WO2017013593A1 - Dérivés d'isoquinolinone utilisés en tant qu'inhibiteurs de parp - Google Patents

Dérivés d'isoquinolinone utilisés en tant qu'inhibiteurs de parp Download PDF

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WO2017013593A1
WO2017013593A1 PCT/IB2016/054310 IB2016054310W WO2017013593A1 WO 2017013593 A1 WO2017013593 A1 WO 2017013593A1 IB 2016054310 W IB2016054310 W IB 2016054310W WO 2017013593 A1 WO2017013593 A1 WO 2017013593A1
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alkyl
substituted
unsubstituted
compound
piperazin
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PCT/IB2016/054310
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English (en)
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Gourhari Jana
Neelima Sinha
Navnath Popat Karche
Ajay Ramchandra TILEKAR
Arun Rangnath JAGDALE
Sanjay Pralhad KURHADE
Ganesh Rajaram Jadhav
Venkata P. Palle
Rajender Kumar Kamboj
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Lupin Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to isoquinolinone derivatives, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, combinations with suitable medicament, pharmaceutical compositions containing them, methods of making of isoquinolinone derivatives, and their use as PARP inhibitors.
  • PARP Poly (ADP-ribose) Polymerase
  • ADP-ribosylation occurs at the carboxylate groups of glutamic acid or aspartic acid residues in acceptor proteins and results in the modulation of catalytic activity and protein-protein interactions of the target proteins (e.g., modulation of chromatin structure, DNA synthesis, DNA repair (Base Excision Repair or BER), transcription, and/or cell cycle progression.
  • PARP binds to DNA single strand as well as double strand breaks. The binding of PARP to damaged DNA leads to activation of the enzyme.
  • PARP carries out ADP ribosylation of proteins involved in DNA repair (e.g., BER) including itself. Automodification of PARP results in its release from DNA which allows the DNA repair machinery to access the DNA damage site and carry out the repair process. Overactivation of PARP leads to necrotic cell death as a result of NAD + and ATP depletion.
  • chemotherapeutic agents that damage DNA e.g., cisplatin, irinotecan, temozolomide
  • Activation of PARP in such cases allows the repair of the damaged DNA, thus leading to an undesirable resistance to the chemotherapeutic agents (and the consequent inefficacy).
  • treatment with a PARP inhibitor is expected to make the repair process inefficient and cause cell death.
  • BRCA1 and BRCA2 play an important role in HR (Homologous
  • PARP has been implicated in a number of disease conditions other than cancer. These include disorders such as stroke, traumatic brain injury, Parkinson's disease, meningitis, myocardial infarction, ischaemic cardiomyopathy and other vasculature-related disorders.
  • PARP-/-mice demonstrated improved motor and memory function after CCI (Controlled Cortical Impact) versus PARP +/+ mice (J Cereb Blood Flow Metab. 1999, Vol. 19. No.8, 835).
  • the present invention provides a compound of formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its combination with suitable medicament, its pharmaceutical composition and its use as PARP inhibitor,
  • R 4 is selected from hydrogen, halogen, substituted- or unsubstituted- alkyl, and substituted- or unsubstituted- heteroarylalkyl;
  • the invention provides a pharmaceutical composition comprising the compound of formula (I) and a pharmaceutically acceptable carrier.
  • the invention provides a method of treating or preventing a disorder responsive to the inhibition of PARP activity in a mammal suffering therefrom, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) .
  • the present invention provides a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its combination with suitable medicament, its pharmaceutical composition, process and intermediates for the preparation of the above compound,
  • R 4 is selected from hydrogen, halogen, substituted- or unsubstituted- alkyl, and substituted- or unsubstituted- heteroarylalkyl;
  • R 1 is independently selected at each occurrence from halogen and substituted- or unsubstituted- alkyl.
  • R 1 is independently selected at each occurrence from fluorine and methyl.
  • p is 0 or 1.
  • R 2 and R 3 are each independently selected from hydrogen, methyl, ethyl, acetyl, isobutyryl, cyclopropanoyl, cyclobutanoyl, cyclopentanoyl, 4-fluorobenzyl, 4-fluorophenylcarbonyl, and 4- fluorophenylmethylcarbonyl.
  • R 4 is selected from hydrogen and substituted- or unsubstituted- heteroarylalkyl. In one of the preferred embodiments, R 4 is selected from hydrogen and (1 methyl- 1H- 1 ,2,4-triazol-5-yl)methyl.
  • q is 0.
  • R 6 is selected from substituted- or
  • R 6a is selected from substituted- or unsubstituted- and substituted- or unsubstituted- heteroaryl; and each R 6b and R 6c are
  • R 6 is selected from
  • R c is selected from halogen and cyano
  • n is selected from 0, 1, and 2.
  • R 6 is selected from 4-cyanophenyl, 4- flurophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 2-methylphenyl, 3-fluoro-4- cyano-phenyl, 2-fluoro-4-cyanophenyl, 4-carbamoylphenyl, 4-N- methylcarbamoylphenyl, 4-(pyrrolidine- l-carbonyl)phenyl, 5-chloropyridin-2-yl, 5- fluoropyridin-2-yl, 5-cyanopyridin-2-yl, 5-methylcarbamoylpyridin-2-yl, 5- methylcarbamoylthiazole-2-yl, 2-phenyl-2-methylpropanoyl, 2-(4-fluorophenyl)-2- methylpropanoyl, 2-(4-cyanophenyl)-2-methylpropanoyl, and thiophen-2- ylcarbonyl.
  • R 1 is independently selected at each occurrence from halogen and substituted- or unsubstituted- alkyl
  • R 4 is selected from hydrogen and substituted- or unsubstituted- heteroarylalkyl;
  • R 1 is independently selected at each occurrence from fluorine and methyl
  • R 2 and R 3 are each independently selected from hydrogen, methyl, ethyl, acetyl, isobutyryl, cyclopropanoyl, cyclobutanoyl, cyclopentanoyl, 4-fluorobenzyl, 4-fluorophenylcarbonyl, and 4- fluorophenylmethylcarbonyl
  • R 4 is selected from hydrogen and (l-methyl- lH- 1,2,4- triazol-5-yl)methyl
  • R 6 is selected from 4-cyanophenyl, 4-flurophenyl, 4- chlorophenyl, 4-trifluoromethylphenyl, 2-methylphenyl, 3-fluoro-4-cyano-phenyl, 2-fluoro-4-cyanophenyl, 4-carbamoylphenyl, 4-N-methylcarbamoylphenyl, 4- (pyrrolidine- l-carbonyl)phenyl
  • alkyl' means a straight chain or branched hydrocarbon containing from 1 to 20 carbon atoms.
  • the alkyl chain may contain 1 to 10 carbon atoms. More preferably alkyl chain may contain up to 6 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, and n-hexyl.
  • alkenyl' means an alkyl group containing at least one double bond.
  • 'perhaloalkyl' means an alkyl group as defined hereinabove wherein all the hydrogen atoms of the said alkyl group are substituted with halogen.
  • the perhaloalkyl group is exemplified by trifluoromethyl, pentafluoroethyl, and the like.
  • 'cycloalkyl' as used herein, means a monocyclic, bicyclic, or tricyclic non- aromatic ring system containing from 3 to 14 carbon atoms, preferably monocyclic cycloalkyl ring containing 3 to 6 carbon atoms.
  • monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Bicyclic ring systems include monocyclic ring system fused across a bond with another cyclic system which may be an alicyclic ring or an aromatic ring.
  • Bicyclic rings also include spirocyclic systems wherein the second ring gets annulated on a single carbon atom.
  • Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge.
  • Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1. l]heptane, bicyclo[2.2.
  • Tricyclic ring systems are the systems wherein the bicyclic systems as described above are further annulated with third ring, which may be an alicyclic ring or aromatic ring. Tricyclic ring systems are also exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge. Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.0 3 7 ]nonane, and tricyclo[3.3.1.1 3 7 ]decane (adamantane) .
  • 'cycloalkenyl' means a cycloalkyl group containing at least one double bond.
  • 'aryl' refers to a monovalent monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system.
  • aryl groups include phenyl, naphthyl, anthracenyl, iluorenyl, indenyl, azulenyl, and the like.
  • Aryl group also include partially saturated bicyclic and tricyclic aromatic hydrocarbons, e.g. tetrahydro-naphthalene.
  • Aryl group also include bicyclic systems like 2,3-dihydro- indene-5-yl, and 2,3-dihydro- l-indenone-5-yl.
  • 'heteroaryl' refers to a 5- 14 membered monocyclic, bicyclic, or tricyclic ring system having 1-4 ring heteroatoms selected from O, N, or S, and the remainder ring atoms being carbon (with appropriate hydrogen atoms unless otherwise indicated), wherein at least one ring in the ring system is aromatic.
  • heteroaryl groups include, but not limited to, pyridyl, 1-oxo-pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, benzoxazolyl, benzofuranyl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyri
  • Heteroaryl groups may be optionally substituted with one or more substituents.
  • 'arylalkyl' refers to -(alkyl)-(aryl), wherein alkyl and aryl are defined above.
  • Examples of 'arylalkyl' groups include 1- naphthylmethyl, benzyl and the like.
  • 'heteroarylalkyl' refers to -(alkyl)-(heteroaryl), wherein alkyl and heteroaryl are defined above.
  • Examples of 'heteroarylalkyl' groups include (l-methyl- lH- l,2,4-triazol-5-yl)methyl and the like.
  • oxo attached to carbon forms a carbonyl
  • oxo substituted on cyclohexane forms a cyclohexanone, and the like.
  • 'annulated' means the ring system under consideration is either annulated with another ring at a carbon atom of the cyclic system or across a bond of the cyclic system as in the case of fused or spiro ring systems.
  • bridged' means the ring system under consideration contain an alkylene bridge having 1 to 4 methylene units joining two non-adjacent ring atoms.
  • a range of the number of atoms in a structure is indicated (e.g., a Ci to C 2 o alkyl, C 2 to C 2 o alkenyl etc.), it is specifically contemplated that any subrange or individual number of carbon atoms falling within the indicated range also can be used.
  • a range of 1-6 carbon atoms e.g., Ci to Ce
  • 2-6 carbon atoms e.g., C 2 to Ce
  • 3-6 carbon atoms e.g., C3 to Ce
  • any chemical group e.g., alkyl, alkenyl, etc.
  • any sub-range thereof e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms as appropriate).
  • the invention provides a compound, its stereoisomers, racemates, and pharmaceutically acceptable salt thereof as described hereinabove wherein the compound of general formula (I) is selected from:
  • the compounds of general formula (I) where all the symbols are as defined earlier can be prepared by methods given in Schemes 1-5 and the examples. Representative procedures are shown below, however; these synthetic methods should not be construed as limiting the invention in any way, which lies in the whole genus described by the compound of formula (I) as disclosed hereinabove.
  • Scheme 1 shows a method of preparation of compounds of formula (I), wherein R 2 is Hydrogen, COR 7c , substituted- or unsubstituted- alkyl, substituted- or unsubstituted- arylalkyl; R 3 is COR 7c , substituted- or unsubstituted- alkyl, substituted- or unsubstituted- arylalkyl; R 4 is hydrogen and all other symbols are as defined under formula (I).
  • the Sonogashira coupling is carried out in a solvent, for example, a halogenated hydrocarbon such as dichloromethane or chloroform, an aromatic hydrocarbon such as xylene, toluene, or benzene, an ether solvent such as diethyl ether, tetrahydrofuran or 1 ,4- dioxane, an aprotic solvent such as dimethylformamide, dimethylsulfoxide, acetonitrile, or N-methyl-2-pyrrolidinone, in the presence of a suitable base such as potassium carbonate, triethylamine, diethylisopropylamine or the like, and a palladium catalyst such as bis(triphenylphosphine)palladium (II) dichloride [(PPh3) 2 PdCl 2 ], bis(triphenylphosphine)palladium (II) diacetate [(PPh 3 ) 2 Pd(OAc) 2 ] combined
  • the compounds of formula (VI), where all symbols are as defined under formula (I) can be treated with ammonia to obtain compounds of formula (VII) .
  • the compounds of formula (VII), where all symbols are as defined under formula (I) can be converted to compounds of formula (VIII) under suitable reduction conditions known for reduction of aromatic nitro compound to aromatic amine.
  • the reduction may be carried out in the presence of iron-acetic acid, zinc - acetic acid, stannous (II) chloride - hydrochloric acid, catalytic hydrogenation in the presence of palladium-charcoal or like in a solvent such as methanol, ethanol, ethyl acetate, or water at a temperature of 0 - 100°C over a period of 1 - 12 h.
  • the reaction may be carried out in solvents such as N,N- dimethylformamide, tetrahydrofuran, chloroform, dichlorome thane, xylene, benzene or mixtures thereof or the like in the presence of bases such as triethylamine, diisopropylethylamine, pyridine or the like at a temperature of 0 - 100°C , optionally using reagent(s) such as thionyl chloride, phosphorous chloride, oxalyl chloride, alkyl chloroformate, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), N,N -dicyclohexylcarbodiimide (DCC), auxiliary reagents such as hydroxybenzotriazole (HOBt), 1 -hydroxy- 7-azabenzotriazole (HOAt) or the like.
  • solvents such as N,N- dimethylformamide, te
  • reductive amination can be carried out in a solvent such as methanol, ethanol, dichlorome thane, dichloroethane, tetrahydrofuran or like, and a reducing agent like sodium borohydride, sodium triacetoxyboro hydride, sodium cyanoborohydride or like in the presence of an acid such as acetic acid, formic acid, or trifluoroacetic acid at 0 - 100°C for 1 - 20 h.
  • a solvent such as methanol, ethanol, dichlorome thane, dichloroethane, tetrahydrofuran or like
  • a reducing agent like sodium borohydride, sodium triacetoxyboro hydride, sodium cyanoborohydride or like in the presence of an acid such as acetic acid, formic acid, or trifluoroacetic acid at 0 - 100°C for 1 - 20 h.
  • Scheme 2 shows a method of preparation of compounds of formula (I) wherein R 2 , R 3 and R 4 are hydrogen; R 6 and all other symbols are as defined under formula (I) .
  • Compounds of formula (I) can be prepared from compounds of formula (II) and compounds of formula (IX) where all symbols are as defined under formula (I).
  • Compounds of formula (II) are reacted with compounds of formula (IX) where Li is leaving group, for example, halogen, OMs, or OTs (other symbols are as defined under formula (I)) to give compounds of formula (X) , wherein the reaction is carried out under the same conditions as used in Scheme 1 to obtain compounds of formula (IV) .
  • the compounds of formula (X), where all symbols are as defined under formula (I), are subjected to Sonogashira coupling with compounds of formula (V) where, L2 is halogen, OTf, or OTs (other symbols are as defined earlier in formula (I)), followed by in situ cyclization to obtain a compound of formula (XI).
  • Sonogashira coupling is carried out under similar reaction conditions as disclosed in Scheme 1 to obtain compounds of formula (VI).
  • the compounds of formula (XI), where all symbols are as defined under formula (I) can be treated with ammonia to obtain compounds of formula (XII).
  • the reaction may be carried out in solvents such as N,N- dime thy lformamide, tetrahydrofuran, chloroform, dichloro methane, xylene, benzene or the like and mixtures thereof in the presence of bases such as triethylamine, diisopropylethylamine, pyridine or the like at a temperature of 0 - 100°C using reagent(s) such as HATU (1- [Bis(dimethylamino)methylene]- 1H- 1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexailuorophosphate), thionyl chloride, phosphorous chloride, oxalyl chloride, alkyl chloroformate, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), or N,N - dicyclohexylcarbodiimide (DCC), auxiliary
  • Compounds of formula (I) can be prepared from compounds of formula (XIV) and compounds of formula (III) where all symbols are as defined under formula (I).
  • the reaction may be carried out in solvents such as ⁇ , ⁇ -dimethylformamide, tetrahydrofuran, chloroform, dichlorome thane, xylene, benzene or the like or mixtures thereof in the presence of bases such as triethylamine, diisopropylethylamine, pyridine or the like at a temperature of 0 - 100°C using reagent(s) such as thionyl chloride, phosphorous chloride, oxalyl chloride, alkyl chlroformate, ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI), N,N -dicyclohexylcarbodiimide (DCC), auxiliary reagents such as hydroxybenzotriazole (HOBt), 1 -hydroxy- 7- azabenzotriazole (HOAt) or the like.
  • solvents such as ⁇ , ⁇ -dimethylformamide, t
  • Sonogashira coupling can be carried out under suitable coupling conditions.
  • the Sonogashira coupling is carried out in a solvent, for example, a halogenated hydrocarbon such as dichloromethane or chloroform, an aromatic hydrocarbon such as xylene, toluene, or benzene, an ether solvent such as diethyl ether, tetrahydrofuran or 1 ,4- dioxane, an aprotic solvent such as dimethylformamide, dimethylsulfoxide, acetonitrile, or N-methyl-2-pyrrolidinone, in the presence of a suitable base such as potassium carbonate, triethylamine, diethylisopropylamine or the like, and a palladium catalyst such as Tris(dibenzylideneacetone
  • Ester hydrolysis can be carried out by using procedures generally used in synthetic organic chemistry or well known in the art by using reagents such as sodium hydroxide, potassium hydroxide, lithium hydroxide or the like in a solvent such as water, alcohol, tetrahydrofuran or the like and mixture thereof.
  • reagents such as sodium hydroxide, potassium hydroxide, lithium hydroxide or the like in a solvent such as water, alcohol, tetrahydrofuran or the like and mixture thereof.
  • sodium hydroxide is used for the reaction.
  • the compounds of formula (XX), where all symbols are as defined under formula (I) can be converted to compounds of formula (I) under suitable reduction conditions known for reduction of aromatic nitro compounds to aromatic amines.
  • the reduction may be carried out in the presence of iron-acetic acid, zinc - acetic acid, stannous (II) chloride - hydrochloric acid, catalytic hydrogenation in the presence of palladium-charcoal or like in a solvent such as methanol, ethanol, ethyl acetate, or water at a temperature of 0 - 100°C over a period of 1 - 12 h.
  • Scheme 4 shows a method of preparation of compounds of the formula (I); where R 2 and R 3 are H, R 6 is substituted aryl and the substituents are CONH2, CONH-alkyl or CO-heterocyclyl, and other symbols are as described in general
  • the reaction may be carried out in suitable solvents such as dimethyl sulfoxide (DMSO), N,N-dimethylformamide, tetrahydrofuran, chloroform, dichloromethane, xylene, benzene or the like and mixtures thereof in the presence of bases such as potassium carbonate, triethylamine, diisopropylethylamine, pyridine or the like at a temperature of 0- 100 °C by using reagent(s) such as thionyl chloride, phosphorous chloride, oxalyl chloride, alkyl chloroformate, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), N,N-dicyclohexylcarbodiimide (DCC), auxiliary reagents such as hydroxybenzotriazole (HOBt), 1 -hydroxy- 7-azabenzotriazole (HOAt), ⁇ , ⁇ , ⁇ ', ⁇ '
  • the reduction may be carried out in the presence of iron-acetic acid, zinc - acetic acid, stannous (II) chloride - hydrochloric acid, catalytic hydrogenation in the presence of palladium-charcoal or the like in a solvent such as methanol, ethanol, ethyl acetate, or water at a temperature of 0- 105°C over a period of 1- 12 hr.
  • a solvent such as methanol, ethanol, ethyl acetate, or water at a temperature of 0- 105°C over a period of 1- 12 hr.
  • the reduction is carried out in ethanol by using iron-acetic acid.
  • Scheme 5 shows a method of preparation of compounds of formula (I) , where R 2 and R 3 are hydrogen, R 4 is substituted- or unsubstituted- heteroarylalkyl, and all other symbols are as described under compound of generic formula (I) .
  • the compounds of formula (XXIII) are prepared from the corresponding substituted benzyl bromides by a cyanation reaction according to the procedure described in literature.
  • the compounds of the formula (XXIII), where R 1 and p are as defined earlier, are reacted with R CHO wherein R 11 is substituted or unsubstituted heteroaryl, in the presence of a base like sodium methoxide, sodium ethoxide, sodium hydride, potassium t-butoxide, potassium carbonate, or cesium carbonate in solvents such as methanol, acetonitrile, N,N-dimethylformamide (DMF), tetrahydrofuran (THF), or acetone to obtain the compounds of formula (XXIV) ; where R 1 , and p are as defined earlier.
  • the condensation reaction is carried out in DMF in the presence of sodium methoxide as base.
  • the compounds of formula (XXIV) as obtained in the previous step are esterified by the use of potassium carbonate and methyl iodide to obtain the compounds of formula (XXV) .
  • Ester hydrolysis of the compounds of the formula (XXV) is followed by cyclization by using phosphoryl chloride and phosphorus pentachloride to give compounds of formula (XXVI).
  • Ester hydrolysis may be carried out by using standard procedures generally used in synthetic organic chemistry or well known in the art with reagents such as sodium hydroxide, potassium hydroxide, lithium hydroxide or the like in solvents such as alcohol, THF, water or the like.
  • solvents such as alcohol, THF, water or the like.
  • an aqueous solution of potassium carbonate and methanol are used for the reaction.
  • the compounds of formula (XXVII) obtained in the previous step are subjected to Suzuki coupling with boronic acids; where X is halogen, in the presence of cyclic amines represented by formula (III) where R 5 , R 6 and q are as defined earlier to obtain compounds of formula (XXVIII).
  • Suzuki coupling with boronic acids can be carried out by following procedures well known in the art (WO200976602).
  • the Suzuki coupling is carried out in a DMSO, in the presence of a base such as cesium carbonate or the like, and Bis(triphenylphosphine)palladium(II)dichloride at a temperature of about 100°C or higher.
  • the compounds of formula (XXVIII) as obtained above are reduced by hydrogenation using palladium catalyst or rhodium catalyst under hydrogen atmosphere in methanol, THF or ethyl acetate to obtain compounds of formula (XXIX).
  • the compounds of formula (XXIX) as obtained in the previous step are treated with reagents such as, but not limited to, hydrochloric acid, sulphuric acid, hydrobromic acid, or trimethyl silyl chloride in combination with sodium iodide, or trimethyl silyl iodide, in alcohol, THF, dioxane, acetonitrile or chlorinated solvent to obtain the compounds of the formula (I), where R 2 , R 3 , R la , R 2a , R lb , R 2b , R lc , and R 2c are hydrogen, R 4 is substituted- or unsubstituted- heteroarylalkyl, and all other symbols are as described under compound of generic formula (I).
  • the intermediates and the compounds of the present invention can be obtained in a pure form in a manner known per se, for example, by distilling off the solvent in vacuum and/or re- crystallizing the residue obtained from a suitable solvent, such as pentane, diethyl ether, isopropyl ether, chloroform, dichlorome thane, ethyl acetate, acetone or their combinations or subjecting them to one of the purification methods, such as column chromatography (e.g. flash chromatography) on a suitable support material such as alumina or silica gel using an eluent such as dichlorome thane, ethyl acetate, hexane, methanol, acetone and their combinations.
  • a suitable solvent such as pentane, diethyl ether, isopropyl ether, chloroform, dichlorome thane, ethyl acetate, acetone or their combinations or subjecting them to one of the purification methods, such as
  • work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulphate, filtration and evaporation of the solvent.
  • Purification includes purification by silica gel chromatographic techniques, generally using a mobile phase with suitable polarity.
  • Salts of compound of formula (I) can be obtained by dissolving the compound in a suitable solvent, for example in a chlorinated hydrocarbon, such as methyl chloride or chloroform or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol, which was then treated with the desired acid or base as described in Berge S.M.
  • the salt can be of an alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g., calcium), or ammonium.
  • the compounds of the invention or a composition thereof can potentially be administered as a pharmaceutically acceptable acid-addition, base neutralized or addition salt, formed by reaction with inorganic acids, such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base, such as sodium hydroxide, potassium hydroxide.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, mal
  • the conversion to a salt is accomplished by treatment of the base compound with at least a stoichiometric amount of an appropriate acid.
  • the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol, methanol, and the like, and the acid is added in a similar solvent.
  • the mixture is maintained at a suitable temperature (e.g., between 0 °C and 50 °C).
  • the resulting salt precipitates spontaneously or can be brought out of solution with a less polar solvent.
  • stereoisomers of the compounds of formula (I) of the present invention may be prepared by stereospecific syntheses or resolution of racemic compound using an optically active amine, acid or complex forming agent, and separating the diastereomeric salt/complex by fractional crystallization or by column chromatography.
  • the compounds of formula (I) of the present invention can exist in tautomeric forms, such as keto-enol tautomers. Such tautomeric forms are contemplated as an aspect of the present invention and such tautomers may be in equilibrium or predominant in one of the forms.
  • the present invention further provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, its tautomeric forms, its stereoisomers, its pharmaceutically acceptable salts in combination with the usual pharmaceutically acceptable carriers, diluents, excipients, and the like.
  • the pharmaceutically acceptable carrier or excipient is preferably one that is chemically inert to the compound of the invention and one that has no detrimental side effects or toxicity under the conditions of use.
  • Such pharmaceutically acceptable carriers or excipients include saline (e.g. , 0.9% saline), Cremophor EL ® (which is a derivative of castor oil and ethylene oxide available from Sigma Chemical Co. , St. Louis, MO) (e.g. , 5% Cremophor EL/5% ethanol/90% saline, 10% Cremophor EL/90% saline, or 50% Cremophor EL/50% ethanol) , propylene glycol (e.g.
  • a preferred pharmaceutical carrier is polyethylene glycol, such as PEG 400, and particularly a composition comprising 40% PEG 400 and 60% water or saline.
  • the choice of carrier will be determined in part by the particular compound chosen, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention.
  • compositions for oral, aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, intrathecal, intraperitoneal, rectal, and vaginal administration are merely exemplary and are in no way limiting.
  • compositions for parenteral administration that comprise a solution of the compound of the invention dissolved or suspended in an acceptable carrier suitable for parenteral administration, including aqueous and non-aqueous, isotonic sterile injection solutions.
  • compositions include solutions containing anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol (for example in topical applications), or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, dime thylsulf oxide, glycerol ketals, such as 2,2- dimethyl- l ,3-dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropy
  • Oils useful in parenteral formulations include petroleum, animal, vegetable, and synthetic oils. Specific examples of oils useful in such formulations include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral oil. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl ⁇ -aminopropionates, and 2- alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.
  • the parenteral formulations typically will contain from about 0.5% or less to about 25% or more by weight of a compound of the invention in solution. Preservatives and buffers can be used. In order to minimize or eliminate irritation at the site of injection, such compositions can contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight ad ducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • HLB hydrophile-lipophile balance
  • parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • sterile liquid excipient for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.
  • Topical formulations, including those that are useful for transdermal drug release, are well known to those of skill in the art and are suitable in the context of the present invention for application to skin.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of a compound of the invention dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a pre-determined amount of the compound of the invention, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • Liquid formulations can include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients.
  • Lozenge forms can comprise the compound ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising a compound of the invention in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the compound of the invention, such excipients as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising a compound of the invention in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the compound of the invention, such excipients as are known in the art.
  • a compound of the present invention can be made into aerosol formulations to be administered via inhalation.
  • a compound or epimer of the invention is preferably supplied in finely divided form along with a surfactant and propellant.
  • Typical percentages of the compounds of the invention can be about 0.01% to about 20% by weight, preferably about 1% to about 10% by weight.
  • the surfactant must, of course, be nontoxic, and preferably soluble in the propellant.
  • Such surfactants are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride.
  • Mixed esters such as mixed or natural glycerides can be employed.
  • the surfactant can constitute from about 0.1% to about 20% by weight of the composition, preferably from about 0.25% to about 5%.
  • the balance of the composition is ordinarily propellant.
  • a carrier can also be included as desired, e.g., lecithin, for intranasal delivery.
  • aerosol formulations can be placed into acceptable pressurized propellants, such as dichlorodifluorome thane, propane, nitrogen, and the like. They also can be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer. Such spray formulations can be used to spray mucosa.
  • acceptable pressurized propellants such as dichlorodifluorome thane, propane, nitrogen, and the like.
  • non-pressured preparations such as in a nebulizer or an atomizer.
  • Such spray formulations can be used to spray mucosa.
  • the compound of the invention can be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases.
  • bases such as emulsifying bases or water-soluble bases.
  • Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the compound ingredient, such carriers as are known in the art to be appropriate.
  • the concentration of the compound in the pharmaceutical formulations can vary, e.g., from less than about 1% to about 10%, to as much as about 20% to about 50% or more by weight, and can be selected primarily by fluid volumes, and viscosities, in accordance with the particular mode of administration selected.
  • a typical pharmaceutical composition for intravenous infusion could be made up to contain 250 ml of sterile Ringer's solution, and 100 mg of at least one compound of the invention.
  • Actual methods for preparing parenterally administrable compounds of the invention will be known or apparent to those skilled in the art and are described in more detail in, for example, Remington's Pharmaceutical Science (17 th ed., Mack Publishing Company, Easton, PA, 1985).
  • the compound of the invention can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes.
  • Liposomes can serve to target a compound of the invention to a particular tissue, such as lymphoid tissue or cancerous hepatic cells. Liposomes can also be used to increase the half-life of a compound of the invention. Many methods are available for preparing liposomes, as described in, for example, Szoka et al., Ann. Rev. Biophys. Bioeng., 9, 467 (1980) and U.S. Patents 4,235,871, 4,501,728, 4,837,028, and 5,019,369.
  • the compounds of the invention can be administered in a dose sufficient to treat the disease, condition or disorder. Such doses are known in the art (see, for example, the Physicians' Desk Reference (2004)).
  • the compounds can be administered using techniques such as those described in, for example, Wasserman et al., Cancer, 36, pp. 1258- 1268 (1975) and Physicians' Desk Reference, 58th ed., Thomson PDR (2004).
  • Suitable doses and dosage regimens can be determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound of the present invention. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
  • the present method can involve the administration of about 0.1 ⁇ g to about 50 mg of at least one compound of the invention per kg body weight of the individual. For a 70 kg patient, dosages of from about 10 ⁇ g to about 200 mg of the compound of the invention would be more commonly used, depending on a patient's physiological response.
  • the dose of the pharmaceutically active agent(s) described herein for methods of treating or preventing a disease or condition as described above can be about 0.001 to about 1 mg/kg body weight of the subject per day, for example, about 0.001 mg, 0.002 mg, 0.005 mg, 0.010 mg, 0.015 mg, 0.020 mg, 0.025 mg, 0.050 mg, 0.075 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.5 mg, 0.75 mg, or 1 mg/kg body weight per day.
  • the dose of the pharmaceutically active agent(s) described herein for the described methods can be about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 0.020 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg, 750 mg, or 1000 mg/kg body weight per day.
  • PARP inhibitors reported herein can be used for the treatment of diseases and/or disorders that include, but are not limited to, cancer, stroke, traumatic brain injury, Parkinson's disease, meningitis, myocardial infarction, ischaemic cardiomyopathy, vascular disease, septic shock, ischemic injury, reperfusion injury, neurotoxicity, inflammatory disease, and haemorrhagic shock.
  • PARP inhibitors mentioned herein can be used as single agents and/or in combination with other chemotherapeutic agents so that they can potentiate the effects of the standard chemotherapeutic agents.
  • Cancers that can be treated with PARP inhibitors include, but are not limited to, breast cancer, glioblastoma, pancreatic cancer, ovarian cancer, prostate cancer, melanoma, colon cancer, leukaemia and lymphoma.
  • treat do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect.
  • the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal.
  • a disorder, including symptoms or conditions thereof may be reduced by, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%.
  • the treatment, prevention, amelioration, or inhibition provided by the inventive method can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer.
  • treatment,” “prevention,” “amelioration,” or “inhibition” can encompass delaying the onset of the disorder, or a symptom or condition thereof.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and! or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • an appropriate "effective" amount in any individual case is determined using techniques, such as a dose escalation study.
  • potentiation means to increase or prolong either in potency or duration a desired effect.
  • potentiating refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • the term subject includes an "animal" which in turn includes a mammal such as, without limitation, the order Rodentia, such as mice, and the order Lagomorpha, such as rabbits.
  • the mammals are from the order Carnivora, including Felines (cats) and Canines (dogs).
  • the mammals are from the order Artiodactyla, including Bovlnes (cows) and Swine (pigs) or of the order Perssodactyla, including Equines (horses).
  • the mammals are of the order Primates, Ceboids, or Simoids (monkeys) or of the order Anthropoids (humans and apes).
  • the mammal is human.
  • the term "patient” encompasses mammals and non-mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non-mammals include, but are not limited to, birds, fish and the like.
  • the mammal is a human.
  • Another aspect of the present invention is a pharmaceutical composition of compound of formula (I) in combination with at least one other known anticancer agent, or a pharmaceutically acceptable salt of said agent.
  • the anticancer agent used in combination may be selected from the group consisting of busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cis-platin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, elliptinium, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxy-uridine, fludarabine, nelarabine, ara-C, alanosine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone
  • Another aspect of the present invention is the provision of a method of treatment or prevention of a disorder responsive to the inhibition of PARP activity in a mammal suffering therefrom, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I).
  • cancer which includes liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphomas, acute or chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, chronic lymphocytic leukemia, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, malignant melanoma, chorio carcinoma, mycosis fungo ide, head or neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's s
  • Another aspect of the present invention is a method of potentiating the efficacy of chemotherapeutic regimen for a patient undergoing chemotherapeutic treatment comprising co- administering to the patient an effective amount of a compound of the present invention, wherein, the compound of the invention may be co-administered simultaneously, sequentially, or cyclically with the anticancer agent.
  • the chemotherapeutic agent mentioned above is selected form busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cis-platin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, elliptinium, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5- fluoro-2'-deoxy-uridine, fludarabine, nelarabine, ara-C, alanosine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vlnorelbine, paclitaxel, ixabepilone,
  • Yet another aspect of the present invention is the provision of a method for sensitizing a patient who has developed or likely to develop resistance for chemotherapic agents comprising administering an effective amount of a compound of the present invention.
  • reaction mixture was diluted with dichloromethane (25 ml), washed with saturated aqueous solution of sodium thiosulfate (2 x 15 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product which was purified by flash column chromatography over silica gel (100-200 mesh) using 2% methanol in dichlorome thane as eluent to obtain the title compound (28.0 g).
  • reaction mixture was filtered over a Celite bed, the residue was washed with ethyl acetate ( 100 ml) and filtrate was concentrated under reduced pressure to obtain a crude product which was purified by flash column chromatography over silica gel (100 - 200 mesh) using 2% methanol in dichloromethane as an eluent to yield the title compound ( 1.1 g, 51.7%).
  • Fuming nitric acid (30 ml, 671 mmol) was added drop wise to a stirred solution of sulfuric acid (400 ml, 7504 mmol) over a period of 10 min at 0°C and the resulting mixture was allowed to stir over a period of 5 min at the same temperature.
  • 2-bromo-5-fluorobenzoic acid 50 g, 228 mmol
  • the progress of the reaction was monitored by TLC.
  • the reaction mixture was poured into ice cold water (2 lit) and yellow colored solid was collected by filtration.
  • Step 6 Synthesis of 4-(4-(3-(5-amino-7-fluoro- l-oxo- l , 2-dihydroisoquinolin-3- yl)propyl)piperazin- l-yl)benzonitrile (Compound 3)
  • Step 7 Synthesis of N-(3-(3-(4-(4-cyanophenyl)piperazin- l-yl)propyl)-7-fluoro- l- oxo- l ,2-dihydroisoquinolin-5-yl)-4-fluorobenzamide (Compound 2)
  • reaction mixture was treated with saturated aqueous sodium bicarbonate ( 10 ml) and extracted with dichloromethane (5 x 20 ml). The combined organic layer was dried over sodium sulphate, filtered and solvent was removed under reduced pressure to obtain a crude product which was purified by flash chromatography over silica gel (100 - 200 mesh) using 3% methanol in dichloromethane as eluent to obtain the title compound (0.015g, 19%).
  • Step 1 Synthesis of 4-(4-(3-(7-fluoro-5-((4- fluorobenzylidene)amino)- 1-oxo- 1 ,2- dihydroisoquinolin-3-yl)propyl)piperazin- l-yl)benzonitrile (Compound la)
  • reaction mixture was diluted with ethyl acetate (50 ml) and washed with saturated aqueous solution of sodium bicarbonate (10 ml).
  • the organic layer was dried over anhydrous sodium sulphate, filtered and solvent was removed under reduced pressure to obtain a crude product which was purified by flash chromatography over silica gel (100 - 200 mesh) using 3% methanol in dichloromethane as eluent to obtain the title compound (0.170 g, 90 % yield).
  • Step 2 Synthesis of 4-(4-(3-(7-fluoro-5-((4-fluorobenzyl)amino)-l-oxo-l,2- dihydroisoquinolin-3-yl)propyl)piperazin- l-yl)benzonitrile (Compound 1)
  • Step 1 Synthesis tert-butyl 4-(pent-4-yn- l-yl)piperazine- l-carboxylate
  • Step 4 Synthesis of 7-fluoro-3-(3-(4-(2-methyl-2-phenylpropanoyl)piperazin- l- yl)propyl)-5-nitroisoquinolin- l(2H)-one (Compound 17d)
  • reaction mixture was diluted with water ( 100 ml) and extracted with ethyl acetate (3 x 50 ml) .
  • the combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a crude product which was purified by flash column chromatography over silica gel (200 - 400 mesh) using 3.5% methanol in dichloromethane as eluent to obtain the title compound (0.220 g, 73.1% yield).
  • Step 1 Synthesis of 3-(3-(4-(5-chloropyridin-2-yl)piperazin- l-yl)propyl)-7-fluoro-5- nitroisoquinolin- l(2H)-one (Compound 28a)
  • reaction mixture was cooled to room temperature, diluted with water (30 ml) and extracted with ethyl acetate (2 x 25 ml). Combined organic layer was washed with water (30 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product which was purified by column chromatography over silica gel to obtain the title compound (0.120 g, 33.3 % yield).
  • Step 2 Synthesis of 5-amino-3-(3-(4-(5-chloropyridin-2-yl)piperazin- l-yl)propyl)-7- fluoroisoquinolin- l(2H)-one (Compound 28)
  • reaction mixture was cooled to room temperature and solvent was removed under reduced pressure to give crude product, which was purified by flash column chromatography over silica gel (100 - 200 mesh) using 2% methanol in dichloromethane as eluent to afford title compound (0.015 g, 13.40 % yield).
  • Step 1 Synthesis of 4-(4-(pent-4-ynoyl)piperazin- l-yl)benzonitrile (Compound 16a)
  • reaction mixture was concentrated under reduced pressure and residue was diluted with water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product which was purified by flash column chromatography over silica gel (200 - 400 mesh) using 70% ethyl acetate in hexane to obtain the title compound (2.2 g, 81% yield).
  • Step 2 Synthesis of methyl 2-(5-(4-(4-cyanophenyl)piperazin- l-yl)-5-oxopent- l-yn- l-yl)-5-fluoro-3-nitrobenzoate (Compound 16b)
  • Step 3 Synthesis of 2-(5-(4-(4-cyanophenyl)piperazin- l-yl)-5-oxopent- l-yn- l-yl)-5- fluoro-3-nitrobenzoic acid (Compound 16c)
  • reaction mixture was cooled to room temperature and solvent was evaporated under reduced pressure, the residue was diluted with water and reaction mixture was neutralized (pH 7) using dilute hydrochloric acid.
  • Precipitate product was obtained by filtration, washed with water and dried under reduced pressure (1.6 g, 3.55 mmol, 82 % yield) which was used for next step without further purification.
  • Step 4 Synthesis of 4-(4-(3-(7-fluoro-5-nitro- l-oxo- l ,2-dihydroisoquinolin-3- yl)propanoyl)piperazin- l-yl)benzonitrile (Compound 16d)
  • reaction mixture was cooled to room temperature, solvents were removed under reduced pressure to give crude product which was purified by flash chromatography over silica gel (200-400 mesh) using 2.5 % methanol in dichloromethane to obtain the title compound (0.090 g, 5.64 % yield).
  • Step 5 Synthesis of 4-(4-(3-(5-amino-7-fluoro- l-oxo- l ,2-dihydroisoquinolin-3- yl)propanoyl)piperazin- l-yl)benzonitrile (Compound 16)
  • Step 1 Synthesis of 4-(4-(3-(7-fluoro-5-nitro- l-oxo-l ,2-dihydroisoquinolin-3- yl)propyl)piperazin- l-yl)benzoic acid (23b)
  • reaction mixture was concentrated under reduced pressure to obtain a crude product which was dissolved in 7N ammonia in methanol ( 15 ml) and concentrated under reduced pressure to get crude product, which was purified by column chromatography over silica gel ( 100 - 200 mesh) in 10% methanol in hexane to obtain the title compound (0.160 g, 74.3% yield).
  • TMS-CN trimethylsilyl cyanide
  • TBAF tetra butyl ammonium fluoride
  • Step 3 Synthesis of methyl 2-(l-cyano-2-(l-methyl- lH- l ,2,4-triazol-5-yl)vinyl)-3- nitrobenzoate (Compound 24c)
  • reaction mixture was filtered and filtrate was concentrated under reduced pressure, the residue was diluted with water (150 ml) and extracted with ethyl acetate (2 X 150 ml). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude compound which was purified by flash column chromatography using 70% ethyl acetate in hexane as eluent to obtain the title compound (10.5 g, 77 %).
  • Step 4 Synthesis of methyl 2-(l-cyano-2-(l -methyl- 1H- 1 ,2,4- triazol-5-yl)ethyl)-3- nitrobenzoate (Compound 24d)
  • Step 5 Synthesis of 2-( l-cyano-2-(l-methyl- lH- l ,2,4-triazol-5-yl)ethyl)-3- nitrobenzoic acid (Compound 24e)
  • Step 6 Synthesis of l ,3-dichloro-4-(( l-methyl- lH- l ,2,4-triazol-5-yl)methyl)-5- nitroisoquinoline (Compound 24f)
  • Step 7 Synthesis of l ,3-dichloro-4-((l-methyl- lH- l,2,4-triazol-5- yl)methyl)isoquinolin-5-amine (Compound 24g)
  • Step 8 Synthesis of 3-chloro- l-methoxy-4-((l-methyl- lH- l ,2,4-triazol-5- yl)methyl)isoquinolin-5-amine (Compound 24h)
  • Step 9 Synthesis of 3-(3-(4-(4-fluorophenyl)piperazin- l-yl)prop- l-en- l-yl)- l- methoxy-4-((l-methyl- IH- 1 ,2,4-triazol-5-yl)methyl)isoquinolin-5-amine (Compound 24i)
  • reaction mixture was degassed for 15 min and then (PPh3) 2 Pd (II)C1 2 (0.097 g, 0.138 mmol) was added in pressure tube.
  • the reaction mixture was heated at 120°C for 24 h.
  • the progress of the reaction was monitored by TLC and LCMS.
  • the reaction mixture was diluted with water (75 ml) and extracted with ethyl acetate (2 x 50 ml). The Combined organic layer was washed with water (50 ml).
  • Step 10 Synthesis of 3-(3-(4-(4-fluorophenyl)piperazin- l-yl)propyl)- l-methoxy-4- ((1-methyl- 1H- 1 ,2,4-triazol-5-yl)methyl)isoquinolin-5-amine (Compound 24j)
  • Step 11 Synthesis of 5-amino-3-(3-(4-(4-fluorophenyl)piperazin-l-yl)propyl)-4-((l- methyl- 1H- 1 ,2,4-triazol-5-yl)methyl)isoquinolin- 1 (2H)-one (Compound 24)
  • reaction mixture was quenched by adding 20% aqueous sodium thiosulfate solution (5ml), diluted with water (15 ml) and extracted with dichloromethane (3 x 25ml). The combined organic layer was concentrated to obtain a crude compound which was purified by flash column chromatography over silica gel using 5% methanol in dichloromethane as eluent to obtain the title compound (0.030 g, 35.1 %).
  • the assay was performed using BPS Bioscience kit.
  • the 96-well strip plate was coated with 50 ul of histone mixture and incubated at 4°C overnight. The next day, the wells were blocked by adding 100 ul of blocking buffer. The plate was washed and 25 ul of appropriate concentration of PARPl (25-75 ng/well) was added in all of the Test and Positive control wells. In the Negative control wells, the enzyme was replaced with 25 ul of water. To it 5 ul each of 10X PARP assay buffer and activated DNA was added in all the wells (Test, Positive and Negative control wells). 10X concentration of test compounds were prepared and 5 ul test compounds were added to the respective wells.
  • Reaction volume was made up to 45 ul by adding water to all of the wells.
  • 5 ul of 10X PARP assay mixture containing biotinilated NAD + was added in each well and the plate was incubated at ambient temperature (25°C) for 60 min.
  • 50 ul of Streptavldin-HRP was added in each well and incubated the plate at RT for 30 min.
  • the plate was washed and the luminescence was read in PHERAStar plate reader after adding 100 ul of chemiluminescent substrate.
  • PARP inhibition was calculated using the following formula:
  • % PARP inhibition 100 - [(RLU test compound treated sample - RLU negative control) /(RLU Positive control - RLU negative control) x 100]
  • IC5 0 values were calculated by plotting % inhibition against the respective concentrations of test compounds using GraphPad Prism 5.
  • PARP 1 inhibition IC5 0 of the compounds of invention is provided in Table 1 below: Compounds with IC5 0 between 0.1 nM and 5 nM are grouped under group A, compounds with IC5 0 between 5.1 nM and 50 nM are grouped under group B, compounds with IC5 0 between 50.1 nM and 150 nM are grouped under group C.

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Abstract

L'invention concerne des composés de formule (I), leurs formes tautomères, leurs stéréoisomères, et des sels pharmaceutiquement acceptables de ceux-ci, dans la formule (I), R1-R6, R1a, R2a, R1b, R2b, R1c, R2c, p et q étant tels que définis dans la description; des compositions pharmaceutiques comprenant un composé, un tautomère, un stéréoisomère, ou un sel de ceux-ci; et des méthodes de traitement ou de prévention de maladies ou de troubles, par exemple, le cancer, dont le traitement ou la prévention peut être réalisé(e) par inhibition de l'enzyme PARP d'un patient.
PCT/IB2016/054310 2015-07-22 2016-07-20 Dérivés d'isoquinolinone utilisés en tant qu'inhibiteurs de parp WO2017013593A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2019194738A1 (fr) * 2018-04-05 2019-10-10 Noviga Research Ab Nouvelles associations d'un inhibiteur de polymérisation de la tubuline et d'un inhibiteur de la poly(adp-ribose) polymérase (parp) destinées à être utilisées dans le traitement du cancer
CN114929673A (zh) * 2019-10-30 2022-08-19 多临生物株式会社 异喹啉酮衍生物、其制备方法、和包含其作为活性成分的用于预防或治疗聚(adp-核糖)聚合酶1(parp-1)相关疾病的药物组合物

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019194738A1 (fr) * 2018-04-05 2019-10-10 Noviga Research Ab Nouvelles associations d'un inhibiteur de polymérisation de la tubuline et d'un inhibiteur de la poly(adp-ribose) polymérase (parp) destinées à être utilisées dans le traitement du cancer
US11590130B2 (en) 2018-04-05 2023-02-28 Noviga Research Ab Combinations of a tubulin polymerization inhibitor and a poly (ADP-ribose) polymerase (PARP) inhibitor for use in the treatment of cancer
CN114929673A (zh) * 2019-10-30 2022-08-19 多临生物株式会社 异喹啉酮衍生物、其制备方法、和包含其作为活性成分的用于预防或治疗聚(adp-核糖)聚合酶1(parp-1)相关疾病的药物组合物
EP4053106A4 (fr) * 2019-10-30 2023-12-06 Digmbio. Inc. Dérivé d'isoquinolinone, son procédé de préparation et composition pharmaceutique le comprenant en tant que principe actif pour la prévention ou le traitement d'une maladie associée à la poly(adp-ribose) polymérase-1 (parp-1)
JP7512380B2 (ja) 2019-10-30 2024-07-08 ディグムバイオ．インコーポレイテッド イソキノリノン誘導体、その製造方法及びそれを有効成分として含有するポリ（ａｄｐ－リボース）ポリメラーゼ－１（ｐａｒｐ－１）関連疾患の予防又は治療用薬学的組成物

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