Anti-Inflammatory And Antioxidant Conjugates Useful For Treating Metabolic Disorders

Abstract

The present invention is directed to methods for treating metabolic disorders with compounds that are conjugates. The conjugates of the present invention are comprised of salicylic acid, triflusal, diflusinal, salsalate, IMD-0354, ibuprofen, diclofenac, licofelone, or HTB, and one or more antioxidants.

We claim: 
     
         1 . A method for treating metabolic disorders that includes type I diabetes, type II diabletes, Latent Autoimmune Diabetes of Adulthood (LADA), hyperglycemia, elevated free fatty acids, elevated triglycerides, insulin resistance, and beta cell protection in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R 1  is hydrogen, (C 1 -C 6 )alkylcarbonyl, or A; 
 R 2 , R 3 , R 4 , and R 5  are independently hydrogen, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxysulfonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylcarbonyloxy, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, formyl, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halogen, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, phenyl, —NZ 1 Z 2 , or (NZ 1 Z 2 )carbonyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxysulfonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylcarbonyloxy, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, formyl, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halogen, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, phenyl, —NZ 3 Z 4 , (NZ 3 Z 4 )carbonyl; 
 Z 1 , Z 2 , Z 3 , and Z 4  are independently hydrogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylcarbonyl; 
 R 6  is hydroxy, —NZ 5 Z 6 , 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         provided that when R 6  is hydroxy, then R 1  is A; 
         Z 5  and Z 6  are independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, phenyl, phenyl(CH 2 )—, or phenyl(CH 2 ) 2 —, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxysulfonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylcarbonyloxy, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, formyl, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halogen, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, phenyl, —NZ 7 Z 8 , or (NZ 7 Z 8 )carbonyl; 
         Z 7  and Z 8  are independently hydrogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylcarbonyl; 
         R 7  is (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, hydroxy, —NZ 9 Z 10 , or —O-phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylcarbonyloxy, carboxy, cyano, formyl, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halogen, hydroxy, or hydroxy(C 1 -C 6 )alkyl; 
         R 8  is hydrogen or (C 1 -C 6 )alkyl; 
         R 9  is hydrogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylcarbonyl; 
         R 10  is (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, hydroxy, or —NZ 9 Z 10 ; 
         Z 9  and Z 10  are independently hydrogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylcarbonyl; 
         X 1  and X 2  are independently O or S; 
         L is (C 1 -C 6 )alkylene; 
         A is 
       
       
         
           
           
               
               
           
         
         R 1a  is hydrogen, (C 1 -C 6 )alkylcarbonyl, or B; 
         R 2a , R 1a , R 4a , and R 5a  are independently hydrogen, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxysulfonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylcarbonyloxy, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, formyl, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halogen, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, phenyl, —NZ 1a Z 2a , or (NZ 1a Z 2a )carbonyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxysulfonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylcarbonyloxy, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, formyl, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halogen, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, phenyl, —NZ 3a Z 4a , or (NZ 3a Z 4a )carbonyl; 
         Z 1a , Z 2a , Z 3a , and Z 4a  are independently hydrogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylcarbonyl; 
         B is 
       
       
         
           
           
               
               
           
         
         R 1b  is hydrogen, (C 1 -C 6 )alkylcarbonyl, or C; 
         R 2b , R 3b , R 4b , and R 5b  are independently hydrogen, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxysulfonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylcarbonyloxy, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, formyl, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halogen, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, phenyl, —NZ 1b Z 2b , or (NZ 1b Z 2b )carbonyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxysulfonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylcarbonyloxy, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, formyl, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halogen, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, phenyl, —NZ 3b Z 4b , or (NZ 3b Z 4b )carbonyl; 
         Z 1b , Z 2b , Z 3b , and Z 4b  are independently hydrogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylcarbonyl; and 
         C is 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The method according to  claim 1  wherein
 R 1  is hydrogen or acetyl; 
 R 2 , R 3 , R 4 , and R 5  are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl. 
 
     
     
         3 . The method according to  claim 1  wherein
 R 1  is hydrogen or acetyl; 
 R 2 , R 3 , R 4 , and R 5  are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; 
 R 7  is (C 1 -C 6 )alkoxy or hydroxy; 
 R 8  is hydrogen; 
 R 9  is (C 1 -C 6 )alkylcarbonyl; 
 X 1  is S; and 
 L is CH 2 . 
 
     
     
         4 . The method according to  claim 1  wherein
 R 1  is hydrogen or acetyl; 
 R 2 , R 3 , R 4 , and R 5  are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; 
 R 7  is ethoxy, methoxy, or hydroxy; 
 R 8  is hydrogen; 
 R 9  is acetyl; 
 X 1  is S; and 
 L is CH 2 . 
 
     
     
         5 . The method according to  claim 1  wherein
 R 1  is hydrogen or acetyl; 
 R 2 , R 3 , R 4 , and R 5  are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and 
 R 6  is (L) N-acetylcysteine. 
 
     
     
         6 . The method according to  claim 1  wherein the conjugate of Formula (I) is Example 13. 
     
     
         7 . A method of treating metabolic disorders that includes type I diabetes, type II diabletes, Latent Autoimmune Diabetes of Adulthood (LADA), hyperglycemia, elevated free fatty acids, elevated triglycerides, insulin resistance, and beta cell protection in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I) and at least one pharmaceutically acceptable carrier. 
     
     
         8 . The method according to  claim 7  wherein the conjugate of Formula (I) is Example 13. 
     
     
         9 . A compound selected from the group consisting of 
       (a) a compound of Formula (XIII) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R 1  is OR 6  or NR 4 R 5 ; 
 R 2  is H or 2,4-difluorophenyl; 
 R 3  is 
 
       
         
           
           
               
               
           
         
         R 4  and R 5  are independently H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 1 Z 2 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; or R 4  and R 5  together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine, or azepane; 
         R 6  is H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 1 Z 2 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; and 
         Z 1  and Z 2  are independently H or (C 1 -C 6 )alkyl; 
       
       (b) a compound of Formula (XIV) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R 1  is OR 6  or NR 4 R 5 ; 
 R 2  is H or 2,4-difluorophenyl; 
 R 3  is H or (C 1 -C 6 )alkyl; 
 R 4  and R 5  are independently H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 1 Z 2 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; or R 4  and R 5  together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine, or azepane; 
 R 6  is H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 1 Z 2 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; and 
 Z 1  and Z 2  are independently H or (C 1 -C 6 )alkyl; 
 
       (c) a compound of Formula (XV) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R 1  is OR 3  or NR 4 R 5 ; 
 R 2  is H or 2,4-difluorophenyl; 
 R 3  is H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 1 Z 2 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; 
 R 4  and R 5  are independently H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 1 Z 2 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; or R 4  and R 5  together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine, or azepane; and 
 Z 1  and Z 2  are independently H or (C 1 -C 6 )alkyl; 
 
       (d) a compound of Formula (XVI) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; 
       (e) a compound of Formula (XVII) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R 1  is OR 2  or NR 4 R 5 ; 
 R 2  is H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 1 Z 2 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; 
 R 4  and R 5  are independently H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 1 Z 2 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; or R 4  and R 5  together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine, or azepane; and 
 Z 1  and Z 2  are independently H or (C 1 -C 6 )alkyl; 
 
       (f) a compound of Formula (XVIII) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R 1  is OR 2  or NR 4 R 5 ; 
 R 2  is H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 1 Z 2 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; 
 R 3  is 
 
       
         
           
           
               
               
           
         
         R 4  and R 5  are independently H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 1 Z 2 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; or R 4  and R 5  together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine, or azepane; and 
         Z 1  and Z 2  are independently H or (C 1 -C 6 )alkyl; 
       
       (g) a compound of Formula (XX) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R 1  is OR 2 , NR 4 R 5 , or 
 
       
         
           
           
               
               
           
         
         R 2  is (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 1 Z 2 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; 
         Z 1  and Z 2  are independently H or (C 1 -C 6 )alkyl; 
         R 3  is H or C(O)R 6 ; 
         R 4  and R 5  are independently H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 1 Z 2 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; or R 4  and R 5  together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine, or azepane; 
         R 6  is H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 3 Z 4 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; 
         Z 3  and Z 4  are independently H or (C 1 -C 6 )alkyl; and 
       
       R 7  is OR 2  or NR 4 R 5 ; 
       provided that the compound is not N-acetyl-S-[(2′,4′-difluoro-4-hydroxy[1,1′-biphenyl]-3-yl)carbonyl]-L-cysteine methyl ester; N-acetyl-S-[(2′,4′-difluoro-4-hydroxy[1,1′-biphenyl]-3-yl)carbonyl]-L-cysteine ethyl ester; N-acetyl-S-[(2′,4′-difluoro-4-acetyloxy[1,1′-biphenyl]-3-yl)carbonyl]-L-cysteine methyl ester; and N-acetyl-S-[(2′,4′-difluoro-4-acetyloxy[1,1′-biphenyl]-3-yl)carbonyl]-L-cysteine ethyl ester; and 
       (h) a compound of Formula (XXI) 
       
         
           
           
               
               
           
         
       
       wherein
 X is absent, halogen, HSO 4 , HPO 4 , CH 3 CO 2 , or CF 3 CO 2 ; 
 R 1  is OR 3  or NR 4 R 5 ; 
 R 2  is H or 2,4-difluorophenyl; 
 R 3  is H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 1 Z 2 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; 
 R 4  and R 5  are independently H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 1 Z 2 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; or R 4  and R 5  together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine, or azepane; and 
 Z 1  and Z 2  are independently H or (C 1 -C 6 )alkyl.