Diarylamine-containing compounds and compositions, and their use as modulators of c-kit receptors

Abstract

Described herein are compounds that include a diarylamine structural feature. Also described herein are methods for making such compounds, methods for using such compounds to modulate the activity of c-kit receptors, and pharmaceutical compositions and medicaments comprising such compounds. Also described herein are methods of using such compounds, pharmaceutical compositions and medicaments to treat and/or prevent and/or inhibit and/or ameliorate the pathology and/or symptomology diseases or conditions associated with the activity of c-kit receptors.

1 . A compound having a structure selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein;
 Q is selected from the group consisting of 
 
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
           Q is selected from the group consisting of 
         
       
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein:
 R A  is selected from —NH 2 , —NEt 2 , and —NH(CH 2 ) n OH, and n is 1 to; 
 R B  is selected from the group consisting of 
 
     
     
       
         
         
             
             
         
       
       
          —CH 2 OH, —CH 2 CH 2 OH, and —CH 2 CH 2 CH 2 OH; 
         R C  is at 2, 3, or 4 position of the piperidine ring; and R C  is selected from the group consisting of —C(O)NHEt, —C(O)NEt 2 , c-butyl, c-pentyl, —C(O)NH-thiazole, oxazole, thiazole, —S(O) 2 NH 2 , —S(O) 2 NHEt, and —S(O) 2 NEt 2 ; 
         each R D  is independently selected from —(CH 2 ) k OH or —(CH 2 ) k CO 2 H, and k is 1 to 6; 
         R E  is at 2, 3, or 4 position of the piperidine ring; and R E  is selected from the group consisting of —C(O)NH 2 , —C(O)NHEt, and —C(O)NEt 2 , and 
         R F  is thiazole, pyrazole, or isoxazole; 
       
       each R 1  is independently selected from the group consisting of H, halogen, and an optionally substituted moiety selected from -L 1 -alkyl, -L 1 -cycloalkyl, -L 1 -heteroalkyl, -L 1 -haloalkyl, -L 1 -aryl, -L 1 -heterocycloalkyl, and -L 1 -heteroaryl; wherein L 1  is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O) 2 —, —C(O)NH(CR″ 2 ) 1-6 C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—; 
       each R 2  is independently selected from the group consisting of H, OH, halogen, and an optionally substituted moiety selected from -L 2 -alkyl, -L 2 -cycloalkyl, -L 2 -heteroalkyl, -L 2 -haloalkyl, -L 2 -aryl, -L 2 -heterocycloalkyl, and -L 2 -heteroaryl; wherein L 2  is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O) 2 —, —C(O)NR″(CR″ 2 ) 1-6 C(O)O—, —OC(O)—, —CR″ 2 NR″CR″ 2 C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—; wherein said optional substituents are selected from halogen, OH, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl and halo-C 1-6 alkoxy; 
       each R″ is independently H, OH, halogen, C 1-6 alkyl, substituted C 1-6 alkyl, C 1-6 alkoxy, halo-C 16 alkyl, halo-C 1-6 alkoxy, aryl, haloaryl, or heteroaryl; 
       or any two adjacent R 2  groups together may form an optionally substituted 6 to 8-membered heterocyclic, cycloalkyl, or aryl ring; 
       R 5  is selected from the group consisting of hydrogen and C 1-6 alkyl; 
     
     or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof. 
   
   
       2 . The compound of  claim 2 , wherein L 2  is selected from a bond, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O) 2 —, —C(O)NH(CR″ 2 ) 1-6 C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—. 
   
   
       3 . The compound of  claim 2 , wherein each R 1  is H. 
   
   
       4 . The compound of  claim 2 , wherein R 5  is H. 
   
   
       5 . A compound selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein;
 each R 2  is independently selected from the group consisting of H, OH, halogen, and an optionally substituted moiety selected from -L 2 -alkyl, -L 2 -cycloalkyl, -L 2 -heteroalkyl, -L 2 -haloalkyl, -L 2 -aryl, -L 2 -heterocycloalkyl, and -L 2 -heteroaryl; wherein L 2  is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O) 2 —, —C(O)NR″ (CR″ 2 ) 1-6 C(O)O—, —OC(O)—, —CR″ 2 NR″CR″ 2 C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—; wherein said optional substituents are selected from halogen, OH, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl and halo-C 1-6 alkoxy; 
 each R″ is independently H, OH, halogen, C 1-6 alkyl, substituted C 1-6 alkyl, C 1-6 alkoxy, halo-C 16 alkyl, halo-C 1-6 alkoxy, aryl, haloaryl, or heteroaryl; 
 or any two adjacent R 2  groups together may form an optionally substituted 5 to 8-membered heterocyclic, cycloalkyl, or aryl ring; 
 each of R 3  and R 4  is independently an optionally substituted moiety selected from -Z, -L 3 -Z, -L 3 -H, -L 3 -alkyl, -L 3 -cycloalkyl, -L 3 -heteroalkyl, -L 3 -haloalkyl, -L 3 -aryl, -L 3 -heterocycloalkyl, and -L 3 -heteroaryl; wherein L 3  is selected from a bond, —C(S)—, —C(O)O—, —C(O)NR″′, —(CR″ 2 ) 1-6 —, —CR′″ 2 S(O)—, —CR′″ 2 S(O) 2 —, —CR′″ 2 S(O)NR′″—, —CR′″ 2 C(O)NR′″—, —(CR′″ 2 ) 1-6 NR′″—, —(CR′″ 2 ) 1-6 O—, —(CR′″ 2 ) 1-6 C(O)O—, —Y 2 C(O)O—, and an optionally substituted C 1-6 alkylene;
 wherein said optional substituents are selected from halogen, —OH, ═O, —Y 3 , C 1-6 alkyl, C 1-6 alkoxy, halogen or OH substituted C 1-6 alkyl, halogen or OH substituted C 1-6 alkoxy, —(CR′″ 2 ) 1-6 C(O)OR 6 , —C(O)NR′″ 2 , —C(O)R 6 , or —C(O)OR 6 ; 
 Y 2  is an optionally substituted cycloalkyl ring or optionally substituted non-aromatic heterocyclic ring;
 wherein said optional substituents are selected from C 1-6 alkyl, halogen, —OH, ═O, and CN. 
 
 Y 3  is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted non-aromatic heterocycle;
 wherein said optional substituents are selected from C 1-6 alkyl, halogen, —OH, ═O, and CN; 
 
 Z is —H, —OH, —CN, —COOR′″, —NR′″ 2 , or —C≡CR′″; 
 each R′″ is independently H, alkyl, or substituted alkyl; 
 or two R′″ together may form a 3-6 membered cycloalkyl or heterocyclic ring; 
 
 or R 3  and R 4  taken together with the N atom to which they are attached may form an optionally substituted 3 to 8-membered heterocyclic ring;
 wherein said optional substituents are selected from halogen, —OH, ═O, —Y 3 , C 1-6 alkyl, C 1-6 alkoxy, halogen or OH substituted C 1-6 alkyl, halogen or OH substituted C 1-6 alkoxy, —(CR′″2) 1-6 Y 4 , —(CR′″2) 1-6 OR 6 , C(O)NR′″R 6 , —C(O)OR 6 , —OR 6 , —NR″′C(O)OR 6 , —NR′″C(O)R 6 , —(CR′″ 2 ) 1-6 C(O)OR 6 , —(CR′″ 2 ) 1-6 NR″′C(O)OR 6 , —(CR″′ 2 ) 1-6 NR 7 R 8 , —S(O) 2 NR′″2, —C(O)R 6 , —OC(O)R 6 , —NR 7 R 8 , —(CR′″ 2 ) 1-6 C(O)NR 7 R 8 , —S(O) 2 R A , or —C(O)R A ; 
 Y 4  is aryl, heteroaryl, cycloalkyl, or non-aromatic heterocycle; 
 R A  is selected from —NH 2 , —NEt 2 , and —NH(CH 2 ) 1-6 OH; 
 R 6  is H, alkyl, substituted alkyl, cycloalkyl, non-aromatic heterocycle, aryl, or heteroaryl; 
 each of R 7  and R 8  is independently H, OH, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, or halo-C 1-6 alkoxy; 
 or R 7  and R 8  taken together with the N atom to which they are attached may form a 3 to 6-membered heterocyclic ring; 
 
 T 1  is an optionally substituted moiety selected from -L 4 -, -alkylene-L 4 -, -L 4 -alkylene-, -L 4 -cycloalkylene-, -L 4 -heteroalkylene-, -L 4 -haloalkylene-, -L 4 -arylene-, -L 4 -heteroarylene-, and -L 4 -heterocycloalkylene-; wherein L 4  is selected from a bond, —O—, —NH—, —S—, —CR″ 2 —, —NR″′C(O)—, —C(O)—, —C(S)—, —C(O)O—, —C(O)NR′″—, —S(O)—, —S(O) 2 —, —OC(O)—, —C(O)NR′″(CR″ 2 ) 1-6 C(O)O—, —C(O)NR′″(CR″ 2 ) 1-6 C(O)—, —CR″ 2 NR″′CR″ 2 C(O)O—, —C(O)NR′″NR″′C(O)O—, —C(O)NR″′(CR″ 2 ) 1-6 —, —CR″ 2 C(O)—, and —S(O)NH—;
 wherein said optional substituents are selected from halogen, OH, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, aryl, haloaryl, and heteroaryl; 
 
 R 5  is selected from the group consisting of hydrogen and C 1-6 alkyl; 
 
       or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof. 
     
   
   
       6 . The compound of  claim 5 , wherein L 2  is selected from a bond, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O) 2 —, —C(O)NH(CR″ 2 ) 1-6 C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—. 
   
   
       7 . The compound of  claim 5 , wherein:
 each of R 3  and R is independently an optionally substituted moiety selected from -L 3 -alkyl, -L 3 -cycloalkyl, -L 3 -heteroalkyl, -L 3 -haloalkyl, -L 3 -aryl, -L 3 -heterocycloalkyl, and -L 3 -heteroaryl; wherein L 3  is selected from a bond, —C(S)—, —C(O)O—, —C(O)NH—, —CR′″ 2 S(O)—, —CR′″ 2 S(O) 2 —, and —CR′″ 2 S(O)NH—; wherein said optional substituents are selected from halogen, OH, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, aryl, haloaryl, and heteroaryl;   or R 3  and R 4  together may form an optionally substituted 3 to 8-membered heterocyclic ring; wherein said optional substituents are selected from halogen, OH, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, aryl, haloaryl, heteroaryl.   
   
   
       8 . The compound of  claim 5 , wherein:
 T 1  is an optionally substituted moiety selected from -L 4 -alkylene-, -L 4 -cycloalkylene-, -L 4 -heteroalkylene-, -L 4 -haloalkylene-, -L 4 -arylene-, -L 4 -heteroarylene-, and -L 4 -heterocycloalkylene-; wherein L 4  is selected from a bond, —O—, —NH—, —S—, —CR″ 2 —, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O) 2 —, —C(O)NH(CR″ 2 ) 1-6 C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—.   
   
   
       9 . The compound of  claim 5 , wherein each R 1  is H. 
   
   
       10 . The compound of  claim 5 , wherein R 5  is H.