Bicyclic heteroaryl derivatives as mnk1 and mnk2 modulators and uses thereof

Abstract

The present invention relates to certain compounds (e.g., imidazopyrazine, imidazopyridine, imidazopyridazine and imidazpyrimidine compounds) that act as inhibitors of the MAP kinase interacting kinases MNK2a, MNK2b, MNK1a, and MNK1b. The present invention further relates to pharmaceutical compositions comprising these compounds, and to the use of the compounds for the preparation of a medicament for the prophylaxis and treatment of diseases (e.g., proliferative diseases (e.g., cancer), neurodegenerative diseases (e.g., Alzheimer's disease), metabolic diseases (e.g. diabetes), neurodevelopmental disorders (e.g. autism), or psychiatric disorders (e.g. schizophrenia or anxiety)) as well as methods of treating these diseases.

1 .- 51 . (canceled) 
     
     
         52 . A method of treating autism comprising administering to a subject in need of treatment a compound of Formula (Ia): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable form thereof, wherein
 X 1 , X 2 , and X 3  are independently N or C; 
 X 4  and X 5  are independently N or CR 4 ; 
 wherein at least one of X 1 , X 2 , X 3 , X 4 , and X 5  is N; 
 X 7  is CR 10 ; 
 X 8  is CR 11 ; 
    is a single or double bond, as valency allows; 
 R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , and R 9 , are independently hydrogen, halogen, optionally substituted aliphatic, —CN, —OR, —SR, —N(R) 2 , —NO 2 , —C(O)R, —CO 2 R, —C(O)NROR, —OC(O)R, or —C(O)NH 2 ; 
 R 1  is independently —C(O)R, —CO 2  (optionally substituted C 1-6  aliphatic), —C 02  (optionally substituted heteroaryl), —CO 2  (optionally substituted heterocyclyl), or —OC(O)(optionally substituted C 1-6  aliphatic); 
 R 10  and R 11  are each independently hydrogen, halogen, optionally substituted aliphatic, —CN, —OR, SR, —N(R) 2 , —NO 2 , —C(O)R, —CO 2 R, or —C(O)NROR; 
 each R is independently hydrogen or optionally substituted C 1-6  aliphatic optionally substituted heteroaryl, or optionally substituted heterocyclyl; and 
 each R 4  is independently hydrogen, halogen, or optionally substituted C 1-6  aliphatic; and 
 R 6  and R 7 , or R 7  and R 8 , may be optionally taken together to form an optionally substituted 5-6 membered fused heterocyclic or 5-6 membered fused heteroaryl ring. 
 
     
     
         53 . The method of  claim 52 , wherein the compound is of Formula (Ia-i): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable form thereof. 
     
     
         54 . The method of  claim 52 , wherein the compound is of Formula (Ib-i) or (Ib-ii): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable form thereof, wherein
 X 1 , X 2 , and X 3  are independently N or C; 
 X 4  and X 5  are independently N or CR 4 ; 
 wherein at least one of X 1 , X 2 , X 3 , X 4 , and X 5  is N; 
 X 7  is CH; 
 X 8  is CH; 
    is a single or double bond, as valency allows; 
 R 1  is —C(O)R, wherein R is an optionally substituted heterocyclyl; 
 R 2 , R 3 , R 6 , and R 7  are independently —H, —F, —Cl, —CN, —CH 3 , —CF 3 , —CHF 2 , —C(O)NH 2 , —OH, —OC 1-4 alkyl, or —OCF 3 ; or R 6  and R 7  are taken together to form a 5-6 membered fused heterocyclyl or 5-6 membered fused heteroaryl; and 
 each R 4  is independently hydrogen or C 1-6  alkyl. 
 
     
     
         55 . The method of  claim 52 , wherein R 7  is —CN. 
     
     
         56 . The method of  claim 52 , wherein R 2  is hydrogen. 
     
     
         57 . The method of  claim 52 , wherein R 3  is hydrogen. 
     
     
         58 . The method of  claim 52 , wherein R 6  is hydrogen. 
     
     
         59 . The method of  claim 52 , wherein both R 2  and R 3  are hydrogen. 
     
     
         60 . The method of  claim 52 , wherein R 2  is —N(R N ) 2  and R 3  is hydrogen, wherein each instance of R N  is independently hydrogen, or optionally substituted C 1-6  aliphatic. 
     
     
         61 . The method of  claim 52 , wherein R 2  is —O O  and R 3  is hydrogen, wherein R O  is hydrogen, or optionally substituted C 1-6  aliphatic. 
     
     
         62 . The method of  claim 52 , wherein R 1  is —C(O)R, wherein R is one of the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         63 . The method of  claim 52 , wherein the compound or or a pharmaceutically acceptable form thereof is of Formula (II), (III), (IV), (V), (VI), or (VII): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         64 . The method of  claim 52 , wherein the compound or a pharmaceutically acceptable form thereof is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable forms thereof. 
     
     
         65 . The method of  claim 52 , wherein the compound or a pharmaceutically acceptable form thereof is administered in combination with a kinase inhibitor selected from a PI3K inhibitor and an mTOR inhibitor. 
     
     
         66 . A method of treating autism comprising administering to a subject in need of treatment a composition comprising a compound of Formula (Ia): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient, wherein
 X 1 , X 2 , and X 3  are independently N or C; 
 X 4  and X 5  are independently N or CR 4 ; 
 wherein at least one of X 1 , X 2 , X 3 , X 4 , and X 5  is N; 
 X 7  is CR 10 ; 
 X 8  is CR 11 ; 
    is a single or double bond, as valency allows; 
 R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , and R 9 , are independently hydrogen, halogen, optionally substituted aliphatic, —CN, —OR, —SR, —N(R) 2 , —NO 2 , —C(O)R, —CO 2 R, —C(O)NROR, —OC(O)R, or —C(O)NH 2 ; 
 R 1  is independently —C(O)R, —CO 2  (optionally substituted C 1-6  aliphatic), —CO 2  (optionally substituted heteroaryl), —CO 2  (optionally substituted heterocyclyl), or —OC(O)(optionally substituted C 1-6  aliphatic); 
 R 10  and R 11  are each independently hydrogen, halogen, optionally substituted aliphatic, —CN, —OR, SR, —N(R) 2 , —NO 2 , —C(O)R, —CO 2 R, or —C(O)NROR; 
 each R is independently hydrogen or optionally substituted C 1-6  aliphatic optionally substituted heteroaryl, or optionally substituted heterocyclyl; and 
 each R 4  is independently hydrogen, halogen, or optionally substituted C 1-6  aliphatic; and 
 R 6  and R 7 , or R 7  and R 8 , may be optionally taken together to form an optionally substituted 5-6 membered fused heterocyclic or 5-6 membered fused heteroaryl ring. 
 
     
     
         67 . The method of  claim 66 , wherein the composition further comprises a kinase inhibitor selected from a PI3K inhibitor and an mTOR inhibitor. 
     
     
         68 . The method of  claim 52 , wherein the compound or a pharmaceutically acceptable form thereof is administered at a dosage level sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg to a subject in need thereof.