Inhibitors of Protein Kinases

Abstract

The present invention relates to inhibitors of cyclin-dependent kinases and therapeutic applications thereof. Furthermore, the invention relates to methods of preventing and/or treating any type of pain, inflammatory disorders, immunological diseases, proliferative diseases, infectious diseases, cardiovascular diseases and neurodegenerative diseases comprising the administration of an effective amount of at least one inhibitor of cyclin-dependent kinases.

1 . A method for treatment of a disease selected from the group of pain, an inflammatory disorder, an immunological disease, a proliferative disease, an infectious disease, a cardiovascular disease and a neurodegenerative disease, 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 disease. 
     
     
         2 . The method of  claim 1 , wherein the pain comprises chronic pain, inflammatory pain, neuropathic pain, or a combination thereof. 
     
     
         3 . A method for treatment of a disease selected from the group of pain, an inflammatory disorder, an immunological disease, a proliferative disease, an infectious disease, a cardiovascular disease and a neurodegenerative disease, 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 disease. 
     
     
         4 . The method of  claim 3 , wherein the pain comprises chronic pain, inflammatory pain, neuropathic pain, or a combination thereof. 
     
     
         5 . A method for treatment of a disease selected from the group of pain, an inflammatory disorder, an immunological disease, a proliferative disease, an infectious disease, a cardiovascular disease and a neurodegenerative disease, 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 disease. 
     
     
         6 . The method of  claim 5 , wherein the pain comprises chronic pain, inflammatory pain, neuropathic pain, or a combination thereof. 
     
     
         7 . A method for treatment of a disease selected from the group of pain, an inflammatory disorder, an immunological disease, a proliferative disease, an infectious disease, a cardiovascular disease and a neurodegenerative disease, 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 disease.   
     
     
         8 . The method of  claim 7 , wherein the pain comprises chronic pain, inflammatory pain, neuropathic pain, or a combination thereof.