NAMPT Inhibitors for Cancer Therapy

Abstract

The invention features compounds of Formula (I), Formula (I)-A and Formula (I)-B as disclosed herein, as well as methods of synthesis, therapy, diagnostics, and assays.

What is claimed is: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Y 1  is —CR 14 — or N, 
 Y 2  is —CR 15 — or N, 
 Y 3  is —C(O)—, 
 Y 4  is —CH 2 , or —N(R 16 )—, 
 or Y 3  and Y 4  together are —C(R 17 )═C(R 18 )—, 
 X is aryl, heteroaryl, arylalkyl, heteroarylalkyl, or amide, 
 Z is C 2  or greater alkyl or alkoxylalkyl, 
 R is H or C 1 -C 6  alkyl, 
 R 1 -R 18  are independently H or C 1 -C 6  alkyl, and 
 Q is N; provided that when R is H, X is not 
 
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1 , wherein R is H. 
     
     
         3 . The compound of  claim 1 , wherein X is heteroarylalkyl. 
     
     
         4 . The compound of  claim 3 , wherein X is pyridinylmethyl, substituted pyridinylmethyl, isoxazolylmethyl, substituted isoxazolylmethyl, or thiazolylmethyl. 
     
     
         5 . The compound of  claim 4 , wherein X is methylisoxazolylmethyl, fluoropyridinylmethyl, or methylpyridinylmethyl. 
     
     
         6 . The compound of  claim 1 , wherein Y 1  is CH or N. 
     
     
         7 . The compound of  claim 1 , wherein Y 2  is CH or N. 
     
     
         8 . The compound of  claim 1 , wherein Y 4  is —CH 2 —. 
     
     
         9 . The compound of  claim 1 , wherein Y 3  and Y 4  together are —C(R 17 )═C(R 18 )—. 
     
     
         10 . The compound of  claim 1 , wherein Z is ethyl, propyl, isopropyl, butyl, cyclobutylmethyl, methoxypropyl, or methoxybutyl. 
     
     
         11 . The compound of  claim 1 , wherein R 1 -R 18  are each —H. 
     
     
         12 . A pharmaceutical composition, comprising the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         13 . A method of inhibition of activated and/or proliferating B cells for therapeutic modulation of immunological disease, comprising administering to a patient in need thereof a composition comprising the compound of  claim 1 . 
     
     
         14 . The method of  claim 13 , wherein the immunological disease is lupus, rheumatoid arthritis, scleroderma, psoriasis, Sjogren's syndrome, type I diabetes or multiple sclerosis. 
     
     
         15 . A method of inducing, modulating or maintaining immunosuppression for transplant, comprising administering to a patient in need thereof a composition comprising the compound of  claim 1 . 
     
     
         16 . A method of suppressing or modulating an immune response to a therapeutic biologic, comprising administering to a patient in need thereof a composition comprising the compound of  claim 1 . 
     
     
         17 . A method of inhibiting tumor cell growth wherein the tumor cells are NAPRT deficient, comprising administering to a patient in need thereof a composition comprising the compound of  claim 1 . 
     
     
         18 . A method of treating leukemia and lymphoma, comprising administering to a patient in need thereof a composition comprising the compound of  claim 1 . 
     
     
         19 . A method of treating a NAD-requiring viral infection, comprising administering to a patient in need thereof a composition comprising the compound of  claim 1 . 
     
     
         20 . The method of  claim 19 , wherein the viral infection is selected from influenza, RSV, HSV, HCV, HBV, HPV, HIV, CMV, EBOV, or EBV.