Compounds modulating c-fms and/or c-kit activity and uses therefor

Abstract

Compounds active on the receptor protein tyrosine kinases c-kit and/or c-fms are provided herewith. Also provided herewith are compositions useful for treatment of c-kit mediated diseases or conditions and/or c-fms-mediated diseases or conditions, and methods for the use thereof.

What is claimed is: 
     
         1 . A compound having the chemical structure of Formula II, 
       
         
           
           
               
               
           
         
       
       all salts, prodrugs, tautomers, and isomers thereof, 
       wherein:
 D has a structure selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         
           in which 
         
       
       
         
           
           
               
               
           
         
       
       indicates the attachment point of D to A 2  of Formula II;
 A 2  is selected from the group consisting of —CR 19 R 20 —, —C(O)—, —C(S)—, —S—, —S(O)—, —S(O) 2 —, —NR 21 —, and —O—, provided, however, that when A 2  is NR 21 , N is not bound to a nitrogen of D; 
 B is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —NH 2 , —NO 2 , —CN, —NHC(O)NH 2 , —NHC(S)NH 2 , —NHS(O) 2 NH 2 , —C(O)NH 2 , —C(S)NH 2 , —S(O) 2 NH 2 , —NR 24 R 25 , —NHR 23 , —OR 23 , —SR 23 , —C(O)R 23 , —C(S)R 23 , —S(O)R 23 , —S(O) 2 R 23 , —C(O)NHR 23 , —C(O)NR 23 R 23 , —C(S)NHR 23 , —C(S)NR 23 R 23 , —S(O) 2 NHR 23 , —S(O) 2 NR 23 R 23 , —NHC(O)R 23 , —NR 23 C(O)R 23 , —NHC(S)R 23 , —NR 23 C(S)R 23 , —NHS(O) 2 R 23 , —NR 23 S(O) 2 R 23 , —NHC(O)NHR 23 , —NR 23 C(O)NH 2 , —NR 23 C(O)NHR 23 , —NHC(O)NR 23 R 23 , —NR 23 C(O)NR 23 R 23 , —NHC(S)NHR 23 , —NR 23 C(S)NH 2 , —NR 23 C(S)NHR 23 , —NHC(S)NR 23 R 23 , —NR 23 C(S)NR 23 R 23 , —NHS(O) 2 NHR 23 , —NR 23 S(O) 2 NH 2 , —NR 23 S(O) 2 NHR 23 , —NHS(O) 2 NR 23 R 23 , and —NR 23 S(O) 2 NR 23 R 23 ; 
 M 4  is —NR 39 CH 2 —, —NR 39 CH(R 40 )—, —NR 39 CH 2 CH 2 —, or —NR 39 C(O)—; 
 M 5 , M 6 , M 7 , M 9 , M 10 , M 11 , M 12 , M 13 , M 14 , M 15  M 16 , M 17  and M 18  are selected from the group consisting of a bond, —(CR 19 R 20 ) u —, —(CR 19 R 20 ) t —C(O)—(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —C(S)—(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —C(O)O—(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —C(S)O—(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —C(O)NR 26 —(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —C(S)NR 26 —(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —S(O)—(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —S(O) 2 —(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —S(O) 2 NR 26 —(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —O—(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —OC(O)—(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —OC(S)—(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —OC(O)NR 26 —(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —OC(S)NR 26 —(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —S—(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —NR 26 —(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —NR 26 C(O)—(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —NR 26 C(S)—(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —NR 26 C(O)O—(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —NR 26 C(S)O—(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —NR 26 C(O)NR 26 —(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —NR 26 C(S)NR 26 —(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —NR 26 S(O) 2 —(CR 19 R 20 ) s —, and —(CR 19 R 20 ) t —NR 26 S(O) 2 NR 26 —(CR 19 R 20 ) s —; 
 M 8  is selected from the group consisting of a bond, —(CR 19 R 20 ) u —, —(CR 19 R 20 ) t —C(O)O—(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —C(S)—(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —C(O)O—(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —C(S)O—(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —C(O)NR 26 —(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —C(S)NR 26 —(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —S(O)—(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —S(O) 2 —(CR 19 R 20 ) s —, —(CR 19 R 20 ) t —S(O) 2 NR 26 —(CR 19 R 20 ) s —, —(CR 19 R 20 ) w —O—(CR 19 R 20 ) s —, —(CR 19 R 20 ) w —OC(O)—R(CR 19 R 20 ) s —, —(CR 19 R 20 ) w —OC(S)—(CR 19 R 20 ) s —, —(CR 19 R 20 ) w —OC(O)NR 26 —(CR 19 R 20 ) s —, —(CR 19 R 20 ) w —OC(S)NR 26 —(CR 19 R 20 ) s —, —(CR 19 R 20 ) w —S—(CR 19 R 20 ) s —, —(CR 19 R 20 ) w —NR 26 —(CR 19 R 20 ) s —, —(CR 19 R 20 ) w —NR 26 C(O)—(CR 19 R 20 ) s —, —(CR 19 R 20 ) w —NR 26 C(S)—(CR 19 R 20 ) s —, —(CR 19 R 20 ) w —NR 26 C(O)O—(CR 19 R 20 ) s —, —(CR 19 R 20 ) w —NR 26 C(S)O—)CR 19 R 20 ) s —, —(CR 19 R 20 ) w —NR 26 C(O)NR 26 —(CR 19 R 20 ) s —, —(CR 19 R 20 ) w —NR 26 C(S)NR 26 —(CR 19 R 20 ) s —, —(CR 19 R 20 ) w , —NR 26 S(O) 2 —(CR 19 R 20 ) s —, and —(CR 19 R 20 ) w , —NR 26 S(O) 2 NR 26 —(CR 19 R 20 ) s —; 
 wherein R 19  and R 20  at each occurrence are independently selected from the group consisting of hydrogen, fluoro, —OH, —NH 2 , lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, and —NR 27 R 28 , 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 
 any two of R 19  and R 20  on the same or different carbons combine to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl and any others of R 19  and R 20  are independently selected from the group consisting of hydrogen, fluoro, —OH, —NH 2 , lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, and —NR 27 R 28 , 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, and 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; 
 R 21  is hydrogen or optionally substituted lower alkyl; 
 R 23  at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that no alkene carbon thereof is bound to any —C(O)—, —C(S)—, —S(O)—, —S(O) 2 —, —O—, —S—, or —N— of any of —NHR 23 , —OR 23 , —SR 23 , —C(O)R 23 , —C(S)R 23 , —S(O)R 23 , —S(O) 2 R 23 , —C(O)NHR 23 , —C(O)NR 23 R 23 , —C(S)NHR 23 , —C(S)NR 23 R 23 , —S(O) 2 NHR 23 , —S(O) 2 NR 23 R 23 , —NHC(O)R 23 , —NR 23 C(O)R 23 , —NHC(S)R 23 , —NR 23 C(S)R 23 , —NHS(O) 2 R 23 , —NR 23 S(O)R 23 , —NHC(O)NHR 23 , —NR 23 C(O)NH 2 , —NR 23 C(O)NHR 23 , —NHC(O)NR 23 R 23 , —NR 23 C(O)NR 23 R 23 , —NHC(S)NHR 23 , —NR 23 C(S)NH 2 , —NR 23 C(S)NHR 23 , —NHC(S)NR 23 R 23 , —NR 23 C(S)NR 23 R 23 , —NHS(O)NHR 23 , —NR 23 S(O)NH 23 , —NR 23 S(O) 2 NHR 23 , —NHS(O) 2 NR 23 R 23 , or —NR 33 S(O) 2 NR 23 R 23 , optionally substituted lower alkynyl, provided, however, that no alkyne carbon thereof is bound to any —C(O)—, —C(S)—, —S(O)—, —S(O) 2 —, —O—, —S—, or —N— of any of —NHR 32 , —OR 23 , —SR 23 , —C(O)R 23 , —C(S)R 23 , —S(O)R 23 , —S(O) 2 R 23 , —C(O)NHR 23 , —C(O)NR 23 R 23 , —C(S)NHR 23 , —C(S)NR 23 R 23 , —S(O) 2 NHR 23 , —S(O) 2 NR 23 R 23 , —NHC(O)R 23 , —NR 23 C(O)R 23 , —NHC(S)R 23 , —NR 23 C(S)R 23 , —NHS(O) 2 R 23 , —NR 23 S(O) 2 R 23 , —NHC(O)NHR 23 , —NR 23 C(O)NH 2 , —NR 23 C(O)NHR 23 , —NHC(O)NR 23 R 25 , —NR 23 C(O)NR 23 R 23 , —NHC(S)NHR 23 , —NR 23 C(S)NH 2 , —NR 23 C(S)NHR 23 , —NHC(S)NR 23 R 23 , —NR 23 C(S)NR 23 R 23 , —NHS(O) 2 NHR 23 , —NR 23 S(O) 2 NH 2 , —NR 23 S(O)NHR 23 , —NHS(O) 2 NR 23 R 23 , or —NR 13 S(O) 2 NR 23 R 23 , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
 R 24  and R 25  at each occurrence are independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that no alkene carbon thereof is bound to the nitrogen of —NR 24 R 25 , optionally substituted lower alkynyl, provided, however, that no alkyne carbon thereof is bound to the nitrogen of —NR 24 R 25 , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or 
 R 24  and R 25  together with the nitrogen to which they are attached form a monocyclic 5-7 membered optionally substituted heterocycloalkyl or a monocyclic 5 or 7 membered optionally substituted nitrogen containing heteroaryl; 
 R 26  at each occurrence is independently selected from the group consisting of hydrogen, lower alkyl, and lower alkyl 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 27 R 28 , provided, however, that when R 26  is substituted lower alkyl, any substitution on the lower alkyl carbon bound to the —N— of —NR 26 — is fluoro; 
 R 27  and R 28  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; 
 Q 1  is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NHS(O) 2 R 43 , —NHC(O)R 43 , —NHR 43 , —NR 43 R 43 , —OR 43 , SR 43 , S(O)R 43 , and —S(O) 2 R 43 ; 
 Q 11 , Q 21 , Q 31 , Q 41 , Q 51 , Q 61 , Q 71 , Q 81 , Q 91 , Q 101 , Q 111 , Q 121 , Q 131  and Q 141  are selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; 
 Q 12  is fluoro, chloro or —CF 3 ; 
 Q 13  and Q 14  are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl; 
 Q 22 , Q 24 , Q 32 , Q 33 , Q 43 , Q 44 , Q 52 , Q 54 , Q 102  and Q 104  are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, —NR 44 R 44 , —OR 44 , and —SR 44 , provided, however, that at least one of Q 22  and Q 24 , at least one of Q 32  and Q 33 , at least one of Q 43  and Q 44 , at least one of Q 52  and Q 54 , and at least one of Q 102  and Q 104  is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl; 
 Q 62 , Q 74 , Q 112 , Q 124 , Q 132 , Q 144 ,and Q 152  are hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, —NR 44 R 44 , —OR 44 , or —SR 44 ; 
 Q 64 , Q 72 , Q 82 , and Q 94  are hydrogen, lower alkyl or fluoro substituted lower alkyl; 
 R 43  at each occurrence is independently optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; 
 R 39  is hydrogen or lower alkyl; 
 R 40  is lower alkyl or fluoro substituted lower alkyl; 
 each R 44  is independently hydrogen, lower alkyl or fluoro substituted lower alkyl; 
 w is 1, 2, or 3; 
 u is 1-6; 
 t is 0-3; and 
 s is 0-3; 
 provided, however, that the compound is not