Carboxamide derivatives useful as rsk inhibitors

Abstract

Described herein are carboxamide derivatives that are useful as inhibitors of p90 ribosomal S6 kinase (RSK), pharmaceutical compositions comprising the derivatives, and methods of using the derivatives in treating diseases or conditions associated with RSK activity.

1 .- 205 . (canceled) 
     
     
         206 . A method of treating breast cancer associated with p90 ribosomal S6 kinase activity in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of formula (II), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 2  is hydrogen, halo, C 1-6 alkyl, or C 1-6 haloalkyl; 
         R 4a  and R 4b  are each independently hydrogen, halo, C 1-6 alkyl, or C 1-6 haloalkyl; 
         each R 6  is independently hydrogen or C 1-6 alkyl; 
         R 11  is halo, C 1-6 haloalkyl, —N(R 6 ) 2 , —C 1-6 alkyl-N(R 6 ) 2 , or —C(O)N(R 6 ) 2 ; 
         each R 12  is independently —OH, —CN, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —N(R 6 ) 2 , —C 1-6 alkyl-N(R 6 ) 2 , —C(O)R 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 , aryl, aralkyl, cycloalkyl, heterocyclyl, or heteroaryl; and 
         n is 0, 1, 2, 3, or 4; 
         wherein the breast cancer is selected from Luminal A, Luminal B, Her-2 positive, triple-negative breast cancer. basal-like breast cancer, inflammatory breast cancer, BRCA1/2 mutated breast cancer, drug resistant breast cancer, murine breast cancer, gefitinib insensitive: MDA-MB-231, and metastatic breast cancer. 
       
     
     
         207 . The method of  claim 206 , wherein R 2  is hydrogen. 
     
     
         208 . The method of  claim 207 , wherein R 4a  is C 1-6 alkyl. 
     
     
         209 . The method of  claim 208 , wherein R 4a  is —CH 3 . 
     
     
         210 . The method of  claim 209 , wherein R 4b  is hydrogen. 
     
     
         211 . The method of  claim 210 , wherein n is 0. 
     
     
         212 . The method of  claim 211 , wherein R 11  is —N(R 6 ) 2 . 
     
     
         213 . The method of  claim 212 , wherein R 11  is —NH 2 . 
     
     
         214 . The method of  claim 211 , wherein R 11  is —C 1-6 alkyl-N(R 6 ) 2 . 
     
     
         215 . The method of  claim 214 , wherein R 11  is —CH 2 NH 2 . 
     
     
         216 . The method of  claim 206 , wherein the compound is:
 (R)—N-(1-(4-(aminomethyl)benzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;   or a pharmaceutically acceptable salt thereof.   
     
     
         217 . The method of  claim 206 , wherein the compound is:
 (R)—N-(1-(4-(aminomethyl)benzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide hydrochloride salt.   
     
     
         218 . The method of  claim 206 , wherein the compound is:
 (R)—N-(1-(4-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;   or a pharmaceutically acceptable salt thereof.   
     
     
         219 . The method of  claim 206 , wherein the compound is:
 (R)—N-(1-(4-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide hydrochloride salt.   
     
     
         220 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         n is 1 or 2; 
         A is —N═ or —C(R 3 )═; 
         B is —O—, —N(R 4 )—, or —S(O) t  (where t is 0, 1 or 2)-; 
         E is —N═ or —C(R 3 )═; 
         R 1  is R 5 —C(O)N(R 6 )—, R 7 —N(R 6 )C(O)—, R 5 —N(R 6 )C(O)N(R 6 )—, or R 5 —N(R 6 )C(═NR 6 )N(R 6 )—; 
         each R 2  is independently hydrogen, alkyl, halo, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; 
         or two R 2 , together with the adjacent carbons to which they are attached, form a fused optionally substituted 6-membered N-heterocyclyl; 
         each R 3  is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; 
         R 4  is hydrogen, alkyl, haloalkyl, optionally substituted aryl or optionally substituted aralkyl; 
         or R 4 , together with the nitrogen to which it is attached, and a R 2 , together with the adjacent carbon to which it is attached, together form a fused 6-membered N-heterocyclyl of the following structure: 
       
       
         
           
           
               
               
           
         
         
           where   indicates the point of fusion and R 4a , R 4b , R 4c , and R 4d  are each independently hydrogen, alkyl, halo or haloalkyl or R 4a  and R 4b , together with the carbon to which they are both attached, form a cycloalkyl or R 4c  and R 4d , together with the carbon to which they are both attached, form a cycloalkyl, and the remaining R 2 , if present, is selected from hydrogen, alkyl, halo or haloalkyl; 
         
         R 5  is optionally substituted aryl or optionally substituted N-heteroaryl; 
         each R 6  is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl or optionally substituted aralkyl; 
         R 7  is optionally substituted aryl or optionally substituted N-heteroaryl when E is —N═; 
         or R 7  is a monocyclic N-heteroaryl substituted with an optionally substituted aralkyl when E is —C(R 3 )═ and one R 2  is halo, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; 
         or R 7  is a monocyclic N-heteroaryl substituted with an optionally substituted aralkyl when E is —C(R 3 )═ and one of R 4a  and R 4b  is not methyl and the other is not hydrogen; 
         or R 7  is a monocyclic N-heteroaryl substituted with an optionally substituted aralkyl when E is —C(R 3 )═ and two of R 4a , R 4b , R 4c , and R 4d  on adjacent carbons are not both methyl and the other two are not both hydrogen; 
         or R 7  is a monocyclic N-heteroaryl substituted with an optionally substituted aralkyl when E is —C(R 3 )═ and R 4a  and R 4b , together with the carbon to which they are both attached, form a cycloalkyl or R 4c  and R 4d , together with the carbon to which they are both attached, form a cycloalkyl; 
         or R 7  is a monocyclic N-heteroaryl substituted by an aralkyl substituted with halo, haloalkyl, —CN, —NO 2 , —N(R 6 ) 2 , —N(R 6 )C(O)OR 6 , —C(O)R 6 , —C(O)OR 6  or —C(O)N(R 6 ) 2  when E is —C(R 3 )═ and R 4a  is methyl and R 4b , R 4c , and R 4d  are each hydrogen or when E is —C(R 3 )═ and R 4a  and R 4c  are each methyl and R 4b  and R 4d  are each hydrogen; 
         or R 7  is a monocyclic N-heteroaryl substituted with optionally substituted N-heterocyclylalkyl when E is —C(R 3 )═; 
         as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof; 
         or a pharmaceutically acceptable salt, solvate, or prodrug thereof.