Inhibitors of protein kinases

1. A compound according to the general Formula I:

wherein

R 1 is selected from the group consisting of —NR 5 R 6 , —R 8 , —C 1-4 alkyl-OH, and —C 2-4 -alkylene-O—C 1-4 alkyl;

wherein

R 5 and R 6 independently of each other are selected from the group consisting of hydrogen, C 1-4 alkyl, C 2-4 alkenyl, hydroxy-C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl or C 4-7 heterocycloalkyl-C 0-4 alkylene, C 4-7 aryl-C 0-4 alkylene, and C 4-7 heteroaryl-C 0-4 alkylene, or

wherein R 5 and R 6 together with the N-atom to which they are bound also form a 5- to 8-membered heterocycloalkyl or a 5- to 6 membered heteroaryl,

wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkyl is further optionally substituted by up to 2 radicals selected from the group consisting of halo, hydroxy, C 1-4 alkyl, hydroxy-C 1-4 alkyl, C 1-4 alkyl-O—C 1-4 alkylene, C 1-4 alkyl-O—, and —NR 5 R 6 ;

R 8 is C 1-4 alkyl, C 2-4 alkenyl, hydroxy-C 2-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl or C 4-7 heterocycloalkyl-C 0-4 alkyl;

wherein said cycloalkyl, heterocycloalkyl or alkyl is further optionally substituted by up to 2 radicals selected from the group consisting of halo, hydroxy, C 1-4 alkyl, hydroxy-C 1-4 alkyl, C 1-4 alkyl-O—C 1-4 alkylene, C 1-4 alkyl-O, and —NR 5 R 6 ;

R 2 can be 0 to 2 independent halo substituents;

R 3 can be 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, hydroxy, C 1-4 alkyl, C 3-7 cycloalkyl, C 1-4 alkyl-cycloalkyl, C 1-4 alkyl-heterocycloalkyl, —O-heterocycloalkyl, C 1-4 alkoxy, C 1-4 alkenyloxy, —OCF 3 , C 2-4 alkanoyl, C 1-4 -alkylsulfonyl, mono- and di-(C 1 -C 4 alkyl)sulfonamido, aminocarbonyl, mono- and di-(C 1 -C 4 alkyl)aminocarbonyl, alkoxy, heteroaryl-C 1-4 alkoxy, heterocycloalkyl-C 1-4 alkoxy, heterocycloalkyl-C 1-4 alkyl, heteroaryl-C 1-4 -alkyl, C 1-4 alkyloxymethyl, hydroxy-C 1-4 alkyloxymethyl, cyano, —COOH, and C 1 -C 4 alkoxycarbonyl, wherein the above mentioned substituents can be further substituted by radicals selected from the group consisting of C 1-4 -alkyl, hydroxyl-C 0-4 -alkyl, aminocarbonyl, halo, and NR 5 R 6 ;

R 4 is hydrogen, C 1-4 alkyl or —NR′R″, wherein R′ and R″ each are independently selected from hydrogen, and C 1-4 alkyl;

and N oxides of such compounds.

2. A compound according to the general Formula Ia:

wherein

R 1 is selected from the group consisting of —NR 5 R 6 , —R 8 , —C 1-4 alkyl-OH, and —C 2-4 -alkylene-O—C 1-4 alkyl;

R 5 and R 6 independently of each other are selected from the group consisting of hydrogen, C 1-4 alkyl, C 2-4 alkenyl, hydroxy-C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl or C 4-7 heterocycloalkyl-C 0-4 alkylene, C 4-7 aryl-C 0-4 alkylene, and C 4-7 heteroaryl-C 0-4 alkylene, or alternatively wherein R 5 and R 6 together with the N-atom to which they are bound form a 5- to 8-membered heterocycloalkyl or a 5- to 6 membered heteroaryl;

R 8 is C 1-4 alkyl, C 2-4 alkenyl, hydroxy-C 2-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl or C 4-7 heterocycloalkyl-C 0-4 alkyl;

X is methylene;

wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkyl is further optionally substituted by up to 2 radicals selected from the group consisting of halo, hydroxy, C 1-4 alkyl, hydroxy-C 1-4 alkyl, C 1-4 alkyl-O—C 1-4 alkylene, C 1-4 alkyl-O—, and —NR 5 R 6 ;

R 2 can be 0 to 2 independent halo substituents;

R 3a is selected from the group consisting of hydrogen, C 1-4 alkoxy, C 1-4 alkenyloxy, aryl-Cl 1-4 alkoxy, and heteroaryl-C 1-4 alkoxy;

R 3b is selected from the group consisting of hydrogen, C 1-4 alkoxy, C 1-4 alkenyloxy, and C 0-4 alkylNR 5 R 6 ;

R 3c is selected from the group consisting of hydrogen and halo;

with the proviso that R 3a and R 3b cannot simultaneously be hydrogen;

and N oxides of such compounds.

3. The compound of claim 2 , wherein

R 1 is selected from the group consisting of NH 2 —, N-methyl-, N-propyl-, N-isopropyl-, N-cyclopropyl-, N-cyclopentyl-, and N,N-diethyl-,

X is methylene;

R 2 is hydrogen;

R 3a is selected from the group consisting of hydrogen, methoxy-, ethoxy-, isopropyloxy-, and benzyloxy-;

R 3b is selected from the group consisting of hydrogen, methoxy-, 3-Hydroxymethyl-piperidin-1-ylmethyl-, 3-Diethylaminomethyl-, 3-Piperidin-1-ylmethyl-, 3-Morpholin-4-ylmethyl-, 4-Methyl-piperazin-1-ylmethyl-, and [1,2,4]Triazol-1-ylmethyl-;

R 3c is hydrogen or halo;

with the proviso that R 3a and R 3b cannot simultaneously be hydrogen;

and N oxides of such compounds.

4. The compound of claim 3 , selected from the group consisting of

C-{4-[6-(2-Ethoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-propyl-methanesulfonamide (Compound 1);

N-Cyclopentyl-C-{4-[6-(2-ethoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 2);

C-{4-[6-(2-Benzyloxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-cyclopentyl-methanesulfonamide (Compound 3);

C-{4-[6-(2-Benzyloxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-isopropyl-methanesulfonamide (Compound 4);

C-{4-[6-(2-Benzyloxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-cyclopropyl-methanesulfonamide (Compound 5);

{4-[6-(2-Ethoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 6);

C-{4-[6-(2-Ethoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-methyl-methanesulfonamide (Compound 7);

{4-[6-(2-Benzyloxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 8);

{4-[6-(2,3-Dimethoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 9);

N,N-Diethyl-C-{4-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 10);

C-{4-[6-(2-Benzyloxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-methyl-methanesulfonamide (Compound 11);

{4-[6-(3-Methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 12);

{4-[6-(2-Methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 13);

N-Cyclopentyl-C-{4-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 14);

N-Cyclopentyl-C-{4-[6-(2-isopropoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 15);

N-Cyclopentyl-C-{4-[6-(4-fluoro-2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 16);

(4-{6-[3-(3-Hydroxymethyl-piperidin-1-ylmethyl)-phenyl]-pyrimidin-4-ylamino}-phenyl)-methanesulfonamide (Compound 17);

{4-[6-(3-Diethylaminomethyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 18);

{4-[6-(3-Piperidin-1-ylmethyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 19);

{4-[6-(3-Morpholin-4-ylmethyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 20);

(4-{6-[3-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-4-ylamino}-phenyl)-methanesulfonamide (Compound 21);

{4-[6-(3-[1,2,4]Triazol-1-ylmethyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 22);

N-Cyclopentyl-C-(4-{6-[3-(3-hydroxymethyl-piperidin-1-ylmethyl)-phenyl]-pyrimidin-4-ylamino}-phenyl)-methanesulfonamide (Compound 23);

N-Cyclopentyl-C-{4-[6-(3-diethylaminomethyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 24);

N-Cyclopentyl-C-{4-[6-(3-piperidin-1-ylmethyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 25);

N-Cyclopentyl-C-{4-[6-(3-morpholin-4-ylmethyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 26);

N-Cyclopentyl-C-(4-{6-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-4-ylamino}-phenyl)-methanesulfonamide (Compound 27); and

N-Cyclopentyl-C-{4-[6-(3-[1,2,4]triazol-1-ylmethyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 28).

5. A pharmaceutical preparation containing the compound of claim 1 , together with a pharmaceutically acceptable carrier.

6. A method for the treatment of neuropathic pain, comprising administering a therapeutically effective amount of at least one of the compounds of claim 1 to a patient suffering from neuropathic pain.

7. A pharmaceutical preparation containing the compound of claim 2 , together with a pharmaceutically acceptable carrier.

8. A method for the treatment of neuropathic pain, comprising administering a therapeutically effective amount of at least one compound of claim 2 to a patient suffering from neuropathic pain.

9. A pharmaceutical preparation containing the compound of claim 3 , together with a pharmaceutically acceptable carrier.

10. A method for the treatment of neuropathic pain, comprising administering a therapeutically effective amount of at least one compound of claim 3 to a patient suffering from neuropathic pain.

11. A pharmaceutical preparation containing the compound of claim 4 , together with a pharmaceutically acceptable carrier.

12. A method for the treatment of neuropathic pain, comprising administering a therapeutically effective amount of at least one compound of claim 4 to a patient suffering from neuropathic pain.