Novel indoles are cannabinoid receptor ligands

Abstract

The present invention provides novel compounds of Formula (I) which are CB 2 selective ligands useful for the treatment of pain.

1 . A compound of Formula (I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein
 R 1  is selected from the group consisting of alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylthioalkyl, arylalkyl, arylalkylcarbonyl, azidoalkyl, cycloalkylalkyl, cycloalkylalkylcarbonyl, haloalkyl, heteroarylalkyl, heteroarylalkylcarbonyl, heterocyclealkyl, heterocyclealkylcarbonyl, hydroxyalkyl, mercaptoalkyl, (NR A R B )carbonylalkyl, (NR A R B )sulfonylalkyl, (NR C R D )alkyl, -LOR 2 , -LSR 2 , -LS(O)R 2 , and -LS(O) 2 R 2 ; 
 L is alkylene; 
 R 2  is selected from the group consisting of alkyl, alkylcarbonyl, aryl, arylalkyl, carboxyalkenylcarbonyl, carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, (NR A R B )carbonylalkenylcarbonyl, (NR A R B )carbonylalkyl, and 
 
       (NR A R B )carbonylalkylcarbonyl;
 R 3  is selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, and haloalkyl; 
 R 4  is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, and cyclooctyl, wherein the cyclopropyl, cyclobutyl, and cyclopentyl are substituted with 1, 2, 3, 4, 5, or 6 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, oxo, —NR E R F , (NR E R F )alkyl, (NR G R H )carbonyl, (NR G R H )carbonylalkyl, (NR G R H )sulfonyl, and (NR G R H )sulfonylalkyl, wherein the cycloheptyl and cyclooctyl are optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, oxo, —NR E R F , (NR E R F )alkyl, (NR G R H )carbonyl, (NR G R H )carbonylalkyl, (NR G R H )sulfonyl, and (NR G R H )sulfonylalkyl; 
 R 5 , R 6 , R 7 , and R 8  are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfonyloxy, alkylthio, alkylthioalkyl, alkynyl, aryl, arylalkoxy, arylalkyl, arylalkylthio, arylcarbonyl, aryloxy, aryloxyalkyl, arylthio, arylthioalkyl, carboxy, carboxyalkenyl, carboxyalkenylcarbonyl, carboxyalkenylcarbonyloxy, carboxy, carboxyalkyl, carboxyalkylcarbonyl, carboxyalkylcarbonyloxy, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkoxy, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkyloxy, cycloalkyloxyalkyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkoxy, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heterocycle, heterocyclealkoxy, heterocyclealkoxycarbonyl, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, —NR J R K , (NR J R K )alkoxy, (NR J R K )alkyl, (NR M R N )carbonyl, (NR M R N )carbonylalkyl, (NR M R N )sulfonyl, and (NR M R N )sulfonylalkyl; 
 R A , R B , R G , R H , R M , and R N  are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl; and 
 R C , R D , R E , R E , R J , R K , are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, aryl, arylalkyl, arylsulfonyl, arylalkylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkylsulfonyl, cycloalkylalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heteroarylalkylsulfonyl, heterocycle, heterocyclealkyl, heterocyclesulfonyl, and heterocyclealkylsulfonyl. 
 
     
     
         2 . A compound according to  claim 1  wherein
 R 1  is selected from the group consisting of alkoxyalkyl, alkylcarbonylalkyl, alkylthioalkyl, arylalkyl, azidoalkyl, cycloalkylalkyl, haloalkyl, heteroarylalkyl, heterocyclealkyl, heterocyclealkylcarbonyl, hydroxyalkyl, mercaptoalkyl, (NR A R B )carbonylalkyl, (NR A R B )sulfonylalkyl, (NR C R D )alkyl, and -LOR 2 ; 
 L is alkylene; 
 R 2  is selected from the group consisting of alkylcarbonyl, arylalkyl, and carboxyalkenylcarbonyl; 
 R 3  is selected from the group consisting of hydrogen and alkyl wherein the alkyl is methyl; 
 R 4  is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cycloheptyl, wherein the cyclopropyl, cyclobutyl, and cyclopentyl are substituted with 1, 2, 3, 4, 5, or 6 substituents selected from the group consisting of alkyl and halogen; 
 R 5 , R 7 , and R 8  are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkoxy, alkyl, alkylsulfonyl, arylalkoxy, carboxy, carboxyalkenylcarbonyloxy, carboxy, carboxyalkylcarbonyloxy, cyano, haloalkoxy, haloalkyl, halogen, heterocyclealkoxycarbonyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, —NR J R K , (NR J R K )alkoxy, (NR J R K )alkyl, and (NR M R N )carbonyl; 
 R A , R B , R M , and R N  are independently selected from the group consisting of hydrogen, alkoxycarbonylalkyl, alkyl, and hydroxyalkyl; and 
 R C , R D , R J , R K , are independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, and alkylsulfonyl. 
 
     
     
         3 . A compound according to  claim 1  wherein
 R 3  is selected from the group consisting of hydrogen and alkyl wherein the alkyl is methyl; and 
 R 4  is 2,2,3,3-tetramethylcyclopropyl. 
 
     
     
         4 . A compound according to  claim 1  wherein
 R 1  is heterocyclealkyl; 
 R 3  is selected from the group consisting of hydrogen and alkyl wherein the alkyl is methyl; and 
 R 4  is 2,2,3,3-tetramethylcyclopropyl. 
 
     
     
         5 . A compound according to  claim 1  wherein
 R 1  is heteroarylalkyl; 
 R 3  is selected from the group consisting of hydrogen and alkyl wherein the alkyl is methyl; and 
 R 4  is 2,2,3,3-tetramethylcyclopropyl. 
 
     
     
         6 . A compound according to  claim 1  wherein
 R 1  is arylalkyl; 
 R 3  is selected from the group consisting of hydrogen and alkyl wherein the alkyl is methyl; and 
 R 4  is 2,2,3,3-tetramethylcyclopropyl. 
 
     
     
         7 . A compound according to  claim 1  wherein
 R 1  is selected from the group consisting of alkoxyalkyl, alkylcarbonylalkyl, alkylthioalkyl, azidoalkyl, cycloalkylalkyl, haloalkyl, heterocyclealkylcarbonyl, mercaptoalkyl, (NR A R B )carbonylalkyl, (NR A R B )sulfonylalkyl, (NR A R B )sulfonylalkyl, and (NR C R D )alkyl; 
 R 3  is selected from the group consisting of hydrogen and alkyl wherein the alkyl is methyl; 
 R 4  is 2,2,3,3-tetramethylcyclopropyl; 
 R A  and R B  are independently selected from the group consisting of hydrogen, alkoxycarbonylalkyl, alkyl, and hydroxyalkyl; and 
 R C  and R D  are independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, and alkylsulfonyl. 
 
     
     
         8 . A compound according to  claim 1  wherein
 R 1  is -LOR 2 ; 
 R 2  is selected from the group consisting of alkylcarbonyl, arylalkyl, and carboxyalkenylcarbonyl; 
 R 3  is selected from the group consisting of hydrogen and alkyl wherein the alkyl is methyl; 
 R 4  is 2,2,3,3-tetramethylcyclopropyl; and 
 L is alkylene. 
 
     
     
         9 . A compound according to  claim 1  wherein
 R 1  is hydroxyalkyl; 
 R 3  is selected from the group consisting of hydrogen and alkyl wherein the alkyl is methyl; and 
 R 4  is 2,2,3,3-tetramethylcyclopropyl. 
 
     
     
         10 . A compound according to  claim 1  wherein
 R 1  is alkylthioalkyl; 
 R 3  is selected from the group consisting of hydrogen and alkyl wherein the alkyl is methyl; and 
 R 4  is 2,2,3,3-tetramethylcyclopropyl. 
 
     
     
         11 . A compound according to  claim 1  wherein R 1  is heterocyclealkyl;
 R 3  is selected from the group consisting of hydrogen and alkyl wherein the alkyl is methyl; and 
 R 4  is 2,2,3,3-tetrafluoro-1-methylcyclobutyl. 
 
     
     
         12 . A compound according to  claim 1  wherein
 R 1  is heterocyclealkyl; 
 R 3  is selected from the group consisting of hydrogen and alkyl wherein the alkyl is methyl; and 
 R 4  is cycloheptyl. 
 
     
     
         13 . A compound selected from the group consisting of
 {1-[(1-methylpiperidin-2-yl)methyl]-1H-indol-3-yl}(2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(2-morpholin-4-ylethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone p-toluenesulfonic acid;   [1-(2-pyridin-2-ylethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone p-toluenesulfonic acid;   {1-[(1-methyl-1H-imidazol-2-yl)methyl]-1H-indol-3-yl}(2,2,3,3-tetramethylcyclopropyl)methanone p-toluenesulfonic acid;   tert-butyl 4-(2-{3-(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-1-yl}ethyl)piperidine-1-carboxylate;   [1-(2-Piperidin-4-yl-ethyl)-1H-indol-3-yl]-(2,2,3,3-tetramethyl-cyclopropyl)-methanone p-toluenesulfonic acid;   {1-[2-(1-methylpiperidin-4-yl)ethyl]-1H-indol-3-yl}(2,2,3,3-tetramethylcyclopropyl)methanone p-toluenesulfonic acid;   [1-(2-tetrahydro-2H-pyran-4-ylethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(2-pyrrolidin-1-ylethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone p-toluenesulfonic acid;   (2,2,3,3-tetramethylcyclopropyl)[1-(2-thien-2-ylethyl)-1H-indol-3-yl]methanone;   [1-(2-methoxyethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   1-(2-{3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-1-yl}ethyl)pyrrolidin-2-one;   1-(2-{3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-1-yl}ethyl)pyrrolidine-2,5-dione,   (1-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone;   {1-[2-(dimethylamino)ethyl]-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone;   (2,2,3,3-tetramethylcyclopropyl)[1-(2-thien-3-ylethyl)-1H-indol-3-yl]methanone;   {1-[2-(1-methylpyrrolidin-2-yl)ethyl]-1H-indol-3-yl}(2,2,3,3tetramethylcyclopropyl)methanone p-toluenesulfonic acid;   [1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(2-pyridin-3-ylethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   {1-[2-(1H-pyrrol-1-yl)ethyl]-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone;   (1-{2-[4-(dimethylamino)phenyl]ethyl}-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(2-pyridin-4-ylethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   {1-[4-(benzyloxy)butyl]-1H-indol-3-yl}(2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(4-hydroxybutyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(2-piperidin-1-ylethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   {1-[4-(methylthio)butyl]-1H-indol-3-yl}(2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(3-morpholin-4-ylpropyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(2-azepan-1-ylethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(2-piperazin-1-ylethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone tris-trifluoroacetic acid;   {1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-indol-3-yl}(2,2,3,3-tetramethylcyclopropyl)methanone;   3-(2-{3-(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-1-yl}ethyl)-1,3-oxazolidin-2-one;   [1-(tetrahydrofuran-3-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   (2,2,3,3-tetramethylcyclopropyl)[1-(4,4,4-trifluorobutyl)-1H-indol-3-yl]methanone;   (1-[2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl]-1H-indol-3-yl}(2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(3,4-dihydroxybutyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(1,3-dioxolan-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   {1-[2-(benzyloxy)ethyl]-1H-indol-3-yl}(2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(2-hydroxyethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   {1-[3-(benzyloxy)propyl]-1H-indol-3-yl}(2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(3-hydroxypropyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   {1-[5-(benzyloxy)pentyl]-1H-indol-3-yl}(2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(5-hydroxypentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(3-methoxypropyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(tetrahydro-2H-pyran-4-ylacetyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   methyl 4-({3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-1-yl}methyl)cyclohexanecarboxylate;   3-{3 [(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-1-yl)propanamide;   6-{3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-1-yl} hexan-2-one;   {1-[(2R)-2,3-dihydroxypropyl]-1H-indol-3-yl}(2,2,3,3-tetramethylcyclopropyl)methanone;   [2-methyl-1-(2-morpholin-4-ylethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(2-morpholin-4-ylethyl)-4-nitro-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [4-amino-1-(2-morpholin-4-ylethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   cycloheptyl[1-(2-morpholin-4-ylethyl)-1H-indol-3-yl]methanone;   (2,2,3,3-tetrafluoro-1-methylcyclobutyl)[1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl]methanone;   4-{3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-1-yl}butyl acetate;   4-oxo-4-(4-{3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-1-yl}butoxy)but-2-enoic acid;   [6-chloro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   4-({3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-1-yl)methyl)phenyl acetate;   [1-(4-hydroxybenzyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone,   [6-(benzyloxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [6-hydroxy-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   4-oxo-4-({1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-6-yl}oxy)but-2-enoic acid;   [6-methoxy-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   {1-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-indol-3-yl}(2,2,3,3-tetramethylcyclopropyl)methanone;   [5-(benzyloxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   (1-benzyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone;   [7-(benzyloxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(4-methoxybenzyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(3-methoxybenzyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [5-hydroxy-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(1,3-benzodioxol-5-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [7-hydroxy-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   4-oxo-4-({1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-7-yl}oxy)but-2-enoic acid;   [7-methoxy-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   methyl 1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-6-carboxylate;   1-(tetrahydro-2H-pyran-4-ylmethyl)-3[{(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-6-carboxylic acid;   {1-[(5-chloro-1,2,4-thiadiazol-3-yl)methyl]-1H-indol-3-yl}(2,2,3,3-tetramethylcyclopropyl)methanone;   4-oxo-4-({1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-5-yl}oxy)but-2-enoic acid;   [1-(1,3-benzothiazol-2-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   ethyl 3-[({1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-6-yl}carbonyl)amino]propanoate;   [5-methoxy-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [4-(benzyloxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-6-carboxamide,   1-(2-morpholin-4-ylethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-7-carboxylic acid;   2-morpholin-4-ylethyl 1-(2-morpholin-4-ylethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-7- carboxylate;   [4-hydroxy-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [4-methoxy-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [6-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropypmethanone;   [6-(benzyloxy)-1-(2-morpholin-4-ylethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [6-hydroxy-1-(2-morpholin-4-ylethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [6-methoxy-1-(2-morpholin-4-ylethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   4-oxo-4-({1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-5-yl}oxy)butanoic acid;   (2,2-dichloro-1-methylcyclopropyl)[1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl]methanone;   [1-(4-azidobutyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(2-azidoethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   N-(4-{3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-1-yl}butyl)methanesulfonamide;   ethyl 4-({1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-5-yl}oxy)butanoate;   [1-(3-azidopropyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   {1-[(2S)-tetrahydrofuran-2-ylmethyl]-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone;   [5-(4-hydroxybutoxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [5-(4-bromobutoxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(5-azidopentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   N-(2-{3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-1-yl}ethyl)methanesulfonamide;   methyl 1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxylate;   N-(3-{3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-1-yl} propyl)methanesulfonamide;   N-(5-{3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-1-yl}pentyl)methanesulfonamide;   [5-(4-aminobutoxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [5-hydroxy-1-(2-morpholin-4-ylethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   (2E)-4-({1-(2-morpholin-4-ylethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-5-yl}oxy)-4-oxobut-2-enoic acid;   [5-methoxy-1-(2-morpholin-4-ylethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   N-[4-({1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-5-yl}oxy)butyl]methanesulfonamide;   1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxamide;   N-(2-hydroxyethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxamide;   N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxamide;   1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]1H-indole-5-carbonitrile;   [5-(benzyloxy)-6-methoxy-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   N,N-dimethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxamide,   N-heptyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxamide;   [5-hydroxy-6-methoxy-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   (2E)-4-({6-methoxy-1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-5-yl}oxy)-4-oxobut-2-enoic acid;   (5-(benzyloxy)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-indol-3-yl}(2,2,3,3-tetramethylcyclopropyl)methanone;   [5-(aminomethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   {5-hydroxy-1-[(2R)-tetrahydrofuran-2-ylmethyl}-1H-indol-3-yl}(2,2,3,3-tetramethylcyclopropyl)methanone;   N-({1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-5-yl}methyl)methanesulfonamide;   {5-(benzyloxy)-1[4-(benzyloxy)butyl]-1H-indol-3-yl}(2,2,3,3-tetramethylcyclopropyl)methanone;   [6-(methylsulfonyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [5-hydroxy-1-(4-hydroxybutyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-6-carbonitrile;   [1-(tetrahydro-2H-pyran-4-ylmethyl)-6-(trifluoromethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [6-(aminomethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   N-({1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-6-yl}methyl)methanesulfonamide;   [5,6-dihydroxy-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   tetrahydro-2H-pyran-4-yl {3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-1-yl}acetic acid;   ethyl tetrahydro-2H-pyran-4-yl{3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-1-yl}acetate;   tert-butyl 1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-5-ylcarbamate;   [5-amino-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanonel; [4,5,6,7-tetrafluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   N-{1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-5-yl}methanesulfonamide;   [5-(hydroxymethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [5-(methoxymethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   3-(2-{5-hydroxy-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-1-yl}ethyl)-1,3-oxazolidin-2-one;   3-(2-{5-(benzyloxy)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indol-1-yl}ethyl)-1,3-oxazolidin-2-one;   N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-6-carboxamide;   N,N-dimethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-6-carboxamide;   N-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-6-carboxamide;   [1-(pyridin-3-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [1-(pyridin-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [5-bromo-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [5-(2-methoxyphenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [5-phenyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [5-(3-methoxyphenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [5-chloro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [6-bromo-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [6-(2-methoxyphenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [6-phenyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone;   [5-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone; and   2-oxatricyclo[3.3.1.1˜3,7˜]dec-1-yl[1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indol-3-yl]methanone.   
     
     
         14 . (canceled) 
     
     
         15 . A method of providing neuroprotection or treating pain, nociceptive pain, or neuropathic pain, or a disorder selected from the group consisting of inflammatory disorders, immune disorders, neurological disorders, cancers of the immune system, respiratory disorders, and cardiovascular disorders in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I) of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         16 .- 19 . (canceled) 
     
     
         20 . A method of treating a disorder selected from the group consisting of inflammatory disorders, immune disorders, neurological disorders, cancers of the immune system, respiratory disorders, and cardiovascular disorders in a mammal in need thereof of such treatment comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I) of  claim 1  or a pharmaceutically acceptable sale thereof.