Hz, 1 H), 7.82 - 7.88 (m, 2H), 7.32 - 7.34 (m, 1 H), 7.18 - 7.23 (m, 1H), 4.32 (s, 2H ), 3.67-3.72 (m, 1H), 3.30-3.40 (m, 2H),2.77-2.96 (m, 2H), 2.582.73 (m, 4H), 2.41-2.44 (m, 1H).

Example 16

4-(4-fluoro-3-(5-(methylsulfonyl)octahydropyrrolo[3,4-c]pynOle-2-carbonyl)benzyl) phthalazin-1 (2H)-one

1H NMR (400 MHz, DMSO-d6): δ 12.58 (s, 1H), 8.26 (dd, J = 8 &1.2 Hz, 1H), 7.96 · (d, J = 8 Hz, 1H), 7.82-7.89 (m, 2H), 7.39-7.41 (brd, 2H), 7.19-7.24 (m,lH),4.32 (s, 2H ), 3.69-3.74 (m, 1H), 3.39-3.50 (m, 5H), 2.98-3.15 (m, 4H), 2.91 (s, 3H).

Example 17

4-(4-fluoro-3-(l-(methylsulfonyl)-l,4,5,6-tetrahydropyrTolo[3,4-c]pyrazole-5carbonyl)benzyl)phthalazin-l (2H)-one o

1H NMR (400 MHz, DMSO-d6): δ 12.59 (brd, 1H), 8.26 (d, J= 7.6 Hz, 1H), 7.97 (d, J= 8 Hz, 1H), 7.72-7.90 (m, 3H), 7.47-7.50 (m, 2H), 7.29-7.30(m, 1 H), 4.81 (brs, 1H), 4.58 (brs, 2H), 4.34 (brs, 1H), 3.52-3.57(brd, 3H).

Example 18

4-(3-(5 -benzoyloctahydropyrrolo[3,4-c] pyrrol e-2-carbonyl)-4-fl uorobenzyl) phthalazin-1 (2H)-one

Ο

1Η NMR (400 MHz, DMSO-d6): δ 12.59 (s, 1H), 8.25 (d, J = 7.2 Hz, 1H), 7.80 -

7.96 (m, 3H), 723-7.50 (m, 7H), 7.21-7.23 (m,lH), 4.30-4.33 (brd, 2H ), 3.38-3.75 (m, 5H).

Example 19

4-(3-(5-(2,4-difluorobenzyI)octahydropyrrolo[3,4-c]pyrro!e-2-carbonyl)-4fluorobenzyl)phthalazin-l (2H)-one

1H NMR (400 MHz, CDC13): δ 12.59 (s, 1H), 8.44-8.46 (m, 1H), 7.69-7.78 (m, 3H),

7.31-7.37 (m, 2H), 7.26-7.29 (m, 1H), 6.99-7.04 (brt, 1H), 6.75-6.86 (m, 2H), 4.27 (s,

2H), 3.83-3.88 (m, 1H), 3.60-3.66 (m, 4H), 3.14-3.18 (m, 1H), 2.51-2.88 (m, 5H),

2.33-2.35 (m, 1H).

Example 20

4-(3-(5,6-dihydro-4H-furo[3,4-c]pyrrole-5-carbonyl)-4-fIuorobenzyl)phthalazin15 l(2H)-one

1H NMR (400 MHz, DMSO-d6): δ 12.59 (s, 1H), 8.26 (dd, J = 7.6 Hz & 1.2 Hz,

1H), 7.97 (d, J = 7.6 Hz, 1H), 7.91 - 7.87 (m, 1H), 7.85 - 7.81 (m, 1H), 7.53 (d, J =

1.2 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.41 - 7.40 (d, J = 1.2 Hz, 1H ), 7.28 - 7.23 (m,

1 H), 4.56 (s, 2H), 4.34 (s, 2H), 4.26 (s, 2H).

Example 21

4-(4-fluoro-3-(5-methyloctahydropynOlo[3,4-c]pyrro]e-2-carbonyl)benzyl)phthalazin· l(2H)-one

1H NMR (400 MHz, CDC13): 69.90 (s, 1H), 8.44-8.47 (m, 1H), 7.70-7.79 (m, 3H),

7.27-7.52 (m, 2H), 6.99-7.04 (brq, 1H), 4.26 (s, 2H ), 3.85-3.90 (m, 1H), 3.62-3.64 (m, 1H), 3.44-3.51 (m, 1H), 3.19-3.21 (m, 1H), 2.73-2.97 (m, 4H).

Example 22

5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l10 yl)methyl)benzoyl)tetrahydropyrrolo[3,4-c]pyrrole-l ,3(2H,3aH)-dione o

1H NMR (400 MHz, DMSO-d6): δ 12.58 (s, 1H), 11.4 (s, 1H), 8.26 (dd, J = 7.6 Hz & 0.8 Hz, 1H), 7.87 - 7.96 (m, 2H), 7.80-7.85 (m, 1H), 7.41-7.43 (m, 1H), 7.37 (dd, J = 6.4 Hz & 2.4 Hz, 1H), 7.20- 7.24 (brt, 1H), 4.31 (s, 2H ), 4.09-4.12 (brd, 1H), 3.3815 3.58 (m,5H).

Example 23

4-(4-fluoro-3-(octahydrocyclopenta[c]pyrrole-2-caibonyl)benzyl)phthalazin-l(2H)one o

1H NMR (400 MHz, CDC13): δ 10.04 (s, 1H), 8.44-8.46 (m, 1H), 7.70-7.77 (m, 3H), 7.24-7.33 (brt, 1H), 7.01-7.03 (τη, 1H), 6.99-7.03 (bit, 1H), 4.26 (s, 2H), 3.79-3.84 (m, 1H), 3.43-3.49 (m, 2H), 3.0-3.04 (m, 1H), 2.60-2.72 (m, 2H), 1.49-1.88 (m, 6H). Example 24

4-(4-fluoro-3-(5-(4-fluorobenzyl)octahydropyTrolo[3,4-c]pyrrole-2-carbony!)benzyl) phthalazin-1 (2H)-one

1H NMR (400 MHz, CDC13): δ 10.18 (s, 1H), 8.44-8.46 (m, 1H), 7.69-7.76 (m, 3H),

7.33-7.35 (m, 1H), 7.25-7.34 (m, 3H), 6.96-7.04 (m, 3H), 4.27 (s, 2H ), 3.83-3.88 (m, 1H), 3.45-3.64 (m, 4H), 3.13-3.17 (m, 1H), 2.80-2.90 (m, 2H), 2.62-2.63 (m, 1H), 2.49-2.52 (m, 2H), 2.28-2.31 (m, 1H).

Example 25

4-(4-fluoro-3-(5-(2-fluorobenzyl)octahydropyrrolo[3,4-c]pyiTole-2-carbonyl)benzy!) phthalazin-1 (2H)-one

1H NMR (400 MHz, CDC13): δ 10.09 (s, 1H), 8.44-8.46 (m, 1H), 7.69-7.76 (m, 3H),

7.34-7.37 (m, 2H), 7.21-7.28 (m, 2H), 6.99-7.12 (m, 3H), 4.26 (s, 2H ), 3.84-3.89 (m, 1H), 3.59-3.65 (m, 3H), 3.45-3.50 (m, 1H), 3.14-3.18 (m, 1H), 2.8-2.9 (m, 2H), 2.672.69 (m, 1H), 2.53-2.61 (m, 2H), 2.33-2.36 (m, 1H).

Example 26

4-(4-fluoro-3-(5-(2-4-(4-fluoro-3-(5-((6-methoxypyridin-2-yl)methyl) octahydropyrTolo[3,4-c]pynOle-2-carbonyl)benzyl)phthalazin-l (2H)-one

IH NMR (400 MHz, CDC13): δ 10.19 (s, 1H), 8.43-8.46 (m, 1H), 7.69-7.76 (m, 3H), 7.51-7.55 (m, 1H), 7.34-7.36 (m, 1H), 7.26-7.28 (m, 1H), 7.0-7.04 (brt, 1H), 6.95 (d, J = 6.8 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 4.26 (s, 2H ), 3.91 (s, 3H), 3.85-3.91 (m,

1H), 3.18-3.22 (m, 1H), 2.60-2.79 (m, 5H), 2.08-2.44 (m, 1H).

Example 27

5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l-yl)methyl)benzoyl)-2-methyl tetrahydropyrrolo[3,4-c]pyrrole-l,3(2H,3aH)-dione

1H NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1H), 8.45-8.47 (m, 1H), 7.74 - 7.82 (m,

2H), 7.69-7.71 (m, 1H), 7.26-7.34 (m, 2H), 7.02- 7.06 (m, 1H), 4.45-4.49 (brd, 1H ),

4.26 (s, 2H), 3.58-3.69 (m, 2H), 3.36-3.46 (m, 2H), 3.0 (s, 3H).

Example 28

Mixture of 4-(4-fluoro-3-(l-methyI-l ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-515 caibonyl)benzyl)phthalazin-l(2H)-one compound with 4-(4-fluoro-3-(2-methyl2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carbonyl)benzyl)phthalazin-l(2H)-one (1:3)

O O

I

1H NMR (400 MHz, DMSO-d6): δ 12.59 (s, 1H), 8.24-8.27 (m, 1H), 7.96-7.99 (m,

1H), 7.81-7.90 (m, 2H), 7.43-7.56 (m, 3H), 7.23-7.27 (m, 1H), 4.54 (s, 2H), 4.33 (s,

2H), 4.23-4.27 (brd, 2H), 3.82 (s, 3H).____

Example 29

4-(3-(2,2-d ioxido-3,4,5,6-tetrahydro-1 H-thieno[3,4-c] pyrrole-5-carbonyl)-4fluorobenzyl)phthalazin-l (2H)-one

1H NMR (400 MHz, DMSO-d6): δ 12.58 (s, 1H), 8.27 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 8 Hz, 1 H), 7.91 (dd, J = 14 Hz & 6.8 Hz, 1 H), 7.85 - 7.81 (m, 1 H), 7.45 - 7.44 (m, 2H), 7.28 - 7.23 (m, 1H), 4.35 - 4.32 (d, 4H ), 4.06 (s, 2H), 4.007 (s, 2H), 3.88 (s, 2H).

Example 30

4-(3-(5,6-dihydro-4H-thieno[3,4-c]pyrrole-5-carbonyl)-4-fluorobenzyl)phthalazinl(2H)-one

1H NMR (400 MHz, DMSO-d6): δ 12.58 (s, 1H), 8.26 (dd, J = 8 Hz & 1.2 Hz, 1 H),

7.97 (d, J = 7.6 Hz, 1H), 7.91 - 7.87 (m, 1H), 7.85 - 7.81 (m, 1H), 7.46 - 7.43 (m, 2H), 7.29 - 7.23 (m, 2H), 7.16 (m, 1H ), 4.59 (s, 2H), 4.34 (s, 2H), 4.29 (s, 2H). Example 31

4-(4-fluoro-3-( 1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzyl) phthal azin-1 (2 H)-one

NH

1H NMR (400 MHz, DMSO-d6): δ 12.59 (s, 1H), 8.26 (m, J = 7.6Hz & 1.2 Hz, 1H),

7.96 (d, J = 7.6 Hz, 1H), 7.90 - 7.84 (m, 1H), 7.82 - 7.80 (m, 1H), 7.44 - 7.40 (m,

2H), 7.22-7.21 (m, 1 H), 4.32 (s, 2H ), 4.26 - 4.19 (d,2H), 3.96-3.87 (d,2H), 3.63

- 3.59 (d, 2H), 3.58 - 3.48 (d, 2H).

Example 32

4-(4-fiuoro-3-(5-phenyloctahydropyrrolo[3,4-c]pyTrole-2-carbonyl)benzyl)phthalazinl(2H)-one

1H NMR (400 MHz, DMSO-d6): δ 12.58 (s, 1H), 8.25 (dd, J=7.6 & 1.2 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.80-7.85 (m, 2H), 7.36-7.42 (m, 2H), 7.14-7.23 (m, 3 H), 6.62 (t, J=7.6 Hz, 1H), 6.52 (d, J=8 Hz, 2H), 4.31 (s, 2H ), 3.74-3.79 (m, 1H), 3.42-3.48 (m, 3H), 3.32-3.36 (m, 1H), 3.18-3.22 (m, 1H), 2.96-3.10 (m, 4H)

Example 33

4-(4-fluoro-3-(5-methyl-1 ^,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole-2-carbonyl) benzyl) phthalazin-l(2H)-one o

1H NMR (400 MHz, DMSO-d6): δ 12.59 (s, 1H), 8.26 (dd, J = 8 Hz & 0.8 Hz, 1H),

7.96 (d, J = 7.6 Hz, 1 H), 7.90 - 7.86 (m, 1 H), 7.84 - 7.80 (m, 1 H), 7.43 - 7.40 (m,

2H), 7.25 - 7.21 (m, 1H), 4.32 (s, 2H ), 4.19 (s, 2H), 3.58 (s, 2H), 3.43 (s, 2H), 2.42 (s,3H).

Example 34

4-(3-((3a/î,8bR)-decahydropyrrolo[3,4-a]pyrrolizine-2-carbonyl)-4-fluorobenzyl) phthalazin-l(2H)-one v\z~

Ο

ÎH NMR (400 MHz, DMSO-d6): δ 10.5 - 10.2 (d, 1H), 8.44 - 8.46 (m, 1H), 7.71 7.77 (m, 3H), 7.41 - 7.38 (m, 1 H), 7.24 (d, J = 2.4 Hz, 1 H), 7.02 - 6.99 (m, 1 H), 4.24 (s, 2H), 3.89 - 0.88 (m, 15H ).

Example 35

4-(4-fl uoro-3-(2-methyl-2,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carbony) )benzyl) phthalazin-1 (2H)-one

1H NMR (400 MHz, CDC13): δ 10.02 (s, 1H), 8.44-8.46 (m, 1H), 7.69-7.79 (m, 3H),

7.29-7.40 (m, 2H), 7.04-7.17 (m, 2H), 4.73-4.77 (brd, 2H), 4.37-4.39 (brd, 2H), 4.28 (s, 2H), 3.89-3.90 (brd, 2H).

Example 36 4-(4-fluoro-3-(l-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazo!e-5-carbonyl)benzy]) phthalazin-1 (2H)-one o

1H NMR (400 MHz, CDC13): δ 9.98 (s, 1H), 8.44-8.47 (m, 1H), 7.70-7.80 (m, 3H), 7.31-7.40 (m, 2H), 7.06-7.30 (m, 2H), 4.72-4.78 (brd, 2H), 4.37-4.44 (brd, 2H), 4.284.29 (brd, 2H), 3.73-3.85 (brd, 3H).

Example 37

2-((5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1 -yl)methyl)benzoyl) hexahydropyrTOlo[3,4-c]pyrrol-2(lH)-yl)methyl)-6-methoxypyridine-l-oxide

1H NMR (400 MHz, DMSO-d6): δ 12.70 (s, 1H), 8.26 (d, J = 8.8 Hz, 1H), 8.83-8.91 (m, 3H), 7.67-7.70 (m, 1H), 7.41-7.45 (m, 1H), 7.28-7.30 (m, 1H), 7.16-7.23 (m, 1H), 6.82 (d, J = 8 Hz, 1H), 4.40-4.41 (brd, 2H ), 4.31 (s, 2H), 3.82 (s, 3H), 3.70-3.73 (brd, 5 1H), 3.37-3.47 (m, 3H), 3.12-3.25 (m, 3H), 2.99-3.02 (brd, 1H).

Example 38

4-(3-(5-(difluoromethyl)octahydropynOlo[3,4-c]pyrrole-2-carbonyl)-4-fluorobenzyl) phthalazin-1 (2H)-one

1H NMR (400 MHz, CDC13): δ 10.25 (s, 1H), 8.45-8.47 (m, 1H), 8.21-8.24 (m, 1H),

7.71-7.79 (m, 3H), 7.30-7.32 (m, 1H), 7.26-7.29 (m, 1H), 7.01-7.05 (m, 1H), 4.27 (s, 2H ), 3.87-3.93 (m, 1H), 3.73-3.82 (m, 1H), 3.56-3.70 (m, 1H), 3.46-3.50 (m, 1H), 3.30-3.34 (m, 1H), 3.18-3.23 (m, 1H), 2.92-2.95 (m, 1H).

Example 39

4-(4-fluoro-3-((3aR,6aS)-5-oxooctahydrocyclopenta[c]pyrrole-2-carbonyl)benzyl) phthalazin-1 (2H)-one o

1H NMR (400 MHz, CDC13): δ 10.63 (s, 1H), 8.47-8.49 (m, 1H), 7.72-7.81 (m, 3H),

7.37-7.39 (m, 1H), 7.30-7.33 (m, 1H), 7.02-7.04 (brt, 1H), 4.30 (s, 2H), 3.95-4.00 _v (m, 1H), 3.55-3.65 (m, 2H), 3.18-3.22 (m, 1H), 2.94-3.10 (m, 2H), 2.44-2.61 (m, 2H),

2.22-2.28 (m, 1H), 2.08-2.18 (m, 1H).

Example 40

Mixture of 1 & 2 Ethyl 4-(3-(2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-cafbonyl)-4fluorobenzyl)phthalazin-l (2H)-one

1H NMR (400 MHz, DMSO-d6): δ 12.60 (s, 1H), 8.25 (ζ 1H), 7.99 (dd, J = 7.6 Hz & 4 Hz, 1H), 7.91 - 7.87 (m, 1H), 7.85 - 7.81 (m, 1H), 7.61 - 7.42 (m, 3H), 7.28 7.23 (m, 1H), 5.31 (s, 1H ), 4.55 (d, 1H), 4.52-4.43 (d, 2H), 4.34 (s, 2H), 4.28 4.20 (t, 2H), 4.14 - 4.08 (m, 2H), 3.39-3.35 (m, 2H), 1.67 -1.10 (m, 6H).

Example 41

4-(3-(2-ethyl-2,4,5,6-tetrahydropynolo[3,4-c]pyrazole-5-carbonyl)-4-fluorobenzyl) ph thaï azin-1 (2 H)-one

1H NMR (400 MHz, DMSO-d6): δ 12.59 (s, 1H), 8.26 (d, J = 8 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 8 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.61 (s, 1H), 7.46 (d, J = 5.6 Hz, 2H), 5.25 (m, 1H ), 4.55 (s, 2H), 4.33 (s, 2H), 4.26 (d, 2H), 4.10 (q, 2H), 1.36-1.32 (m,3H).

Example 42

4-(3-(1-ethyl -1,4,5,6-tetrahydropyrrolo[3,4-c] pyrazole-5-carbonyl)-4-fluorobenzyl) phthalazin-l(2H)-one

1H NMR (400 MHz, DMSO-d6): δ 10.37 -10.34 (d, 2H), 8.47 - 8.45 (dd, 1 H), 7.82 -7.22(m,3H),7.41-7.33 (m,2H),720(s, 1H),7.13-6.99(m, 1H), 4.82(s, IH), 4.72 (s, 1H), 4.46 (s, 1H),4.37 (s, 1H),4.37-4.31 (d,2H),4.15 (q,2H), 1.48 (t,2

H), 1.37 (t, 1H).

Example 43

4-(4-fluoro-3-(l-isopropyl-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carbonyl) benzyl)phthalazin-1 (2H)-one o

1H NMR (400 MHz, DMSO-d6): δ 12.56 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.95 (t,

1H), 7.87 (t, 1H), 7.81 (t, 1H), 7.46-7.42 (m, 2H), 7.27-7.22 (m, 1H), 7.15 (s, 1H), 4.74 (s, 1H), 4.48 (s, 1H), 4.45 (m, 1 H), 4.32 (s, 2H), 4.30-4.26 (m, lH),4.16(s, 1 H), 1.37 (d, 3H), 123 (t,3H).

Example 44

Mixture of (1 & 2 isopropyl ) 4-(4-fluoro-3-(l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole· 5-carbonyl)benzyl)phthal azin-1 (2H)-one

1H NMR (400 MHz, DMSO-d6): δ 12.58 (s, 1H), 8.26 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 8 Hz, 1H), 7.91 - 7.81 (m, 2H), 7.48 - 7.42 (m, 2H), 7.29 - 723 (m, 1H), 7.17 (s,

IH), 4.55 (s, 1H), 4.49-4.44 (m, 1H ), 4.33 (s, 2H), 4.29 (s, 1H), 4.24 (s, 1H), 1.40 (dd, 5H), 1.25 (t, 1H).

Example 45

4-(4-fluoro-3-(2-isopropy!-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5carbonyl)benzyl) phthalazin-l(2H)-one o

1H NMR (400 MHz, DMSO-d6): 6 12.57 (s, 1H), 8.26 (d, J = 7.6 Hz & 1.2 Hz, 1H), 7.98 (t, 1H), 7.91-7.87 (m, 1H), 7.85-7.81 (m, 1H), 7.64-7.50 (d, 1H), 7.467.42 (m, 2H), Ί2Ί (ζ 1H), 4.55 (s, 2H), 4.49 - 4.46 (m, 1H ), 4.33 (s, 2H), 4.29 (s, 1H), 4.24 (s, 1H), 1.40-1.38 (dd, 6H).

Example 46

4-(3-((3a/ï,6aS)-5,5-difIuorooctahydrocyc!openta[c]pyTTOle-2-carbonyl)-4fluorobenzyl)phthalazin-1 (2H)-one o

1H NMR (400 MHz, CDC13): 5 10.07 (s, 1H), 8.45-8.47 (m, 1H), 7.70-7.79 (m, 3H), 7.35-7.37 (m, 1H), 7.24-7.31 (m, 1H), 7.01-7.05 (bit, 1H), 4.27 (s, 2H), 3.82-3.87 (m, 1H), 3.65-3.70 (m, 1H), 3.51-3.56 (m, 1H), 3.18-3.22 (m, 1H), 2.80-2.94 (m, 2H), 2.26-2.45 (m, 2H), 1.87-2.08 (m, 2H).

Example 47

4-(4-fluoro-3-(5-(2-methoxyethyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzyl) phthal azin-1 (2 H)-one —

1H NMR (400 MHz, CDC13): δ 10.25 (s, 1H), 8.44-8.47 (m, 1H), 7.71-7.79 (m, 3H), 7.34-7.36 (m, 1H), 7.26-7.30 (m, 1H), 6.99-7.04 (brt, 1H), 4.27 (s, 2H ), 3.64-3.79 (m, 2H), 3.50-3.53 (m, 2H), 3.42-3.47 (m, 1H), 3.36 (s, 3H), 3.16-3.18 (brd, 1H), 2.802.97 (m, 2H), 2.64-2.68 (m, 2H), 2.41-2.42 (brd, 1H).

Example 48

N-((3 a/?,6a5)-2-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1 -yl)methyl)benzoyl) octahydrocyclopenta[c]pyrrol-5-yl)cyclopropanecarboxamide

1H NMR (400 MHz, CDC13): δ 10.38 (s, 1H), 8.44-8.46 (m, 1H), 7.72-7.78 (m, 3H),

7.42-7.44 (m, 1H), 7.26-7.29 (m, 1H), 6.98-7.03 (brt, 1H), 5.57 (brd, 1H), 4.40-4.42 (m, 1H), 4.27 (s, 2H), 3.79-3.85 (m, 1H), 3.48-3.60 (m, 2H), 3.06-3.10 (m, 1H), 2.782.85 (m, 2H), 1.90-2.00 (m, 1H), 1.70-1.88 (m, 1H), 1.00-1.03 (m, 2H), 0.83-0.90 (m, 1H), 0.73-0.75 (m, 2H)

Example 50

4-(4-fluoro-3-(l-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carbonyl)benzyl) phthalazin-l(2H)-one hydrobromide

1H NMR (400 MHz, DMSO-d6): δ 12.59 (d, J = 3.6 Hz, 1H), 8.26(d, J = 7.6 Hz,

1H), 8.005 - 7.92 (m, 1H), 7.911 -7.87 (m, 1H), 7.85-7.81 (m, 1H), 7.48 -7.43 (m,

2H), 7.30-7.25 (m, 1H), 7.15 (brs, 1H), 4.69 (s, 1H), 4.53 (s, 1H ), 4.42 (s, 1H),

4.34 (s, 2H), 4.21 (s, 1H), 3.78 - 3.66 (brd, 3H).

Example 51

4-(4-fluoro-3-(l-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-cafbonyl)benzyl) phthalazîn-l(2H)-onehydrochloride l HCl

1H NMR (400 MHz, DMSO-d6): δ 12.59-12.59 (d, J = 3.6Hz, 1H), 8.26 (d, J =

7.6Hz, 1H), 7.98 (t, J = 8Hz, 1H), 7.89 (t, J = 3.4Hz, 1H), 7.83 (t, J = 7.4Hz, 1H), 7.43-7.48 (m, 2H), 7.26-7.28 (m, 1H), 7.15-7.27 (brd, 1H), 4.53-4.69 (brd, 2H), 4.34 10 (s, 2H), 4.21-4.42 (brd, 2H), 3.66-3.78 (brd, 3H).

Example 52

4-(4-fluoro-3-(l-methyI-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carbonyl)benzyl) phthalazin-l(2H)-one sulfate / H2SO4

1H NMR (400 MHz DMSO-d6): δ 12.59-12.58 (d, J = 3.2Hz, 1H), 8.26 (d, J = 8Hz,

1H), 7.97 (m, 1H), 7.89 (m, 1H), 7.84 (m, 1H), 7.48-7.43 (m, 2H), 7.15 (s, 1H), 4.53 (s, 1H), 4.41 (s, 1H), 4.34 (s, 2H), 4.21 (s, 1H), 3.78 (s, 3H), 3.73 (m, 1H).

Example 53

4-(4-fluoro-3-(l-methyI-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-caibonyl)benzyl) phthalazin-1 (2H)-one 4-methylbenzenesulfonate

1H NMR (400 MHz, DMSO-d6): δ 12.59-12.58 (d, J = 32Hz, 1H), 8.26 (d, J = 7.6Hz, 1H), 7.98 (m, 1H), 7.904 (m, 1H), 7.87-7.81 (m, 1H), 7.48-7.43 (m, 4H), 7.37.28 (m, 1H), 7.11 (m, 2H), 4.69 (s, 1H), 4.53 (s, 1H), 4.41 (s, 1H), 4.21 (s, 1H), 3.72 (s, 3H), 2.28 (s,3H)

Example 54

4-(4-fluoro-3-( 1 -methyl-1,4,5,6-tetrahydropyirolo[3,4-c]pyrazo!e-5-carbonyI)benzyl) phthalazin-1 (2H)-one benzenesulfonate

1H NMR (400 MHz, DMSO-d6): δ 12.59-12.59 (d, J = 3.2Hz, 1H), 8.26 (d, J = 8Hz, 1H), 7.87-7.92 (m, 1H), 7.83 (t, J = 7.6Hz, 1H), 7.58-7.61(m, 2H), 7.43-7.48 (m, 2H), 7.15-7.34 (m, 7H), 4.53-4.69 (brd, 2H), 4.34 (s, 2H), 4.21-4.41 (brd, 2H), 3.66-3.78 (brd, 3H).

Example 55

5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l-yl)methyl)benzoyl)-2-isopropyl2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-2-iumhydrogensulfate

1H NMR (400 MHz, DMSO-d6): δ 12.58 (s, 1H), 8.26 (dd, J = 8 Hz & 1.2 Hz, 1H), 7.98 (dd, J = 7.6 Hz & 2.4 Hz, 1 H), 7.91 - 7.87 (m, 1 H), 7.85 - 7.81 (m, 1 H), 7.64 7.51 (brd, 1 H), 7.47 - 7.42 (m, 2H), 7.28 - 7.23 (m, 1 H), 4.55 (s, 2H), 4.51 - 4.45 (m, 1H ), 4.33 (s, 2H), 4.29 - 424 (brd, 2H), 1.40 - 1.38 (brd, 4H).

Example 56

4-(3-( 1 -cyclopropyl-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazole-5-carbonyl)-4fluorobenzyl)phthalazin-l(2H)-0ne —

Ο

‘Η NMR (400 MHz, DMSO-J_e): δ 12.58 (d, J = 2.4 Hz, IH), 8.24(d, J = 7.6 Hz, 1H), 7.98 7.37 (m, 1H), 7.89-7.85 (m, 1H), 7.81 (t, 1H), 7.47 - 7.39 (m, 2H), 7.28-7.22 (m, 1H), 7.14 (d, 1H), 4.70 (s, 1H), 4.48 (s, 1H ), 4.42 (s, 1H), 4.32 (s, 2H), 4.16 (s, 1H), 3.57 - 3.44 (m, 5 1H), 0.98-0.82 (m,4H).

The following compounds can be synthesized following the same procedure as described for example 1 and are considered to be encompassed within the scope of the présent invention.

4-(4-f! uoro-3-( 1 -propyl-1,4,5,6-tetrahydropyrrolo[3,4-c] pyrazole-5-carbonyl)benzyl) phthalazin-l(2H)-one

O

2-(cyclopropanecarbonyl)-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1 -yl)methyl) benzoyljtetrahydropyrrolo [3,4-c]pyrrole-1,3 (2 H,3 aH)-dione o

5-(cyclopropanecarbonyl)-2-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l-yl)methyl) benzoyl)tetrahydropyrrolo[3,4-c]pyrrole-l ,3(2H,3aH)-dione

Ο

ο

4-(4-fluoro-3-(2-(trifluoromethyl)-5,6-dihydro-4H-pynOlo[3,4-d]oxazoIe-5-carbonyl) benzyl)phthalazin-1 (2 H)-one ο

4-(3 -(2-(cyclopropanecarbonyl)-5,6-dihydro-4H-pyrrolo[ 3,4-d] oxazole-5 -carbonyl )-4fl uorobenzyl)phthalazin-1 (2H)-one o

o

4-(4-fluoro-3-(2-(trifluoromethyl)-4,5,6,6a-tetrahydro-3aH-pyrTOlo[3,4-d]thiazole-5 caibonyl )benzyl)phtha!azin-1 (2H)-one o

5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazm-l-yl)methyl)benzoyl)dihydro-1 Hfuro[3,4-c]pyrrole-4,6(5H,6aH)-dione o

5-(cyclopropanecarbonyl)-2-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l-yl)methyl) benzoyl)pyrrolo[3,4-c]pyrrole-l,3(2H,5H)-dione o

4-(3-(5-benzyM ,2,3,4,5,6-hexahydropyrrolo[3,4-c] pyrrol e-2-carbonyl )-4 fluorobenzyl)phthalazin-l(2H)-one o

5-(cyclopropylmethyl)-2-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l yl)methyl)benzoyl)pyrrolo[3,4-c]pyrrole-l,3(2H,5H)-dione

4-(3-(5-(cyclopropanecarbonyl)-l,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole-2 carbonyl)-4-fluorobenzyl)phthalazin-1 (2H)-one

2-(cyclopropylmethyl)-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l-yl)methyl) benzoyljtetrahydropyrrolo [3,4-c] pyrrole-1,3 (2H,3 aH )-dione o

Biological activity- In vitro study

In vitro study

Potentiation of cell killing activity of Methyl Methane Sulphonate (MMS) by selected compounds according to présent invention was evaluated in MCF-7 cell line obtained 5 from National Centre for Cell Science, Pune, by using MTT assay according to general protocol described in Methods in Molecular Biology, Voltime-43, In vitro Toxicity Testing Protocol, Chapter-6, page:137-I49. Compounds were tested for PARP 1 activity based on percent cell survival of MCF-7 cells with alkylating agent MMS.

The compounds were tested for PARP-1 inhibitory activity by using HT universal colorimétrie PARP assay kit obtained from Trevigen, following manufacturées protocol.

The results of the compounds are provided in Table 1.

Resuit of Table 1 shows that the compounds are found to possess PARP 1 inhibitory 15 activity, thus hâve potential to be developed as compounds for therapeutic use.

In vivo study

On basis of the in vitro data, the ability of selected compounds to potentiate the antitumor activity of the methylating chemotherapeutic agent, temozolomide, was evaluated in an SW 620 tumor model.

Animais bearing SW 620 xenograft tumors were treated with the compounds in combination with TMZ (50 mg/Kg, po) once daily for 5 consecutive days, after which the tumors were left to grow out. A considérable inhibition of tumor volumes as compared with that of the TMZ alone group was observed for the TMZ plus compounds combinations (mean values given as relative tumor volumes (RTV) [table 25 2]. The compounds did not exacerbate the systemic toxicity of TMZ, with a maximum mean body weight loss of 9-10% on day 6 with full recovery of body weight within 3 days and with no mortalities, which indicates that the combination therapy was well tolerated by compounds under the dosing regimen.

Female athymie nude mice were used for antitumor in vivo studies. SW620 colorectal 30 tumor cells (1x10 cells per animal) were implanted s.c. into one flank of each mouse. When tumors were palpable (10-12 days after implantation), animais were treated (n= 6-8/group) with five daily doses of temozolomide administered per os as a suspension in 0.5% methyl cellulose at 50 mg/kg either alone or in combination with a five daily per os administrations of PARP inhibitor at different doses. Tumor growths were measured using two-dimensional caliper measurements. Tumor volume was calculated using the équation a² x b / 2, where a is the smallest measurement and 5 b is the largest. Data are presented as médian relative tumor volumes (RTV), defined as the calculated tumor volume divided by the calculated tumor volume on the initial day of treatment (day 0). Thus, on day 0, the RTV value is 1 and RTV4 is when the tumor is four times as large as its initial value. Control animais were treated with vehicle (15 tween 80 in methyl cellulose) alone tumor growth delay (TGD) = Time to 10 RTV4 in treated group - time to RTV4 control.

Table 1: In-Vitro PARP-1 activity

Compound	PARP-1 activity in vitro IC50(nM)*	Compound	PARP-1 activity in vitro IC50(nM)*
Olaparib	8.39 + 2.3	Compound 29	18.43
Compound 1	11.54	Compound 30	9.87
Compound 2	8.41	Compound 31	24.25
Compound 3	14.55	Compound 32	11.54
Compound 6	46.71	Compound 33	28.5
Compound 7	38.63	Compound 34	11.68
Compound 9	23.97	Compound 35	29.87
Compound 12	14.15	Compound 36	27.87
Compound 14	46.45	Compound 38	90.95
Compound 15	11.64	Compound 39	54.52
Compound 16	103.8	Compound 40	9.9
Compound 17	3027	Compound 41	8.9
Compound 19	34.41	Compound 42	48.6
Compound 20	11.78	Compound 43	55.1
Compound 21	22.56	Compound 44	19.87
Compound 22	20.22	Compound 45	13.8
Compound 23	67.85	Compound 46	27.8
Compound 24	9.85	Compound 47	48.3
Compound 25	27.81	Compound 48	74.5
Compound 26	35.95	Compound 54	15.4
Compound 27	12.47	Compound 55	1323
Compound 28	20.73

^a PARP 1 IC» are estimation as calculated from a 4 point dose response curve

Table 2: In vivo antitumor efïïcacy of compounds in combination with temozolomide (TMZ) in an SW620 tumor model^b.

Compounds	Médian time to RTV4(days)	Tumor growth delay(days)
Vehicleicontrol)	10
Temozolomide (50 mg/kg, po)	22	12
TMZ (50 mg/kg, po) + example 20 (50 mg/kg, po)	43	33
TMZ (50 mg/kg, po) + example 35(10 mg/kg, po)	50	40
TMZ (50 mg/kg, po) + example 36(10 mg/kg, po)	37	27
TMZ (50 mg/kg, po) + example 36 (30 mg/kg, po)	44	34
TMZ (50 mg/kg, po) + example 36 (100 mg/kg, po)	65	55

^b Mice were orally dosed once daily for 5 consecutive days. The compounds were administered 45 min beforeTMZ.

Claims (18)

1. We claim:

   1. Compound having the structure of general formula (I) wherein R¹ at each occurrence is independently selected from H, halogen, or the groups selected from (Ci-C]2)alkyl, haloalkyl, cycloalkyl, alkylthio or the group (0S02)alkyl, wherein each of these groups are further optionally substituted with suitable substituents;

   R’ at each occunence is independently selected from hydrogen, halogen, alkyl, alkoxy, hydroxyl, haloalkyl, haloalkoxy, cyano, thioalkyl, cycloalkyl groups

   5 m = 1-4; L=-O, -S,-NH;n = 0-4

   R² is selected from substituent groups consisting of hydrogen atom, hydroxyl, alkyl, cycloalkyl, oxo, C(O)OR^S, -C(O)R⁵, or-C(O)NR⁶R⁷, wherein said alkyl and cycloalkyl groups are further substituted by one or more substituents selected from halogen, hydroxyl, alkyl or alkoxy groups;

   10 R³ and R⁴ are each independently selected from hydrogen atom, alkyl, hydroxyl, alkoxy, cycloalkyl, - C(O)OR^S, -OC(O)R⁵, -O(CH₂)_PC(O)OR⁵, C(O)R⁵, -NHC(O)R⁵, -NR⁶R⁷, -OCfOiNR^⁷ or-QOJNR^⁷ or altematively, R³ and R⁴ together forms an oxo group;

   Each of the ring atoms ‘D* and Έ’ is independently selected from C or N atoms;

   15 Each of the ring atoms ‘F*, ‘G* and Ή is independently selected from C, N, O and S atoms

   The ring formed by ‘D’, ‘E’, ‘F’, ‘G’ and ‘H’ represents a substituted or nonsubstituted fîve- membered bicyclic aromatic or non-aromatic heterocyclic ring;

   20 R⁵ at each occurrence is independently selected from hydrogen atom, optionally substituted groups selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups; Each of R⁶ or R⁷ at each occurrence are independently selected from H, optionally substituted groups selected from hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. Altematively, R⁶ and R⁷ are

   25 joined together with nitrogen atom to form a heterocyclyl ring; wherein said heterocyclyl ring contains one or more heteroatoms selected from N, O, S(O)_n, n is 0,1 or 2 and p is 0,1 or 2.
2. 2. The compound as claimed in claim 1, wherein heterocycles representing is selected from the following bicyclic rings mentioned below
3. 3. The compound as claimed in claim 1, wherein the substituents on R¹ is selected from hydroxyl, oxo, halo, thio, nitro, amino, alkyl, alkoxy, haloalkyl or haloalkoxy groups alone or in combination with other radicals.
4. 4. The compound as claimed in claim 1 wherein the substituents on R⁵ is selected from alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid ester substituents.
5. 5. The compound as claimed in claim 1 wherein the substituents on R⁶ & R⁷ at each occurrence is independently selected from alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid ester substituents.
6. 6. The compound as claimed in claim 1, wherein the substituents on substituted or non-substituted bicyclic aromatic or non-aromatic five membered heterocyclic ring is selected from halogen, hydroxyl, oxo, optionally substituted groups selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzyl, OR^S, -C(O)OR⁵, -OC(O)R⁵, -OCCHjipCiOJOR⁵, C(O)R⁵, S(O)„R^s, -NHC(O)R^S, NR⁶R⁷, -OC(O)NR⁶R⁷ or -C(ONR⁶R⁷, wherein each of R^s, R⁶ & R⁷ are as defîned in claim 1 and wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or benzyl group are each independently substituted further with one or more substituents selected from alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo,- C(O)OR⁵, OC(O)R^S, O(CH₂)_PC(O)OR⁵, -C(O)R^S, -S(O)nR^s„ -NHC(O)R^S, NR⁶R⁷, OC(O)NR⁶R⁷ or -C(O)NR⁶R⁷ groups.
7. 7. The compound as claimed in claim 1, wherein “aryl” groups is selected from phenyl, naphthyl, tetrahydronaphthyl, indenyl, dihydroindenyl, biphenyl groups.
8. 8. The compound as claimed in claim 1, wherein the substituents on aryl groups

   5 are independently selected from hydrogen, halogen, alkyl, alkoxy, hydroxyl, haloalkyl, haloalkoxy, cyano, thioalkyl, cycloalkyl groups.
9. 9. The compound as claimed in claim 1, wherein the heteroaryl or heteroaromatic group is selected from pyridyl, thienyl, furyl, pyrrolyl, indolinyl, indolyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl,
10. 10 pyrazolyl, quinazolinyl, pyridazinyl, purinyl groups.

    10. The compound as claimed in claim 1, where in the substitution on heteroaryl or heteroaromatic group is selected from hydrogen, halogen, alkyl, alkoxy, hydroxyl, haloalkyl, haloalkoxy, aryl, aralkyl, cyano, alkylthio, thioalkyl groups.

    15
11. 11. The compound as claimed in claim 1, wherein the heterocyclyl group is selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidînyl, piperazinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2-oxopiperazinyl, 3oxopiperazinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, 20 dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thienopiperidinyl, groups.

    25
12. 12. The compound as claimed in claim 1, wherein the substituents on heterocyclyl group is selected from hydrogen, halogen, alkyl, alkoxy, hydroxyl, haloalkyl, haloalkoxy, aryl, aralkyl, cyano, alkylthio, thioalkyl groups.
13. 13. A compound as claimed in claim 1 selected from the group comprising of:

    0 /V* NH UM . WQ?.jO 0 nh Ui _o 0 0 ₀ 0 r^V^NH υγ . O uy ₀ UÔQ-'T'v \^N O îT^t'nh υγ . WQ?.^ 0 Uy _o uÔQ-» ^^F X^-N^CFj O /V%H Uy o vCO?^ 0 Ιι'ύ'ΝΗ 'γ „ Wu3 HCl 0 Ij^l' NU vCQ?.^.x O O ii^r nh UU o 0 0 ii^^r nh Wî 0 O if'^Y'^NH ΜγΝ ₀ XX^Q-i ^F O ¹ 0 ΜγΝ _o

    C 0 ^NH t* Wh N' 4 0 ότ υ o d’Q'^ F \^N 0 0 A •^NH ΤΤ^Η γ* o V Cn j? 0 w> o o υ CÆv o 0 r^NH ο ΊΤ'ΝΗ M U o VÿN o F υ· 0 I li O ^NH 0 r νπ w γ^Λ o kx kjN 9 o Yy\Vⁿ U 4? F0^\,0 ο ^NH ΓΠ 0 r^NH γ” ο ° Μ 0 ο ΎΧ /Q}jO ο ^ΝΗ (Π o /'nh γ* ο ° kx L^n η< o «Λμ XX o O Ο ^ΝΗ 0
14. 14. The compound as claimed in any preceding claim preferably selected from the group comprising of:

    0 0 (Γτ Μγύ ₀ UM _o W-^îjO O 0 o IXn _o Μγ _o ucVy·)» O o |^ΛνΗ (Γί?^η y O y O ^^F VN m?u O o iCt V” ΜγΝ _Q U> 0 o o IÎ^Anh Ci ΜγΝ _Q Μγ ₀ Wi HCt o O o [Γγ'ΝΠ iXY^NH γ 0 î ⁰ W 0
15. 15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) as claimed in any of the preceding daims and optionally one or more pharmaceutically acceptable carriers, diluents or excipients.
16. 16. A pharmaceutical composition comprising compound of formula (I) along with suitable excipients suitable for the treatment of diseases through the inhibition of poly (ADP-ribose) polymerase-1.
17. 17. A medicine for the treatment of diseases medicated by the PARP-1 protein which comprises administering a therapeutically effective amount of compound of Formula (I) or its pharmaceutical composition as defined in any of the preceding daims to a patient or subject in need thereof.
18. 18. The use of the compound of formula (I) or its pharmaceutical composition as claimed in any of the preceding daims for the manufacture of a médicament for the inhibition ofpoly (ADP-ribose) polymerase-1.