3-arylthioindole-2-carboxamide derivatives and analogs thereof as inhibitors of casein kinase I

1. A method for inhibiting casein kinase Iε activity in a patient comprising the administration to said patient a therapeutically effective amount of a compound of formula I, or a stereoisomer, enantiomer, racemate, tautomer or a pharmaceutically acceptable salt thereof,

wherein

X is H, Cl, F, Br, NO 2 , CN, OR 2 , NR 2 R 2 , HNSO 2 —C 1-3 alkyl, or NHCO—C 1-3 alkyl;

Y is —S— or —O—;

R 1 is

1) aryl, unsubstituted or substituted with one or more:

a) C 1-5 alkoxy,

b) OH,

c) halogen,

d) NR 2 R 2 ,

e) C 1-5 alkyl, unsubstituted or substituted with one or more:

i) OH or

ii) C 1-5 alkoxy;

2) a heterocycle, substituted or un-substituted with one or more:

a) C 1-5 alkyl, substituted or un-substituted with one or more:

i) OH or

ii) C 1-5 alkoxy,

b) C 1-5 alkoxy,

c) OH,

d) halogen, or

e) NR 2 R 2 ;

3) C 1-5 alkyl, substituted or un-substituted with one or more of:

a) C 1-5 alkyl,

b) C 1-5 alkoxy,

c) OH, or

d) aryl, substituted or un-substituted with one or more of:

i) C 1-5 alkyl,

ii) C 1-5 alkoxy,

iii) OH,

iv) halogen, or

v) NR 2 R 2 ;

Z is

1) C(═O)NR 2 R 3 or

2) C(═O)R 4 ;

R 2 is hydrogen or C 1-3 alkyl;

R 3 is hydrogen, C 1-5 alkyl, or C 3-6 cycloalkyl; and

R 4 is 1-piperidinyl, 1-pyrrolidinyl, 1-piperazinyl or 4-morpholinyl, unsubstituted or substituted with one or more of:

1) C 1-5 alkyl,

2) C 1-5 alkoxy,

3) OH,

4) halogen, or

5) NR 2 R 2 .

2. The method as recited in claim 1 wherein the inhibition of casein kinase Iε activity results in altering of circadian rhythm period.

3. The method of claim 1 wherein

Y is S,

Z is C(═O)NHCH 3 , and

R 1 is phenyl or pyridinyl.

4. The method of claim 3 wherein the compound is selected from the group consisting of:

3-phenylsulfanyl-1H-indole-2-carboxylic acid methylamide, and

3-(pyridin-2-ylsulfanyl)-1H-indole-2-carboxylic acid methylamide.

5. The method of claim 1 wherein

Y is O,

Z is C(═O)NH 2 , and

R 1 is phenyl, substituted phenyl, C 1-5 alkyl or substituted C 1-5 alkyl.

6. The method of claim 5 wherein the compound is selected from the group consisting of:

3-phenoxy-1H-indole-2-carboxylic acid amide,

3-(4-methoxy-phenoxy)-1H-indole-2-carboxylic acid amide,

3-(4-fluoro-phenoxy)-1H-indole-2-carboxylic acid amide,

3-(2-fluoro-phenoxy)-1H-indole-2-carboxylic acid amide,

3-(4-chloro-phenoxy)-1H-indole-2-carboxylic acid amide,

3-methoxy-1H-indole-2-carboxylic acid amide,

3-ethoxy-1H-indole-2-carboxylic acid amide,

3-isopropoxy-1H-indole-2-carboxylic acid amide,

3-tert-butoxy-1H-indole-2-carboxylic acid amide, and

3-benzyloxy-1H-indole-2-carboxylic acid amide.

7. The method of claim 1 wherein:

Y is S,

Z is C(═O)R 4 , and

R 4 is 1-piperidinyl, 1-pyrrolidinyl, 1-piperazinyl or 4-morpholinyl.

8. The method of claim 7 wherein the compound is selected from the group consisting of:

(5-fluoro-3-p-tolylsulfanyl-1H-indol-2-yl)-pyrrolidin-1-yl-methanone,

(3-phenylsulfanyl-1H-indol-2-yl)-piperidin-1-yl-methanone,

(5-fluoro-3-phenylsulfanyl-1H-indol-2-yl)-pyrrolidin-1-yl-methanone,

[3-(2-amino-phenylsulfanyl)-1H-indol-2-yl]-pyrrolidin-1-yl-methanone,

[3-(2-amino-phenylsulfanyl)-1H-indol-2-yl]-piperidin-1-yl-methanone,

[3-(2-amino-phenylsulfanyl)-5-fluoro-1H-indol-2-yl]-piperidin-1-yl-methanone,

(3-phenylsulfanyl-1H-indol-2-yl)-piperazin-1-yl-methanone hydrochloride,

[5-fluoro-3-(pyridin-2-ylsulfanyl)-1H-indol-2-yl]-pyrrolidin-1-yl-methanone,

[3-(pyridin-2-ylsulfanyl)-1H-indol-2-yl]-pyrrolidin-1-yl-methanone, piperidin-1-yl-[3-(pyridin-2-ylsulfanyl)-1H-indol-2-yl]-methanone, and

[5-fluoro-3-(pyridin-2-ylsulfanyl)-1H-indol-2-yl]-piperidin-1-yl-methanone.

9. The method of claim 1 wherein

Y is S,

Z is C(═O)NH 2 , and

R 1 is pyridinyl.

10. The method of claim 9 wherein the compound is 3-(pyridin-2-ylsulfanyl)-1H-indole-2-carboxylic acid amide.

11. The method of claim 1 wherein

Y is S,

Z is C(═O)NH 2 , and

R 1 is phenyl or substituted phenyl.

12. The method of claim 11 wherein the compound is selected from the group consisting of:

3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

5-bromo-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

3-(2-amino-phenylsulfanyl)-5-methoxy-1H-indole-2-carboxylic acid amide,

3-(3-fluoro-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

3-(2-amino-phenylsulfanyl)-5-bromo-1H-indole-2-carboxylic acid amide, and

3-(2-amino-phenylsulfanyl)-1H-indole-2-carboxylic acid amide.