5-Lipoxygenase-Activating Protein (FLAP) Inhibitors

Abstract

Described herein are compounds and pharmaceutical compositions containing such compounds, which modulate the activity of 5-lipoxygenase-activating protein (FLAP). Also described herein are methods of using such FLAP modulators, alone and in combination with other compounds, for treating respiratory, cardiovascular, and other leukotriene-dependent or leukotriene mediated conditions or diseases.

1 - 45 . (canceled) 
     
     
         46 . A compound having the structure of Formula (H): 
       
         
           
           
               
               
           
         
         wherein, 
         Z is selected from C(R 1 ) 2 [C(R 2 ) 2 ] n , [C(R 2 ) 2 ] n C(R 1 ) 2 O, OC(R 1 ) 2 [C(R 2 ) 2 ] n , [C(R 2 ) 2 ] n O[C(R 1 ) 2 ] n , [C(R 1 ) 2 ] n O[C(R 2 ) 2 ] n , wherein each R 1  is independently H, CF 3 , or an optionally substituted lower alkyl or two R 1  on the same carbon may join to form a oxo (═O); and each R 2  is independently H, OH, OMe, CF 3 , or an optionally substituted lower alkyl or two R 2  on the same carbon may join to form a oxo (═O); m is 0, 1 or 2; each n is independently 0, 1, 2, or 3; 
         Y is —CO 2 H, —CONH 2 , —C(═O)N(R 4b ) 2 , CO 2 R 4b , —OR 3b , —C(═O)(C 1 -C 5  fluoroalkyl), —C(═NOH)R 4b , C(═NOR 3b )R 4b , -L 1 -(substituted or unsubstituted alkyl), -L 1 -(substituted or unsubstituted alkenyl), -L 1 -(substituted or unsubstituted alkynyl), -L 1 -(substituted or unsubstituted cycloalkyl), -L 1 -(substituted or unsubstituted phenyl), -L 1 -(substituted or unsubstituted heteroaryl), or -L 1 -(substituted or unsubstituted heteroalicyclic group);
 where L 1  is —C(═O), CR 8 OH, CR 8 OMe, C(═NOH), C(═NOR 4b ), C(═O)NH, C(═O)NR 4b , —NHC(═O), NR 4b C(═O), S, S(═O), S(═O) 2 , —NHC(═O)NH, or NR 4b C(═O)NR 4b ; 
 where each substituent on Y or Z is (L s R s ) j , wherein each L s  is independently selected from a bond, —NH, —O—, —C(═O)—, —S—, —S(═O)—, —S(═O) 2 —, —NHC(O)—, —C(O)NH—, S(═O) 2 NH—, —NHS(═O) 2 , —OC(O)NH—, —NHC(O)O—, —OC(O)O—, —NHC(O)NH—, —C(O)O—, —OC(O)—, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, —C 1 -C 6  fluoroalkyl, phenyl; and each R s  is independently selected from H, halogen, —N(R 4 ) 2 , —CN, —NO 2 , N 3 , —S(═O) 2 NH 2 , lower alkyl, lower cycloalkyl, —C 1 -C 6  fluoroalkyl, heteroaryl, or heteroalkyl; where j is 0, 1, 2, 3, or 4; 
 each R 3b  is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; 
 each R 4  is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl; 
 each R 4b  is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroalicyclic group; 
 
         R 6  is H, L 2 -(substituted or unsubstituted alkyl), L 2 -(substituted or unsubstituted cycloalkyl), L 2 -(substituted or unsubstituted alkenyl), L 2 -(substituted or unsubstituted cycloalkenyl), L 2 -(substituted or unsubstituted heteroalicyclic group), L 2 -(substituted or unsubstituted heteroaryl), or L 2 -(substituted or unsubstituted aryl), where L 2  is a bond, O, S, —S(═O), —S(═O), —S(═O) 2 , C(O), —CH(OH), -(substituted or unsubstituted C 1 -C 6  alkyl), or -(substituted or unsubstituted C 2 -C 6  alkenyl); 
         R 7  is L 3 -X-L 4 -G 1 , wherein,
 L 3  is a bond, or substituted or unsubstituted alkyl; 
 X is a bond, O, —C(═O), —CR 9 (OR 9 ), S, —S(═O), —S(═O) 2 , —NR 9 , —NR 9 C(O), —C(O)NR 9 , —S(═O) 2 NR 9 , —NR 9 S(═O) 2 , —OC(O)NR 9 —, —NR 9 C(O)O—, —CH═NO—, —ON═CH—, —NR 9 C(O)NR 9 —, heteroaryl, aryl, —NR 9 C(═NR 10 )NR 9 —, —NR 9 C(═NR 10 )—, —C(═NR 10 )NR 9 —, —OC(═NR 10 )—, or —C(═NR 10 )O—; 
 L 4  is a bond or substituted or unsubstituted alkyl; 
 G 1  is H, tetrazolyl, —NHS(═O) 2 R 8 , S(═O) 2 N(R 9 ) 2 , —OR 9 , —C(═O)CF 3 , —C(O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(O)R 9 , CN, N(R 9 ) 2 , —N(R 9 )C(O)R 9 , —C(═NR 10 )N(R 9 ) 2 , —NR 9 C(═NR 10 )N(R 9 ) 2 , —NR 9 C(═CR 10 )N(R 9 ) 2 , —C(O)NR 9 C(═NR 10 )N(R 9 ) 2 , —C(O)NR 9 C(═CR 10 )N(R 9 ) 2 , —CO 2 R 9 , —C(O)R 9 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , —S(═O) 2 R 8 , -L 5 -(substituted or unsubstituted alkyl), -L 5 -(substituted or unsubstituted alkenyl), -L 5 -(substituted or unsubstituted heteroaryl), or -L 5 -(substituted or unsubstituted aryl), wherein L 5  is —OC(O)O—, —NHC(O)NH—, —NHC(O)O, —O(O)CNH—, —NHC(O), —C(O)NH, —C(O)O, or —OC(O); 
 each R 8  is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl; 
 each R 9  is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl; or two R 9  groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or R 8  and R 9  can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring and 
 each R 10  is independently selected from H, —S(═O) 2 R 8 , —S(═O) 2 NH 2 —C(O)R 8 , —CN, —NO 2 , heteroaryl, or heteroalkyl; 
 
         R 5  is H, halogen, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted O—C 1 -C 6  alkyl; 
         R 11  is L 7 -L 10 -G 6 ; wherein L 7  is a bond;
 L 10  is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), or (substituted or unsubstituted heteroalicyclic group); 
 G 6  is H, CN, SCN, N 3 , NO 2 , halogen, OR 9 , —C(═O)CF 3 , —C(═O)R 9 , —SR 8 , —S(═O)R 8 , —S(═O) 2 R 8 , N(R 9 ) 2 , tetrazolyl, —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —C(O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(O)R 9 , —C(═NR 10 )N(R 9 ) 2 , —NR 9 C(═NR 10 )N(R 9 ) 2 , —NR 9 C(═CR 10 )N(R 9 ) 2 , -L 5 -(substituted or unsubstituted alkyl), -L 5 -(substituted or unsubstituted alkenyl), -L 5 -(substituted or unsubstituted heteroaryl), or -L 5 -(substituted or unsubstituted aryl), wherein L 5  is —NHC(O)O, —NHC(O)NH—, —OC(O)O—, —OC(O)NH—, —NHC(O), —C(O)NH, —C(O)O, or —OC(O); 
 or G 6  is W-G 7 , wherein W is (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroalicyclic group) or a (substituted or unsubstituted heteroaryl) and G 7  is H, halogen, CN, NO 2 , N 3 , CF 3 , OCF 3 , C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, —C 1 -C 6  fluoroalkyl, tetrazolyl, —NHS(═O) 2 R 8 , S(═O) 2 N(R 9 ) 2 , OH, —OR 8 , —C(═O)CF 3 , —C(O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(O)R 9 , CN, N(R 9 ) 2 , —N(R 9 )C(O)R 9 , —C(═NR 10 )N(R 9 ) 2 , —NR 9 C(═NR 10 )N(R 9 ) 2 , —NR 9 C(═CR 10 )N(R 9 ) 2 , —C(O)NR 9 C(═NR 10 )N(R 9 ) 2 , —C(O)NR 9 C(═CR 10 )N(R 9 ) 2 , —CO 2 R 9 , —C(O)R 9 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , or —S(═O) 2 R 8 , -L 5 -(substituted or unsubstituted alkyl), -L 5 -(substituted or unsubstituted alkenyl), -L 5 -(substituted or unsubstituted heteroalkyl), -L 5 -(substituted or unsubstituted heteroaryl), -L 5 -(substituted or unsubstituted heteroalicyclic group), or -L 5 -(substituted or unsubstituted aryl), wherein L 5  is a bond, —O—, C(═O), S, S(═O), S(═O) 2 , —NH, —NHC(O)O, —NHC(O)NH—, —OC(O)O—, —OC(O)NH—, —NHC(O), —C(O)NH, —C(O)O, or —OC(O); 
 
         R 12  is H; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         47 . The compound of  claim 46 , wherein Z is [C(R 2 ) 2 ] n C(R 1 ) 2 O. 
     
     
         48 . The compound of  claim 47 , wherein:
 Y is —CO 2 H, —CONH 2 , —C(═O)N(R 4b ) 2 , CO 2 R 4b , —OR 3b , —C(═O)(C 1 -C 5  fluoroalkyl), —C(═NOH)R 4b , C(═NOR 3b )R 4b , -L 1 -(substituted or unsubstituted alkyl), -L 1 -(substituted or unsubstituted cycloalkyl), or -L 1 -(substituted or unsubstituted phenyl).   
     
     
         49 . The compound of  claim 48 , wherein:
 Y is —CO 2 H, —CONH 2 , —C(═O)N(R 4b ) 2 , CO 2 R 4b , —OR 3b , —C(—NOH)R 4b , C(═NOR 3b )R 4b , -L 1 -(substituted or unsubstituted alkyl), or -L 1 -(substituted or unsubstituted phenyl).   
     
     
         50 . The compound of  claim 49 , wherein:
 R 6  is L 2 -(substituted or unsubstituted alkyl), or L 2 -(substituted or unsubstituted cycloalkyl), L 2 -(substituted or unsubstituted aryl), where L 2  is a bond, O, S, —S(O) 2 , —C(O), —CH(OH), or substituted or unsubstituted alkyl.   
     
     
         51 . (canceled) 
     
     
         52 . (canceled) 
     
     
         53 . The compound of  claim 50 , wherein:
 G 6  is W-G 7 , wherein W is (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroalicyclic group) or a (substituted or unsubstituted heteroaryl).   
     
     
         54 . The compound of  claim 53 , wherein:
 G 7  is H, halogen, CN, NO 2 , N 3 , CF 3 , OCF 3 , C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, —C 1 -C 6  fluoroalkyl, tetrazolyl, —OH, —OR 8 , —C(═O)CF 3 , —CN, —CO 2 R 9 , —C(O)R 9 , or —CON(R 9 ) 2 .   
     
     
         55 . The compound of  claim 52 , wherein:
 L 10  is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted heteroaryl), or (substituted or unsubstituted aryl); and   G 6  is H, CN, SCN, N 3 , NO 2 , halogen, OR 9 , —C(═O)CF 3 , —C(═O)R 9 , tetrazolyl, or -L 5 -(substituted or unsubstituted alkyl).   
     
     
         56 . The compound of  claim 46 , wherein L 3  is a bond. 
     
     
         57 . The compound of  claim 56 , wherein:
 L 4  is a bond or substituted or unsubstituted alkyl;   G 1  is H, tetrazolyl, —NHS(═O) 2 R 8 , S(═O) 2 N(R 9 ) 2 , —OR 9 , —C(═O)CF 3 , —C(O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(O)R 9 , CN, N(R 9 ) 2 , —N(R 9 )C(O)R 9 , —C(═NR 10 )N(R 9 ) 2 , —NR 9 C(═NR 10 )N(R 9 ) 2 , —NR 9 C(═CR 10 )N(R 9 ) 2 , —C(O)NR 9 C(═NR 10 )N(R 9 ) 2 , —C(O)NR 9 C(═CR 10 )N(R 9 ) 2 , —CO 2 R 9 , —C(O)R 9 , or —CON(R 9 ) 2 .   
     
     
         58 . The compound of  claim 57 , wherein X is a bond. 
     
     
         59 . The claim of  claim 58 , wherein:
 G 1  is H, tetrazolyl, —OR 9 , —C(═O)CF 3 , —CN, —CO 2 R 9 , —C(O)R 9 , or —CON(R 9 ) 2 .   
     
     
         60 . (canceled) 
     
     
         61 . (canceled) 
     
     
         62 . (canceled) 
     
     
         63 . A pharmaceutical composition comprising an effective amount of a compound of  claim 46  and a pharmaceutically acceptable excipient. 
     
     
         64 . A method for treating inflammation in a mammal comprising administering a therapeutically effective amount of a compound of  claim 46  to the mammal in need. 
     
     
         65 . A method for treating respiratory disease in a mammal comprising administering a therapeutically effective amount of a compound of  claim 46  to the mammal in need. 
     
     
         66 . A method for treating cardiovascular disease in a mammal comprising administering a therapeutically effective amount of a compound of  claim 46  to the mammal in need. 
     
     
         67 . A compound selected from among:
 3-[3-tert-butylsulfanyl-5-carbamoylmethoxy-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid; 3-[5-((S)-2-tert-butoxycarbonylamino-2-phenyl-ethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid; 3-[5-((R)-2-tert-butoxycarbonylamino-2-phenyl-ethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid; 3-[5-((R)-2-amino-2-phenyl-ethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid; 3-[5-((S)-2-amino-2-phenyl-ethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid; 3-[5-((R)-2-acetylamino-2-phenyl-ethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid; 3-[5-((S)-2-acetylamino-2-phenyl-ethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid; 3-[5-[(3-tert-butoxycarbonylamino-propylcarbamoyl)-methoxy]-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid; 3-[5-[(3-amino-propylcarbamoyl)-methoxy]-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid; 3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[2-(4-fluoro-phenyl)-2-oxo-ethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic acid; 3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[2-(4-fluoro-phenyl)-2-hydroxy-ethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic acid; 3-(3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-{2-(4-fluoro-phenyl)-2-[(Z)-hydroxyimino]-ethoxy}-1H-indol-2-yl)-2,2-dimethyl-propionic acid; 3-(3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-{2-(4-fluoro-phenyl)-2-[(Z)-methoxyimino]-ethoxy}-1H-indol-2-yl)-2,2-dimethyl-propionic acid; 3-[3-tert-butylsulfanyl-5-carbamoylmethoxy-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester; 3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-cyanomethoxy-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester; 3-[5-(benzylcarbamoyl-methoxy)-1-(4-bromo-benzyl)-3-tert-butylsulfanyl-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester; 3-[3-tert-butylsulfanyl-5-carboxymethoxy-1-(4-thiazol-2-yl-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid; 3-[3-tert-butylsulfanyl-5-(2-hydroxy-propoxy)-1-(4-thiazol-2-yl-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid; 3-[3-tert-butylsulfanyl-5-carbamoylmethoxy-1-(4-thiazol-2-yl-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid; 3-[3-tert-butylsulfanyl-5-(1-carbamoyl-1-methyl-ethoxy)-1-(4-thiazol-2-yl-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid; 3-[3-tert-butylsulfanyl-5-(1-carboxy-1-methyl-ethoxy)-1-(4-thiazol-2-yl-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid; 3-{3-tert-butylsulfanyl-5-(2-methoxy-propoxy)-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid; 3-{3-tert-butylsulfanyl-5-(2-hydroxy-propoxy)-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid; 3-{3-tert-butylsulfanyl-5-(2-hydroxy-2-methyl-propoxy)-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid; 3-{3-tert-butylsulfanyl-5-(2-hydroxy-3,3-dimethyl-butoxy)-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid; 3-{3-tert-butylsulfanyl-5-[2-(4-fluoro-phenyl)-2-hydroxy-ethoxy]-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid; 3-[3-tert-butylsulfanyl-5-carbamoylmethoxy-1-(4-thiazol-2-yl-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester; 2-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(2-hydroxy-2-methyl-propyl)-1H-indol-5-yloxy]-acetamide; 2-[3-tert-butylsulfanyl-2-(2-hydroxy-2-methyl-propyl)-1-pyridin-4-ylmethyl-1H-indol-5-yloxy]-acetamide; 2-[3-tert-Butylsulfanyl-1-(4-cyano-benzyl)-2-(2-hydroxy-2-methyl-propyl)-1H-indol-5-yloxy]-acetamide; 2-[3-tert-butylsulfanyl-2-(2-hydroxy-2-methyl-propyl)-1-(4-iodo-benzyl)-1H-indol-5-yloxy]-acetamide; 2-[3-tert-butylsulfanyl-1-cyclopropylmethyl-2-(2-hydroxy-2-methyl-propyl)-1H-indol-5-yloxy]-acetamide; 2-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(2-hydroxy-2-methyl-propyl)-1H-indol-5-yloxy]-N,N-diethyl-acetamide; 2-[3-tert-butylsulfanyl-2-(2-hydroxy-2-methyl-propyl)-1-pyridin-4-ylmethyl-1H-indol-5-yloxy]-N-(4-fluoro-phenyl)-acetamide; 2-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(2-hydroxy-2-methyl-propyl)-1H-indol-5-yloxy]-N-(4-chloro-benzyl)-N-pyridin-3-yl-acetamide; 2-[3-tert-butylsulfanyl-2-(2-hydroxy-2-methyl-propyl)-1-pyridin-4-ylmethyl-1H-indol-5-yloxy]-N-cyclopropyl-acetamide; 2-[3-tert-butylsulfanyl-2-(2-hydroxy-2-methyl-propyl)-1-(4-iodo-benzyl)-1H-indol-5-yloxy]-N-(4-iodo-benzyl)-acetamide; 2-[3-tert-butylsulfanyl-2-(2-hydroxy-2-methyl-propyl)-1-(4-pyridin-3-yl-benzyl)-1H-indol-5-yloxy]-acetamide; [3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(2-hydroxy-2-methyl-propyl)-1H-indol-5-yloxy]-acetic acid; [3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(2-hydroxy-2-methyl-propyl)-1H-indol-5-yloxy]-acetic acid ethyl ester; 1-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-(2-hydroxy-2-methyl-propoxy)-1H-indol-2-yl]-2-methyl-propan-2-ol; 1-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-(2-hydroxy-propoxy)-1H-indol-2-yl]-2-methyl-propan-2-ol; 1-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(2-hydroxy-2-methyl-propyl)-1H-indol-5-yloxy]-propan-2-one.   
     
     
         68 . The compound of  claim 46 , wherein
 Z is [C(R 2 ) 2 ] n C(R 1 ) 2 O;   Y is —CO 2 H, —CONH 2 , —C(═O)N(R 4b ) 2 , CO 2 R 4b , —OR 3b , —C(═O)(C 1 -C 5  fluoroalkyl), —C(═NOH)R 4b , C(═NOR 3b )R 4b , -L 1 -(substituted or unsubstituted alkyl), -L 1 -(substituted or unsubstituted cycloalkyl), or -L 1 -(substituted or unsubstituted phenyl);   R 6  is L 2 -(substituted or unsubstituted alkyl) or L 2 -(substituted or unsubstituted cycloalkyl);
 wherein L 2  is a bond, C═O or S; 
   L 3  is a bond;   X is a bond;   L 4  is a substituted or unsubstituted alkyl;   G 1  is H, tetrazolyl, —OR 9 , —C(═O)CF 3 , —CN, —CO 2 R 9 , —C(O)R 9 , or —CON(R 9 ) 2 ; and   L 7  is a bond;   L 10  is a (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted heteroaryl), or (substituted or unsubstituted aryl).   
     
     
         69 . The compound of  claim 68 , wherein:
 G 6  is H, CN, SCN, N 3 , NO 2 , halogen, OR 9 , —C(═O)CF 3 , —C(═O)R 9 , tetrazolyl, or -L 5 -(substituted or unsubstituted alkyl); or   G 6  is —W-G 7 , wherein W is (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroalicyclic group) or a (substituted or unsubstituted heteroaryl); G 7  is H, halogen, CN, NO 2 , N 3 , CF 3 , OCF 3 , C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, —C 1 -C 6  fluoroalkyl, tetrazolyl, —OH, —OR 8 , —C(═O)CF 3 , —CN, —CO 2 R 9 , —C(O)R 9 , or —CON(R 9 ) 2 .   
     
     
         70 . The compound of  claim 69 , wherein:
 G 1  is —OR 9  or —CO 2 R 9 ; and   L 10  is a (substituted or unsubstituted heteroaryl), or (substituted or unsubstituted aryl).