Calpain modulators and therapeutic uses thereof

Abstract

Disclosed herein are small molecule calpain modulator compositions, pharmaceutical compositions, the use and preparation thereof.

What is claimed is: 
     
         1 . A compound having the structure selected from the formulas: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         A 2  is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C 3-10  carbocyclyl, —S—, —S(═O)—, —SO 2 —, —C(═S)—, —CH═CH—, —C≡C—, 
         —OC(O)NH—, —NHC(O)NH—, —NHC(O)O—, —NHC(S)NH—, —NHC(S)O—, —NHC(S)—, and single bond; 
         A 4  is selected from the group consisting of optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3-10  carbocyclyl, —(CR 2 ) n —S—(CR 2 ) n —, —(CR 2 ) n —S(═O)—(CR 2 ) n —, —(CR 2 ) n —SO 2 —(CR 2 ) n —, —(CR 2 )nO—(CR 2 ) n —, —(CR 2 ) n —C(═S)—(CR 2 ) n —, —(CR 2 ) n —C(═O)—(CR 2 ) n —, —(CR 2 ) n —CH═CH—(CR 2 ) n —, —(CR 2 ) n —OC(O)NH—(CR 2 ) n —, —(CR 2 ) n —NHC(O)NH—(CR 2 ) n —, —(CR 2 ) n —NHC(O)O—(CR 2 ) n —, —(CR 2 ) n —NHC(S)NH—(CR 2 ) n —, —(CR 2 ) n —NHC(S)O—(CR 2 ) n —, —(CR 2 ) n —NHC(S)—(CR 2 ) n —, and single bond; 
         when A 2  and A 4  are single bond, A 3  is directly attached to the ring-atom to which A 2  is attached; 
         A 3  is selected from the group consisting of optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted C 3-10  carbocyclyl, or if A 2  is selected from optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted C 3-10  carbocyclyl, then A 3  is selected from the group consisting of hydrogen, optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3-10  carbocyclyl, —C≡CH, and optionally substituted 2- to 5-membered polyethylene glycol; 
         A 5  is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C 3-10  carbocyclyl, optionally substituted C 1-8  alkyl, —S—, —S(═O)—, —SO 2 —, —O—, —C(═S)—, —C(═O)—, —NR—, —CH═CH—, —OC(O)NH—, —NHC(O)NH—, —NHC(O)O—, —NHC(O)—, —NHC(S)NH—, —NHC(S)O—, —NHC(S)—, and single bond; 
         A 6  is selected from the group consisting of optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3-10  carbocyclyl, optionally substituted C 1-8  alkyl, optionally substituted C 2-8  alkenyl, optionally substituted —O-C 1-6  alkyl, optionally substituted —O C 2-6  alkenyl, —OSO 2 CF 3 , and any natural or non-natural amino acid side chain; 
         A 7  is selected from the group consisting of optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3-10  carbocyclyl, optionally substituted C 1-8  alkyl, —S—, S(═O)—, —SO 2 —, —O—, —C(═S)—, —C(═O)—, —NR—, —CH═CH—, —OC(O)NH—, —NHC(O)NH—, —NHC(O)O—, —NHC(O)—, —NHC(S)NH—, —NHC(S)O—, —NHC(S)—, and single bond; 
         when A 5  and A 7  are single bond, A 6  is directly attached to the carbon to which 
         —COR 1  is attached; 
         R 1  is selected from the group consisting of H, —COOH, —CH 2 NO 2 , —C(═O)NOR, —CONR 2 R 3 , —CH(CH 3 )═CH 2 , —CH(CF 3 )NR 2 R 3 , 
         —C(F)═CHCH 2 CH 3 , 
       
       
         
           
           
               
               
           
         
         R 14  is halo; 
         each R, R 2 , and R 3  are independently selected from —H, optionally substituted C 1-4  alkyl, optionally substituted C 1-8  alkoxyalkyl, optionally substituted 2- to 5-membered polyethylene glycol, optionally substituted C 3-7  carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C 6-10  aryl, optionally substituted C 6-10  aryl(C 1 -C 6 )alkyl, and optionally substituted 5-10 membered heteroaryl; 
         R 6  is independently selected from —H and optionally substituted C 1-4  alkyl; 
         each n is independently selected to be an integer from 0 to 3; 
         A, B, D, X, and Z are each independently selected from the group consisting of C(R 4 ) and N; 
         each R 4  is independently selected from the group consisting of —H, C 1-4  alkyl, C 1-4  haloalkyl, C 3-7  carbocyclyl (optionally substituted with halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkoxy), halo, hydroxy, and C 1 -C 6  alkoxy; 
         Y is selected from the group consisting of NR 5 , O, S, and SO 2 ; 
         R 5  is selected from the group consisting of —H, C 1-4  alkyl, C 1-4  haloalkyl, and C 3-7  carbocyclyl (optionally substituted with halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkoxy); and 
         when the structure is of formula I-m, E is selected from the group consisting of an optionally substituted C 5-6  carbocyclyl and an optionally substituted 5- to 6-membered heterocyclyl; and 
         when the structure is of formula I-n, E is selected from the group consisting of an optionally substituted C 5-6  carbocyclyl, an optionally substituted 5- to 6-membered heterocyclyl, an optionally substituted 5- to 6-membered heteroaryl, and an optionally substituted phenyl. 
       
     
     
         2 . The compound of  claim 1 , wherein:
 A 2  is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C 3-10  carbocyclyl, —S—, —S(═O)—, —SO 2 —, —C(═S)—, —CH═CH—, —OC(O)NH—, —NHC(O)NH—, —NHC(O)O—, —NHC(S)NH—, —NHC(S)O—, —NHC(S)—, and single bond;   A 4  is selected from the group consisting of optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3-10  carbocyclyl, —S—, S(═O)—, —SO 2 —, —O—, —C(═S)—, —C(═O)—, —CH═CH—, —OC(O)NH—, —NHC(O)NH—, —NHC(O)O—, —NHC(S)NH—, —NHC(S)O—, —NHC(S)—, and single bond;   A 3  is selected from the group consisting of optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted C 3-10  carbocyclyl;   A 6  is selected from the group consisting of optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3-10  carbocyclyl, optionally substituted C 1-8  alkyl, optionally substituted —O-C 1-6  alkyl, optionally substituted —O C 2-6  alkenyl, and any natural or non-natural amino acid side chain; and   each R, R 2 , and R 3  are independently selected from —H, optionally substituted C 1-4  alkyl, optionally substituted C 3-7  carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C 6-10  aryl, and optionally substituted 5-10 membered heteroaryl.   
     
     
         3 . The compound of  claim 1 , having the structure of formula I-a; wherein A, B, and D are independently selected from the group consisting of CH and N. 
     
     
         4 . The compound of  claim 3 , wherein A is N, B is CH, and D is CH. 
     
     
         5 . The compound of  claim 3 , wherein A is CH, B is N, and D is CH. 
     
     
         6 . The compound of  claim 3 , wherein A is N, B is N, and D is N. 
     
     
         7 . The compound of  claim 1 , having the structure of formula I-b; wherein A, B, and D are independently selected from the group consisting of CH and N. 
     
     
         8 . The compound of  claim 1 , having the structure of formula I-c; wherein X and Z are independently selected from the group consisting of CH and N. 
     
     
         9 . The compound of  claim 1 , having the structure of formula I-d; wherein X and Z are independently selected from the group consisting of CH and N 
     
     
         10 . The compound of  claim 1 , having the structure of formula I-e; wherein X and Z are independently selected from the group consisting of CH and N. 
     
     
         11 . The compound of  claim 1 , wherein Z is N, Y is NR 5 , and X is CH. 
     
     
         12 . The compound of  claim 11 , wherein R 5  is selected from the group consisting of —H, C 1-4  alkyl, C 1 -C 4  haloalkyl, and cyclopropyl. 
     
     
         13 . The compound of  claim 1 , wherein Z is N, Y is O, and X is C(R 4 ). 
     
     
         14 . The compound of  claim 1 , wherein Z is N, Y is S, and X is C(R 4 ). 
     
     
         15 . The compound of  claim 1 , wherein Z is C(R 4 ), Y is S, and X is C(R 4 ). 
     
     
         16 . The compound of  claim 1 , wherein Z is C(R 4 ), Y is O, and X is C(R 4 ). 
     
     
         17 . The compound of  claim 1 , wherein Z is N, Y is S, and X is N. 
     
     
         18 . The compound of  claim 1 , wherein Z is N, Y is O, and X is N. 
     
     
         19 . The compound of  claim 1 , having the structure of formula I-g; wherein X and Z are independently selected from the group consisting of CH and N. 
     
     
         20 . The compound of  claim 1 , having the structure of formula I-g; wherein Y is NR 5 , Z is N, and X is CH. 
     
     
         21 . A compound having the structure of formula I-k: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         A 2  is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C 3-10  carbocyclyl, —S—, —S(═O)—, —SO 2 —, —C(═S)—, —CH═CH—, —C≡C—, —OC(O)NH—, —NHC(O)NH—, —NHC(O)O—, —NHC(S)NH—, —NHC(S)O—, —NHC(S)—, and single bond; 
         A 4  is selected from the group consisting of optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3-10  carbocyclyl, —(CR 2 ) n —S—(CR 2 ) n —, —(CR 2 ),—S(═O)—(CR 2 ) n —, —(CR 2 ) n —SO 2 —(CR 2 ) n —, —(CR 2 ) n —O—(CR 2 ) n —, —(CR 2 ) n —C(═S)—(CR 2 ) n —, —(CR 2 ) n —C(═O)—(CR 2 ) n —, —(CR 2 ) n —CH═CH-(CR 2 ) n —, —(CR 2 ) n —OC(O)NH—(CR 2 ) n —, —(CR 2 ) n —NHC(O)NH—(CR 2 ) n —, —(CR 2 ) n —NHC(O)O—(CR 2 ) n —, —(CR 2 ) n —NHC(S)NH—(CR 2 ) n —, —(CR 2 ) n —NHC(S)O—(CR 2 ) n —, —(CR 2 ) n —NHC(S)—(CR 2 ) n —, and single bond; 
         when A 2  and A 4  are single bond, A 3  is directly attached to the ring nitrogen; 
         A 3  is selected from the group consisting of optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted C 3-10  carbocyclyl, or if A 2  is selected from optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted C 3-10  carbocyclyl, then A 3  is selected from the group consisting of hydrogen, optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3-10  carbocyclyl, —C═CH, and optionally substituted 2- to 5-membered polyethylene glycol; 
         A 5  is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C 3-10  carbocyclyl, optionally substituted C 1-8  alkyl, —S—, —S(═O)—, —SO 2 —, —O—, —C(═S)—, —C(═O)—, —NR—, —CH═CH—, —OC(O)NH—, —NHC(O)NH—, —NHC(O)O—, —NHC(O)—, —NHC(S)NH—, —NHC(S)O—, —NHC(S)—, and single bond; 
         A 6  is selected from the group consisting of optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3-10  carbocyclyl, optionally substituted C 1-8  alkyl, optionally substituted C 2-8  alkenyl, optionally substituted —O-C 1-6  alkyl, optionally substituted —O C 2-6  alkenyl, —OSO 2 CF 3 , and any natural or non-natural amino acid side chain; 
         A 7  is selected from the group consisting of optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3-10  carbocyclyl, optionally substituted C 1-8  alkyl, —S—, S(═O)—, —SO 2 —, —O—, —C(═S)—, —C(═O)—, —NR—, —CH═CH—, —OC(O)NH—, —NHC(O)NH—, —NHC(O)O—, —NHC(O)—, —NHC(S)NH—, —NHC(S)O—, —NHC(S)—, and single bond; 
         when A 5  and A 7  are single bond, A 6  is directly attached to the carbon to which COR 1  is attached; 
         R 1  is selected from the group consisting of H, —COOH, —CH 2 NO 2 , —C(═O)NOR, —CONR 2 R 3 , —CH(CH 3 )═CH 2 , —CH(CF 3 )NR 2 R 3 , 
         —C(F)═CHCH 2 CH 3 , 
       
       
         
           
           
               
               
           
         
         R 14  is halo; 
         each R, R 2 , and R 3  are independently selected from —H, optionally substituted C 1-4  alkyl, optionally substituted C 1-8  alkoxyalkyl, optionally substituted 2- to 5-membered polyethylene glycol, optionally substituted C 3-7  carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C 6-10  aryl, optionally substituted C 6-10  aryl(C 1 -C 6 )alkyl, and optionally substituted 5-10 membered heteroaryl; 
         R 6  is independently selected from —H and optionally substituted C 1-4  alkyl; and 
         each n is independently selected to be an integer from 0 to 3; 
         X is selected from the group consisting of C(OR 5 ), C(R 4 ), and N; 
         R 4  is selected from the group consisting of —H, C 1-4  alkyl, C 1-4  haloalkyl, C 3-7  carbocyclyl (optionally substituted with halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkoxy), halo, hydroxy, and C 1 -C 6  alkoxy; and 
         R 5  is selected from the group consisting of —H, C 1-4  alkyl, C 1-4  haloalkyl, and C 3-7  carbocyclyl (optionally substituted with halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkoxy). 
       
     
     
         22 . The compound of  claim 21 , wherein X is independently selected from the group consisting of CH and N. 
     
     
         23 . The compound of  claim 1 , wherein at least one of the optionally substituted moieties of A 2 , A 4 , and A 3  is substituted with  18 F. 
     
     
         24 . The compound of  claim 1 , wherein at least one of the optionally substituted moieties of A 2 , A 4 , and A 3  is substituted with C 1 -C 6  alkyl containing one or more  11 C. 
     
     
         25 . The compound of  claim 1 , wherein A 3  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       and p 1  A 9  is selected from the group consisting of H, C 6-10  aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, and C 3-10  carbocyclyl, C 1-4  alkyl;
 X 2 , X 1 , and Z are each independently selected from the group consisting of C(R 4 ) and N; 
 Y 1  is selected from the group consisting of NR 5 , O, and S; 
 J, L, M 1  and M 2  are each independently selected from the group consisting of C(R 4 ) and N; 
 R 4  is selected from the group consisting of —H, C 1-4  alkyl, C 1-4  haloalkyl, C 3-7  carbocyclyl (optionally substituted with halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkoxy), halo, hydroxy, and C 1 -C 6  alkoxy; 
 R 5  is selected from the group consisting of —H, C 1-4  alkyl, C 1-4  haloalkyl, and C 3-7  carbocyclyl (optionally substituted with halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkoxy). 
 
     
     
         26 . The compound of  claim 1 , wherein A 3  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         27 . The compound of  claim 1 , wherein A 3  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         28 . The compound of  claim 1  wherein A 2  is selected from the group consisting of single bond, —CH═CH—, —S—, and phenyl. 
     
     
         29 . The compound of  claim 1 , wherein A 2  is a single bond, A 4  is a single bond, and A 3  is an optionally substituted C 6-10  aryl or an optionally substituted 5-10 membered heteroaryl. 
     
     
         30 . The compound of  claim 29 , wherein A 3  has the structure: 
       
         
           
           
               
               
           
         
       
       wherein
 J, L, M 1 , M 2 , and M 3  are each independently selected from the group consisting of C(R 4 ) and N; and 
 each R 4  is independently selected from the group consisting of —H, C 1-4  alkyl, C 1-4  haloalkyl, C 3-7  carbocyclyl (optionally substituted with halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkoxy), halo, hydroxy, and C 1 -C 6  alkoxy. 
 
     
     
         31 . The compound of  claim 30 , wherein each of J, L, M 1 , M 2 , and M 3  are C(R 4 ). 
     
     
         32 . The compound of  claim 31 , wherein each R 4  is independently selected from —H and halo. 
     
     
         33 . The compound of  claim 30 , wherein M 1  is C(R 4 ); R 4  is halo and each of J, L, M 2 , and M 3  are CH. 
     
     
         34 . The compound of  claim 30 , wherein L is C(R 4 ); R 4  is halo and each of J, M 1 , M 2 , and M 3  are CH. 
     
     
         35 . The compound of  claim 29 , wherein A 3  has a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein
 J, L, M 1 , M 2 , M 3 , M 4 , and M 5  are each independently selected from the group consisting of C(R 4 ) and N; and 
 each R 4  is independently selected from the group consisting of —H, C 1-4  alkyl, C 1-4  haloalkyl, C 3-7  carbocyclyl (optionally substituted with halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkoxy), halo, hydroxy, and C 1 -C 6  alkoxy. 
 
     
     
         36 . The compound of  claim 29 , wherein A 3  has the structure: 
       
         
           
           
               
               
           
         
       
       wherein
 X is selected from the group consisting of C(R 4 ) and N; 
 Y is selected from O and S; and 
 R 4  is selected from the group consisting of —H, C 1-4  alkyl, C 1-4  haloalkyl, C 3-7  carbocyclyl (optionally substituted with halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkoxy), halo, hydroxy, and C 1 -C 6  alkoxy. 
 
     
     
         37 . A compound having the structure of formula I-o: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Y is selected from the group consisting of NR 5 , O, S, and SO 2 ; 
         X 1  is selected from the group consisting of C(R 4 ) and N; 
         J, L, M 1 , M 2 , and M 3  are each independently selected from the group consisting of C(R 4 ) and N; 
         A 5  is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C 3-10  carbocyclyl, optionally substituted C 1-8  alkyl, —S—, —S(═O)—, —SO 2 —, —O—, —C(═S)—, —C(═O)—, —NR—, —CH═CH—, —OC(O)NH—, —NHC(O)NH—, —NHC(O)O—, —NHC(O)—, —NHC(S)NH—, —NHC(S)O—, —NHC(S)—, and single bond; 
         A 6  is selected from the group consisting of optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3-10  carbocyclyl, optionally substituted C 1-8  alkyl, optionally substituted C 2 -8 alkenyl, optionally substituted —O-C 1-6  alkyl, optionally substituted —O C 2-6  alkenyl, —OSO 2 CF 3 , and any natural or non-natural amino acid side chain; 
         A 7  is selected from the group consisting of optionally substituted C 6-10  aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3-10  carbocyclyl, optionally substituted C 1-8  alkyl, —S—, S(═O)—, —SO 2 —, —O—, —C(═S)—, —C(═O)—, —NR—, —CH═CH—, —OC(O)NH—, —NHC(O)NH—, —NHC(O)O—, —NHC(O)—, —NHC(S)NH—, —NHC(S)O—, —NHC(S)—, and single bond; 
         when A 5  and A 7  are single bond, A 6  is directly attached to the carbon to which R 6  is attached; 
         R 4  is selected from the group consisting of —H, C 1-4  alkyl, C 1-4  haloalkyl, C 3-7  carbocyclyl (optionally substituted with halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkoxy), halo, hydroxy, and C 1 -C 6  alkoxy; 
         R 5  is selected from the group consisting of —H, C 1-4  alkyl, C 1-4  haloalkyl, and C 3-7  carbocyclyl (optionally substituted with halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkoxy); 
         R 1  is selected from the group consisting of H, —COOH, —CH 2 NO 2 , —C(═O)NOR, —CONR 2 R 3 , —CH(CH 3 )═CH 2 , —CH(CF 3 )NR 2 R 3 , 
         —C(F)═CHCH 2 CH 3 , 
       
       
         
           
           
               
               
           
         
         R 14  is halo; 
         each R, R 2 , and R 3  are independently selected from —H, optionally substituted C 1-4  alkyl, optionally substituted C 1-8  alkoxyalkyl, optionally substituted 2- to 5-membered polyethylene glycol, optionally substituted C 3-7  carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C 6-10  aryl, optionally substituted C 6-10  aryl(C 1 -C 6 )alkyl, and optionally substituted 5-10 membered heteroaryl; 
         R 6  is independently selected from —H and optionally substituted C 1-4  alkyl; and each n is independently selected to be an integer from 0 to 3. 
       
     
     
         38 . The compound of  claim 37 , wherein J, L, M 1 , M 2 , and M 3  are independently selected from the group consisting of CH and N. 
     
     
         39 . The compound of  claim 1 , wherein at least one of the optionally substituted moieties of A 5 , A 7 , and A 6  is substituted with  18 F. 
     
     
         40 . The compound of  claim 1 , wherein at least one of the optionally substituted moieties of A 5 , A 7 , and A 6  is substituted with C 1 -C 6  alkyl containing one or more  11 C. 
     
     
         41 . The compound of  claim 1 , wherein A 6  is phenyl. 
     
     
         42 . The compound of  claim 1 , wherein A 7  is selected from the group consisting of single bond, —CH 2 —, O, —CH═CH—, and —S. 
     
     
         43 . The compound of  claim 1 , wherein A 7  is selected from the group consisting of single bond, optionally substituted C 6-10  aryl, and phenyl. 
     
     
         44 . The compound of  claim 1 , wherein A 5  is —CH 2 —. 
     
     
         45 . The compound of  claim 1 , wherein A 5  is —CH 2 — or —CH 2 CH 2 —; A 7  is a single bond; and A 6  is selected from the group consisting of C 1 -C 4  alkyl, optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl. 
     
     
         46 . The compound of  claim 45 , wherein A 6  is selected from the group consisting of optionally substituted phenyl, phenyl and phenyl optionally substituted with one or more C 1-4  alkyl, C 3-7  carbocyclyl, halo, hydroxy, and C 1 -C 6  alkoxy. 
     
     
         47 . The compound of  claim 45 , wherein A 6  has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         48 . The compound of  claim 1 , wherein A 5  is a single bond, A 7  is a single bond; and A 6  is C 1 -C 5  alkyl. 
     
     
         49 . The compound of  claim 48 , wherein A 6  is selected from the group consisting of ethyl, n-propyl, isopropyl, isobutyl, 2,2-dimethylpropyl, and 1,2-dimethylpropyl. 
     
     
         50 . The compound of  claim 1 , wherein R 1  is CONR 2 R 3 . 
     
     
         51 . The compound of  claim 50 , wherein R 2  is —H and R 3  is optionally substituted C 1-4  alkyl. 
     
     
         52 . The compound of  claim 50 , wherein R 2  is —H and R 3  is selected from the group consisting of —H, C 1 -C 4  alkyl optionally substituted with C-amido, and C 3 -C 6  cycloalkyl. 
     
     
         53 . The compound of  claim 52 , wherein R 3  is selected from the group consisting of —H, ethyl, cyclopropyl, and methyl substituted with C-amido. 
     
     
         54 . The compound of  claim 50 , wherein R 3  is selected from the group consisting of optionally substituted C 1-4  alkyl and benzyl. 
     
     
         55 . The compound of  claim 1 , wherein R 6  is selected from the group consisting of —H, methyl, and optionally substituted C 1-4  alkyl. 
     
     
         56 . A compound having the structure selected from the group consisting of:
 compounds 1 to 94, compounds 96 to 235, compounds 238 to 274, compounds 276 to 299, compounds 303 to 411, compounds 413 to 424, compounds 428 to 445, compound 447, compound 448, compounds 454 to 532, compounds 540-541, compounds 546 to 588, compounds 591 to 605, compounds 607 to 611, compounds 613 to 630, and pharmaceutically acceptable salts thereof.   
     
     
         57 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         58 . A method of treating fibrotic disease or a secondary disease state or condition thereof, comprising administering to a subject in need thereof, a compound according to  claim 1 . 
     
     
         59 . The method of  claim 58 , wherein the disease is selected from the group consisting of liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis.