Compounds and methods for kinase modulation, and indications therefor

Abstract

Compounds of formula I active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases. Formula (I) wherein Ar is optionally substituted heteroaryl; R 2 is hydrogen, lower alkyl or halogen; U is selected from the group consisting of —S(O) 2 —, —C(X)—, —C(X)—N(R 10 )—, and —S(O) 2 —N(R 10 )—; R 3 is optionally substituted lower alkyl, optionally substituted C3.6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and wherein R 1 , R 3 , R 4 , m, L 1 , X R 10 are as described herein.

1 . A compound having the chemical structure of Formula I, 
     
       
         
         
             
             
         
       
     
     or a salt, a prodrug, a tautomer or an isomer thereof, 
     wherein:
 Ar is optionally substituted heteroaryl; 
 R 1  at each occurrence is independently selected from the group consisting of halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —NO 2 , —CN, —O—R 5 , —N(R 5 )—R 6 , —C(X)—N(R 5 )—R 6 , —C(X)—R 7 , —S(O) 2 —N(R 5 )—R 6 , —S(O)—R 7 , —O—C(X)—R 7 , —C(X)—O—R 5 , —C(NH)—N(R 8 )—R 9 , —N(R 5 )—C(X)—R 7 , —N(R 5 )—S(O) 2 —R 7 , —N(R 5 )—C(X)—N(R 5 )—R 6 , and —N(R 5 )—S(O) 2 —N(R 5 )—R 6 ; 
 m is 0, 1, 2, 3, 4 or 5; 
 n is 0, 1 or 2; 
 R 2  is hydrogen, lower alkyl or halogen; 
 L 2  is selected from the group consisting of —S(O) 2 —, —C(X)—, —C(X)—N(R 19 )—, and —S(O) 2 —N(R 10 )—; 
 R 3  is optionally substituted lower alkyl, optionally substituted C 3-6  cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; 
 L 1  is selected from the group consisting of a bond, —N(R 11 )—, —O—, —S—, —C(X)—, —C(R 12 R 13 )—X—, —X—C(R 12 R 13 )—, —C(R 12 R 13 )—N(R 11 )—, —N(R 11 )—C(R 12 R 13 )—, —O—C(X)—, —C(X)—O—, —C(X)—N(R 11 )—, —N(R 11 )—C(X)—, —S(O)—, —S(O) 2 —, —S(O) 2 —N(R 11 )—, —N(R 11 )—S(O) 2 —, —C(NH)—N(R 11 )—, —N(R 11 )—C(NH)—, —N(R 11 )—C(X)—N(R 11 )—, and —N(R 11 )—S(O) 2 —N(R 11 )—; 
 X is O or S; 
 R 4 , R 16  and each R 11  are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, fluoro substituted mono-alkylamino, di-alkylamino, fluoro substituted di-alkylamino, and —NR 14 R 15 ; 
 R 5 , R 6 , R 8 , and R 9  at each occurrence are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted C 3-6  alkenyl, optionally substituted C 3-6  alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or 
 R 8  and R 9  combine with the nitrogen to which they are attached to form a 5-7 membered optionally substituted nitrogen containing heterocycloalkyl or a 5 or 7 membered optionally substituted nitrogen containing heteroaryl; 
 R 7  at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted C 3-6  alkenyl, optionally substituted C 3-6  alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
 R 12  and R 13  are independently selected from the group consisting of hydrogen, fluoro, —OH, —NH 2 , lower alkyl, lower alkoxy, lower alklylthio, mono-alkylamino, di-alkylamino, and —NR 14 R 15 , wherein the alkyl chain(s) of lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; or 
 R 12  and R 13  combine with the carbon to which they are attached to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; and 
 R 14  and R 15  at each occurrence independently combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl or 5-7 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio,
 provided, however, that when L 1  is a bond, —NR 11 —, —O—, —S—, —C(X)—, —S(O)—, or —S(O) 2 —, Ar is not 1H-pyrrolo[2,3-b]pyridine-3-yl, 1H-pyrazolo[3,4-b]pyridine-3-yl, 5H-pyrrolo[2,3-b]pyrazine-7-yl, 7H-pyrrolo[2,3-d]pyrimidine-5-yl, or 7H-pyrrolo[2,3-c]pyridazine-5-yl, i.e. is not 
 
 
     
       
         
         
             
             
         
       
     
     indicates the attachment point to L 1 . 
   
   
       2 . The compound of  claim 1 , wherein L 1  is a bond, —N(R 11 )—, —N(R 11 )—C(X)—, —N(R 11 )—S(O) 2 —, —N(R 11 )—C(NH)—, —N(R 11 )—C(X)—N(R 11 )—, or —N(R 11 )—S(O) 2 —N(R 11 )—, and R 2  is hydrogen, fluoro, or chloro. 
   
   
       3 . The compound of  claim 2 , wherein L 1  is —N(R 11 )—, —N(R 11 )—C(X)—, or —N(R 11 )—S(O) 2 —. 
   
   
       4 . The compound of  claim 3 , wherein L 1  is —N(R 11 )—C(O)—. 
   
   
       5 . The compound of  claim 1 , wherein L 1  is —C(X)—N(R 11 )—, —C(R 12 R 13 )—X—, —X—C(R 12 R 13 )—, —C(R 12 R 13 )—N(R 11 )—, or —N(R 11 )—C(R 12 R 13 )—, and R 2  is hydrogen, fluoro, or chloro. 
   
   
       6 . The compound of  4 , wherein 
     
       
         
         
             
             
         
       
     
     is selected from the group consisting of, 
     
       
         
         
             
             
         
       
     
     indicates the attachment point of the Ar ring to L 1 ;
 p is 0, 1, 2 or 3; 
 R 16  at each occurrence is independently selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —C(O)—OH, —S(O) 2 —NH 2 , —C(O)—NH 2 , —O—R 17 , —S—R 17 , —N(R 19 )—R 17 , —N(R 19 )—C(O)—R 17 , —N(R 19 )—S(O) 2 —R 17 , —S(O) 2 —R 17 , —C(O)—R 17 , —C(O)—O—R 17 , —C(O)—N(R 19 )—R 17 , —S(O) 2 —N(R 19 )—R 17 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 16 , or as substituents of lower alkyl, are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —C(O)—OH, —S(O) 2 —NH 2 , —C(O)—NH 2 , —O—R 18 , —S—R 18 , —N(R 19 )—R 18 , —N(R 19 )—C(O)—R 18 , N(R 19 )—S(O) 2 —R 18 , —S(O) 2 —R 18 , —C(O)—R 18 , —C(O)—O—R 18 , —C(O)—N(R 19 )—R 18 , —S(O) 2 —N(R 19 )—R 18 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; 
 R 17  at each occurrence is independently selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 17  or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —C(O)—OH, —S(O) 2 —NH 2 , —C(O)—NH 2 , —O—R 18 , —S—R 18 , —N(R 19 )—R 18 , —N(R 19 )—(O)—R 18 , —N(R 19 )—S(O) 2 —R 18 , —S(O) 2 —R 18 , —C(O)—R 18 , —C(O)—O—R 18 , —C(O)—N(R 19 )—R 18 , —S(O) 2 —N(R 19 )—R 18 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; 
 R 18  at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; and 
 R 19  at each occurrence is independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio. 
 
   
   
       7 . The compound of  claim 6 , wherein L 2  is —S(O) 2 —. 
   
   
       8 . A composition comprising a pharmaceutically acceptable carrier and a compound according to  claim 4 . 
   
   
       9 . A kit comprising a compound according to  claim 4 . 
   
   
       10 . A kit comprising a composition according to  claim 8 . 
   
   
       11 . A method for treating a subject suffering from or at risk of a Raf mediated disease or condition, comprising administering to the subject an effective amount of a compound of  claim 4 . 
   
   
       12 . A method for treating a subject suffering from or at risk of a Raf mediated disease or condition, comprising administering to the subject an effective amount of a composition according to  claim 8 . 
   
   
       13 . A composition comprising a pharmaceutically acceptable carrier and a compound according to  claim 7 . 
   
   
       14 . A kit comprising a compound according to  claim 7 . 
   
   
       15 . A kit comprising a composition according to  claim 13 . 
   
   
       16 . A method for treating a subject suffering from or at risk of a Raf mediated disease or condition, comprising administering to the subject an effective amount of a compound of  claim 7 . 
   
   
       17 . A method for treating a subject suffering from or at risk of a Raf mediated disease or condition, comprising administering to the subject an effective amount of a composition according to  claim 13 .