Pyrrolo-, pyrazolo-, imidazo-pyrimidine and pyridine compounds that inhibit mnk1 and mnk2

Abstract

The present invention provides synthesis, pharmaceutically acceptable formulations and uses of compounds in accordance with Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. For Formula I compounds A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , W 1 , R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6 , R 7 , R 7a , R 7b , R 8 , R 8a , R 8b , R 9 , R 9a , R 9b and R 10 and subscripts “m” and “n” are as defined in the specification. The inventive Formula I compounds are inhibitors of Mnk and find utility in any number of therapeutic applications, including but not limited to treatment of inflammation and various cancers.

1 . A compound according to Formula (I): 
       
         
           
           
               
               
           
         
       
       a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof wherein:
 A 1  and A 2  independently are —N— or —CR 5a ; 
 A 3  is —N— or —CR 6 ; 
 A 4  is —N— or —CR 5b ; 
 A 5  is —NR′ or —CR 7a R 7b ; 
 A 6  and A 7  are independently —N— or —CR 8a  when represents a bond, otherwise A 6  and A 7  are independently —NR 8  or —CR 8a R 8b ; 
 W 1  is O, S, NH, NO(R 9 ) or CR 9a R 9b ; 
 m and n independently are 1, 2 or 3; 
 R 1  and R 2  independently are —H, —NHR 10 , NHR 10 -alkylene, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, arylalkylene, cycloalkylalkylene, heterocyclylalkylene or heteroarylalkylene; or 
 R 1  and R 2  together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring; 
 R 3  and R 4  independently are —H, —OH, —CN, —SR 10 , S(O) 2 (C 1 -C 8 ) alkyl, —C(O)NHR 10 , —C(O)NR 10 R 10 , —NHR 10 , —NR 10 R 10 , NHR 10 -alkylene, NR 10 R 10 -alkylene, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )haloalkyl, —O(C 1 -C 8 )alkyl, —O(C 1 -C 8 )haloalkyl, —O(C 1 -C 8 )alkyleneNHR 10 , —O(C 1 -C 8 )alkyleneNR 10 R 10 , cycloalkyl, heterocyclyl, heteroaryl, aryl, arylalkylene, cycloalkylalkylene, heterocyclylalkylene, heteroarylalkylene, alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl, or heterocyclylaminyl; 
 R 5a  is —H, —OH, halogen, —CN, acetyl, —(C 1 -C 8 )alkyl, —S(C 1 -C 8 )alkyl, —(C 2 -C 8 )alkenyl, —(C 2 -C 8 )alkynyl, —O(C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, —NHR 10 , —NR 10 R 10 , NHR 10 -alkylene, NR 10 R 10 -alkylene, or —O(C 1 -C 8 )haloalkyl; 
 R 5b  and R 6  is —H, —OH, —SH, —CN, —S(O) 2 R 10 , halogen, —S(C 1 -C 8 )alkyl, —NHR 10 , —NR 10 R 10 , (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )haloalkyl, —O(C 1 -C 8 )haloalkyl, —O(C 1 -C 8 )alkyl, —O(C 1 -C 8 )alkyleneNHR 10 , —O(C 1 -C 8 )alkyleneNR 10 R 10 , —(C 1 -C 8 )alkyleneNHR 10 , —(C 1 -C 8 )alkyleneNR 10 R 10 , —S(C 1 -C 8 )alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl; 
 R 7  is —H, —OH, acetyl, —(C 1 -C 8 )alkyl, —C(O)alkyl, —C(O)cycloalkyl, —C(O)O—(C 1 -C 8 )alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; 
 R 7a  and R 7b  independently are —H, —OH, acetyl, —(C 1 -C 8 )alkyl, —O(C 1 -C 8 )alkyl, —C(O)alkyl, —C(O)cycloalkyl, —C(O)O—(C 1 -C 8 )alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; 
 R 8  is —H, —OH, acetyl, (C 1 -C 8 )alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl; 
 R 8a  and R 8b  independently are —H, —OH, —CN, acetyl, —SH, —S(O) 2 R 10 , halogen, —S(C 1 -C 8 )alkyl, —NHR 10 , —NR 10 R 10 , (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, —O(C 1 -C 8 )alkyl, —O(C 1 -C 8 )alkylNHR 10 , —O(C 1 -C 8 )alkylNR 10 R 10 , —(C 1 -C 8 )alkylNHR 10 , —(C 1 -C 8 )alkylNR 10 R 10 , cycloalkyl, heterocyclyl, heteroaryl or aryl; 
 R 9 , R 9a  and R 9b  are independently —H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, arylalkylene, cycloalkylalkylene, heterocyclylalkylene, or heteroarylalkylene, or 
 R 9a  and R 9b  together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring; 
 R 10  is —H, —OH, —C(O)O(C 1 -C 8 )alkyl, —C(O)(C 1 -C 8 )alkyl, —C(O)—NH 2 , —C(O)—NH(C 1 -C 8 )alkyl, NH 2 —C(O)-alkylene, —S(C 1 -C 8 )alkyl, acetyl, —(C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, —O(C 1 -C 8 )alkyl, (C 1 -C 8 ) haloalkyl, alkylcarbonylaminyl, alkylaminyl, —C(O)alkyl, —C(O)cycloalkyl, —C(O)O—(C 1 -C 8 )alkyl, aryl, heteroaryl, heterocyclyl or cycloalkyl; 
 wherein any alkyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, arylalkylene, cycloalkylalkylene, heterocyclylalkylene, heteroarylalkylene, alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl or heterocyclylaminyl is optionally substituted with 1, 2 or 3 groups selected from —OH, —CN, —SH, —S(O)NH 2 , —S(O)NH 2 , halogen, —NH 2 , —NH(C 1 -C 4 )alkyl, —N[(C 1 -C 4 )alkyl] 2 , —C(O)NH 2 , —COOH, —COOMe, acetyl, —(C 1 -C 8 )alkyl, —O(C 1 -C 8 )alkyl (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, NH 2 —C(O)-alkylene, NH 2 —C(O)-alkylene, —NH(Me)-C(O)-alkylene, —CH 2 —C(O)-lower alkyl, —C(O)-lower alkyl, alkylcarbonylaminyl, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, cycloalkylcarbonylaminyl, cycloalkylaminyl, —CH 2 —C(O)-cycloalkyl, —C(O)-cycloalkyl, —CH 2 —C(O)-aryl, —CH 2 -aryl, —C(O)-aryl, —CH 2 —C(O)-heterocycloalkyl, —C(O)-heterocycloalkyl, heterocyclylaminyl or heterocyclyl; and 
 --- represents the option of having a double bond. 
 
     
     
         2 . The compound according to  claim 1  wherein “m” and “n” are both 1, A 5  is —NR 7 , W 1  is O and R 7  is —H. 
     
     
         3 . The compound according to  claim 1  wherein R 1  and R 2  independently are —H, methyl, ethyl, i-propyl, —NH 2 , aminomethylene or —CH 3 O—C(O)NH-methylene. 
     
     
         4 . The compound according to  claim 1  wherein R 1  and R 2  together with the carbon atom to which they are attached form a cycloalkyl ring selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, 1-(2,2-difluoroethyl)piperidine or 1-methylpiperidine. 
     
     
         5 . The compound according to  claim 1  wherein A 2  is —CR 5a , A 3  is —CR 6  and A 4  is —CR 5b . 
     
     
         6 . The compound according to  claim 5  wherein R 5a  and R 6  independently are —H, chlorine, fluorine, or methyl and R 5b  is —H. 
     
     
         7 . The compound according to  claim 1  wherein A 2  is —CR 5a , A 3  is —CR 6 , A 4  is —N and R 5a  and R 6  independently are —H, chlorine, fluorine or methyl. 
     
     
         8 . The compound according to  claim 1  wherein A 2  is —N, A 3  is —CR 6  and A 4  is CR 5b . 
     
     
         9 . The compound according to  claim 8  wherein R 6  is —C(Me) or —CH and R 5b  is —H. 
     
     
         10 . The compound according to  claim 1  wherein R 3  and R 4  independently are —H. 
     
     
         11 . The compound according to  claim 1  wherein R 3  is —H and R 4  is chlorine, fluorine, methyl, ethyl or —NH 2 . 
     
     
         12 . The compound according to  claim 1  wherein A 6  and A 7  are —CR 8a  --- represents a bond, and R 8a  is —H, heteroaryl or aryl. 
     
     
         13 . The compound according to  claim 12  wherein A 6  and A 7  are —CH. 
     
     
         14 . The compound according to  claim 12  wherein A 6  is —CH and A 7  is —C(heteroaryl) or —C(aryl). 
     
     
         15 . The compound according to  claim 1  selected from the following table: 
       
         
           
                 
               
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         16 . A pharmaceutical composition comprising (i) a therapeutically effective amount of at least one compound according to  claim 1  or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof; (ii) in combination with a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         17 . A method for attenuating or inhibiting the activity of MnK in at least one cell overexpressing Mnk comprising contacting the at least one cell with a compound according to  claim 1  or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. 
     
     
         18 . The method of  claim 17  wherein the at least one cell is a colon cancer cell, a gastric cancer cell, a thyroid cancer cell, a lung cancer cell, a leukemia cell, a B-cell lymphoma, a T-cell lymphoma, a hairy cell lymphoma, Hodgkin's lymphoma cell, non-Hodgkin's lymphoma cell, Burkitt's lymphoma cell, a pancreatic cancer cell, a melanoma cell, a multiple melanoma cell, a brain cancer cell, a CNS cancer cell, a renal cancer cell, a prostate cancer cell, an ovarian cancer cell, or a breast cancer cell. 
     
     
         19 . A method for treating a Mnk dependent condition in a mammal in need thereof comprising administering to the mammal (i) a therapeutically effective amount of at least one compound according to  claim 1  or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or (ii) a pharmaceutical composition of  claim 16 . 
     
     
         20 . The method of  claim 19  wherein the Mnk dependent condition is colon cancer, colorectal cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, pancreatic cancer, melanoma, multiple melanoma, brain cancer, CNS cancer, renal cancer, prostate cancer, ovarian cancer, breast cancer, Alzheimer's, Parkinson's, Fragile X Syndrome and autism disorders.