3-amino-pyridine derivatives for the treatment of metabolic disorders

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof,

wherein

Ar is an isoquinoline moiety which is substituted or unsubstituted;

B is —O—;

R 1 is hydrogen or S(O) 2 R 4 ;

R 2 is S(O) 2 R 4 ;

R 3 is halogen, cyano, C(O)OR 7 , or C(O)NR 8 R 9 ;

R 4 is substituted or unsubstituted aryl;

R 7 is hydrogen or (C 1 -C 4 )alkyl; and

R 8 and R 9 are independently hydrogen or (C 1 -C 6 )alkyl.

2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein

Ar is an isoquinoline moiety which is substituted or unsubstituted;

B is —O—

R 1 is H;

R 2 is S(O) 2 R 4 ;

R 3 is chlorine; and

R 4 is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2-chloro-4-trifluoromethylphenyl, 3-fluoro-4-methylphenyl, 3-chloro-4-methylphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-fluoro-4-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-chloro-4-trifluoromethylphenyl, 3-chloro-4-methylphenyl, 2-chloro-4-fluorophenyl), 4-cyanophenyl, phenyl-3-carboxylic acid [phenyl-3-COOH], or 4-acetamidophenyl [CH 3 CONH-phenyl].

3. A compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein

Ar is isoquinolin-3-yl;

B is —O—;

R 1 is H;

R 2 is —S(O) 2 R 4 ;

R 3 is chlorine; and

R 4 is 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 3-chloro-4-methylphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 4-chlorophenyl, 2-chloro-4-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-fluoro-4-chlorophenyl); 4-cyanophenyl, phenyl-3-carboxylic acid [phenyl-3-COOH] or 4-acetamidophenyl [CH 3 CONH-phenyl].

4. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein

Ar is an isoquinoline moiety which is substituted or unsubstituted;

B is —O—;

R 1 is S(O) 2 R 4 ;

R 2 is S(O) 2 R 4 ;

R 3 is halogen; and

R 4 is substituted aryl.

5. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

2,4-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,

3-(N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)sulfamoyl)benzoic acid,

3-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-methylbenzenesulfonamide,

N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2,4,6-trimethyl benzenesulfonamide,

N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-cyanobenzenesulfonamide,

3,5-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,

N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2-methylbenzenesulfonamide,

N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-3-methylbenzenesulfonamide,

N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide,

N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethyl)benzenesulfonamide,

4-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,

4-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2-fluorobenzenesulfonamide,

N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2,4-difluorobenzenesulfonamide,

2-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-fluorobenzenesulfonamide,

N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-methylbenzenesulfonamide,

3,4-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,

N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide,

N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2,5-dimethoxybenzenesulfonamide,

2-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4(trifluoromethyl)benzene sulfonamide,

N-(4-(N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)sulfamoyl)phenyl)acetamide,

N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide,

N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2,4-dimethoxybenzenesulfonamide,

N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-methoxybenzenesulfonamide, and

N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-fluorobenzenesulfonamide.

6. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

2,4-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,

2-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-fluorobenzenesulfonamide,

N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-methylbenzenesulfonamide, and

3,4-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide.

7. A process for the preparation of a compound of general formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 :

wherein

Ar is an isoquinoline moiety which is substituted or unsubstituted;

B is —O—;

R 3 is halogen, cyano, C(O)OR 7 , or C(O)NR 8 R 9 ;

R 7 is hydrogen or (C 1 -C 4 )alkyl;

R 8 and R 9 are independently hydrogen or (C 1 -C 6 )alkyl;

R 1 is H, R 2 is S(O) 2 R 4 , and R 4 is substituted or unsubstituted aryl, which comprises:

a) reacting a compound of general formula (II):

wherein Hal is fluorine, chlorine, bromine, or iodine and R 3 is as defined above; with a compound of formula (III): Ar—BH wherein Ar and B are as defined above; in presence of a base such as cesium carbonate, to obtain a compound of general formula (IV);

wherein Ar, B and R 3 are as defined above;

b) subjecting the nitro compound of formula (IV) above to reduction to obtain a corresponding amino compound of general formula (V);

wherein Ar, B and R 3 are as defined above;

c) reacting the amino compound of general formula (V) with one equivalent of Hal-SO 2 R 4 wherein Hal is fluorine, chlorine, bromine, or iodine and R 4 is as defined above, in the presence of a base to obtain the compound of formula (I); and,

d) optionally, converting the resulting compound into a pharmaceutically acceptable salt.

8. A process for the preparation of a compound of general formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 :

wherein

Ar is an isoquinoline moiety which is substituted or unsubstituted;

B is —O—;

R 3 is halogen, cyano, C(O)OR 7 or C(O)NR 8 R 9 ;

R 7 is hydrogen or (C 1 -C 4 )alkyl;

R 8 and R 9 are independently hydrogen or (C 1 -C 6 )alkyl;

R 1 and R 2 are S(O) 2 R 4 , and R 4 is substituted or unsubstituted aryl, which comprises:

a) reacting a compound of general formula (II):

wherein Hal is F, Cl, Br, or I and R 3 is as defined above; with a compound of formula (III): Ar—BH wherein Ar and B are as defined above; in presence of a base such as cesium carbonate, to obtain a compound of general formula (IV);

wherein Ar, B and R 3 are as defined above;

b) subjecting the nitro compound of formula (IV) above to reduction to obtain a corresponding amino compound of general formula (V);

wherein Ar, B and R 3 are as defined above,

c) reacting the amino compound of general formula (V) with two equivalents of Hal-SO 2 R 4 wherein Hal is fluorine, chlorine, bromine, or iodine and R 4 is as defined above, at 45° C., in the presence of triethyl amine as a base, to obtain the compound of formula (I); and,

d) optionally, converting the resulting compound into a pharmaceutically acceptable salt.

9. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of general formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

10. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of general formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one further pharmaceutically active compound, together with a pharmaceutically acceptable carrier or diluent.

11. A method for the treatment of a metabolic disorder related to insulin resistance or hyperglycemia, wherein the metabolic disorder related to insulin resistance or hyperglycemia is type 2 diabetes or dyslipidemia, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

12. The method according to claim 11 , wherein the metabolic disorder related to insulin resistance or hyperglycemia is type 2 diabetes.

13. The method according to claim 11 , wherein the metabolic disorder related to insulin resistance or hyperglycemia is dyslipidemia.