Substituted pyridones as inhibitors of poly(ADP-ribose) polymerase (PARP)

1. A compound, or an enantiomer, stereoisomer, or a tautomer of said compound or a pharmaceutically acceptable salt thereof, with said compound having the structure shown in formula I:

wherein

R is hydrogen or C 1-6 alkyl;

R 1 is C 1-4 alkyl, C 1-4 alkenyl, fluoroalkyl or fluoroalkoxy of the formula C n H x F y or OC n H x F y wherein n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9 and sum of x and y is 2n+1, wherein said alkyl or alkenyl is optionally substituted with one or more hydroxy or chlorine;

R 2 is Ar—Y, wherein

Ar is optionally substituted thienyl wherein said substituents are selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkenyl, fluoroalkyl or fluoroalkoxy of the formula C n H x F y or OC n H x F y wherein n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9 and the sum of x and y is 2n+1, —NO 2 , —CH 2 NH 2 , —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CN, —C(O)R 11 , —NHC(O)(C 1-4 alkyl), —SO 2 Cl, —SO 2 (C 1-4 alkyl), halogen and hydroxy; and

Y is —SO 2 NR 5 R 6 , —(CH 2 ) n NR 7 R 8 , and —C(O)NR 7 R 8 ;

R 3 is hydrogen, C 1-4 alkyl, C 1-4 alkenyl, fluoroalkyl or fluoroalkoxy of the formula C n H x F y or OC n H x F y wherein n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9 and the sum of x and y is 2n+1, wherein said alkyl or alkenyl is optionally substituted with one or more hydroxy or chlorine;

R 4 is C 1-6 alkyl, C 1-6 alkenyl, C 3-8 cycloalkyl, fluoroalkyl or fluoroalkoxy of the formula C n H x F y or OC n H x F y wherein n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9 and the sum of x and y is 2n+1;

R 5 and R 6 taken together with the nitrogen atom to which they are attached form an unsubstituted or at least monosubstituted pyrrolidine; or

R 7 and R 8 taken together with the nitrogen atom to which they are attached form an unsubstituted or at least monosubstituted pyrrolidine;

wherein said substituents are selected from: aryl, oxo, fluorine, chlorine, bromine, —CF 3 , —OCF 3 , —NO 2 , —CN, —C(O)R ii , —NHC(O)(C 1-3 alkyl), —NH 2 , hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —NH(C 1-3 alkyl), —N(C 1-3 alkyl) 2 , —SO 2 NH 2 , —SO 2 (C 1-3 alkyl) and —NH—SO 2 (C 1-3 alkyl), and aryl may optionally be at least monosubstituted with fluorine, chlorine, bromine, hydroxy, C 1-3 alkyl or C 1-3 alkoxy;

R 11 is hydroxy, C 1-3 alkoxy, —O-phenyl, —NH 2 , —NH(C 1-3 alkyl), —N(C 1-3 alkyl) 2 or phenyl;

n is an integer from 1 to 4; and wherein

aryl is a 6 to 10-membered, aromatic mono- or bicyclic ring.

2. The compound as set forth in claim 1 , wherein Ar is optionally substituted thienyl and Y is SO 2 NR 5 R 6 wherein

R 5 and R 6 taken together with the nitrogen atom to which they are attached form a pyrrolidine;

and wherein the aforementioned groups are optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, bromine, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, hydroxy-C 1-6 alkoxy-C 1-6 alkyl, C 3-8 cycloalkyl-C 1-4 alkyl, trifluoromethyl, C 1-6 alkoxycarbonyl, C 1-6 alkylsulfonyl, amino-C 1-6 alkyl, C 1-6 alkyl-aminio-C 1-6 alkyl, C 1-6 dialkyl-amino-C 1-6 alkyl, substituted or unsubstituted phenyl-C 0-4 alkyl, substituted or unsubstituted phenyl-amino-C 0-4 alkyl and substituted or unsubstituted benzoyl.

3. The compound as set forth in claim 2 , wherein R is hydrogen, R 1 is methyl, R 3 is hydrogen and R 4 is ethyl.

4. A compound which is selected from the group consisting of:

5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophene-2-sulfonic acid [3-(3-hydroxy-pyrrolidin-1-yl)-propyl]-amide hydrochloride;

5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonic Acid [2-(1-methylpyrrolidin-2-yl)ethyl]amide hydrochloride;

5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophene-2-sulfonic acid [3-(3,3-difluoro-pyrrolidin-1-yl)-propyl]-amide hydrochloride;

5-[5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl]thiophene-2-sulfonic acid [3-(2-oxopyrrolidin-1-yl)propyl]amide;

5-[5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl]thiophene-2-sulfonic acid methyl (1-methylpyrrolidin-3-yl)amide hydrochloride;

3-ethyl-5-[5-(3-hydroxypyrrolidine-1-sulfonyl)thiophen-2-yl]-6-methyl-1H-pyridin-2-one;

5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonic acid (2-pyrrolidin-1-yl)ethylamide hydrochloride;

5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-thiophene-2-sulfonic acid (1-ethyl-pyrrolidin-2-ylmethyl)amide hydrochloride;

3-ethyl-6-methyl-5-[5-((S)-2-phenylaminomethylpyrrolidine-1-sulfonyl)-thiophen-2-yl]-1H-pyridin-2-one hydrochloride;

5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophene-2-sulfonic acid [3-(2R-hydroxymethyl-pyrrolidin-1-yl)-propyl]-amide hydrochloride;

5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophene-2-sulfonic acid [2-(2R-hydroxymethyl-pyrrolidin-1-yl)-ethyl]-amide hydrochloride;

5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophene-2-sulfonic acid [2-(3,3-difluoro-pyrrolidin-1-yl)-ethyl]-amide; and

1-{2-[5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophene-2-sulfonylamino]-ethyl}-pyrrolidine-2-carboxylic acid.

5. A pharmaceutical composition comprising one or more compounds of claim 1 in combination with one or more pharmaceutically acceptable carriers, diluents or excipients.

6. A pharmaceutical composition comprising one or more compounds of claim 3 in combination with one or more pharmaceutically acceptable carriers, diluents or excipients.