3-AMINO-PYRIDINE DERIVATIVES FOR THE TREATMENT OF METABOLIC DISORDERS

1 . A compound of general formula (I) or a pharmaceutically acceptable salt thereof, the general formula (I) being represented by:

wherein:

Ar is a quinoline 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 , C(O)R 5 , or C(O)(CH 2 ) n —C(O)OR 6 ;

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

R 4 is substituted or unsubstituted aryl;

R 5 is (C 1 -C 6 )alkyl or substituted or unsubstituted aryl;

R 6 is hydrogen, (C 1 -C 4 )alkyl, or substituted or unsubstituted aryl;

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

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

n is an integer from 1-3.

2 . The compound according to claim 1 ;

wherein:

Ar is a quinoline 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 . The compound according to claim 2 ;

wherein:

Ar is quinolin-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 phenyl, 4-methylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 3-fluoro-4-methylphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-chloro-4-trifluoromethylphenyl, or 2-fluoro-4-chlorophenyl.

4 . The compound according to claim 2 ;

wherein:

Ar is quinolin-6-yl;

B is —O—;

R 1 is H;

R 2 is —S(O) 2 R 4 ;

R 3 is chlorine; and

R 4 is 3,4 dimethoxyphenyl, 2,4-difluorophenyl, or 2,4-dichlorophenyl.

5 . The compound according to claim 1 ;

wherein:

Ar is a quinoline 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.

6 . The compound according to claim 5 ;

wherein:

Ar is quinolin-3-yl;

B is —O—;

R 1 is S(O) 2 R 4 ;

R 2 is S(O) 2 R 4 ;

R 3 is chlorine; and

R 4 is 2,4-dichlorophenyl.

7 . The compound according to claim 1 ;

wherein:

Ar is a quinoline moiety which is substituted or unsubstituted;

B is —O—;

R 1 is H;

R 2 is C(O)OR 5 ;

R 3 is halogen; and

R 5 is (C 1 -C 6 )alkyl or substituted or unsubstituted aryl.

8 . The compound according to claim 7 ;

wherein:

Ar is quinolin-3-yl;

B is —O—;

R 1 is H;

R 2 is C(O)OR 5 ;

R 3 is chlorine; and

R 5 is phenyl.

9 . The compound according to claim 1 ;

wherein:

Ar is a quinoline moiety which is substituted or unsubstituted;

B is —O—;

R 1 is H;

R 2 is C(O)(CH 2 ) n —C(O)OR 6 ;

R 3 is halogen;

R 6 is hydrogen, (C 1 -C 4 )alkyl, or substituted or unsubstituted aryl; and

n is an integer from 1-3.

10 . The compound according to claim 9 ;

wherein:

Ar is quinolin-3-yl;

B is —O—;

R 1 is H:

R 2 is C(O)(CH 2 ) 2 —C(O)OR 6 ;

R 3 is chlorine; and

R 6 is hydrogen.

11 . The compound according to claim 1 ;

wherein the compound is selected from:

N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-methoxybenzenesulfonamide;

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

N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-methylbenzenesulfonamide;

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

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

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

N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide;

2-Chloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethyl) benzenesulfonamide;

N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-2,4-difluorobenzenesulfonamide;

N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-fluorobenzenesulfonamide;

4-Chloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide;

N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,4-difluorobenzenesulfonamide;

N-(5-(Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,6-difluorobenzenesulfonamide;

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

N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3-fluoro-4-methylbenzenesulfonamide:

N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,5-dimethylbenzenesulfonamide;

N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-1)-2,4,6-trimethylbenzenesulfonamide;

4-chloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2-fluorobenzenesulfonamide;

N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide;

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

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

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

2,4-Dichloro-N-[(2,4-dichlorophenyl)sulfonyl]-N-[5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl]-benzenesulfonamide;

Phenyl 5-chloro-6-(quinolin-3-yloxy)pyridin-3-ylcarbamate; and

4-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-ylamino)-4-oxobutanoic acid.

12 . The compound according to claim 1 ;

wherein the compound is selected from:

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

N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide; and

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

13 . A process for the preparation of a compound of general formula (I) according to claim 1 , the general formula (I) being represented by:

wherein:

Ar is a quinoline 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;

wherein the process comprises:

a) reacting a compound of general formula (II) with a compound of formula (III), in presence of a base, to obtain a compound of general formula (IV);

wherein the general formula (II)is represented by:

wherein:

 Hal is fluorine, chlorine, bromine, or iodine; and

 R 3 is as defined above;

wherein the formula (III) is represented by:

Ar—BH;

wherein Ar and B are as defined above; and

wherein the general formula (IV) is represented by:

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; and

c) reacting the amino compound of general formula (V) with one equivalent of Hal-SO 2 R 4 , in the presence of a base, to obtain the compound of formula (I);

wherein:

Hal is fluorine, chlorine, bromine, or iodine; and

R 4 is as defined above; and

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

14 . A process for the preparation of a compound of general formula (I) according to claim 1 , the general formula (I) being represented by:

wherein:

Ar is a quinoline 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;

wherein the process comprises:

a) reacting a compound of general formula (II) with a compound of formula (III), in presence of a base, to obtain a compound of general formula (IV);

wherein the general formula (II) is represented by:

wherein:

 Hal is F, Cl, Br, or I; and

 R 3 is as defined above;

wherein the formula (III) is represented by:

Ar—BH

wherein Ar and B are as defined above;

wherein the general formula (IV) is represented by:

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; and

c) reacting the amino compound of general formula (V) with two equivalents of Hal-SO 2 R 4 at 45° C., in the presence of triethyl amine as a base, to obtain the compound of formula (I);

wherein:

Hal is fluorine, chlorine, bromine, or iodine; and

R 4 is as defined above; and

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

15 . A process for the preparation of a compound of general formula (I) according to claim 1 , the general formula (I) being represented by:

wherein:

Ar is a quinoline 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 C(O)(CH 2 ) n —C(O)OR 6 ;

n is an integer from 1-3; and

R 6 is hydrogen, (C 1 -C 4 )alkyl, or substituted or unsubstituted aryl,

wherein the process comprises:

a) reacting a compound of general formula (II) with a compound of formula (III) in presence of cesium carbonate as a base, to obtain a compound of general formula (IV);

wherein the general formula (II) is represented by:

wherein:

Hal is fluorine, chlorine, bromine, or iodine; and

R 3 is as defined above,

wherein the formula (III) is represented by:

Ar—BH;

wherein Ar and B are as defined above;

wherein the general formula (IV) is represented by:

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; and

c) refluxing the amino compound of the general formula (V) above with an anhydride [(CH 2 ) n (CO) 2 O] to obtain an acid of formula (I); and

d) optionally, converting the acid of formula (I) to an ester of formula (I);

wherein:

R 2 is C(O)(CH 2 ) n —C(O)OR 6 ;

n is an integer from 1-3; and

R 6 is (C 1 -C 4 )alkyl or substituted or unsubstituted aryl; and

e) optionally, converting the resulting acid or ester into a pharmaceutically acceptable salt.

16 . A process for the preparation of a compound of general formula (I) according to claim 1 , the general formula (I) being represented by:

wherein:

Ar is a quinoline 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 C(O)OR 5 ; and

R 5 is (C 1 -C 6 )alkyl or substituted or unsubstituted aryl;

wherein the process comprises:

a) reacting a compound of general formula (II) with a compound of formula (III), in presence of cesium carbonate as a base, to obtain a compound of general formula (IV);

wherein the general formula (II) is represented by:

wherein:

 Hal is fluorine, chlorine, bromine, or iodine; and

 R 3 is as defined above;

wherein the formula (III) is represented by:

Ar—BH;

wherein Ar and B are as defined above;

wherein the general formula (IV) is represented by:

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

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

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

c) refluxing the amino compound of general formula (V) with R 5 -carbonochloridate, in the presence of pyridine or triethyl amine as a base, to obtain the compound of formula (I):

wherein R 5 is as defined above; and

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

17 . 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.

18 . A pharmaceutical composition, comprising:

a therapeutically effective amount of a compound of general formula (I) according to claim 1 , or a pharmaceutically acceptable salt or thereof;

at least one further pharmaceutically active compound; and

a pharmaceutically acceptable carrier or diluent.

19 . A method for the treatment of a metabolic disorder related to insulin resistance or hyperglycemia, 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.

20 . The method according to claim 19 ;

wherein the metabolic disorder related to insulin resistance or hyperglycemia is selected from:

type 2 diabetes, obesity, glucose intolerance, dyslipidemia, hyperinsulinemia, atherosclerotic disease, polycystic ovary syndrome, coronary artery disease, hypertension, and non alcoholic fatty liver disease.

21 . The method according to claim 20 ;

wherein the metabolic disorder related to insulin resistance or hyperglycemia is type 2 diabetes.

22 . The method according to claim 20 ;

wherein the metabolic disorder related to insulin resistance or hyperglycemia is dyslipidemia.