Tricyclic inhibitors of 5-lipoxygenase

Abstract

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

1 . A compound having a structure represented by Formula (V): 
       
         
           
           
               
               
           
         
         wherein:
 G 1  is CR 1 ; 
 each R 1  is independently H, halide, —CN, —NO 2 , —OH, —OR 3 , —SR 3 , —S(═O)R 3 , —S(═O) 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —CH(R 3 ) 2 , —N(R 3 ) 2 , —NHCH 2 C(═O)OR 3 , —C(═O)N(R 3 ) 2 , —NHC(═O)R 3 , —C(OH)(R 3 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 3 -C 8 cycloalkyl, or C 1 -C 6 fluoroalkoxy; or 
 R 1  is Q 1 -Q 2  where Q 1  is aryl, or monocyclic heteroaryl; and Q 2  is H, halide, —CN, —NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —OR 3 , —SR 3 , —S(═O)R 3 , —S(═O) 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —CH(R 3 ) 2 , —N(R 3 ) 2 , or —C(═O)N(R 3 ) 2 ; 
 each R 3  is independently H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, phenyl, or benzyl; 
 L 1  is —(CHR 4 ) n X 1 (CHR 4 ) n — wherein,
 each n is independently 0, or 1; 
 X 1  is a bond, O, S, S(═O), or S(═O) 2 ; 
 each R 4  is H 
 R 6  and R 7  are independently H, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl 
 
 or R 6  and R 7  can together form an optionally substituted 5-, or 6-membered non-aromatic monocyclic ring containing 0, or 1 oxygen atom, wherein the ring is optionally substituted with F, —CH 3 , or —CF 3 ; 
 R 8  is H, —OH, —CONH 2 , tetrazolyl, —CN, —CO 2 H, —OR 12 , —CON(R 12 ) 2 , —CO 2 —R 12 , C(═O)R 12 , C(OH)(R 12 ) 2 , —CH═N—OR 12 , —N(R 12 ) 2 , NHC(═O)R 12 , or —OC(═O)R 12 ; where each R 12  is independently H, or C 1 -C 6 alkyl; 
 R 9  is H; 
 R 13  is H, C 1 -C 6 alkyl, or halide; 
 R 14  is H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halide; 
 
         or a pharmaceutically acceptable salt, or pharmaceutically acceptable N-oxide thereof. 
       
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1 , wherein:
 L 1  is selected from among —(CHR 4 ) n —, —(CHR 4 ) n O—, —(CHR 4 ) n S—, —O(CHR 4 ) n —, and —S(CHR 4 ) n —; each R 4  is H;
 n is 0, or 1. 
   
     
     
         4 . (canceled) 
     
     
         5 . The compound of  claim 3 , wherein:
 R 13  is H or halide;   R 14  is H; or   R 8  and R 14  taken together can form an optionally substituted 5-, or 6-membered ring   
     
     
         6 . The compound of  claim 5 , wherein:
 each R 1  is independently H, halide, —CN, —NO 2 , —OH, —OR 3 , —SR 3 , —S(═O)R 3 , —S(═O) 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —CH(R 3 ) 2 , —N(R 3 ) 2 , —NHCH 2 C(═O)OR 3 , —C(═O)N(R 3 ) 2 , —NHC(═O)R 3 , —C(OH)(R 3 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 alkenyl, or C 1 -C 6 fluoroalkoxy; or   R 1  is Q 1 -Q 2  where Q 1  is aryl, monocyclic heteroaryl; and Q 2  is H, halide, —CN, —NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —OR 3 , —SR 3 , —S(═O)R 3 , —S(═O) 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —CH(R 3 ) 2 , —N(R 3 ) 2 , or —C(═O)N(R 3 ) 2 .   
     
     
         7 . The compound of  claim 6 , wherein:
 R 6  and R 7  are independently H, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl,   R 6  and R 7  can together form an optionally substituted 5-, or 6-membered monocyclic ring containing 0, or 1 oxygen atom.   
     
     
         8 . The compound of  claim 7 , wherein:
 R 6  and R 7  are independently H, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl; or   R 6  and R 7  can together form an optionally substituted cyclohexyl or tetrahydropyran.   
     
     
         9 . The compound of  claim 8 , wherein:
 R 8  is H, —OH, —CONH 2 , tetrazolyl, —CN, —CO 2 H, —OR 12 , —CON(R 12 ) 2 , —CO 2 —R 12 , C(═O)R 12 , C(OH)(R 12 ) 2 , —CH═N—OR 12 , or —OC(═O)R 12 ; where each R 12  is independently H, or C 1 -C 6 alkyl.   
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . A compound selected from among:
 6-[3-Fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-1); 5-Chloro-6-[3-fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-2); 7-[3-(4-Methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-3); 4-[3-(1-Pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylmethoxy)-phenyl]-tetrahydro-pyran-4-carboxylic acid amide (Compound 5-4); 4-[3-(1-Pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylmethoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-5); 4-[3-Fluoro-5-([1,2,4]triazolo[4,3-a]quinolin-7-ylmethoxy)-phenyl]-tetrahydro-pyran-4-carboxylic acid ethyl ester (Compound 5-6); 7-[3-Fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-1-thiazol-2-yl-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-7); 7-[3-Fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-5-furan-3-yl-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-8); 5-Bromo-7-[3-fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-9); 7-[3-Fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-1-phenyl-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-10); 7-[3-Fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-1-methyl-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-11); 4-[3-Fluoro-5-([1,2,4]triazolo[4,3-a]quinolin-7-ylmethoxy)-phenyl]-tetrahydro-pyran-4-ol (Compound 5-12); 7-[3-Fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-1-quinolin-2-yl-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-13); 7-[3-Fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-1-pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-14); 4-[3-Fluoro-5-([1,2,4]triazolo[4,3-a]quinolin-7-ylmethoxy)-phenyl]-tetrahydro-pyran-4-carboxylic acid (Compound 5-15); 4-[3-Fluoro-5-([1,2,4]triazolo[4,3-a]quinolin-7-ylmethoxy)-phenyl]-tetrahydro-pyran-4-carboxylic acid amide (Compound 5-16); 7-[3-Fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-1-trifluoromethyl-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-17); 7-[3-Fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-[1,2,4]triazolo[4,3-a]quinoline-1-carboxylic acid ethyl ester (Compound 5-18); 7-[3-Fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-[1,2,4]triazolo[4,3-a]quinolin-1-ylamine (Compound 5-19); 7-[3-Fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-[1,2,4]triazolo[4,3-a]quinoxaline (Compound 5-20); 4-[3-([1,2,4]Triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-21); 4-[3-([1,2,4]Triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid amide (Compound 5-22); 4-[3-(1-Thiazol-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-23); 4-[3-(1-Phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-24); 4-[3-(1-Phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid amide (Compound 5-25); 4-[3-(1-Thiazol-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid amide (Compound 5-26); 4-[3-(1-Methyl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-27); 4-[3-(1-Pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-28); 4-[3-(1-Pyridin-3-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-29); 4-[3-(1-Pyridin-4-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-30); 4-{3-[1-(1H-Imidazol-2-yl)-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl]-phenyl}-tetrahydro-pyran-4-carbonitrile (Compound 5-31); 4-{3-[1-(4-Fluoro-phenyl)-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl]-phenyl}-tetrahydro-pyran-4-carbonitrile (Compound 5-32); 3-{7-[3-(4-Cyano-tetrahydro-pyran-4-yl)-phenylsulfanyl]-[1,2,4]triazolo[4,3-a]quinolin-1-yl}-benzoic acid (Compound 5-33); 4-{7-[3-(4-Cyano-tetrahydro-pyran-4-yl)-phenylsulfanyl]-[1,2,4]triazolo[4,3-a]quinolin-1-yl}-benzoic acid (Compound 5-34); 4-{3-[1-(4-Methoxy-phenyl)-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl]-phenyl}-tetrahydro-pyran-4-carbonitrile (Compound 5-35); 4-[3-(1-Trifluoromethyl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-36); 4-{3-[1-(2-Fluoro-phenyl)-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl]-phenyl}-tetrahydro-pyran-4-carbonitrile (Compound 5-37); 4-{3-[1-(3-Fluoro-phenyl)-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl]-phenyl}-tetrahydro-pyran-4-carbonitrile (Compound 5-38); 4-[3-(1-Cyclohexyl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-39); 4-[3-(1-Ethyl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-40); 4-[3-(1-Isopropyl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-41); 4-[3-(1-Isobutyl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-42); 2-Methyl-4-[3-(1-phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-43); 4-[3-(1-Phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-ol (Compound 5-44); 7-[3-(4-Methoxy-tetrahydro-pyran-4-yl)-phenylsulfanyl]-1-phenyl-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-45); 7-[3-(4-Cyclopropylmethoxy-tetrahydro-pyran-4-yl)-phenylsulfanyl]-1-phenyl-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-46); 4-[3-(1-Cyclopentyl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-47); 4-[3-(1-Cyclopropyl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-48); 4-{3-[1-(1-Methyl-1H-imidazol-2-yl)-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl]-phenyl}-tetrahydro-pyran-4-carbonitrile (Compound 5-49); 4-[3-(1-Pyridin-3-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid amide (Compound 5-50); 4-[3-(1-Pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid amide (Compound 5-51); 4-[3-(1-Pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-ol (Compound 5-52); (2S,4R)-2-Methyl-4-[3-(1-pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-ol (Compound 5-53); 4-[3-(1-Pyridin-3-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-ol (Compound 5-54); 4-{7-[3-(4-Cyano-tetrahydro-pyran-4-yl)-phenylsulfanyl]-[1,2,4]triazolo[4,3-a]quinolin-1-yl}-benzamide (Compound 5-55); {7-[3-(4-Cyano-tetrahydro-pyran-4-yl)-phenylsulfanyl]-[1,2,4]triazolo[4,3-a]quinolin-1-ylmethyl}-carbamic acid tert-butyl ester (Compound 5-56); (2-{7-[3-(4-Cyano-tetrahydro-pyran-4-yl)-phenylsulfanyl]-[1,2,4]triazolo[4,3-a]quinolin-1-yl}-ethyl)-carbamic acid benzyl ester (Compound 5-57); (S)-2-{7-[3-(4-Cyano-tetrahydro-pyran-4-yl)-phenylsulfanyl]-[1,2,4]triazolo[4,3-a]quinolin-1-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (Compound 5-58); (R)-2-{7-[3-(4-Cyano-tetrahydro-pyran-4-yl)-phenylsulfanyl]-[1,2,4]triazolo[4,3-a]quinolin-1-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (Compound 5-59); 3-{7-[3-(4-Cyano-tetrahydro-pyran-4-yl)-phenylsulfanyl]-[1,2,4]triazolo[4,3-a]quinolin-1-yl}-propionic acid (Compound 5-60); 4-[3-(1-Aminomethyl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-61); 4-[3-((S)-1-Pyrrolidin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-62); 4-[3-((R)-1-Pyrrolidin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-63); 4-{3-[1-(6-Methoxy-pyridin-2-yl)-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl]-phenyl}-tetrahydro-pyran-4-carbonitrile (Compound 5-64); N-{7-[3-(4-Cyano-tetrahydro-pyran-4-yl)-phenylsulfanyl]-[1,2,4]triazolo[4,3-a]quinolin-1-ylmethyl}-acetamide (Compound 5-65); 4-[3-(1-Dimethylaminomethyl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-66); 4-{3-[1-((S)-1-Methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl]-phenyl}-tetrahydro-pyran-4-carbonitrile (Compound 5-67); 4-{3-[1-((R)-1-Methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3a]quinolin-7-ylsulfanyl]-phenyl}-tetrahydro-pyran-4-carbonitrile (Compound 5-68); 4-{3-[1-((S)-1-Acetyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl]-phenyl}-tetrahydro-pyran-4-carbonitrile (Compound 5-69); 4-{3-[1-((R)-1-Acetyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl]-phenyl}-tetrahydro-pyran-4-carbonitrile (Compound 5-70); 5-{7-[3-(4-Cyano-tetrahydro-pyran-4-yl)-phenylsulfanyl]-[1,2,4]triazolo[4,3-a]quinolin-1-yl}-pentanoic acid methyl ester (Compound 5-71); 4-{3-[1-(6-Methoxy-pyridin-3-yl)-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl]-phenyl}-tetrahydro-pyran-4-carbonitrile (Compound 5-72); 4-{3-[1-(3-Methoxy-pyridin-4-yl)-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl]-phenyl}-tetrahydro-pyran-4-carbonitrile (Compound 5-73); 4-{3-[1-(5-Methoxy-pyridin-3-yl)-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl]-phenyl}-tetrahydro-pyran-4-carbonitrile (Compound 5-74); 5-{7-[3-(4-Cyano-tetrahydro-pyran-4-yl)-phenylsulfanyl]-[1,2,4]triazolo[4,3-a]quinolin-1-yl}-pentanoic acid (Compound 5-75); 2-Methyl-4-[3-(1-pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-76); 7-[3-(4-Cyano-tetrahydro-pyran-4-yl)-phenylsulfanyl]-1-pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinoline-4-carboxylic acid methyl ester (Compound 5-77); 2-Methyl-4-[3-(1-pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid amide (Compound 5-78); 4-[3-(1-Pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbaldehyde O-methyl-oxime (Compound 5-79); 4-[3-(1-Pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (Compound 5-80); {4-[3-(1-Pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-yl}-methanol (Compound 5-81); 1-{4-[3-(1-Pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-yl}-ethanol (Compound 5-82); 7-[3-(4-Methanesulfonyl-tetrahydro-pyran-4-yl)-phenylsulfanyl]-1-pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-83); 4-[3-(1-Pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-sulfonic acid dimethylamide (Compound 5-84); 4-[3-(1-Pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid (Compound 5-85); 4-[3-(1-Pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid methylamide (Compound 5-86); 4-[3-(1-Pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid (2-hydroxy-ethyl)-amide (Compound 5-87); 4-[3-(1-Pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid dimethylamide (Compound 5-88); 1-{4-[3-(1-Pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-yl}-ethanone (Compound 5-89); 2-{4-[3-(1-Pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-yl}-propan-2-ol (Compound 5-90); 1-Pyridin-2-yl-7-[3-(4-vinyl-tetrahydro-pyran-4-yl)-phenylsulfanyl]-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-91); 7-[3-(4-Ethyl-tetrahydro-pyran-4-yl)-phenylsulfanyl]-1-pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-92); 4-[3-Fluoro-5-(1-phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-93); 4-{3-Fluoro-5-[1-(1-hydroxy-1-methyl-ethyl)-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl]-phenyl}-tetrahydro-pyran-4-carbonitrile (Compound 5-94); 4-[3-Fluoro-5-(1-pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-95); 4-[3-Fluoro-5-(1-pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid amide (Compound 5-96); 4-[3-Fluoro-5-([1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-97); 7-[3-Fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenylsulfanyl]-1-pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-98); 4-[3 (1-Phenyl-[1,2,4]triazolo[4,3-a]quinoline-7-sulfinyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-118); 4-[3-(1-Pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinoline-7-sulfinyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid amide (Compound 5-119); 4-[3-(1-Phenyl-[1,2,4]triazolo[4,3-a]quinoline-7-sulfonyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-120); 4-[3-(1-Pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinoline-7-sulfonyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid amide (Compound 5-121); 8-[3-Fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-122); 5-Bromo-8-[3-fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-123); 8-[3-Fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-5-furan-3-yl-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-124); 5-Chloro-8-[3-fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-125); 8-[3-Fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-5-phenyl-[1,2,4]triazolo[4,3-a]quinoline (Compound 5-126); 3-{8-[3-Fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-[1,2,4]triazolo[4,3-a]quinolin-5-yl}-benzoic acid (Compound 5-127); 4-[3-(5-Chloro-[1,2,4]triazolo[4,3-a]quinolin-8-ylmethoxy)-5-fluoro-phenyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (Compound 5-128); 4-[3-Fluoro-5-(5-methylsulfanyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylmethoxy)-phenyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (Compound 5-129); 4-[3-Fluoro-5-(5-methoxy-[1,2,4]triazolo[4,3-a]quinolin-8-ylmethoxy)-phenyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (Compound 5-130); 4-[3-Fluoro-5-([1,2,4]triazolo[4,3-a]quinolin-8-ylmethoxy)-phenyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (Compound 5-131); 4-[3-Fluoro-5-(5-pyridin-3-yl-[1,2,4]triazolo[4,3-a]quinolin-8-ylmethoxy)-phenyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (Compound 5-132); 4-[3-Fluoro-5-(5-pyridin-4-yl-[1,2,4]triazolo[4,3-a]quinolin-8-ylmethoxy)-phenyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (Compound 5-133); 4-[3-Fluoro-5-(5-thiophen-3-yl-[1,2,4]triazolo[4,3-a]quinolin-8-ylmethoxy)-phenyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (Compound 5-134); 4-{3-[5-(3-Cyano-phenyl)-[1,2,4]triazolo[4,3-a]quinolin-8-ylmethoxy]-5-fluoro-phenyl}-tetrahydro-pyran-4-carboxylic acid methyl ester (Compound 5-135); 4-{3-Fluoro-5-[5-(3-methoxy-phenyl)-[1,2,4]triazolo[4,3-a]quinolin-8-ylmethoxy]-phenyl}-tetrahydro-pyran-4-carboxylic acid methyl ester (Compound 5-136); 4-[3-Fluoro-5-(5-m-tolyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylmethoxy)-phenyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (Compound 5-137); 4-[3-Fluoro-5-(5-phenyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylmethoxy)-phenyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (Compound 5-138); 4-[3-(5-Chloro-[1,2,4]triazolo[4,3-a]quinolin-8-ylmethoxy)-5-fluoro-phenyl]-tetrahydro-pyran-4-carboxylic acid amide (Compound 5-139); 4-{3-Fluoro-5-[5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]quinolin-8-ylmethoxy]-phenyl}-tetrahydro-pyran-4-carboxylic acid amide (Compound 5-140); 4-[3-Fluoro-5-(5-m-tolyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylmethoxy)-phenyl]-tetrahydro-pyran-4-carboxylic acid amide (Compound 5-141); 4-{3-Fluoro-5-[5-(4-fluoro-phenyl)-[1,2,4]triazolo[4,3-a]quinolin-8-ylmethoxy]-phenyl}-tetrahydro-pyran-4-carboxylic acid amide (Compound 5-142); 4-[3-(1-Thiazol-2-yl-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-143); 4-[3-([1,2,4]Triazolo[4,3-a]quinolin-8-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-144); 4-[3-(5-Chloro-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-145); 4-[3-(5-m-Tolyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-146); 4-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl]-phenyl}-tetrahydro-pyran-4-carbonitrile (Compound 5-147); 4-{3-[5-(4-Fluoro-phenyl)-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl]-phenyl}-tetrahydro-pyran-4-carbonitrile (Compound 5-148); 4-[3-(5-Phenyl-[1,2,4]thiazolo[4,3-a]quinolin-8-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-ol (Compound 5-149); 4-[3-(5-Phenyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-150); 4-[3-(5-Methyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-151); 4-[3-(1-Methyl-5-phenyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-153); 4-[3-(1-Methyl-5-phenyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-ol (Compound 5-154); 4-[3-(1-Amino-5-phenyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-ol (Compound 5-155); 4-[3-(5-Phenyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid amide (Compound 5-156); 4-[3-(5-Phenyl-1-trifluoromethyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-157); 4-[3-(5-Phenyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid (Compound 5-158); 4-[3-(5-Chloro-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-5-fluoro-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 5-159); 4-[2-Methoxy-5-(1-pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (Compound 5-161); Dicyclopropyl-[3-(1-phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-methanol (Compound 10-11); Dicyclopropyl-[3-(1-pyridin-2-yl-[1,2,4]triazolo[4,3-a]quinolin-7-ylsulfanyl)-phenyl]-methanol (Compound 10-12); 4,4,4-Trifluoro-3-hydroxy-3-[2-([1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-thiazol-5-yl]-butyric acid (Compound 10-13); 1-[3-(5-Phenyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-phenyl]-cyclohexanol (Compound 10-17); 3-[3-(5-Phenyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-phenyl]-pentan-3-ol (Compound 10-18); 3 (5 Phenyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-benzoic acid (Compound 11-8); 3-(5-Phenyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-benzamide (Compound 11-9); N-Methyl-3-(5-phenyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-benzamide (Compound 11-10); N,N-Dimethyl-3-(5-phenyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-benzamide (Compound 11-11); N-(2-Hydroxy-ethyl)-3-(5-phenyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-benzamide (Compound 11-12); Morpholin-4-yl-[3-(5-phenyl-[1,2,4]triazolo[4,3-a]quinolin-8-ylsulfanyl)-phenyl]-methanone (Compound 11-13); 8-(3-Cyclopent-1-enyl-phenylsulfanyl)-5-phenyl-[1,2,4]triazolo[4,3-a]quinoline (Compound 11-14); or a pharmaceutically acceptable salt thereof.   
     
     
         18 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . The compound of  claim 1 , wherein:
 L 1  is selected from among —(CHR 4 ) n O—, —(CHR 4 ) n S—, —O(CHR 4 ) n —, and —S(CHR 4 ) n —;   each R 4  is H; n is 0 or 1;   R 6  and R 7  are independently C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl;   or R 6  and R 7  can together form an optionally substituted tetrahydropyran;   R 8  is H, —OH, —CONH 2 , —CN, —CF 3 , —CO 2 H, —OR 12 , —CON(R 12 ) 2 , —CO 2 —R 12 , or —OC(═O)R 12 ; where each R 12  is independently H, or C 1 -C 6 alkyl.   
     
     
         24 . The compound of  claim 23 , wherein:
 each R 1  is independently H, halide, —CN, —NO 2 , —OH, —OR 3 , —SR 3 , —S(═O)R 3 , —S(═O) 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —CH(R 3 ) 2 , —N(R 3 ) 2 , —NHCH 2 C(═O)OR 3 , —C(═O)N(R 3 ) 2 , —NHC(═O)R 3 , or —C(OH)(R 3 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 3 -C 8 cycloalkyl, or C 1 -C 6 fluoroalkoxy; or   R 1  is Q 1 -Q 2  where Q 1  is phenyl, or monocyclic heteroaryl; and Q 2  is H, halide, —CN, —NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —OR 3 , —SR 3 , —S(═O)R 3 , —S(═O) 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —CH(R 3 ) 2 , —N(R 3 ) 2 , or —C(═O)N(R 3 ) 2 ;   each R 3  is independently H or C 1 -C 6 alkyl;   R 13  is H or halide;   R 14  is H.