Benzazole derivatives and their use as JNK modulators

1. A benzothiazole compound according to formula I

as well as its tautomers, its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof, wherein:

G is an unsubstituted or substituted pyrimidinyl group;

R 1 is selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, optionally substituted by halogen;

R 2 is hydrogen;

with the proviso that if R 1 is H, G may be neither of the following pyrimidines:

2. A benzothiazole compound according to claim 1 of formula I, as well as their tautomers according to formula II below,

their geometrical isomers, their optically active forms as enantiomers, diastereomers and their racemate forms, as well as pharmaceutically acceptable salts thereof.

3. A benzothiazole compound according to claim 1 , wherein:

G is a pyrimidinyl group

L is selected from the group consisting of hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, unsubstituted or substituted C 1 -C 6 thioalkoxy, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, primary, secondary or tertiary amino groups, aminoacyl, aminocarbonyl, amino-(C 1 -C 10 )alkyl, amino-unsubstituted or substituted (C 1 -C 10 )-alkyl-aryl, amino-unsubstituted or substituted (C 1 -C 10 )alkyl-heteroaryl, unsubstituted or substituted C 1 -C 6 alkoxycarbonyl, carboxyl, cyano, halogen, hydroxy, nitro, sulfoxy, sulfonyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted 3-8 membered cycloalkyl, optionally containing at least one heteroatom selected from N, O, S, and unsubstituted or substituted hydrazido groups, wherein the term “substituted” means that said groups can be substituted with from 1 to 5 substituents selected from the group consisting of C 1 -C 6 -alkyl, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, primary, secondary or tertiary amino groups or quarternary ammonium moieties, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, aryl, heteroaryl, carboxyl, cyano, halogen, hydroxyl, mercapto, nitro, sulfoxy, sulfonyl, alkoxy, thioalkoxy, and trihalomethyl; and

said substitution may optionally include situations where neighboring substituents have undergone ring closure wherein said substituents form lactams, lactones, cyclic anhydrides, acetals, thioacetals, or aminals formed by ring closure.

4. A benzothiazole compound according to claim 3 , wherein L is a group —N(R a , R b ) or —OR a , with R a and R b being each independently selected from the group consisting of H, unsubstituted or substituted (C 1 -C 10 )-alkyl, unsubstituted or substituted C 1 -C 6 alkyl-aryl, unsubstituted or substituted C 1 -C 6 -alkyl-heteroaryl, unsubstituted or substituted aryl, heteroaryl and unsubstituted or substituted 4-8 membered saturated or unsaturated cycloalkyl.

5. A benzothiazole compound according to claim 4 wherein L is selected from

wherein n is 1 to 10,

R 5 and R 5, are independently selected from each other from the group consisting of H, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted aryl or heteroaryl, substituted or unsubstituted C 1 -C 6 alkyl-aryl and substituted or unsubstituted C 1 -C 6 -alkyl-heteroaryl.

6. A benzothiazole compound according to claim 5 , wherein R 1 is H.

7. A benzothiazole compound according to claim 1 , wherein R 1 is hydrogen, G is a pyrimidinyl group

with L being either

wherein n is 0, 1or 2and R 5 is an arylor heteroaryl.

8. A benzothiazole compound according to claim 7 , wherein R 5 is phenyl, pyridyl, imidazolyl.

9. A benzothiazole compound according to claim 1 selected from the following group:

1,3-benzothiazol-2-yl(2-chloro-4-pyrimidinyl)acetonitrile;

1,3-benzothiazol-2-yl(2, 6-dimethoxy-4-pyrimidinyl)acetonitrile;

1,3-benzothiazol-2-yl(2-chloro-6-methyl-4-pyrimidinyl)acetonitrile;

1,3-benzothiazol-2-yl[2-(methylsulfanyl)-4-pyrimidinyl]acetonitrile;

1,3-benzothiazol-2-yl{6-chloro-5-nitro-4 -pyrimidinyl}acetonitrile;

1,3-benzothiazol-2-yl(2-hydroxy-pyrimidinyl-4-yl) acetonitrile;

(2-chloropyrimidin-4-yl)[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]acetonitrile;

(2E)-(2-chloro-4-pyrimidinyl)(3-methyl-1,3-benzothiazol-2(3H)-ylidene)ethanenitrile;

1,3-benzothiazol-2-yl(2-{[2-(1H-imidazol-5-yl)ethyl]amino}-4-pyrimidinyl)-acetonitrile;

1,3-benzothiazol-2-yl[2-(1-piperazinyl)-4 -pyrimidinyl]acetonitrile;

1,3-benzothiazol-2-yl[2-(4benzyl1piperidinyl)4 pyrimidinyl]acetonitrile;

1,3-benzothiazol-2-yl[2-(4-methyl-1-piperazinyl)-4-pyrimidinyl]acetonitrile;

1,3-benzothiazol-2-yl[2-(4morpholinyl)4 -pyrimidinyl]acetonitrile;

1,3-benzothiazol-2-yl[2-(methylamino)-4-pyrimidinyl]acetonitrile;

1,3-benzothiazol-2-yl(2-{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}-4-pyrimidinyl)acetonitrile;

1,3-benzothiazol-2-yl{2-[4-(benzyloxy)-1-piperidinyl]-4-pyrimidinyl}acetonitrile;

1,3-benzothiazol-2-yl[2-(4-hydroxy-1-piperidinyl)-4-pyrimidinyl]acetonitrile;

1,3-benzothiazol-2-yl(2hydrazino4 pyrimidinyl)acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(dimethylamino)ethyl]amino}-4-pyrimidinyl)acetonitrile;

1,3-benzothiazol-2-yl[2-(dimethylamino)-4-pyrimidinyl]acetonitrile;

1,3-benzothiazol-2-yl{2-[(2-methoxyethyl)amino]-4-pyrimidinyl}acetonitrile;

1,3-benzothiazol-2-yl{2-[(2-hydroxyethyl)amino]-4-pyrimidinyl}acetonitrile;

1,3-benzothiazol-2-yl[2-(propylamino)4 pyrimidinyl]acetonitrile;

1,3-benzothiazol-2-yl(2-{[3(1H-imidazol1yl)propyl]amino}4-pyrimidinyl)acetonitrile;

1,3-benzothiazol-2-yl[2-(1pyrrolidinyl)4 pyrimidinyl]acetonitrile;

1,3-benzothiazol-2-yl{2-[(2-phenylethyl)amino]-4-pyrimidinyl}acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(2pyridinyl)ethyl]amino}-4-pyrimidinyl)acetonitrile;

1,3-benzothiazol-2-yl{2-[(2-pyridinylmethyl)amino]-4-pyrimidinyl}acetonitrile;

1,3-benzothiazol-2-yl{2-[4(1H1, 2, 3benzotriazol1yl)-1-piperidinyl]-4-pyrimidinyl}acetonitrile;

1,3-benzothiazol-2-yl{2-[4(2pyrazinyl)1piperazinyl]-4-pyrimidinyl}acetonitrile;

1,3-benzothiazol-2-yl{2-[4(2pyrimidinyl)1piperazinyl]-4-pyrimidinyl}acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(3pyridinyl)ethyl]amino}-4-pyrimidinyl)acetonitrile;

1,3-benzothiazol-2-yl(5bromo2{[2-(dimethylamino)ethyl]amino}-4-pyrimidinyl)acetonitrile;

1,3-benzothiazol-2-yl{2-[(2morpholin-4-ylethyl)amino]pyrimidin-4-yl}acetonitrile;

1,3-benzothiazol-2-yl[2-(4{3(trifluoromethyl)sulfonyl]anhlino}piperidin-1-yl)pyrimidin-4-yl]acetonitrile;

1,3-benzothiazol-2-yl(2-{[3(2oxopyrrolidin-1-yl)propyl]amino }pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl(2-{methyl[3-(methylamino)propyl]amino }pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl(2-{[3-(4-methylpiperazin-1-yl)propyl]amino }pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl{2-[(3morpholin-4-ylpropyl)amino]pyrimidin-4-yl}acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(1methyl1Himidazol-4-yl)ethyl]amino }pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(1H-indol-3-yl)ethyl]amino }pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(4-hydroxyphenyl)ethyl]amino }pyrimidin-4-yl)acetonitrile;

tert-butyl({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)acetate

{2-[(3-aminopropyl)amino]pyrimidin-4-yl}(1,3-benzothiazol-2-yl)acetonitrile;

{2-[(2-aminoethyl)amino]pyrimidin-4-yl}(1,3-benzothiazol-2-yl)acetonitrile;

1,3-benzothiazol-2-yl(2-{[3-(dimethylamino)propyl]amino}pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl{2-[(2piperidin-1-ylethyl)amino]pyrimidin-4-yl}acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(1-methyl-1H-imidazol-5-yl)ethyl]amino }pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl[2-(benzylamino)pyrimidin-4-yl]acetonitrile;

isopropyl3({4[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)propanoate

1,3-benzothiazol-2-yl{2-[(3-hydroxypropyl)amino]pyrimidin-4-yl}acetonitrile;

1,3-benzothiazol-2-yl{2-[(pyridin-3-ylmethyl)amino]pyrimidin-4-yl}acetonitrile;

(2-aminopyrimidin-4-yl)(1,3-benzothiazol-2-yl)acetonitrile;

1,3-benzothiazol-2-yl{2-[(pyridin-4-ylmethyl)amino]pyrimidin-4-yl}acetonitrile;

tert-butyl4-[2-({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)ethyl]phenylcarbamate (2-{[2-(4-aminophenyl)ethyl]amino}pyrimidin-4-yl)(1,3-benzothiazol-2-yl)acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(3,4-dimethoxyphenyl)ethyl]amino }pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(3-methoxyphenyl)ethyl]amino }pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(2-fluorophenyl)ethyl]amino }pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl[2-({2-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrimidin-4-yl]acetonitrile;

1,3-benzothiazol-2-yl{2-[(2-hydroxy-2-phenylethyl)amino]pyrimidin-4-yl}acetonitrile;

1,3-benzothiazol-2-yl{2-[(2-{[3(trifluoromethyl)pyridin-2-yl]amino}ethyl)amino]pyrimidin-4-yl}acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(3-chiorophenyl)ethyl]amino }pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(3,4-dichiorophenyl)ethyl]amino }pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(4-methoxyphenyl)ethyl]amino }pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(4-methylphenyl)ethyl]amino }pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(3-fluorophenyl)ethyl]amino }pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(4-phenoxyphenyl)ethyl]amino }pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(2-phenoxyphenyl)ethyl]amino }pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(4-bromophenyl)ethyl]amino }pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(4-fluorophenyl)ethyl]amino }pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl{2-[(2-[1,1′biphenyl]-4-ylethyl)amino]pyrimidin-4-yl}acetonitrile;

1,3-benzothiazol-2-yl{2-[(2-{4-[hydroxy(oxido)amino]phenyl}ethyl)amino]pyrimidin-4-yl}acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(1H1,2,4triazol-1-yl)ethyl]amino }pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl(2-{[3(1H-pyrazol-1-yl)propyl]amino }pyrimidin-4-yl)acetonitrile; 4-[2-({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)ethyl]benzenesulfonamide

{2-[(2-pyridin-3-ylethyl)amino]pyrimidin-4-yl}[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]acetonitrile;

1,3-benzothiazol-2-yl{2-[(1H-tetraazol-5-ylmethyl)amino]pyrimidin-4-yl}acetonitrile;

1,3-benzothiazol-2-yl[2-(benzyloxy)pyrimidin-4-yl]acetonitrile;

1,3-benzothiazol-2-yl{2-[(4pyridin-3-ylbenzyl)oxy]pyrimidin-4-yl}acetonitrile;

1,3-benzothiazol-2-yl[2-(pyridin-4-ylmethoxy)pyrimidin-4-yl]acetonitrile;

1,3-benzothiazol-2-yl[2-(pyridin-2-ylmethoxy)pyrimidin-4-yl]acetonitrile;

1,3-benzothiazol-2-yl[2-(3-pyridin-2-ylpropoxy)pyrimidin-4-yl]acetonitrile;

1,3-benzothiazol-2-yl{2-[(4-methoxybenzyl)oxy]pyrimidin-4-yl}acetonitrile;

1,3-benzothiazol-2-yl[2-(pyridin-3-ylmethoxy)pyrimidin-4-yl]acetonitrile;

1,3-benzothiazol-2-yl{2-[2-(4-methoxyphenyl)ethoxy]pyrimidin-4-yl}acetonitrile;

1,3-benzothiazol-2-yl[2-([1,1′biphenyl]-3-ylmethoxy)pyrimidin-4-yl]acetonitrile;

1,3-benzothiazol-2-yl{2-[(3,4,5-trimethoxybenzyl)oxy]pyrimidin-4-yl}acetonitrile;

1,3-benzothiazol-2-yl{2-[(3,4-dichlorobenzyl)oxy]pyrimidin-4-yl}acetonitrile;

1,3-benzothiazol-2-yl[2-({3[-(dimethylamino)methyl]benzyl}oxy)pyrimidin-4-yl]acetonitrile;

1,3-benzothiazol-2-yl{2-[(1oxidopyridin-3-yl)methoxy]pyrimidin-4-yl}acetonitrile;

1,3-benzothiazol-2-yl(2-{[4(morpholin-4-ylmethyl)benzyl]oxy}pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl{2-[(4pyridin-2-ylbenzyl)oxy]pyrimidin-4-yl}acetonitrile;

1,3-benzothiazol-2-yl(2-{[4(piperidin-1-ylmethyl)benzyl]oxy}pyrimidin-4-yl)acetonitrile;

1,3-benzothiazol-2-yl[2-(4-methoxyphenoxy)pyrimidin-4-yl]acetonitrile;

1,3-benzothiazol-2-yl[2-(4-butoxyphenoxy)pyrimidin-4-yl]acetonitrile;

{2-[4-(4-acetylpiperazin-1-yl)phenoxy]pyrimidin-4-yl}(1,3-benzothiazol-2-yl)acetonitrile;

[2-(4-methoxyphenoxy)pyrimidin-4-yl][5-(trifluoromethyl)-1,3-benzothiazol-2-yl]acetonitrile;

1,3-benzothiazol-2-yl(pyrimidin-4-yl)acetonitrile; and

N-[2-({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)ethyl]-4-chlorobenzamidel, 3-benzothiazol-2-yl(2-methoxy-4-pyrimidin-yl)acetonitrile.

10. A -benzothiazol-e compound according to claim 9 , selected from the group consisting of:

1,3-benzothiazol-2-yl(2-chloro-4-pyrimidin-yl)acetonitrile;

1,3-benzothiazol-2-yl[2-(methylsulfanyl)-4-pyrimidin-yl]acetonitrile;

1,3-benzothiazol-2-yl(2-{[2-(1H-imidazol5yl)ethyl]amino}-4-pyrimidin-yl)acetonitrile; 1,3-benzothiazol-2-yl[2-(methylamino)-4-pyrimidin-yl]acetonitrile;

1,3-benzothiazol-2-yl{2-[(2-hydroxyethyl)amino]-4-pyrimidin-yl}acetonitrile; 1,3-benzothiazol-2-yl[2-(benzyloxy)pyrimidin-4-yl]acetonitrile;

1,3-benzothiazol-2-yl[2-(4-methoxyphenoxy)pyrimidin-4-yl]acetonitrile;

1,3-benzothiazol-2-yl(2-methoxy-4-pyrimidinyl)acetonitrile; and

1,3-benzothiazol-2-yl(2-{[2-(3pyridinyl)ethyl]amino}-4-pyrimidinyl)acetonitrile.

11. A benzothiazole compound according to claim 1 , which is 1,3-benzothiazol-2-yl([2-{[4-(morpholin-4-ylmethyl)benzyl]oxy}-pyrimidin-4-yl)acetonitrile.

12. A benzothiazole compound according to claim 5 , wherein n is 1to 6.

13. Process for the preparation of a benzothiazole compound according to claim 1 ,

wherein the following reaction is performed:

whereby G is as described above and Y is a suitable leaving group like halogen.

14. Process according to claim 13 , wherein the following reactions are performed:

with R 1 , R 2 , Y and L being as described above.

15. A pharmaceutical composition containing at least one benzothiazole compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient thereof.