3-substituted-5- and 6-aminoalkyl indole-2-carboxylic acid amides and related analogs as inhibitors of casein kinase I

1. A compound selected from the group consisting of formula I and formula II, or a stereoisomer, an enantiomer, a racemate or a tautomer of said compound, or a pharmaceutically acceptable salt thereof,

wherein

X is S or S(O) n ;

R 1 is H or C 1 -C 6 alkyl;

R 2 is NR 5 R 6 ;

R 3 is aryl or heterocycle;

R 4 is C 1 -C 6 alkyl or halogen;

R 5 is H or C 1 -C 6 alkyl;

R 6 is H or C 1 -C 6 alkyl;

R 7 is CH 2 NR 8 R 9 wherein

R 8 is H, C 1 -C 10 alkyl, C 3 -C 8 cycloalkyl, aryl, aryl(C 1 -C 6 alkyl), aryl(C 2 -C 6 alkenyl), diaryl(C 2 -C 6 alkenyl), heterocycle, heterocycle(C 1 -C 6 alkyl), heterocycle(C 2 -C 6 alkenyl), hydroxy(C 1 -C 6 alkyl), dihydroxy(C 2 -C 6 alkyl), acyl, C 1 -C 6 alkoxycarbonyl, aryl(C 1 -C 6 alkoxy)carbonyl, carbamoyl(C 1 -C 6 alkyl), or P;

R 9 is H, C 1 -C 10 alkyl, heterocycle(C 1 -C 6 alkyl) or heterocycle(C 2 -C 6 alkenyl); or

R 8 and R 9 together with the nitrogen to which they are attached form a heterocycle;

and wherein P is Gly, or L- or D-Ala, Val, Leu, Ile, Ser, Cys, Thr, Met, Pro, Phe, Tyr, Trp, His, Lys, Arg, Asp, Gly, Asn or Gln;

m is 0, 1 or 2; and

n is 1.

2. The compound selected from the group consisting of formula I and formula II as recited in claim 1 wherein X is S.

3. The compound selected from the group consisting of formula I and formula II as recited in claim 2 wherein R 2 is NH 2 .

4. The compound selected from the group consisting of formula I and formula II as recited in claim 3 wherein m is 0 and R 7 is CH 2 NR 8 R 9 .

5. The compound selected from the group consisting of formula I and formula II as recited in claim 4 wherein R 1 is C 1 -C 6 alkyl.

6. The compound of formula I as recited in claim 5 wherein the compound is 1-methyl-5-methylaminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide.

7. The compound selected from the group consisting of formula I and formula II as recited in claim 4 wherein R 1 is H.

8. The compound of formula I as recited in claim 7 wherein R 8 is H, C 1 -C 10 alkyl, C 3 -C 8 cycloalkyl, hydroxy(C 1 -C 6 alkyl), dihydroxy(C 2 -C 6 alkyl) or C 1 -C 6 alkoxycarbonyl and R 9 is H.

9. The compound of formula I as recited in claim 8 selected from the group consisting of:

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

(2-carbamoyl-3-phenylsulfanyl-1H-indol-5-ylmethyl)-carbamic acid tert-butyl ester,

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

3-(3-chlorophenylsulfanyl)-5-methylaminomethyl-1H-indole-2-carboxylic acid amide,

3-(3-fluorophenylsulfanyl)-5-methylaminomethyl-1H-indole-2-carboxylic acid amide,

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

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

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

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

5-(bicyclo[2.2.1]hept-2-ylaminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

5-[(2-hydroxy-1-hydroxymethyl-1-methyl-ethylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

5-[(2-hydroxy-1-methyl-ethylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

5-[(2,3-dihydroxypropylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

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

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

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

10. The compound of formula I as recited in claim 7 wherein R 8 is aryl, aryl(C 1 -C 6 alkyl), heterocycle or carbamoyl(C 1 -C 6 alkyl), and R 9 is H.

11. The compound of formula I as recited in claim 10 selected from the group consisting of:

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

3-phenylsulfanyl-5-(quinolin-6-ylaminomethyl)-1H-indole-2-carboxylic acid amide,

5-[(2-cyano-4,5-dimethoxyphenylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

3-phenylsulfanyl-5-[(3-trifluoromethyl-phenylamino)methyl]-1H-indole-2-carboxylic acid amide,

5-[(1-carbamoylethylamino)methyl]-3-phenyl sulfanyl-1H-indole-2-carboxylic acid amide,

5-[(3-methoxyphenylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

5-[(4-butylphenylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide, and

5-[(2-fluorophenylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide.

12. The compound of formula I as recited in claim 7 wherein R 8 and R 9 together with the nitrogen to which they are attached form a heterocycle.

13. The compound of formula I as recited in claim 12 selected from the group consisting of:

5-(4-hydroxymethylpiperidin-1-ylmethyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

5-morpholin-4-ylmethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

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

5-(3-carbamoylpiperidin-1-ylmethyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

3-phenylsulfanyl-5-(4-pyrimidin-2-yl-piperazin-1-ylmethyl)-1H-indole-2-carboxylic acid amide,

5-[4-(3-phenylpropenyl)piperazin-1-ylmethyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

4-(2-carbamoyl-3-phenylsulfanyl-1H-indol-5-ylmethyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester,

5-[1,4]diazepan-1-ylmethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

5-(2-hydroxymethyl-pyrrolidin-1-ylmethyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

5-(1,4-dioxa-8-aza-spiro[4,5]dec-8-ylmethyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide, and

5-[4-(4-fluorophenyl)piperazin-1-ylmethyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide.

14. The compound of formula II as recited in claim 7 wherein R 8 is H, C 1 -C 10 alkyl, aryl(C 1 -C 6 alkyl), heterocycle(C 1 -C 6 alkyl) or C 1 -C 6 alkoxycarbonyl and R 9 is H or heterocycle(C 1 -C 6 alkyl).

15. The compound of formula II as recited in claim 14 selected from the group consisting of:

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

(2-carbamoyl-3-phenylsulfanyl-1H-indol-6-ylmethyl)-carbamic acid tert-butyl ester,

6-(benzylaminomethyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(4-nitrobenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(4-dimethylaminobenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(4-methylbenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(4-methoxybenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(4-bromobenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(4-chlorobenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-{[(biphenyl-4-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(3-nitrobenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(2-nitrobenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

3-phenylsulfanyl-6-[(4-trifluoromethylbenzylamino)methyl]-1H-indole-2-carboxylic acid amide,

6-[(3-fluoro-5-trifluoromethylbenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-{[(2-methoxynaphthalen-1-ylmethyl)amino]-methyl]}-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(2,4-dimethoxybenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(3-phenoxybenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(3-methoxybenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(2-methylbenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(3-methylbenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(2-fluoro-3-trifluoromethylbenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(2-methoxybenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-{[(10-chloro-anthracen-9-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(3,5-dichloro-2-hydroxybenzylamino)methyl]-1-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(3-bromo-4,5-dimethoxybenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(4-benzyloxy-3-methoxybenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(3-benzyloxy-4-methoxybenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-{[(5-nitrothiophen-2-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

4-{[(2-carbamoyl-3-phenylsulfanyl-1H-indol-6-ylmethyl)amino]methyl}benzoic acid methyl ester,

3-phenylsulfanyl-6-[(4-styrylbenzylamino)methyl]-1H-indole-2-carboxylic acid amide,

6-[(2-fluoro-6-trifluoromethylbenzylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-({[5-(2-chlorophenyl)-furan-2-ylmethyl]amino}methyl)-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-{[(1-benzenesulfonyl-1H-pyrrol-2-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-{[bis-(5-nitrofuran-2-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide, and

6-{[(5-nitrofuran-2-ylmethyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide.

16. The compound of formula II as recited in claim 7 wherein R 8 is P and R 9 is H.

17. The compound of formula II as recited in claim 16 selected from the group consisting of:

6-[(2-aminopropionylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(2-aminoacetylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(2-amino-3-methylpentanoylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

2-aminopentanedioic acid 5-amide 1-[(2-carbamoyl-3-phenylsulfanyl-1H-indol-6-ylmethyl)amide],

6-{[(2-amino-3-(1H-indol-3-yl)propionylamino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(2-amino-3-phenylpropionylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(2-amino-4-methylsulfanylbutyrylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-[(2,6-diaminohexanoylamino)methyl]-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide, and

3-amino-N-(2-carbamoyl-3-phenylsulfanyl-1H-indol-6-ylmethyl)succinamic acid.

18. The compound of formula II as recited in claim 7 wherein R 8 is aryl(C 2 -C 6 alkenyl), diaryl(C 2 -C 6 alkenyl) or heterocycle(C 2 -C 6 alkenyl) and R 9 is H or heterocycle(C 2 -C 6 alkenyl).

19. The compound of formula II as recited in claim 18 selected from the group consisting of:

6-{[(bis-(3-furan-2-yl-allyl)amino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide,

6-{[(3,3-diphenylallylamino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide, and

6-{[3-(4-hydroxy-3-methoxyphenyl)allylamino]methyl}-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide.

20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound selected from the group consisting of formula I or formula II as recited claim 1 , or a stereoisomer, an enantiomer, a racemate or a tautomer of said compound, or a pharmaceutically acceptable salt thereof.

21. A method for the preparation of a pharmaceutical composition useful for inhibiting casein kinase Iε activity comprising the formulation of a compound of formula I or formula II, or a stereoisomer, an enantiomer, a racemate or a tautomer of said compound, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers, diluents or excipients,

wherein

X is S or S(O) n ;

R 1 is H or C 1 -C 6 alkyl;

R 2 is NR 5 R 6 ;

R 3 is aryl or heterocycle;

R 4 is C 1 -C 6 alkyl or halogen;

R 5 is H or C 1 -C 6 alkyl;

R 6 is H or C 1 -C 6 alkyl;

R 7 is CH 2 NR 8 R 9 wherein

R 8 is H, C 1 -C 10 alkyl, C 3 -C 8 cycloalkyl, aryl, aryl(C 1 -C 6 alkyl), aryl(C 2 -C 6 alkenyl), diaryl(C 2 -C 6 alkenyl), heterocycle, heterocycle(C 1 -C 6 alkyl), heterocycle(C 2 -C 6 alkenyl), hydroxy(C 1 -C 6 alkyl), dihydroxy(C 2 -C 6 alkyl), acyl, C 1 -C 6 alkoxycarbonyl, aryl(C 1 -C 6 alkoxy)carbonyl, carbamoyl(C 1 -C 6 alkyl), or P;

R 9 is H, C 1 -C 10 alkyl, heterocycle(C 1 -C 6 alkyl) or heterocycle(C 2 -C 6 alkenyl); or

R 8 and R 9 together with the nitrogen to which they are attached form a heterocycle;

and wherein P is Gly, or L- or D-Ala, Val, Leu, Ile, Ser, Cys, Thr, Met, Pro, Phe, Tyr, Trp, His, Lys, Arg, Asp, Gly, Asn or Gln;

m is 0, 1 or 2; and

n is 1 or 2.

22. The method of claim 21 wherein said inhibition of casein kinase Iε activity results in a lengthening of circadian rhythm period.