Indene derivatives useful in treating pain and inflammation

Abstract

Compounds of formula (I): wherein, R1, R2, R3, R4a, R4b and R5 are described herein, or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof, are described herein, as well as other compounds. These compounds are useful in treating inflammation and/or pain. Compositions comprising a compound of the invention are also disclosed, as are methods of using the compounds to treat inflammation and/or pain.

1 . A pharmaceutical composition comprising a compound of formula (I), or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof,
 wherein formula (I) is:   
       
         
           
           
               
               
           
         
         wherein: 
       
       
         
           
           
               
               
           
         
       
       is an optionally substituted fused 5- or 6-membered N-heteroaryl;
 R 1  is hydrogen; 
 R 2  is —R 6 —OR 7 ; 
 R 3  is —R 6 —OR 7  or —R 6 —N(R 8 ) 2 ; 
 R 4a  is —R 9 —OR 7  and R 4b  is hydrogen, alkyl or optionally substituted heteroaryl; 
 or R 4a  is an optionally substituted aryl and R 4b  is a bond to C16; 
 or R 4a  and R 4b  together form alkylidene, provided that 
 
       
         
           
           
               
               
           
         
       
       is a fused 5- or 6-membered N-heteroaryl substituted by substituted aryl, substituted aralkyl, substituted cycloalkyl or substituted heteroaryl;
 or R 4a  is alkyl and R 4b  is hydrogen, provided that 
 
       
         
           
           
               
               
           
         
       
       is a fused 5- or 6-membered N-heteroaryl substituted by substituted aryl, substituted aralkyl, substituted cycloalkyl or substituted heteroaryl;
 or R 4a  and R 1  together form an optionally substituted bicyclic heterocyclyl and R 4b  is hydrogen; 
 or R 4a , R 4b  and R 1  together form a fused optionally substituted heteroaryl; 
 R 5  is alkyl or R 5  is a direct bond to the carbon at C14; 
 each R 6  is independently selected from a direct bond or a straight or branched alkylene chain; 
 each R 7  is independently selected from hydrogen or alkyl; 
 each R 8  is independently selected from hydrogen or alkyl; and 
 R 9  is a direct bond or a straight or branched alkylene chain; 
 or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof; 
 and wherein in the compound of formula (I) one or more of the H, C, N, O, P, S, F, Cl, or I is an isotope. 
 
     
     
         2 . The pharmaceutical composition of  claim 1  wherein in formula (I): 
       
         
           
           
               
               
           
         
       
       is an optionally substituted fused 5- or 6-membered N-heteroaryl;
 R 1  is hydrogen; 
 R 2  is —R 6 —OR 7 ; 
 R 3  is —R 6 —OR 7  or —R 6 —N(R 8 ) 2 ; 
 R 4a  is —R 9 —OR 7  and R 4b  is hydrogen, alkyl or optionally substituted heteroaryl; 
 R 5  is alkyl or R 5  is a direct bond to the carbon at C14; 
 each R 6  is independently selected from a direct bond or a straight or branched alkylene chain; 
 each R 7  is independently selected from hydrogen or alkyl; 
 each R 8  is independently selected from hydrogen or alkyl; and 
 R 9  is a direct bond or a straight or branched alkylene chain. 
 
     
     
         3 . The pharmaceutical composition of  claim 2  wherein the compound of formula (I) is selected from:
 (1S,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyloctahydro-1H-inden-1-ol; 
 (1R,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyloctahydro-1H-inden-1-ol; 
 (1S,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-1,7a-dimethyloctahydro-1H-inden-1-ol; 
 (1S,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(pyridin-2-yl)octahydro-1H-inden-1-ol; 
 (1S,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(thiazol-2-yl)octahydro-1H-inden-1-ol; 
 (1S,3aS,4R,5S,7aS)-4-(aminomethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(thiazol-2-yl)octahydro-1H-inden-1-ol; and 
 (1S,3aS,4R,5S,7aS)-4-(aminomethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(pyridin-2-yl)octahydro-1H-inden-1-ol. 
 
     
     
         4 . The pharmaceutical composition of  claim 2  wherein the compound of formula (I) is:
 (2S,5R)-5-ethyl-2-((1R,3aS,4S,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyloctahydro-1H-inden-1-yl)-6-methylheptan-3-ol. 
 
     
     
         5 . The pharmaceutical composition of  claim 1  wherein in formula (I): 
       
         
           
           
               
               
           
         
       
       is an optionally substituted fused 5- or 6-membered N-heteroaryl;
 R 1  is hydrogen; 
 R 2  is —R 6 —OR 7 ; 
 R 3  is —R 6 —OR 7  or —R 6 —N(R 8 ) 2 ; 
 R 4a  and R 1  together form an optionally substituted bicyclic heterocyclyl and R 4b  is hydrogen; 
 R 5  is alkyl or R 5  is a direct bond to the carbon at C14; 
 each R 6  is independently selected from a direct bond or a straight or branched alkylene chain; 
 each R 7  is independently selected from hydrogen or alkyl; and 
 each R 8  is independently selected from hydrogen or alkyl. 
 
     
     
         6 . The pharmaceutical composition of  claim 5  wherein the compound of formula (I) is selected from:
 ((5R,6S)-5-((2R,3S,3aR,3bS,5′R,6S,7R,7aS,8aS)-7-(hydroxymethyl)-3,3b,5′-trimethyltetradecahydrospiro[indeno[2,1-b]furan-2,2′-pyran]-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol; and 
 ((5R,6S)-5-((2R,3S,3aR,3bS,5′R,6S,7R,7aS,8aS)-7-(aminomethyl)-3,3b,5′-trimethyltetradecahydrospiro[indeno[2,1-b]furan-2,2′-pyran]-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol. 
 
     
     
         7 . The pharmaceutical composition of  claim 1  wherein in formula (I): 
       
         
           
           
               
               
           
         
       
       is an optionally substituted fused 5- or 6-membered N-heteroaryl;
 R 1  is hydrogen; 
 R 2  is —R 6 —OR 7 ; 
 R 3  is —R 6 —OR 7  or —R 6 —N(R 8 ) 2 ; 
 or R 4a , R 4b  and R 1  together form a fused optionally substituted heteroaryl; 
 R 5  is alkyl or R 5  is a direct bond to the carbon at C14; 
 each R 6  is independently selected from a direct bond or a straight or branched alkylene chain; 
 each R 7  is independently selected from hydrogen or alkyl; and 
 each R 8  is independently selected from hydrogen or alkyl. 
 
     
     
         8 . The pharmaceutical composition of  claim 7  wherein the compound of formula (I) is selected from:
 ((4aS,5R,6S,8aS)-6-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-8a-methyl-1,4,4a,5,6,7,8,8a-octahydroindeno[1,2-c]pyrazol-5-yl)methanol; 
 ((5R,6S)-5-((4aS,5R,6S,8aS)-5-(aminomethyl)-8a-methyl-1,4,4a,5,6,7,8,8a-octahydroindeno[1,2-c]pyrazol-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((5aS,6R,7S,9aS)-6-(aminomethyl)-9a-methyl-5a,6,7,8,9,9a-hexahydro-5H-indeno[1,2-b]pyridin-7-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol; and 
 ((5aS,6R,7S,9aS)-7-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-9a-methyl-5a,6,7,8,9,9a-hexahydro-5H-indeno[1,2-b]pyridin-6-yl)methanol. 
 
     
     
         9 . The pharmaceutical composition of  claim 1  wherein in formula (I): 
       
         
           
           
               
               
           
         
       
       is an optionally substituted fused 5- or 6-membered N-heteroaryl;
 R 1  is hydrogen; 
 R 2  is —R 6 —OR 7 ; 
 R 3  is —R 6 —OR 7  or —R 6 —N(R 8 ) 2 ; 
 R 4a  is an optionally substituted aryl and R 4b  is a bond to C16. 
 R 5  is alkyl or R 5  is a direct bond to the carbon at C14; 
 each R 6  is independently selected from a direct bond or a straight or branched alkylene chain; 
 each R 7  is independently selected from hydrogen or alkyl; and 
 each R 8  is independently selected from hydrogen or alkyl. 
 
     
     
         10 . The pharmaceutical composition of  claim 9  wherein the compound of formula (I) is selected from:
 ((5R,6S)-5-((3aS,6S,7R,7aS)-7-(aminomethyl)-3a-methyl-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol; and 
 ((5R,6S)-5-((3aS,6S,7R,7aS)-7-(hydroxymethyl)-3a-methyl-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol. 
 
     
     
         11 . The pharmaceutical composition of  claim 1  wherein in formula (I): 
       
         
           
           
               
               
           
         
       
       is a fused 5- or 6-membered N-heteroaryl substituted by substituted aryl, substituted aralkyl, substituted cycloalkyl or substituted heteroaryl;
 R 1  is hydrogen; 
 R 2  is —R 6 —OR 7 ; 
 R 3  is —R 6 —OR 7  or —R 6 —N(R 8 ) 2 ; 
 R 4a  and R 4b  together form alkylidene; 
 R 5  is alkyl or R 5  is a direct bond to the carbon at C14; 
 each R 6  is independently selected from a direct bond or a straight or branched alkylene chain; 
 each R 7  is independently selected from hydrogen or alkyl; and 
 each R 8  is independently selected from hydrogen or alkyl. 
 
     
     
         12 . The pharmaceutical composition of  claim 11  wherein the compound of formula (I) is selected from:
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol; 
 4-(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenoxy)benzoic acid; 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-methoxyphenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol; 
 (4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)(phenyl)methanone; 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(2-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(2,4-difluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(3,4-difluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(3-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(3,4-difluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-5-methyl-1-(4-phenoxyphenyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-5-methyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol; 
 (4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)(phenyl)methanone; 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(2-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(2,4-difluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol; 
 4-(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenoxy)benzoic acid; 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(3-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol; 
 (4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)(4-(pent-4-yn-1-yloxy)phenyl)methanone; 
 (4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)(4-(pent-4-yn-1-yloxy)phenyl)methanone; 
 4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzoic acid; and 
 4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)benzoic acid. 
 
     
     
         13 . The pharmaceutical composition of  claim 11  wherein the compound of formula (I) is selected from:
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-fluorobenzyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol; and 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-fluorobenzyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol. 
 
     
     
         14 . The pharmaceutical composition of  claim 11  wherein the compound of formula (I) is selected from:
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4,4-difluorocyclohexyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol; and 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4,4-difluorocyclohexyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol. 
 
     
     
         15 . The pharmaceutical composition of  claim 11  wherein the compound of formula (I) is selected from:
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(5-fluoropyridin-2-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(5-fluoropyrimidin-2-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(5-fluoropyrimidin-2-yl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol; and 
 ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(5-fluoropyridin-2-yl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol. 
 
     
     
         16 . The pharmaceutical composition of  claim 1  wherein: 
       
         
           
           
               
               
           
         
       
       is a fused 5- or 6-membered N-heteroaryl substituted by substituted aryl, substituted aralkyl, substituted cycloalkyl or substituted heteroaryl;
 R 1  is hydrogen; 
 R 2  is —R 6 —OR 7 ; 
 R 3  is —R 6 —OR 7  or —R 6 —N(R 8 ) 2 ; 
 R 4a  is alkyl and R 4b  is hydrogen; 
 R 5  is alkyl or R 5  is a direct bond to the carbon at C14; 
 each R 6  is independently selected from a direct bond or a straight or branched alkylene chain; 
 each R 7  is independently selected from hydrogen or alkyl; and 
 each R 8  is independently selected from hydrogen or alkyl. 
 
     
     
         17 . The pharmaceutical composition of  claim 16  wherein the compound of formula (I) is selected from:
 (4-((5R,6S)-5-((1 S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)(phenyl)methanone; 
 (4-((5R,6S)-5-((1 S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)(phenyl)methanone; 
 ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-methoxyphenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-methoxyphenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol hydrochloride; 
 ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-2-(4-(pyridin-2-yloxy)phenyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-1-(4-(pyridin-2-yloxy)phenyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-2-(4-(pyridin-4-yloxy)phenyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-1-(4-(pyridin-4-yloxy)phenyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol; 
 ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-1-(4-(pyrimidin-5-yloxy)phenyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol; and 
 ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-2-(4-(pyrimidin-5-yloxy)phenyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol. 
 
     
     
         18 . The pharmaceutical composition of  claim 16  wherein the compound of formula (I) is selected from:
 ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol; and 
 ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol. 
 
     
     
         19 . The pharmaceutical composition of  claim 1 , wherein the isotope is selected from the group consisting of  2 H,  3 H,  11 C,  13 C,  14 C,  13 N,  15 N,  15 O,  17 O,  18 O,  31 P,  32 P,  35 S,  18 F,  36 Cl,  123 I, and  125 I.