Sulfonamide derivatives and use thereof for the modulation of metalloproteinases

1. A compound of Formula (Ia),

wherein:

R 2 and R 3 are independently selected from:

hydrogen,

halogen,

linear or branched C 1 -C 6 alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, linear or branched C 1 -C 6 alkoxy, phenoxy,

linear or branched C 1 -C 6 alkoxy,

phenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, linear or branched C 1 -C 6 alkyl,

phenyl-linear or branched C 1 -C 6 alkyl, said phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, linear or branched C 1 -C 6 alkyl,

a three to six member heterocyclic group having at least a heteroatom selected from the group consisting of oxygen, nitrogen and sulfur;

R 13 is selected from H, linear or branched C 1 -C 6 alkyl;

R 14 is selected from

linear or branched C 1 -C 8 alkyl, optionally substituted with one or more halogen atoms and/or hydroxy groups, said C 1 -C 8 alkyl optionally containing one or more unsaturated C—C bonds or containing one or more oxygen or sulfur atoms in the alkyl chain,

C 3 -C 8 cycloalkyl, optionally substituted with a carboxy or a linear or branched C 1 -C 4 alkoxycarbonyl group,

phenyl,

phenyl-linear or branched C 1 -C 6 alkyl, said C 1 -C 6 alkyl optionally containing one oxygen atom,

a heterocyclic or heterocycloalkyl group selected from the group consisting of: 1,3-dioxolane, 2,2-dimethyl-1,3-dioxolane, thiophene, 1-methyl-1-morpholino-4-ylethyl, pyrimidine, pyridine, said pyridine optionally substituted with a hydroxy or C 1 -C 6 alkoxy group; pyridinyl-linear or branched C 1 -C 4 alkyl; piperidine, said piperidine optionally substituted with phenyl-C 1 -C 4 alkyl; furan, tetrahydrofuran; 2-tetrahydrofuran-2-ylethyl, pyrrolidine N-carboxylic acid, C 1 -C 4 linear or branched N-alkoxycarbonylpyrrolidin-2-yl; tetrahydropyran; or

R 13 and R 14 taken together form a C 3 -C 8 cycloalkyl;

n is an integer selected from 0 and 1;

as well as its geometrical isomers, its optically active forms as enantiomers, diastereomers, tautomers, racemate forms, as well as pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 wherein R 2 and R 3 are independently selected from H and alkoxy.

3. A compound according to claim 1 wherein R 13 is H.

4. A compound according to claim 1 wherein R 13 is H; R 2 is selected from H and alkoxy; R 14 and n are as defined in the preceding claims.

5. A compound according to claim 1 wherein R 14 is selected from phenyl and a heterocyclic or heterocycloalkyl group selected from the group consisting of: 1,3-dioxolane, 2,2-dimethyl-1,3-dioxolane, thiophene, 1-methyl-1-morpholino-4-ylethyl, pyrimidine, pyridine, said pyridine optionally substituted with a hydroxy or C 1 -C 6 alkoxy group; pyridinyl-linear or branched C 1 -C 4 alkyl; piperidine, said piperidine optionally substituted with phenyl-C 1 -C 4 alkyl; furan, tetrahydrofuran; 2-tetrahydrofuran-2-ylethyl, pyrrolidine N-carboxylic acid, C 1 -C 4 linear or branched N-alkoxycarbonylpyrrolidin-2-yl; tetrahydropyran.

6. A compound according to claim 1 wherein n is 0.

7. A compound according to claim 1 wherein n is 1.

8. A compound according to claim 1 , wherein R 13 is selected from H, linear or branched C 1 -C 6 alkyl and R 14 is linear or branched C 1 -C 8 alkyl, optionally substituted with one or more halogen atoms and/or hydroxy groups, said C 1 -C 8 alkyl optionally containing one or more unsaturated C—C bonds or containing one or more oxygen or sulfur atoms in the alkyl chain.

9. A compound according to claim 1 , wherein R 13 is selected from H, linear or branched C 1 -C 6 alkyl and R 14 is C 3 -C 8 cycloalkyl, optionally substituted with a carboxy or a linear or branched C 1 -C 4 alkoxycarbonyl group.

10. A compound according to claim 1 , wherein R 13 is selected from H, linear or branched C 1 -C 6 alkyl and R 14 is phenyl or phenyl-linear or branched C 1 -C 6 alkyl, said C 1 -C 6 alkyl optionally containing one oxygen atom.

11. A compound according to claim 1 , wherein R 13 is selected from H, linear or branched C 1 -C 6 alkyl and R 14 is a heterocyclic or heterocycloalkyl group selected from the group consisting of: 1,3-dioxolane, 2,2-dimethyl-1,3-dioxolane, thiophene, 1-methyl-1-morpholino-4-ylethyl, pyrimidine, pyridine, said pyridine optionally substituted with a hydroxy or C 1 -C 6 alkoxy group; pyridinyl-linear or branched C 1 -C 4 alkyl; piperidine, said piperidine optionally substituted with phenyl-C 1 -C 4 alkyl; furan, tetrahydrofuran; 2-tetrahydrofuran-2-ylethyl, pyrrolidine N-carboxylic acid, C 1 -C 4 linear or branched N-alkoxycarbonylpyrrolidin-2-yl; tetrahydropyran.

12. A compound according to claim 1 , wherein R 13 and R 14 taken together form a cyclopentyl group.

13. A compound according to claim 1 , selected from the following group:

N-{1-[(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)methyl]-3-phenylpropyl}-N-hydroxy formamide;

N-{2-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl}-N-hydroxyformamide;

N-{1-[(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)methyl]hexyl}-N-hydroxyformamide;

N-[1-cyclopropyl-2-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)ethyl]-N-hydroxy formamide;

N-[2-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)-1-(2-thienyl)ethyl]-N-hydroxyformamide;

N-{1-[(1,3-dihydro-2H-isoindol-2-ylsulfonyl)methyl]-3-phenylpropyl}-N-hydroxy formamide;

N-[2-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)-1-(3-thienyl)ethyl]-N-hydroxyformamide;

N-{1-[(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)methyl]-2-methyl-2-morpholin-4-yl propyl}-N-hydroxyformamide;

N-[2-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)-1-pyrimidin-5-ylethyl]-N-hydroxy formamide;

N-[2-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)-1-pyridin-3-ylethyl]-N-hydroxy formamide;

N-[2-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)-1-pyridin-3-ylethyl]-N-hydroxy formamide; hydrochloride salt;

N-(1-{[(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}-3-phenyl propyl)-N-hydroxyformamide;

N-[2-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)-1-(6-methoxypyridin-3-yl)ethyl]-N-hydroxyformamide;

N-{2-[(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl}-N-hydroxyformamide;

N-{1-cyclopentyl-2-[(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]ethyl}-N-hydroxyformamide;

N-{2-(1,3-dihydro-2H-isoindol-2-ylsulfonyl)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl}-N-hydroxyformamide;

N-(1-{[(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}-2-ethylbutyl)-N-hydroxyformamide;

N-{1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-[(6-isopropyl-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]ethyl}-N-hydroxyformamide;

N-{2-[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl}-N-hydroxyformamide;

N-(1-{[(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-methyl}-2,2-dimethylpropyl)-N-hydroxyformamide;

N-{2-[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-1-cyclopentylethyl}-N-hydroxyformamide;

N-{(1R)-2-[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-1-[(2R)-tetrahydrofuran-2-yl]ethyl}-N-hydroxyformamide,

N-{(1S)-2-[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-1-[(2R)-tetrahydrofuran-2-yl]ethyl}-N-hydroxyformamide;

N-((1S,2S)-1-{[(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}-2,3-dihydroxypropyl)-N-hydroxyformamide;

N-(1-cyclopentyl-2-{[6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}ethyl)-N-hydroxyformamide;

N-(1-{[(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)sulfonyl]methyl}-3,3-dimethylbutyl)-N-hydroxyformamide;

N-hydroxy-N-((1S)-1-[(2R)-tetrahydrofuran-2-yl]-2-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}ethyl)formamide;

N-(1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}ethyl)-N-hydroxyformamide;

N-{(1S)-2-[(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)sulfony]-1-[(2R)-tetrahydrofuran-2-yl]ethyl}-N-hydroxyformamide;

N-[2,2-dimethyl-1-({[6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}methyl)hept-4-yn-1-yl]-N-hydroxyformamide;

N-[2,2-dimethyl-3-phenyl-1-({[6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}methyl)propyl]-N-hydroxyformamide;

N-hydroxy-N-((1R)-1-[(2R)-tetrahydrofuran-2-yl]-2-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}ethyl)formamide;

N-hydroxy-N-[1-{[(7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}-3-(tetrahydrofuran-2-yl)propyl]formamide;

N-(1-{[(6,7-dichloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}-2-ethylbutyl)-N-hydroxyformamide;

N-(2-ethyl-1-{[(6-isopropyl-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}butyl)-N-hydroxyformamide;

N-(1-{[(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}-2-ethylbutyl)-N-hydroxyformamide;

N-[2-ethyl-1-({[6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}methyl)butyl]-N-hydroxyformamide;

N-(2-ethyl-1-{[(7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}butyl)-N-hydroxyformamide;

N-(1-{[(6,7-dichloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}-2-methylpropyl)-N-hydroxyformamide;

N-(3,3-dimethyl-1-{[(7-propoxy-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}butyl)-N-hydroxyformamide;

N-(1-{[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}-3,3-dimethylbutyl)-N-hydroxyformamide;

N-(1-{[(6,7-dichloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}-3,3-dimethylbutyl)-N-hydroxyformamide;

N-[3,3-dimethyl-1-({[6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}methyl)butyl]-N-hydroxyformamide;

tert-butyl (2RS)-2-{(1SR)-2-[(6,7-dichloro-3,4-dihydroisoquinolin-2(1H)-yl)sul-fon-yl]-1-[formyl(hydroxy)amino]ethyl}pyrrolidine-1-carboxylate

N-hydroxy-N-{(1S)-2-[(6-isopropyl-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-1-[(2R)-tetrahydrofuran-2-yl]ethyl}formamide;

tert-butyl (2RS)-2-{(1RS)-2-[(6,7-dichloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfon-yl]-1-[formyl(hydroxy)amino]ethyl}pyrrolidine-1-carboxylate

N-hydroxy-N-(1-[(2R)-tetrahydrofuran-2-yl]-2-{[6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}ethyl)formamide;

N-(1-{[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}-3-hydroxypropyl)-N-hydroxyformamide;

N-[2-[(6,7-dichloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-1-(hydroxymethyl)ethyl]-N-hydroxyformamide;

N-[1-({[7-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}methyl)-2-methylpropyl]-N-hydroxyformamide;

N-hydroxy-N-(1-{[(7-isopropoxy-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}-3-methylbutyl)formamide;

N-[2-[(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-1-(3-furyl)ethyl]-N-hydroxyformamide;

N-{1-(1-benzylpiperidin-4-yl)-2-[(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]ethyl}-N-hydroxyformamide;

N-[1-{[(7-tert-butyl-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}-3-(methylthio)propyl]-N-hydroxyformamide;

N-(1-{[(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}-3-methylbutyl)-N-hydroxyformamide;

N-{2-[(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-1,1-dimethylethyl}-N-hydroxyformamide;

N-(2-(benzyloxy)-1-{[(7-tert-butyl-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}ethyl)-N-hydroxyformamide;

N-(2-(benzyloxy)-1-{[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}ethyl)-N-hydroxyformamide;

N-[2-(benzyloxy)-1-({[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}methyl)ethyl]-N-hydroxyformamide;

N-{1-cyclopentyl-2-[(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]ethyl}-N-hydroxyformamide;

N-[2-[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-1-(phenoxymethyl)ethyl]-N-hydroxyformamide;

N-(1-{[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}cyclopentyl)-N-hydroxyformamide;

N-[2,2-dimethyl-1-({[6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}methyl)heptyl]-N-hydroxyformamide;

N-{2-[(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-1-cyclopentylethyl}-N-hydroxyformamide;

N-(1-{[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}-2,2-dimethylpropyl)-N-hydroxyformamide;

N-[2-[(7-tert-butyl-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-1-(tetrahydro-2H-pyran-4-yl)ethyl]-N-hydroxyformamide;

ethyl 2-{2-[(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-1-[formyl-(hydroxy)amino]ethyl}cyclopropanecarboxylate

N-(1-cyclopentyl-2-{[7-(3-thienyl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}ethyl)-N-hydroxyformamide;

N-{1-cyclopentyl-2-[(7-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]ethyl}-N-hydroxyformamide;

N-(1-cyclopentyl-2-{[7-(3-hydroxyphenyl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}ethyl)-N-hydroxyformamide;

2-{2-[(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-1-[formyl(hydroxy)amino]ethyl}cyclopropanecarboxylic acid

N-[1-cyclopropyl-2-(1,3-dihydro-2H-isoindol-2-ylsulfonyl)ethyl]-N-hydroxyformamide;

N-{2-[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-1-cyclopropylethyl}-N-hydroxyformamide;

N-(1-cyclopropyl-2-{[6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}ethyl)-N-hydroxyformamide;

N-(1-cyclopropyl-2-{[7-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}ethyl)-N-hydroxyformamide;

N-(1-{[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}-4,4,4-trifluorobutyl)-N-hydroxyformamide;

N-{1-cyclopentyl-2-[(6,7-dichloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]ethyl}-N-hydroxyformamide;

N-{1-cyclopentyl-2-[(7-isopropoxy-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]ethyl}-N-hydroxyformamide;

N-{1-cyclopentyl-2-[(7-pyridin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]ethyl}-N-hydroxyformamide;

N-{1-cyclopentyl-2-[(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)sulfonyl]ethyl}-N-hydroxyformamide;

N-{1-cyclopentyl-2-[(6-isopropyl-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]ethyl}-N-hydroxyformamide;

N-(1-cyclopentyl-2-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}ethyl)-N-hydroxyformamide;

N-(1-cyclopropyl-2-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}ethyl)-N-hydroxyformamide;

N-{1-cyclopropyl-2-[(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]ethyl}-N-hydroxyformamide;

N-{1-cyclopropyl-2-[(6-isopropyl-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]ethyl}-N-hydroxyformamide;

N-(1-{[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}-3-pyridin-3-ylpropyl)-N-hydroxyformamide.

14. A compound according to claim 1 for use as medicament for the modulation of metalloproteinases MMP1, MMP2, MMP9, MMP12, MMP13, and MMP14 and/or TACE.

15. A pharmaceutical composition comprising at least one compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient thereof.

16. A process for the preparation of a compound, according to claim 1 , comprising the step of reacting a compound of Formula (II) with a formylating agent of formula (FA):

wherein R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , are hydrogen, R 2 , R 3 , R 13 , R 14 and n are as defined in the preceding claims and LG 1 is a leaving group selected from selected from —OH, —OAc, —OPiv, —OCH 2 CN, —OCH 2 CF 3 , —OPh and —OPfp.

17. A compound according to claim 1 for use in the treatment of a disease selected from pulmonary fibrosis, pancreatic fibrosis, psoriasis, skin fibrosis and liver fibrosis.