Inhibitors of protein kinases

1. A method for amelioration of pain comprising administering a therapeutically effective amount of at least one compound represented by the general Formula I

wherein

R 1 is —XSO 2 NR 5 R 6 or —XSO 2 R 8 ;

X is a branched or unbranched C 1-4 alkylene, wherein said C 1-4 alkylene optionally can be bound to R 5 or R 6 to form a 5- or 6-membered heterocycle;

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

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

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, aminocarbonyl, C 1-4 alkyl, hydroxy-C 1-4 alkyl, C 1-4 alkyl-O—C 1-4 alkyl, C 1-4 alkyl-O—, and —NR 5 R 6 ;

R 8 is C 1-4 alkyl, hydroxy-C 2-4 alkyl, C 3-4 alkenyl, 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 alkyl, C 1-4 alkyl-O, and —NR 5 R 6 ;

R 2 is one or two substituents independently selected from halogen and hydrogen;

R 3 can be 1 to 3 substituents each 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 2-4 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, aryl-C 1-4 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, C 1-4 -alkoxy, aminocarbonyl, halo, and NR 5 R 6 ;

R 4a and R 4b are the same or different and each is independently hydrogen, C 1-4 alkyl, or —NR′R″, wherein R′ and R″ are each independently hydrogen or C 1-4 alkyl;

and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts, solvates, and hydrates of such compounds to a patient suffering from said pain.

2. The method of claim 1 , wherein the pain comprises chronic pain, inflammatory pain, neuropathic pain, or a combination thereof.

3. A method for amelioration of pain comprising administering a therapeutically effective amount of at least one compound represented by general Formula I wherein R 3 is 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, hydroxymethyl, hydroxy, methoxy, ethoxy, isopropoxy, benzyloxy, hydrogen, fluoro, chloro, trifluoromethyl, 2-methoxy-ethoxy, methoxymethyl, 2-methoxy-ethyl, tetrahydro-furan-3-yloxy, tetrahydro-furan-2-yl-methoxy, —N(CH 3 )SO 2 CH 3 , piperidin-1-yl-methyl, 2-hydroxymethyl-piperidin-1-yl-methyl, 3-hydroxymethyl-piperidin-1-yl-methyl, 3-(2-hydroxy-ethyl)-piperidin-1-yl-methyl, 3-aminocarbonyl-piperidin-1-yl-methyl, dimethylaminomethyl, diethylaminomethyl, (ethyl-isopropyl-amino)-methyl, morpholin-4-ylmethyl, 4-methyl-piperazin-1-yl-methyl, [1,2,4]triazol-1-yl-methyl, pyridine-3-yl-methoxy, and pyridine-4-yl-methoxy to a patient suffering from said pain.

4. The method of claim 3 , wherein the pain comprises chronic pain, inflammatory pain, neuropathic pain, or a combination thereof.

5. A method for amelioration of pain comprising administering a therapeutically effective amount of at least one compound represented by general Formula Ia

wherein

R 1 is —CH 2 SO 2 NR 5 R 6 or —CH 2 SO 2 R 8 ,

R 2 is hydrogen,

R 3a is hydrogen or C 1-4 alkoxy,

R 3b is hydrogen, C 1-4 alkyl optionally substituted by dialkylamine, heterocycloalkyl-C 1-4 -alkyl optionally substituted by C 1-4 -alkyl or by hydroxyl-C 0-4 -alkyl, or heteroaryl-C 1-4 -alkyl; R 3c is hydrogen or halogen,

R 4a and R 4b are each independently C 1-4 alkyl or hydrogen,

R 5 is selected from the group consisting of hydrogen, methyl, 2-hydroxyethyl, cyclobutyl, cyclopentyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, tetrahydro-furan-3-yl, pyrrolidin-3-yl, pyridine-3-yl, pyridin-4-yl, and 4-piperidinyl;

R 6 is hydrogen or methyl,

R 8 is hydroxy-C 2-4 -alkyl,

and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts, solvates, and hydrates of such compounds to a patient suffering from said pain.

6. The method of claim 5 , wherein the pain comprises chronic pain, inflammatory pain, neuropathic pain, or a combination thereof.

7. A method for amelioration of pain comprising administering a therapeutically effective amount of at least one compound selected from the group consisting of:

{4-[4-(2-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-methanesulfonamide (Compound 1);

C-{4-[4-(2-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-N-methyl-methanesulfonamide (Compound 2); and

{4-[4-(2-Methoxy-phenyl)-6-methyl-pyrimidin-2-ylamino]-phenyl}-methanesulfonamide (Compound 3)

to a patient suffering from said pain.

8. The method of claim 7 , wherein the pain comprises chronic pain, inflammatory pain, neuropathic pain, or a combination thereof.