Inhibitors of Protein Kinases

Abstract

Compounds of general Formula I: wherein R 1 , R 2 , R 3 , x, A and R a are as defined herein are inhibitors of cyclin-dependent kinases and are useful for preventing and/or treating any type of pain, inflammatory disorders, immunological diseases, proliferative diseases, infectious diseases, cardiovascular diseases and neurodegenerative diseases.

1 - 30 . (canceled) 
     
     
         31 . A method for the treatment of diseases and conditions mediated by the activity of CDK9, the method comprising administering to a patient in need of such treatment an effective amount of a compound of general Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof wherein: 
         A is N and B is CH, C(C 1-4 alkyl) or C(NH 2 ), 
         R a  is H or methyl; 
         R 1  is selected from the group consisting of: 
         C 1-8  alkyl; —NR 6 R 7 , C 1-6  alkyl-NR 6 R 7 , R 20 , —C 1-6  alkyl-C(O)OR 4 , C 1-6 alkyl-C(O)R 4 , —NR 10 —(C 1-6  alkyl)-NR 6 R 7 , —NR 10 —(C 1-6  alkyl)-R 20 , —NR 10 —(C 1-6  alkyl)-C(O)OR 4 , —NR 10 R 20 , O—(C 1-6  alkyl)-NR 6 R 7 , —O—(C 1-6 alkyl)-C(O)OR 4 , —OR 20 , C 1-6  alkyl —OR 20 , C 1-6  alkyl-SR 20 , C 1 -C 6  alkyl-NR 20 , (C 1-6  alkyl)-O—(C 1-6  alkyl)-R 20 , (C 1-6  alkyl)-R 20 , C(O)R 20 ;
 where alkyl moieties may be straight or branched and may be substituted by one or more substituents chosen from halo, methoxy, ethoxy NR 6 R 7  or a nitrogen-containing heterocyclic ring; 
 R 4  represents H or C 1-4 -alkyl; 
 R 6  and R 7  are each independently selected from the group consisting of H, C 1-6 alkyl, hydroxy-C 2-6 alkyl-; 
 R 10  represents H or C 1-4 alkyl; 
 R 20  is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl and may be substituted by one or more substituents selected from: 
 C 2-6 alkenyl, C 2-6 alkynyl any of which may be substituted by one or more halo or OH substituents; 
 R 21 , —C 1-4  alkyl-R 21 ; OR 21 , O(C 1-4  alkyl)R 21 , SR 21 , SOR 21 , SO 2 R 21 , C(O)R 21 , C 1-4 alkyl-OR 21 , 
 —O(C 2-6 alkenyl), —O(C 2-6 alkynyl), any of which may be substituted by one or more halo or OH substituents; 
 OR 22 , —SR 22 —SOR 22 , —SO 2 R 22 , —C(O)R 22 , —C(O)OR 22 , —C 1-4  alkyl-O—R 22 , —C 1-4 alkyl-O—C 14 alkyl-O—R 22 , C 1-4 alkyl-C(O)R 22 , —C 1-4 alkyl-C(O)R 22 , NR 11 C(O)OR 22 , NR 11 C(O)R 22 , —SO 2 —NR 11 R 12 , —C(O)—NR 11 R 12 , —C 1-4 alkyl-C(O)—NR 11 R 12 , —NH—SO 2 R 15 , —N(C 1-4 alkyl)-SO 2 R 15 , —(C 1-4 alkyl)NR 11 R 12 , NR 11 R 12 , —(C 1-6 alkyl)NR 11 R 12 , nitro, halogen, cyano and hydroxyl; and when R 20  is carbocyclyl or heterocyclyl or an aromatic group in which an aromatic ring is fused to a non-aromatic ring, R 20  may additionally be substituted by oxo;
 R 21  is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl and may be substituted by one or more substituents as defined below;
 when R 21  is an aryl or heteroaryl group, it may be substituted by one or more substituents selected from: wherein phenyl is optionally substituted by methyl, methoxy, halogen, halomethyl fluoromethoxy or trifluoromethoxy; 
 when R 21  is a carbocyclic or heterocyclic group it may be substituted by one or more substituents selected from methyl, oxo or halogen; 
 
 R 22  is hydrogen or C 1-6  alkyl optionally substituted by halo or hydroxyl; 
 R 11  and R 12  each independently represent a substituent selected from H or C 1-4 alkyl or R 11  and R 12  are joined such that together they form a 3-8 membered non-aromatic ring; 
 R 15  represents H or C 1-4 alkyl; 
 
 
         R 2  represents H, C 1-6 alkyl or NH 2 ; 
         each R 3  independently represents a substituent selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl (optionally substituted by methyl, oxo or halogen), phenyl (optionally substituted by methyl, methoxy, halogen, halomethyl fluoromethoxy or trifluoromethoxy), —C 1-6 alkyl-OH, —C 1-4 alkylphenyl (optionally substituted by methyl, methoxy, halogen, halomethyl fluoromethoxy or trifluoromethoxy), C 1-6 alkoxy-, C 1-6 alkenyloxy, C 3-6 alkynyloxy-, C 1-6 haloalkoxy-, —O—C 3-8 cycloalkyl, —O—C 1-4 alkyl-C 3-8 cycloalkyl, —O-phenyl (optionally substituted by methyl, methoxy, halogen, halomethyl fluoromethoxy or trifluoromethoxy), —O—C 1-4 alkylphenyl (optionally substituted by methyl, methoxy, halogen, halomethyl fluoromethoxy or trifluoromethoxy), —S(C 1-6 alkyl), —SO(C 1-6 alkyl), —SO 2 C 1-6 alkyl, —SO 2 C 3-8 cycloalkyl, —SO 2 —NR 31 R 32 , —C(O)C 1-6 alkyl, —C(O)C 3-8 cycloalkyl, —C(O)OH, —C(O)OC 1-6 alkyl, —C(O)—NR 31 R 32 , —C 1-4 alkyl-O—C 1-4 alkyl-OH, —C 1-4 alkyl-O—C 3-7 cycloalkyl, —C 1-4 alkyl-C(O)C 1-6 alkyl, —C 1-4 alkyl-C(O)OH, —C 1-4 alkyl-C(O)—NR 31 R 32 , —NH—SO 2 R 33 , —N(C 1-4 alkyl)-SO 2 R 33 , —(C 1-4 alkyl)NR 31 R 32 , —NR 31 R 32 , —(C 1-6 alkyl)NR 31 R 32 , nitro, halogen, cyano, hydroxyl;
 R 31  and R 32  each independently represent a substituent selected from H, C 1-4 alkyl or C 1-4 haloalkyl or R 31  and R 32  are joined such that together they form a 3-8 membered non-aromatic ring; 
 R 33  represents H or C 1-4 alkyl; 
 
         x represents the number of independently selected R 3  substituents on the phenyl ring, in the range 0-4. 
       
     
     
         32 . The method of  claim 31  wherein:
 A is N and B is CH, C(C 1-4 alkyl) or C(NH 2 ), 
 R 1  is selected from the group consisting of: 
 C 1-8 alkyl; 
 C 1-8 haloalkyl; 
 
       
         
           
           
               
               
           
         
         aryl; 
         heteroaryl; 
         C 3-12  carbocyclyl; 
         heterocyclyl; 
         —C 1-6 alkyl-heteroaryl; 
         —C 1-6 alkyl-carbocyclyl; 
         —C 1-6 alkyl-heterocyclyl; 
         —C 1-6 alkyl-C(O)OH; 
         —C 1-6 alkyl-C(O)OC 1-4 alkyl; 
       
       
         
           
           
               
               
           
         
         —NR 10 C 1-6 alkyl-aryl; 
         —NR 10 C 1-6 alkyl-heteroaryl; 
         —NR 10 C 1-6 alkyl-carbocyclyl; 
         —NR 10 C 1-6 alkyl-heterocyclyl; 
         —NR 10 C 1-6 alkyl-C(O)OH; 
         —NR 10 C 1-6 alkyl-C(O)OC 1-4 alkyl; 
         —NR 10 aryl; 
         —NR 10 heteroaryl; 
         —NR 10 carbocyclyl; 
         —NR 10 heterocyclyl; 
       
       
         
           
           
               
               
           
         
         —OC 1-6 alkyl-aryl; 
         —OC 1-6 alkyl-heteroaryl; 
         —OC 1-6 alkyl-carbocyclyl; 
         —OC 1-6 alkyl-heterocyclyl; 
         —OC 1-6 alkyl-C(O)OH; 
         —OC 1-6 alkyl-C(O)OC 1-4 alkyl; 
         —Oaryl; 
         —Oheteroaryl; 
         —Ocarbocyclyl; and 
         —Oheterocyclyl; 
         wherein any of the aforesaid aryl and heteroaryl may optionally be substituted by one or more groups independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl (optionally substituted by methyl, oxo or halogen), phenyl (optionally substituted by methyl, methoxy, halogen, halomethyl fluoromethoxy or trifluoromethoxy)-C 1-6 alkyl-OH, —C 1-4 alkylphenyl (wherein phenyl is optionally substituted by methyl, methoxy, halogen, halomethyl fluoromethoxy or trifluoromethoxy), C 1-6 alkoxy-, C 1-6 alkenyloxy, C 3-6 alkynyloxy-, C 1-6 haloalkoxy-, —O—C 3-8 cycloalkyl, —O—C 1-4 alkyl-C 3-8 cycloalkyl, —O-phenyl (optionally substituted by methyl, methoxy, halogen, halomethyl fluoromethoxy or trifluoromethoxy), —O—C 1-4 alkylphenyl (optionally substituted by methyl, methoxy, halogen, halomethyl fluoromethoxy or trifluoromethoxy), —SO(C 1-6 alkyl), —SO 2 C 1-6 alkyl, —SO 2 C 3-8 cycloalkyl, —SO 2 —NR 11 R 12 , —C(O)C 1-6 alkyl, —C(O)C 3-8 cycloalkyl, —C(O)OH, —C(O)OC 1-6 alkyl, —C(O)—NR 11 R 12 , —C 1-4 alkyl-O—C 1-4 alkyl, —C—C 1-4 alkyl, —C 1-4 alkyl-O—C 3-7 cycloalkyl, C(O)OH, —C 1-4 alkyl-C(O)—NR 11 R 12 , —NH—SO 2 R 15 , —N(C 1-4 alkyl)-SO 2 R 15 , —(C 1-4 alkyl)NR 11 R 12 , NR 11 R 12 , —(C 1-6 alkyl)NR 11 R 12 , nitro, halogen, cyano and hydroxyl; and 
         wherein any of the aforesaid carbocyclyl and heterocyclyl may optionally be substituted by one or more groups independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl (optionally substituted by methyl, oxo or halogen), phenyl (optionally substituted by methyl, methoxy, halogen, halomethyl fluoromethoxy or trifluoromethoxy), —C 1-6 alkyl-OH, —C 1-4 alkylphenyl (wherein phenyl is optionally substituted by methyl, methoxy, halogen, halomethyl fluoromethoxy or trifluoromethoxy), C 1-6 alkoxy-, C 1-6 alkenyloxy, C 3-6 alkynyloxy-, C 1-6 haloalkoxy-, —O—C 3-8 cycloalkyl, —O—C 1-4 alkyl-C 3-8 cycloalkyl, —O-phenyl (optionally substituted by methyl, methoxy, halogen, halomethyl fluoromethoxy or trifluoromethoxy), —O—C 1-4 alkylphenyl (optionally substituted by methyl, methoxy, halogen, halomethyl fluoromethoxy or trifluoromethoxy), —SO(C 1-6 alkyl), —SO 2 C 1-6 alkyl, —SO 2 C 3-8 cycloalkyl, —SO 2 —NR 11  R 12 , —C(O)C 1-6 alkyl, —C(O)C 3-8 cycloalkyl, —C(O)OH, —C(O)OC 1-6 alkyl, —C(O)—NR 11 R 12 , —C 1-4 alkyl-O—C 1-4 alkyl, —C 1-4 alkyl-O—C 1-4 alkyl-O—C 1-4 alkyl, —C 1-4 alkyl-O—C 3-7 cycloalkyl, —C 1-4 alkyl-C(O)OH, —C 1-4 alkyl-C(O)OC 1-4 alkyl, —C 1-4 alkyl-C(O)—NR 11 R 12 , —NH—SO 2 R 15 , —N(C 1-4 alkyl)-SO 2 R 15 , —(C 1-4 alkyl)NR 11 R 12 , —NR 11 R 12 , —(C 1-6 alkyl)NR 11 R 12 , nitro, halogen, cyano, hydroxyl and oxo; 
         R 2  represents H, C 1-6 alkyl or NH 2 ; 
         R 3  represents a substituent, selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl (optionally substituted by methyl, oxo or halogen), phenyl (optionally substituted by methyl, methoxy, halogen, halomethyl fluoromethoxy or trifluoromethoxy), —C 1-6 alkyl-OH, —C 1-4 alkylphenyl (optionally substituted by methyl, methoxy, halogen, halomethyl fluoromethoxy or trifluoromethoxy), C 1-6 alkoxy-, C 1-6 alkenyloxy, C 3-6 alkynyloxy-, C 1-6 haloalkoxy-, —O—C 3-8 cycloalkyl, —O—C 1-4 alkyl-C 3-8 cycloalkyl, —O-phenyl (optionally substituted by methyl, methoxy, halogen, halomethyl fluoromethoxy or trifluoromethoxy), —O—C 1-4 alkylphenyl (optionally substituted by methyl, methoxy, halogen, halomethyl fluoromethoxy or trifluoromethoxy), —S(C 1-6 alkyl), —SO(C 1-6 alkyl), —SO 2 C 1-6 alkyl, —SO 2 C 3-8 cycloalkyl, —SO 2 —NR 31 R 32 , —C(O)C 1-6 alkyl, —C(O)C 3-8 cycloalkyl, —C(O)OH, —C(O)OC 1-6 alkyl, —C(O)—NR 31 R 32 , —C 1-4 alkyl, —C 1-4 alkyl-O—C 1-4 alkyl-OH, —C 1-4 alkyl-O—C 1-4 alkyl-O—C 1-4 alkyl, —C 1-4 alkyl-O—C 3-7 cycloalkyl, —C 1-4 alkyl-C(O)C 1-6 alkyl, —C 1-4 alkyl-C(O)OH, —C 1-4 alkyl-C(O)OC 1-4 alkyl, —C 1-4 alkyl-C(O)—NR 31 R 32 , —NH—SO 2 R 33 , —N(C 1-4 alkyl)-SO 2 R 33 , —(C 1-4 alkyl)NR 31 R 32 , —NR 31 R 32 , —(C 1-6 alkyl)NR 31 R 32 , nitro, halogen, cyano, hydroxyl; 
         R 4  and R 5  independently represent H or C 1-4 -alkyl; 
         R 6  and R 7  are each independently selected from the group consisting of H, C 1-6 alkyl, hydroxy-C 2-6 alkyl-; 
         R 10  represents H or C 1-4 alkyl, 
         R 11  and R 12  each independently represent a substituent selected from H or C 1-4 alkyl or R 11  and R 12  are joined such that together they form a 3-8 membered non-aromatic ring; 
         R 15  represents H or C 1-4 alkyl; 
         R 31  and R 32  each independently represent a substituent selected from H, C 1-4 alkyl or C 1-4 haloalkyl or R 31  and R 32  are joined such that together they form a 3-8 membered non-aromatic ring; 
         R 33  represents H or C 1-4 alkyl; 
         x represents the number of independently selected R 3  substituents on the phenyl ring, in the range 0-4; 
         m represents an integer 1-4; and 
         n represents an integer 2-4. 
       
     
     
         33 . The method of  claim 31  wherein, independently or in any combination:
 R a  is hydrogen; 
 B is CH or C 1-4  alkyl; 
 R 2  is hydrogen or C 1-4  alkyl, 
 R 3  is halogen, C 1-6 alkoxy, —O—C 1-4 alkylphenyl (e.g. —O-benzyl) or —O—C 1-4 alkyl-C 3-8 cycloalkyl; and 
 x is 1 or 2. 
 
     
     
         34 . The method of  claim 31  wherein, independently or in any combination:
 B is CH; 
 R 2  is hydrogen or methyl; and 
 R 3  is halogen, methoxy, ethoxy, isopropyloxy, benzyloxy or —OCH 2 cyclopropyl. 
 
     
     
         35 . The method of  claim 31  wherein The compound as defined in  claim 31  and selected from the group consisting of Example compounds 1 to 156