Bicyclic heterocyclic 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), inflammatory diseases, Alzheimer's disease), as well as methods of treating these diseases.

1 .- 33 . (canceled) 
     
     
         34 . A compound of Formula (Ib-i): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt 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 N or CH; 
 X 8  is N or 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 heteroaryl; and 
 each R 4  is independently hydrogen or C 1-6  alkyl. 
 
     
     
         35 . The compound of  claim 34 , or a pharmaceutically acceptable salt thereof, wherein X 2  is C. 
     
     
         36 . The compound of  claim 34 , or a pharmaceutically acceptable salt thereof, wherein X 3  is N. 
     
     
         37 . The compound of  claim 34 , or a pharmaceutically acceptable salt thereof, wherein X 7  and X 8  are each CH. 
     
     
         38 . The compound of  claim 34 , wherein the compound is of Formula (Ib-ii): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         39 . The compound of  claim 34 , wherein the compound is of Formula (IIa), (IIIa), (IVa), (Va), (VIa), or (VIIa): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         40 . The compound of  claim 35 , or a pharmaceutically acceptable salt thereof, wherein R 1  is —C(O)R, wherein:
 R is of the formula: 
 
       
         
           
           
               
               
           
         
         each R c  is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; 
         each R d  is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, —COR e , S(O)R c , S(O) 2 R c , optionally substituted alkylaryl, or optionally substituted aryl; 
         each R e  is independently hydrogen, halo, —OH, —OR c , —NH 2 , —NHR c , —NHSO 2 R, —NR f SO 2 R c , —NR c R f , —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, —COR c , or —NHCOR c ; 
         each R f  is independently —H or C 1-6  alkyl; 
         each R g  is independently hydrogen, halo, —OH, —OR c , —NH 2 , —NHR c , —NHSO 2 R, —NR f SO 2 R, —NR c R f , —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, —COR c , or —NHCOR c ; and 
         n is 1, or 2. 
       
     
     
         41 . The compound of  claim 35 , or a pharmaceutically acceptable salt thereof, wherein R 1  is —C(O)R, wherein R is one of the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         42 . The compound of  claim 40 , or a pharmaceutically acceptable salt thereof, wherein R is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         43 . The compound of  claim 40 , or a pharmaceutically acceptable salt thereof, wherein R is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         44 . The compound of  claim 35 , or a pharmaceutically acceptable salt thereof, wherein both R 2  and R 3  are hydrogen. 
     
     
         45 . The compound of  claim 35 , or a pharmaceutically acceptable salt thereof, wherein R 6  is —H. 
     
     
         46 . The compound of  claim 35 , or a pharmaceutically acceptable salt thereof, wherein R 7  is —F, —Cl, or —CN. 
     
     
         47 . A compound of formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         48 . A pharmaceutical composition comprising a compound of  claim 34 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         49 . A method of treating an MNK1-related disorder or MNK2-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of  claim 34 , or a pharmaceutically acceptable salt thereof. 
     
     
         50 . The method of  claim 49 , wherein the MNK1-related disorder or MNK2-related disorder is cancer, an inflammatory condition, Alzheimer's disease, or a metabolic disorder. 
     
     
         51 . The method of  claim 49 , wherein the disorder is a hematological cancer or solid tumor. 
     
     
         52 . The method of  claim 49 , wherein the compound is administered in combination with an additional therapeutic agent. 
     
     
         53 . A kit comprising a compound of  claim 34 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of  claim 48 ; and instructions for administering the compound or the composition to a subject.