Pyrazolylbenzothiazole derivatives and their use as therapeutic agents

1. A method for relieving or causing regression of psoriasis or irritant contact dermatitis in a patient in need thereof, comprising topically applying a therapeutically effective amount of a topical composition comprising a dermatologically acceptable excipient and a compound of Formula (1):

as a single tautomer, a mixture of tautomers, a single stereoisomer, a mixture of stereoisomers, or a racemic mixture; or a pharmaceutically acceptable salt thereof; wherein:

R 1 at each occurrence is independently selected from amino, aminosulfinyl, aminosulfonyl, aryl, azido, halogen, heteroalkyl, heteroaryl, hydrazinyl, hydrocarbyl, hydrogen, hydroxyl, nitro, nitroso, phosphate, phosphinate, phosphonate, phosphonium, phosphorothioate, phosphoryl, sulfamoyl, sulfate, sulfinic acid, sulfonamido, sulfonate, sulfonic acid, thiol, thioureido, and ureido;

R 2 is amino, aminosulfinyl, aminosulfonyl, azido, halogen, heteroaryl, hydrazinyl, hydroxyl, nitro, nitroso, phosphate, phosphinate, phosphonate, phosphonium, phosphorothioate, phosphoryl, sulfamoyl, sulfate, sulfinic acid, sulfonamido, sulfonate, sulfonic acid, thiol, thioureido, or ureido;

R 3 is hydrogen, heteroalkyl, heterocycle, halogen-substituted hydrocarbyl, hydrocarbyl, or -0-hydrocarbyl; and

R 4 is hydrogen, heteroalkyl, heteroaryl, or hydrocarbyl,

and wherein heteroalkyl is selected from amido, carboxylic acid, cyano, dihydrocarbylamido, dihydrocarbylamino, di(hydrocarbyl)phosphido, formyl, hydrocarboyloxy, hydrocarbylamino, hydrocarbyloxy, hydrocarbylsiloxy, hydrocarbylsilylamino, hydrocarbylsulfido, hydrocarbylthio, hydrocarbylamido, isothiocyanate, N-heterocycle, perfluorohydrocarbyl, thiocyanate, and hydrocarbyl substituted with one or more groups selected from alkylamino, amino, aminosulfinyl, aminosulfonyl, azido, dialkylamino, halogen, heteroalkyl, heteroaryl, hydrazinyl, hydroxyl, nitro, nitroso, phosphate, phosphinate, phosphonate, phosphonium, phosphorothioate, phosphoryl, sulfamoyl, sulfate, sulfinic acid, sulfonamido, sulfonate, sulfonic acid, thiol, thioureido, and ureido.

2. The method of claim 1 wherein, in the compound of Formula (1):

R 1 at each occurrence is independently selected from amino, aminosulfinyl, aminosulfonyl, aryl, azido, halogen, heteroalkyl, heteroaryl, hydrazinyl, hydrocarbyl, hydrogen, hydroxyl, nitro, nitroso, phosphate, phosphinate, phosphonate, phosphonium, phosphorothioate, phosphoryl, sulfamoyl, sulfate, sulfinic acid, sulfonamido, sulfonate, sulfonic acid, thiol, thioureido, and ureido;

R 2 is amino;

R 3 is selected from hydrocarbyl or halogen-substituted hydrocarbyl; and

R 4 is selected from hydrogen.

3. The method of claim 2 wherein the compound of Formula (1) is:

[2-(3-Amino-5-methyl-1H-pyrazol-4-yl)-5-fluoro-benzothiazol-6-yl]-methanol;

[2-(5-Amino-3-methyl-1H-pyrazol-4-yl)-benzothiazol-5-yl]-methanol;

[2-(5-Amino-3-methyl-1H-pyrazol-4-yl)-benzothiazol-6-yl]-methanol;

2-(5-Amino-3-methyl-1H-pyrazol-4-yl)-benzothiazol-5-ol;

4-(4-fluorobenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine;

4-(5-Fluoro-6-methoxy-benzothiazol-2-yl)-5-(2-phenyl-cyclopropyl)-2H-pyrazol-3-ylamine;

4-(5-Fluoro-6-methoxy-benzothiazol-2-yl)-5-methyl-1H-pyrazol-3-ylamine;

4-(5-Fluoro-6-methoxy-benzothiazol-2-yl)-5-phenyl-2H-pyrazol-3-ylamine;

4-(5-Fluoro-6-methyl-benzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine;

4-(5-Fluoro-benzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine;

4-(5-Methoxy-benzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine;

4-(6-Bromo-5-fluoro-benzothiazol-2-yl)-5-methyl-1H-pyrazol-3-ylamine;

4-(6-Bromo-benzothiazol-2-yl)-5-methyl-1H-pyrazol-3-ylamine;

4-(6-Chlorobenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine;

4-(6-Dimethylaminomethyl-5-fluoro-benzothiazol-2-yl)-5-methyl-1H-pyrazol-3-ylamine;

4-(6-Dimethylaminomethyl-benzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine;

4-(6-Fluoro-benzothiazol-2-yl)-5-methyl-1H-pyrazol-3-ylamine;

4-(6-Methoxy-benzothiazol-2-yl)-5-methyl-1H-pyrazol-3-ylamine;

4-(7-chloro-4-methoxy-benzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine;

4-(7-Chloro-5-fluoro-6-methoxy-benzothiazol-2-yl)-5-methyl-1H-pyrazol-3-ylamine;

4-Benzothiazol-2-yl-5-cyclopropyl-2H-pyrazol-3-ylamine;

4-Benzothiazol-2-yl-5-ethyl-1H-pyrazol-3-ylamine;

4-Benzothiazol-2-yl-5-methyl-1H-pyrazol-3-ylamine;

4-Benzothiazol-2-yl-5-methylsulfanyl-1H-pyrazol-3-ylamine;

4-Benzothiazol-2-yl-5-phenyl-1H-pyrazol-3-ylamine;

4-(5-Fluoro-6-methoxy-benzothiazol-2-yl)-5-(2-fluoro-phenyl)-2H-pyrazol-3-ylamine;

4-(5-Fluoro-6-methoxy-benzothiazol-2-yl)-5-(3-fluoro-phenyl)-2H-pyrazol-3-ylamine

5-Cyclopropyl-4-(5-fluoro-6-methoxy-benzothiazol-2-yl)-2H-pyrazol-3-ylamine;

5-Methyl-4-(4,5,6-trifluoro-benzothiazol-2-yl)-1H-pyrazol-3-ylamine;

5-Methyl-4-(5-trifluoromethylbenzothiazol-2-yl)-1H-pyrazol-3-ylamine;

5-Methyl-4-(6-methylaminomethyl-benzothiazol-2-yl)-2H-pyrazol-3-ylamine;

N-[2(5-Amino-3-methyl-1H-pyrazol-4-yl)-benzothiazol-6-yl]-acetamide;

5-Methyl-4-(6-morpholin-4-ylmethyl-benzothiazol-2-yl)-2H-pyrazol-3-ylamine;

5-Methyl-4-(6-pyrrolidin-1-ylmethyl-benzothiazol-2-yl)-2H-pyrazol-3-ylamine; or 2- { [2-(5-Amino-3 -methyl-1H-pyrazol-4-yl)-benzothiazol-6-ylmethyl]-amino}-ethanol.

4. The method of claim 2 wherein, in the compound of Formula (1), at least one of R 1 is sulfamoyl.

5. The method of claim 4 , wherein the compound of Formula (1) is

2-(3-Amino-5-methyl-1H-pyrazol-4-yl)-4,5,6-trifluoro-benzothiazole-7-sulfonic acid amide;

2-(5-Amino-3-methyl-1H-pyrazol-4-yl)-4-fluorobenzothiazole-6-sulfonic acid amide;

2-(5-Amino-3-methyl-1H-pyrazol-4-yl)-5-fluoro-benzothiazole-6-sulfonic acid amide; or

2-(5-Amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonic acid amide.

6. The method of claim 1 wherein, in the compound of Formula (1), R 3 is heterocycle.

7. The method of claim 6 , wherein the compound of Formula (1) is

4-Benzothiazol-2-yl-5-piperazin-1-yl-2H-pyrazol-3-ylamine;

4-Benzothiazol-2-yl-5-piperidin-4-yl-2H-pyrazol-3-ylamine;

4-Benzothiazol-2-yl-5-pyridin-4-yl-2H-pyrazol-3-ylamine;

4-Benzothiazol-2-yl-5-pyrrolidin-1-yl-1H-pyrazol-3-ylamine;

4-Benzothiazol-2-yl-5-thiophen-2-yl-2H-pyrazol-3-ylamine;

4-Benzothiazol-2-yl-5-pyridin-3-yl-2H-pyrazol-3-ylamine;

4-(5-Fluoro-6-methoxy-benzothiazol-2-yl)-5-piperazin-1-yl-2H-pyrazol-3-ylamine;

4-(5-Fluoro-6-methoxy-benzothiazol-2-yl)-5-pyridin-4-yl-2H-pyrazol-3-ylamine;

4-(5-Fluoro-6-methoxy-benzothiazol-2-yl)-5-thiophen-2-yl-2H-pyrazol-3-ylamine;

4-(5-Fluoro-6-methoxy-benzothiazol-2-yl)-5-furan-2-yl-2H-pyrazol-3-ylamine; or

2-(5-Amino-3-pyridin-4-yl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonic acid amide.

8. The method of claim 1 wherein, in the compound of Formula (1), R 3 is heteroalkyl.

9. The method of claim 8 , wherein the compound of Formula (1) is:

3-(5-Amino-4-benzothiazol-2-yl-1H-pyrazol-3-yl)-propan-1-ol;

4-(5-Amino-4-benzothiazol-2-yl-1H-pyrazol-3-yl)-butan-1-ol; or

5-(3-Amino-propyl)-4-benzothiazol-2-yl-2H-pyrazol-3-ylamine.

10. A method for relieving or causing regression of psoriasis or irritant contact dermatitis in a patient in need thereof, comprising topically applying a therapeutically effective amount of a topical composition comprising a dermatologically acceptable excipient and a compound of formula (2):

as a single tautomer, a mixture of tautomers, a single stereoisomer, a mixture of stereoisomers, or a racemic mixture; or a pharmaceutically acceptable salt or solvate thereof; wherein:

R 1 at each occurrence is independently selected from amino, aminosulfinyl, aminosulfonyl, aryl, azido, halogen, heteroalkyl, heteroaryl, hydrazinyl, hydrocarbyl, hydrogen, hydroxyl, nitro, nitroso, phosphate, phosphinate, phosphonate, phosphonium, phosphorothioate, phosphoryl, sulfamoyl, sulfate, sulfinic acid, sulfonamido, sulfonate, sulfonic acid, thiol, thioureido, and ureido;

R 4 is selected from hydrogen, heteroalkyl, heteroaryl, and hydrocarbyl; and

R 5 , R 6 , R 7 and R 8 at each occurrence is independently selected from heteroalkyl, heteroaryl, hydrocarbyl and hydrogen, with the proviso that R 7 and R 8 may join together to form a heterocyclic ring including the nitrogen to which they are both bonded,

wherein heteroalkyl is selected from amido, carboxylic acid, cyano, dihydrocarbylamido, dihydrocarbylamino, di(hydrocarbyl)phosphido, formyl, hydrocarboyloxy, hydrocarbylamino, hydrocarbyloxy, hydrocarbylsiloxy, hydrocarbylsilylamino, hydrocarbylsulfido, hydrocarbylthio, hydrocarbylamido, isothiocyanate, N-heterocycle, perfluorohydrocarbyl, thiocyanate, and hydrocarbyl substituted with one or more groups selected from alkylamino, amino, aminosulfinyl, aminosulfonyl, azido, dialkylamino, halogen, heteroalkyl, heteroaryl, hydrazinyl, hydroxyl, nitro, nitroso, phosphate, phosphinate, phosphonate, phosphonium, phosphorothioate, phosphoryl, sulfamoyl, sulfate, sulfinic acid, sulfonamido, sulfonate, sulfonic acid, thiol, thioureido, and ureido.

11. The method of claim 10 wherein the compound of Formula (2) is:

2-(5-Amino-4-benzothiazol-2-yl-2H-pyrazol-3-ylamino)-cyclopentanol;

4-(6-Methoxy-benzothiazol-2-yl)-5-piperazin-1-yl-2H-pyrazol-3-ylamine;

3-(5-Amino-4-benzothiazol-2-yl-1H-pyrazol-3-ylamino)-propan-1-ol;

3-[5-Amino-4-(5-fluoro-6-methoxy-benzothiazol-2-yl)-1H-pyrazol-3-ylamino]-propan-1-ol;

4-(5-Amino-4-benzothiazol-2-yl-1H-pyrazol-3-ylamino)-butan-1-ol;

4-(5-Amino-4-benzothiazol-2-yl-1H-pyrazol-3-ylamino)-butyric acid;

4-(5-Fluoro-6-methoxy-benzothiazol-2-yl)-N 3 -[2(3H-imidazol-4-yl)-ethyl]-1H-pyrazole-3,5-diamine;

4-[(5-Amino-4-benzothiazol-2-yl-1H-pyrazol-3-ylamino)-methyl]-benzenesulfonamide;

4-[2-(5-Amino-4-benzothiazol-2-yl-1H-pyrazol-3-ylamino)-ethyl]-phenol;

4-Benzothiazol-2-yl-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl-N 3 -(1H-imidazol-2-ylmethyl)-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl-N 3 -(1H-imidazol-2-ylmethylene)-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl-N 3 -(2-dimethylamino-ethyl)-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl-N 3 -(2-ethylamino-ethyl)-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl-N 3 -(2-methoxy-ethyl)-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl-N 3 -(2-pyrrolidin-1-yl-ethyl)-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl-N 3 -(3-dimethylamino-propyl)-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl-N 3 -(3-imidazol-1-yl-propyl)-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl-N 3 -[2-(1H-indol-3-yl)-ethyl]-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl-N 3 -piperidin-4-ylmethyl-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl-N 5 -(2-morpholin-4-yl-ethyl)-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl-N 5 -ethyl-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl-N 5 -pyridin-3-ylmethyl-1H-pyrazole-3,5-diamine;

N-[2-(5-Amino-4-benzothiazol-2-yl-1H-pyrazol-3-ylamino)-ethyl]-acetamide;

N-{2-[Amino-4-(5-fluoro-6-methoxy-benzothiazol-2-yl)-1H-pyrazol-3-ylamino]-ethyl }-acetamide;

N 3 -(2-Amino-ethyl)-4-benzothiazol-2-yl-1H-pyrazole-3,5-diamine;

N 3 -(2-Dimethylamino-ethyl)-4-(5-fluoro-6-methoxy-benzothiazol-2-yl)-1H-pyrazole-3,5-diamine;

N 3 -(3-Dimethylamino-propyl)-4-(5-fluoro-6-methoxy-benzothiazol-2-yl)-1H-pyrazole-3,5-diamine;

N 3 -(4-Amino-phenyl)-4-benzothiazol-2-yl-1H-pyrazole-3,5-diamine;

N 3 -[2(3H-Imidazol-4-yl)-ethyl]-4-(6-methoxy-benzothiazol-2-yl)-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl-N 5 -benzyl-1H-pyrazole-3,5-diamine; 4-Benzothiazol-2-yl-N 5 -(3,5-dichlorophenyl)-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl-N 5 -quinolin-6-yl-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl-N 3 -quinolin-5-yl-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl-N 5 -pyridin-3-yl-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl-N 5 -pyridin-4-ylmethyl-1H-pyrazole-3,5-diamine; or 4-Benzothiazol-2-yl-N 3 -(3-methylbutyl)-1H-pyrazole-3,5-diamine.

12. The method of claim 1 wherein, in the compound of Formula (1):

R 1 at each occurrence is independently hydrogen, halogen or sulfamoyl;

R 2 is amino;

R 3 is selected from hydrogen, hydrocarbyl or heterocycle; and

R 4 is selected from hydrogen.

13. The method of claim 12 wherein, the compound of Formula (1) is

2-(3-Amino-5-methyl-1H-pyrazol-4-yl)-4,5,6-trifluoro-benzothiazole-7-sulfonic acid amide;

2-(5-Amino-3-methyl-1H-pyrazol-4-yl)-4-fluorobenzothiazole-6-sulfonic acid amide;

2-(5-Amino-3-methyl-1H-pyrazol-4-yl)-5-fluoro-benzothiazole-6-sulfonic acid amide;

2-(3-Amino-5-methyl-1H-pyrazol-4-yl)-4,5,6-trifluoro-benzothiazole-7-sulfonic acid amide;

2-(5-Amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonic acid amide; or

2-(5-Amino-3-pyridin-4-yl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonic acid amide.

14. The method of claim 10 wherein, in the compound of Formula (II),

R 1 at each occurrence is independently selected from hydrogen, halogen and heteroalkyl;

R 4 is hydrogen;

R 5 and R 6 are each hydrogen; and

R 7 and R 8 at each occurrence is independently selected from heteroalkyl, heteroaryl, hydrocarbyl and hydrogen, or R 7 and R 8 may join together to form a heterocyclic ring including the nitrogen to which they are both bonded.

15. The method of claim 14 wherein the compound is

(4-Benzothiazol-2-yl-1H-pyrazol-3 -yl)[2-(1H-imidazol-4-yl)-ethyl]-amine;

3[5-Amino-4-(5-fluoro-6-methoxy-benzothiazol-2-yl)-1H-pyrazol-3 -ylamino]-propan-1-ol;

2-(5-Amino-4-benzothiazol-2-yl-1H-pyrazol-3-ylamino)-ethanol;

3-(5-Amino-4-benzothiazol-2-yl-1H-pyrazol-3 -ylamino)-propan-1-ol;

4-(5-Amino-4-benzothiazol-2-yl-1H-pyrazol-3-ylamino)-butan-1ol;

4-(5-Fluoro-6-methoxy-benzothiazol-2-yl)-5-piperazin-1-yl-2H-pyrazol-3-ylamine;

4-(5-Fluoro-6-methoxy-benzothiazol-2-yl)-N 3 -[2(3H-imidazol-4-yl)-ethyl]-1H-pyrazole-3,5-diamine;

4-(6-Methoxy-benzothiazol-2-yl)-5-piperazin-1-yl-2H-pyrazol-3-ylamine;

4-Benzothiazol-2-yl- N 3 -(2-dimethylamino-ethyl)-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl- N 3 -(2-ethylamino-ethyl)-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl- N 3 -(2-methoxy-ethyl)-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl- N 3 -(3-dimethylamino-propyl)-1H-pyrazole-3,5-diamine;

4-Benzothiazol-2-yl- N 3 -(3-imidazol-1-yl-propyl)-1H-pyrazole-3,5-diamine;

N 3 -(2-Dimethylamino-ethyl)-4-(5-fluoro-6-methoxy-benzothiazol-2-yl)-1H-pyrazole-3,5-diamine;

N 3 -[2-(3H-Imidazol-4-yl)-ethyl]-4-(6-methoxy-benzothiazol-2-yl)-1H-pyrazole-3,5-diamine; or

N 3 -(2-Dimethylamino-ethyl)-4-(5-fluoro-6-methoxy-benzothiazol-2-yl)-1H-pyrazole-3,5-diamine.

16. A method for relieving or causing regression of psoriasis or irritant contact dermatitis in a patient in need thereof, comprising topically applying a therapeutically effective amount of a topical composition comprising a dermatologically acceptable excipient and a compound selected from the group consisting of:

2-(3-Amino-5-methyl-1H-pyrazol-4-yl)-5-fluoro-benzothiazole-6-carboxylic acid methyl ester;

2-(3-Amino-5-methyl-1H-pyrazol-4-yl)-benzothiazole-6-carboxylic acid;

2-(3 -Amino-5-methyl-1H-pyrazol-4-yl)-benzothiazole-6-carboxylic acid methyl ester;

2-(3 -Amino-5-methyl-1H-pyrazol-4-yl)-benzothiazole-7-carboxylic acid methyl ester;

2-(5-Amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-carboxylic acid amide;

5-Methyl-4-[6-(4-methyl-piperazin-1 -ylmethyl)-benzothiazol-2-yl]-2H-pyrazol-3-ylamine;

5-Methyl-4-[6-(4-methyl-piperazine-1 -sulfonyl)-benzothiazol-2-yl]-2H-pyrazol-3 -ylamine;

2-(5-Amino-3-methyl-1H-pyrazol-4-yl)benzothiazole-5-carboxylic acid ethyl ester; and

4-(5-Fluoro-6-methoxy-benzothiazol-2-yl)-5-(4-methoxy-phenyl)-2H-pyrazol-3-ylamine.