Piperidine-Substituted Mnk Inhibitors and Methods Related Thereto

Abstract

The present invention relates to compounds according to Formula (I): or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof wherein X 1 , X 2 , R 1 , R 2 , R 3 and n are as defined herein. Also described are pharmaceutically acceptable compositions of Formula (I) compounds as well as methods for utilizing the compounds of Formula (I) and the pharmaceutically acceptable compositions of Formula (I) compounds as inhibitors of Mnk as well as therapeutics for the treatment of diseases such as cancer.

1 . A compound according to Formula (I): 
       
         
           
           
               
               
           
         
         or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: 
         X 1  is CH 2  and X 2  is NR 2  or X 1  is NR 2  and X 2  is CH 2 ; 
         R 1  is H, (C 1 -C 4 )alkyl, halogen or cyano; 
         R 2  is H, (C 1 -C 8 )alkyl or (C 1 -C 8 )haloalkyl; 
         R 3  is (C 1 -C 8 )alkyl, or R 2  and an adjacent R 3 , or R 3  and an adjacent R 3 , together with the ring atoms to which they are attached, form a fused five- or six-membered heterocycle or cycloalkyl ring; and 
         n is 0, 1, 2, 3 or 4; 
         wherein alkyl, heterocycle and cycloalkyl are optionally substituted with OH, CN, NH 2 , NO 2 , halogen, alkyl and alkoxy. 
       
     
     
         2 . The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to  claim 1  wherein X 1  is NR 2  and X 2  is CH 2 . 
     
     
         3 . The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to  claim 1  wherein R 1  is methyl. 
     
     
         4 . The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to  claim 1  wherein R 1  is Cl. 
     
     
         5 . The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to  claim 1  wherein R 1  is cyano. 
     
     
         6 . The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to  claim 1  wherein R 2  is H. 
     
     
         7 . The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to  claim 1  wherein R 2  is methyl. 
     
     
         8 . The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to  claim 1  wherein R 2  is ethyl. 
     
     
         9 . The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to  claim 1  wherein R 2  is isopropyl. 
     
     
         10 . The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to  claim 1  wherein R 2  is tert-butyl. 
     
     
         11 . The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to  claim 1  wherein R 2  is 3,3,3-trifluoropropyl. 
     
     
         12 . The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to  claim 1  wherein R 2  is 2,2-difluoroethyl. 
     
     
         13 . The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to  claim 1  wherein R 2  is methylcyclopropane. 
     
     
         14 . The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to  claim 1  wherein R 3  is H or methyl. 
     
     
         15 . The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to  claim 1  selected from compounds 3A, 3B, 3C, 3D, rac-1F, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N, 3O, 3P, 3Q, 3R, 3S, 3T, 3U, rac-2F, 3V, 3W, 3X, 3Y, 1Fa, 1Fb, 2Fa, 2Fb, 3Z, 3AA, 3BB, 3CC, 3DD, 3EE, 3FF, 3GG and 3HH. 
     
     
         16 . The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to  claim 1  selected from compounds 3D, 3K, 3L, 3X, 3Y, rac-1F, 1Fa, 1Fb, rac-2F, 2Fa and 2Fb. 
     
     
         17 . The compound according to  claim 1 , wherein the pharmaceutically acceptable salt of the Formula (I) compound is an organic or inorganic acid salt selected from the group consisting of acetate, mesylate, sulfate, citrate, oxalate, hydrochloride, dihydrochloride, isothionate, lactate, and laurate. 
     
     
         18 . A pharmaceutical composition comprising (i) a therapeutically effective amount of at least one compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to  claim 1 ; (ii) in combination with a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         19 . A method for treating a Mnk dependent condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of at least one compound according Formula (I) of  claim 1 , or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the Mnk dependent condition is cancer or inflammation. 
     
     
         20 . A method for treating a solid tumor, colorectal cancer, bladder cancer, gastric cancer, esophageal cancer, head and neck cancer, CNS cancer, malignant glioma, glioblastoma, hepatocellular cancers, thyroid cancer, lung cancer, non-small cell cancer, small cell lung cancer, melanoma, myeloma, pancreatic cancer, pancreatic carcinoma, renal cell carcinoma, cervical cancer, urothelial cancer, prostate cancer, castration-resistant prostate cancer, ovarian cancer, breast cancer, triple-negative breast cancer, leukemia, Hodgkins lymphoma, non-Hodgkins lymphoma, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, diffuse large B-cell lymphoma, Burkitts lymphoma, multiple myeloma, and myelodysplastic syndrome in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound according to Formula I of  claim 1 , or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.