Thio-oxindole derivatives

Abstract

This invention relates to methods of co-administering compounds of formula 1 which are agonists of the progesterone receptor which have the general structure: wherein: R 1 , R 2 , R 3 , R 4 , R 5 and Q 1 are as defined herein, or a pharmaceutically acceptable salt thereof, with estrogen, an estrone, or an estrogen receptor agonist for contraception, hormone replacement therapy, or treating progesterone-related carcinomas and adenocarcinomas.

1 . A method of providing hormone replacement therapy comprising the step of delivering to a female a composition comprising a compound of formula I and an estrogen to said female, wherein formula I is:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  and R 2  are independently selected from the group consisting of H, alkyl, substituted alkyl, OH, O(alkyl), O(substituted alkyl), O(Acetyl), aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, alkylaryl, substituted alkylaryl, alkylheteroaryl, substituted alkylheteroaryl, 1-propynyl, substituted 1-propynyl, 3-propynyl, and substituted 3-propynyl;  
 or R 1  and R 2  form a double bond to C(CH 3 ) 2 , C(cycloalkyl), O, or C(cycloether);  
 R 3  is selected from the group consisting of H, OH, NH 2 , C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 6  alkenyl, substituted C 3  to C 6  alkenyl, alkynyl, substituted alkynyl, and CORA;  
 R A  is selected from the group consisting of H, C 1  to C 3  alkyl, substituted C 1  to C 3  alky, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, and substituted C 1  to C 3  aminoalkyl;  
 R 4  is selected from the group consisting of H, halogen, CN, NH 2 , C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 1  to C 6  alkoxy, substituted C 1  to C 6  alkoxy, C 1  to C 6  aminoalkyl, and substituted C 1  to C 6  aminoalkyl;  
 R 5  is selected from the group consisting of a), b) and c):  
 a) a substituted benzene ring having the structure:  
                     X is selected from the group consisting of halogen, OH, CN, C 1  to C 3  alkyl, substituted C 1  to C 3  alky, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  thioalkyl, substituted C 1  to C 3  thioalkyl, C 1  to C 3  thioalkoxy, substituted C 1  to C 3  thioalkoxy, S(O)alkyl, S(O) 2 alkyl, C 1  to C 3  aminoalkyl, substituted C 1  to C 3  aminoalkyl, NO 2 , C 1  to C 3  perfluoroalkyl, substituted C 1  to C 3  perfluoroalkyl, 5 or 6 membered heterocyclic ring having in its backbone 1 to 3 heteroatoms, CONH 2 , CSNH 2 , CNHNHOH, CNH 2 NOH, CNHNOH, COR B , CSR B , OCOR B , and NR C COR B ;    R B  is selected from the group consisting of H, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, aryl, substituted aryl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, and substituted C 1  to C 3  aminoalkyl;    R C  is H, C 1  to C 3  alkyl, or substituted C 1  to C 3  alkyl;    Y and Z are independently selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 4  alkyl, substituted C 1  to C 4  alkyl, C 1  to C 3  thioalkyl, and substituted C 1  to C 3  thioalkyl;    
 b) a five or six membered heterocyclic ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2  and NR 6  and having one or two independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 4  alkyl, substituted C 1  to C 4  alkyl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, substituted C 1  to C 3  aminoalkyl, COR D , CSR D , and NR E COR D ; 
 R D  is H, NH 2 , C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, aryl, substituted aryl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, or substituted C 1  to C 3  aminoalkyl;  
 R E  is H, C 1  to C 3  alkyl, or substituted C 1  to C 3  alkyl;  
 R 6  is H, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, or C 1  to C 4  CO 2 alkyl; or  
 
 c) an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, wherein said moiety is optionally substituted by from 1 to 3 substituents selected from the group consisting of halogen, alkyl, substituted alkyl, CN, NO 2 , alkoxy, substituted alkoxy, and CF 3 ;  
 Q 1  is S, NR 7 , or CR 8 R 9 ;  
 R 7  is selected from the group consisting of CN, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 8  cycloalkyl, substituted C 3  to C 8  cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, SO 2 CF 3 , OR 11 , and NR 11 R 12 ;  
 R 8  and R 9  are independently selected from the group consisting of H, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 8  cycloalkyl, substituted C 3  to C 8  cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, NO 2 , CN, and CO 2 R 10 ;  
 R 10  is C 1  to C 3  alkyl or substituted C 1  to C 3  alkyl;  
 or CR 8 R 9  comprise a six membered ring having the structure:  
                     
 R 11  and R 12  are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and substituted sulfonyl; or a tautomer or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The method according to  claim 1 , wherein said compound of formula I is delivered at a daily dosage of about 2 to about 80 mg.  
     
     
         3 . The method according to  claim 1 , wherein said compound is of the structure:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 5  is (i) or (ii):  
 (i) a substituted benzene ring having the structure:  
                     X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1  to C 3  alkoxy, C 1  to C 3  alkyl, NO 2 , C 1  to C 3  perfluoroalkyl, 5 membered heterocyclic ring having in its backbone 1 to 3 heteroatoms, and C 1  to C 3  thioalkoxy;    Y is selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkoxy, C 1  to C 4  alkyl, and C 1  to C 3  thioalkyl; or    
 (ii) a six membered ring having the structure:  
                     X 1  is N or CX 2 ;    X 2  is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2  or NO 2 ; or a tautomer or a pharmaceutically acceptable salt thereof.    
 
     
     
         4 . The method according to  claim 1 , wherein said compound is of the structure:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 11  is selected from the group consisting of H, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and substituted sulfonyl;  
 R 5  is (i), (ii), or (iii):  
 (i) a substituted benzene ring having the structure:  
                     X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , CNHNHOH, CNH 2 NOH, C 1  to C 3  alkoxy, C 1  to C 3  alkyl, NO 2 , C 1  to C 3  perfluoroalkyl, 5 membered heterocyclic ring having in its backbone 1 to 3 heteroatoms, and C 1  to C 3  thioalkoxy;    Y is selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkoxy, C 1  to C 4  alkyl, and C 1  to C 3  thioalkyl;    
 (ii) a five membered ring having the structure:  
                     U is O, S, or NR 6 ;    R 6  is H, C 1  to C 3  alkyl, or C 1  to C 4  CO 2 alkyl;    X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CNHNHOH, CNH 2 NOH, CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1  to C 3  alkyl, and C 1  to C 3  alkoxy;    Y′ is selected from the group consisting of H, F, and C 1  to C 4  alkyl; or    
 (iii) a six membered ring having the structure:  
                     X 1  is N or CX 2 ;    X 2  is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2  or NO 2 ; or a tautomer or a pharmaceutically acceptable salt thereof.    
 
     
     
         5 . The method according to  claim 1 , wherein said compound is of the structure:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 5  is (i), (ii), or (iii):  
 (i) a substituted benzene ring having the structure:  
                     X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , CNHNOH, C 1  to C 3  alkoxy, C 1  to C 3  alkyl, NO 2 , C 1  to C 3  perfluoroalkyl, 5 membered heterocyclic ring having in its backbone 1 to 3 heteroatoms, and C 1  to C 3  thioalkoxy;    Y is selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkoxy, C 1  to C 4  alkyl, and C 1  to C 3  thioalkyl;    
 (ii) a five membered ring having the structure:  
                     U is O, S, or NR 6 ;    R 6  is H, C 1  to C 3  alkyl, or C 1  to C 4  CO 2 alkyl;    X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1  to C 3  alkyl, and C 1  to C 3  alkoxy;    Y′ is selected from the group consisting of H, F and C 1  to C 4  alkyl; or    
 (iii) a six membered ring having the structure:  
                     X 1  is N or CX 2 ;    X 2  is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2  or NO 2 ; or a tautomer or a pharmaceutically acceptable salt thereof.    
 
     
     
         6 . The method according to  claim 1 , where said compound is of the structure:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 15  is selected from the group consisting of H, CO 2 R, acyl, substituted acyl, aroyl, substituted aroyl, alkyl, substituted alkyl, and CN;  
 R 5  is (i), (ii), or (iii):  
 (i) a substituted benzene ring having the structure:  
                     X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , CNHNOH, C 1  to C 3  alkoxy, C 1  to C 3  alkyl, NO 2 , C 1  to C 3  perfluoroalkyl, 5 membered heterocyclic ring having in its backbone 1 to 3 heteroatoms, and C 1  to C 3  thioalkoxy;    Y is a substituent on the 4′ or 5′ position selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkoxy, C 1  to C 4  alkyl, and C 1  to C 3  thioalkyl;    
 (ii) a five membered ring having the structure:  
                     U is O, S, or NR 6 ;    R 6  is H, C 1  to C 3  alkyl, or C 1  to C 4  CO 2 alkyl;    X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1  to C 3  alkyl, and C 1  to C 3  alkoxy;    Y′ is selected from the group consisting of H, F and C 1  to C 4  alkyl;    
 (iii) a six membered ring having the structure:  
                     X 1  is N or C 2      X 2  is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2  or NO 2 ; or a tautomer or a pharmaceutically acceptable salt thereof.    
 
     
     
         7 . The method according to  claim 1 , wherein said compound is of the structure:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 5  is (i), (ii), or (iii):  
 (i) a substituted benzene ring having the structure:  
                     X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , CNHNOH, C 1  to C 3  alkoxy, C 1  to C 3  alkyl, NO 2 , C 1  to C 3  perfluoroalkyl, 5 membered heterocyclic ring having in its backbone 1 to 3 heteroatoms, and C 1  to C 3  thioalkoxy;    Y is a substituent on the 4′ or 5′ position selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkoxy, C 1  to C 4  alkyl, and C 1  to C 3  thioalkyl;    
 (ii) a five membered ring having the structure:  
                     U is O, S, or NR 6 ;    R 6  is H, C 1  to C 3  alkyl, or C 1  to C 4  CO 2 alkyl;    X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1  to C 3  alkyl, and C 1  to C 3  alkoxy;    Y′ is selected from the group consisting of H, F, and C 1  to C 4  alkyl;    
 (iii) a six membered ring having the structure:  
                     X 1  is Nor CX 2 ;    X 2  is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2  or NO 2 ; or a tautomer or a pharmaceutically acceptable salt thereof.    
 
     
     
         8 . The method according to  claim 1 , wherein R 5  is a five membered ring of the structure:  
       
         
           
           
               
               
           
         
       
       wherein: 
 U is O, S, or NR 6 ;  
 R 6  is H, or C 1  to C 3  alkyl, or C 1  to C 4  CO 2 alkyl;  
 X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CNHNHOH, CNH 2 NOH, CSNH 2 , CONHalkyl, CSNHalkyl, CONalkyl 2 , CSNalkyl 2 , C 1  to C 3  alkyl, and C 1  to C 3  alkoxy;  
 Y′ is selected from the group consisting of H, F and C 1  to C 4  alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         9 . The method according to  claim 1 , wherein R 5  is a thiophene or furan ring.  
     
     
         10 . The method according to  claim 1 , wherein R 5  is a six membered ring of the structure:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X 1  is N or CX 2 ,  
 X 2  is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CONalkyl 2 , CSNalkyl 2  or NO 2 ;  
 R 7  is selected from the group consisting of CN, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 8  cycloalkyl, substituted C 3  to C 8  cycloalkyl, aryl, substituted aryl, -heterocyclic, substituted heterocyclic, and SO 2 CF 3 ;  
 R 10  is C 1  to C 3  alkyl; or pharmaceutically acceptable salt thereof.  
 
     
     
         11 . The method according to  claim 1 , wherein the compound is selected from the group consisting of 3-(1′,2′-Dihydro-2′-thioxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzonitrile; 5′-(5-Cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide; 5-(1,2-Dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5′-yl)-1H-pyrrole-2-carbonitrile; 5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1 tert-butoxycarbonyl)-pyrrole-2-carbonitrile; 5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-H-pyrrole-2-carbonitrile; 5-(2′-thioxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1-methyl-pyrrole-2-carbonitrile; 5-(1,2-Dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-3-thiophenecarbonitrile; 5-(1,2-Dihydro-thioxospiro(cyclopentane-1,3-[3H]indol)-5-yl)-2-thiophenecarbonitrile; 5-(3-Fluoro-4methoxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(2-Amino-5-pyrimidinyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 3-(1,2-Dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-5-fluorobenzonitrile; 3-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-2-yl)-4-fluorobenzonitrile; 5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-2-yl)-3-pyridinecarbonitrile; 5-(3,4-Difluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(5-Chloro-2-thienyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-3-furancarbonitrile; 5-(3-Chloro-4-fluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(3-Chloro-5-fluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(3,5-Difluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-propyl-2-thiophenecarbonitrile; 5-(3-Fluoro-4-nitrophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 4-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-furancarbonitrile; 5″-(3-Chlorophenyl)spiro[cyclobutane-1,3″-[3H]indole]-2″(1″H)-thione; 5″-(2-Chlorophenyl)spiro[cyclohexane-1,3″-[3H]indole]-2″(1″H)-thione; 5″-(4-Chlorophenyl)spiro[cyclohexane-1,3″-[3H]indole]-2″(1″H)-thione; 5-(1″,2″-Dihydro-2″-thioxospiro[cyclohexane-1,3″-[3H]indol]-5″-yl)-4-methyl-2-thiophenecarbonitrile; 5′-(1″,2″-Dihydro-2″-thioxospiro[cyclohexane-1,3″-[3H]indol]-5″-yl)-2-thiophenecarbonitrile; 5″-(3-Fluorophenyl)spiro[cyclohexane-1,3″-[3H]indole]-2″(1″H)-thione; 5-(3-Hydroxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-[4-Fluoro-3-(trifluoromethyl)phenyl]spiro[cyclohexane-1,3-[3H]indol]-2(1H)-thione; 4-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-fluorobenzonitrile; 5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-n-butyl-2-thiophenecarbonitrile; 5-(3-Fluoro-5-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(3-Chlorophenyl)-N-hydroxyspiro[cyclohexane-1,3′-[3H]indol]-2-amine; N-(Acetyloxy)-5′-(3-chlorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2″-amine; 5″-(3-Fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 5′-(2-Fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 5′-(4-Fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 5′-(3,4-Difluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 5′(3-methoxyphenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 5′(3-nitrophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 5′(3-cyanophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 3-[1′,2′-Dihydro-2′-(hydroxyimino)spiro[cyclohexane-1,3′-[3H]indol]-5′-yl]-5-fluorobenzonitrile; 5-(spiro[cyclohexane-1,3′-[3H]indol]-2′-(hydroxyimino)-5′-yl)-4-methyl-2-thiophenecarbonitrile; 5-(spiro[cyclohexane-1,3′-[3H]indole]-2′-hydroxyimino)-5′-yl-2-thiophenecarbonitrile; 4-Spiro[cyclohexane-1,3′-[3H]indole]-2′-hydroxyimino)-5′-yl)-2thiophenecarbonitrile; 5-(spiro[cyclohexane-1,3′-[3H]indole]-2′-(hydroxyimino)-5′-yl)-1H-pyrrole-1-methyl-2-carbonitrile; 5-(spiro[cyclohexane-1,3′-[3H]indol]-2′-(hydroxyimino)-5′-yl)-1H-pyrrole-2-carbonitrile; 4-(spiro[cyclohexane-1,3′-[3H]indole]-2′-(acetoxyimino)-5′-yl)-2-thiophenecarbonitrile; 3-Fluoro-N′-hydroxy-5-[2′-(hydroxyamino)spiro[cyclohexane-1,3′-[3H]indol]-5′-yl]benzenecarboximidamide; N′-hydroxy-5-(spiro[cyclohexane-1,3′-[3H]indole]-2′-(hydroxyimino)-5′-yl)-4-methyl-2-thiophenecarboximidamide; N′-Hydroxy-4-(spiro[cyclohexane-1,3′-[3H]indole]-2′-(hydroxyimino)-5′-yl-2-thiophenecarboximidamide; N′-Hydroxy-5-(spiro[cyclohexane-1,3′-[3H]indol]-2′-(hydroxyimino)-5′-yl)-2-thiophenecarboximidamide; 5′-3-Chlorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide; 5′-(3-Cyano-5-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide; 5-(3-chlorophenyl)-3,3-dimethyl-1,3-dihydro-2H-indole-2-thione; 3-benzyl-5-(3-chlorophenyl)-3-methyl-1,3-dihydro-2H-indole-2-thione; 4-(3,3-dimethyl-2-thioxo-2,3-dihydro-1H-indol-5-yl)-2-furonitrile; 5-(3-methoxyphenyl)-3,3-dimethyl-1,3-dihydro-2H-indole-2-thione; and 5-(3-chlorophenyl)-3,3-diethyl-1,3-dihydro-2H-indole-2-thione; or a pharmaceutically acceptable salt thereof.  
     
     
         12 . A method of providing hormone replacement therapy comprising the step of delivering to a female a composition comprising a compound of formula I and an estrone to said female, wherein formula I is:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  and R 2  are independently selected from the group consisting of H, alkyl, substituted alkyl, OH, O(alkyl), O(substituted alkyl), O(Acetyl), aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, alkylaryl, substituted alkylaryl, alkylheteroaryl, substituted alkylheteroaryl, 1-propynyl, substituted I-propynyl, 3-propynyl, and substituted 3-propynyl;  
 or R 1  and R 2  form a double bond to C(CH 3 ) 2 , C(cycloalkyl), O, or C(cycloether);  
 R 3  is selected from the group consisting of H, OH, NH 2 , C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 6  alkenyl, substituted C 3  to C 6  alkenyl, alkynyl, substituted alkynyl, and COR A ;  
 R A  is selected from the group consisting of H, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, and substituted C 1  to C 3  aminoalkyl;  
 R 4  is selected from the group consisting of H, halogen, CN, NH 2 , C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 1  to C 6  alkoxy, substituted C 1  to C 6  alkoxy, C 1  to C 6  aminoalkyl, and substituted C 1  to C 6  aminoalkyl;  
 R 5  is selected from the group consisting of a), b) and c):  
 a) a substituted benzene ring having the structure:  
                     X is selected from the group consisting of halogen, OH, CN, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  thioalkyl, substituted C 1  to C 3  thioalkyl, C 1  to C 3  thioalkoxy, substituted C 1  to C 3  thioalkoxy, S(O)alkyl, S(O) 2 alkyl, C 1  to C 3  aminoalkyl, substituted C 1  to C 3  aminoalkyl, NO 2 , C 1  to C 3  perfluoroalkyl, substituted C 1  to C 3  perfluoroalkyl, 5 or 6 membered heterocyclic ring having in its backbone 1 to 3 heteroatoms, CONH 2 , CSNH 2 , CNHNHOH, CNH 2 NOH, CNHNOH, COR B , CSR B , OCOR B , and NR C COR B ;    R B  is selected from the group consisting of H, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, aryl, substituted aryl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, and substituted C 1  to C 3  aminoalkyl;    R C  is H, C 1  to C 3  alkyl, or substituted C 1  to C 3  alkyl;    Y and Z are independently selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 4  alkyl, substituted C 1  to C 4  alkyl, C 1  to C 3  thioalkyl, and substituted C 1  to C 3  thioalkyl;    
 b) a five or six membered heterocyclic ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2  and NR 6  and having one or two independent substituents from the group consisting of H, halogen, CN, NO 2 , C 1  to C 4  alkyl, substituted C 1  to C 4  alkyl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, substituted C 1  to C 3  aminoalkyl, COR D , CSR D , and NR E COR D ; 
 R D  is H, NH 2 , C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, aryl, substituted aryl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, or substituted C 1  to C 3  aminoalkyl;  
 R E  is H, C 1  to C 3  alkyl, or substituted C 1  to C 3  alkyl;  
 
 R 6  is H, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, or C 1  to C 4  CO 2 alkyl; or  
 c) an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, wherein said moiety is optionally substituted by from 1 to 3 substituents selected from the group consisting of halogen, alkyl, substituted alkyl, CN, NO 2 , alkoxy, substituted alkoxy, and CF 3 ;  
 Q 1  is S, NR 7 , or CR 8 R 9 ;  
 R 7  is selected from the group consisting of CN, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 8  cycloalkyl, substituted C 3  to C 8  cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, SO 2 CF 3 , OR 11  and NR 11 R 12 ;  
 R 8  and R 9  are independently selected from the group consisting of H, C 1  to C 6  alky, substituted C 1  to C 6  alkyl, C 3  to C 8  cycloalkyl, substituted C 3  to C 8  cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, NO 2 , CN, and CO 2 R 10 ;  
 R 10  is C 1  to C 3  allyl or substituted C 1  to C 3  alkyl;  
 or CR 8 R 9  comprise a six membered ring having the structure:  
                     
 R 11  and R 12  are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and substituted sulfonyl;  
 or a tautomer or a pharmaceutically acceptable salt thereof.  
 
     
     
         13 . The method according to  claim 12 , wherein said compound is of the structure:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 5  is (i), (ii), or (iii): (i) a substituted benzene ring having the structure:  
                     X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , CNHNOH, C 1  to C 3  alkoxy, C 1  to C 3  alkyl, NO 2 , C 1  to C 3  perfluoroalkyl, 5 membered heterocyclic ring having in its backbone 1 to 3 heteroatoms, and C 1  to C 3  thioalkoxy;    Y is a substituent on the 4′ or 5′ position selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkoxy, C 1  to C 4  alkyl, and C 1  to C 3  thioalkyl;    
 (ii) a five membered ring having the structure:  
                     U is O, S, or NR 6 ;    R 6  is H, C 1  to C 3  alkyl, or C 1  to C 4  CO 2 alkyl;    X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1  to C 3  alky, and C 1  to C 3  alkoxy;    Y′ is selected from the group consisting of H, F, and C 1  to C 4  alkyl;    
 (iii) a six membered ring having the structure:  
                     X 1  is N or CX 2 ;    X 2  is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2  or NO 2 ; or a tautomer or a pharmaceutically acceptable salt thereof.    
 
     
     
         14 . The method according to  claim 12 , wherein said compound is of the structure:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 15  is selected from the group consisting of H, CO 2 R, acyl, substituted acyl, aroyl, substituted aroyl, alkyl, substituted alkyl, and CN;  
 R 5  is (i), (ii), or (iii):  
 (i) a substituted benzene ring having the structure:  
                     X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , CNHNOH, C 1  to C 3  alkoxy, C 1  to C 3  alkyl, NO 2 , C 1  to C 3  perfluoroalkyl, 5 membered heterocyclic ring having in its backbone 1 to 3 heteroatoms, and C 1  to C 3  thioalkoxy;    Y is a substituent on the 4′ or 5′ position selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkoxy, C 1  to C 4  alkyl, and C 1  to C 3  thioalkyl;    
 (ii) a five membered ring having the structure:  
                     U is O, S, or NR 6 ;    R 6  is H, C 1  to C 3  alky, or C 1  to C 4  CO 2 alkyl;    X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1  to C 3  alkyl, and C 1  to C 3  alkoxy;    Y′ is selected from the group consisting of H, F and C 1  to C 4  alkyl;    
 (iii) a six membered ring having the structure:  
                     X 1  is Nor CX 2 ;    X 2  is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2  or NO 2 ; or a tautomer or a pharmaceutically acceptable salt thereof.    
 
     
     
         15 . The method according to  claim 12 , wherein said compound is of the structure:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 5  is (i), (ii), or (iii):  
 (i) a substituted benzene ring having the structure:  
                     X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , CNHNOH, C 1  to C 3  alkoxy, C 1  to C 3  alkyl, NO 2 , C 1  to C 3  perfluoroalkyl, 5 membered heterocyclic ring having in its backbone 1 to 3 heteroatoms, and C 1  to C 3  thioalkoxy;    Y is a substituent on the 4′ or 5′ position selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkoxy, C 1  to C 4  alkyl, and C 1  to C 3  thioalkyl;    
 (ii) a five membered ring having the structure:  
                     U is O, S, or NR 6 ;    R 6  is H, C 1  to C 3  alkyl, or C 1  to C 4  CO 2 alkyl;    X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1  to C 3  alkyl, and C 1  to C 3  alkoxy;    Y′ is selected from the group consisting of H, F, and C 1  to C 4  alkyl;    
 (iii) a six membered ring having the structure:  
                     X 1  is N or CX 2 ;    X 2  is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2  or NO 2 ; or a tautomer or a pharmaceutically acceptable salt thereof.    
 
     
     
         16 . The method according to  claim 12 , wherein R 5  is the substituted benzene ring of the structure:  
       
         
           
           
               
               
           
         
         X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CONalkyl 2 , CSNalkyl 2 , C 1  to C 3  alkoxy, C 1  to C 3  alkyl, NO 2 , C 1  to C 3  perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 heteroatoms, and C 1  to C 3  thioalkoxy; and  
         Y is a substituent on the 4′ or 5′position selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkoxy, C 1  to C 4  alkyl, and C 1  to C 3  thioalkyl; and  
         Q 1  is S, NR 7 , or CR 8 R 9 ; or a pharmaceutically acceptable salt thereof.  
       
     
     
         17 . The method according to  claim 12 , wherein R 5  is a five membered ring of the structure:  
       
         
           
           
               
               
           
         
       
       wherein: 
 U is O, S, or NR 6 ;  
 R 6  is H, or C 1  to C 3  alkyl, or C 1  to C 4  CO 2 alkyl;  
 X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CNHNHOH, CNH 2 NOH, CSNH 2 , CONHalkyl, CSNHalkyl, CONalkyl 2 , CSNalkyl 2 , C 1  to C 3  alkyl, and C 1  to C 3  alkoxy;  
 Y′ is selected from the group consisting of H, F and C 1  to C 4  alkyl; or a pharmaceutically acceptable salt thereof.  
 
     
     
         18 . The method according to  claim 12 , wherein R 5  is a thiophene or furan ring.  
     
     
         19 . The method according to  claim 12 , wherein R 5  is a six membered ring of the structure:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X 1  is N or CX 2 ,  
 X 2  is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CONalkyl 2 , CSNalkyl 2  or NO 2 ;  
 R 7  is selected from the group consisting of CN, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 8  cycloalkyl, substituted C 3  to C 8  cycloalkyl, aryl, substituted aryl, -heterocyclic, substituted heterocyclic, and SO 2 CF 3 ;  
 R 10  is C 1  to C 3  alkyl; or pharmaceutically acceptable salt thereof.  
 
     
     
         20 . The method according to  claim 14 , wherein the compound is selected from the group consisting of 3-(1′,2′-Dihydro-2′-thioxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzonitrile; 5′-(5-Cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide; 5-(1,2-Dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5′-yl)-1H-pyrrole-2-carbonitrile; 5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-(tert-butoxycarbonyl)-pyrrole-2-carbonitrile; 5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-H-pyrrole-2-carbonitrile; 5-(2′-thioxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1-methyl-pyrrole-2-carbonitrile; 5-(1,2-Dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-3-thiophenecarbonitrile; 5-(1,2-Dihydro-thioxospiro(cyclopentane-1,3-[3H]indol)-5-yl)-2-thiophenecarbonitrile; 5-(3-Fluoro-4-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(2-Amino-5-pyrimidinyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 3-(1,2-Dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-5-fluorobenzonitrile; 3-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-2-yl)-4-fluorobenzonitrile; 5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-2-yl)-3-pyridinecarbonitrile; 5-(3,4-Difluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(5-Chloro-2-thienyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3[3H]indol]-5-yl)-3-furancarbonitrile; 5-(3-Chloro-4-fluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(3-Chloro-5-fluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(3,5-Difluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-propyl-2-thiophenecarbonitrile; 5-(3-Fluoro-4-nitrophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 4-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-furancarbonitrile; 5″-(3-Chlorophenyl)spiro[cyclobutane-1,3″-[3H]indole]-2″(1″H)-thione; 5″-(2-Chlorophenyl)spiro[cyclohexane-1,3″-[3H]indole]-2″(1″H)-thione; 5″-(4-Chlorophenyl)spiro[cyclohexane-1,3″-[3H]indole]-2″(1″H)-thione; 5-(1″,2″-Dihydro-2″-thioxospiro[cyclohexane-1,3″-[3H]indol]-5″-yl)-4-methyl-2-thiophenecarbonitrile; 5′-(1″,2″-Dihydro-2″-thioxospiro[cyclohexane-1,3″-[3H]indol]-5″-yl)-2-thiophenecarbonitrile; 5″-(3-Fluorophenyl)spiro[cyclohexane-1,3″-[3H]indole]-2″(1″H)-thione; 5-(3-Hydroxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-[4-Fluoro-3-(trifluoromethyl)phenyl]spiro[cyclohexane-1,3-[3H]indol]-2(1H)-thione; 4-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-fluorobenzonitrile; 5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-n-butyl-2-thiophenecarbonitrile; 5-(3-Fluoro-5-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(3-Chlorophenyl)-N-hydroxyspiro[cyclohexane-1,3′-[3H]indol]-2-amine; N-(Acetyloxy)-5′-(3-chlorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2″-amine; 5″-(3-Fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 5′-(2-Fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 5′-(4-Fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 5′-(3,4-Difluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 5′(3-methoxyphenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 5′(3-nitrophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 5′(3-cyanophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 3-[1′,2′-Dihydro-2′-(hydroxyimino)spiro[cyclohexane-1,3′-[3H]indol]-5′-yl]-5-fluorobenzonitrile; 5-(spiro[cyclohexane-1,3′-[3H]indol]-2′-(hydroxyimino)-5′-yl)-4-methyl-2-thiophenecarbonitrile; 5-(spiro[cyclohexane-1,3′-[3H]indole]-2′-(hydroxyimino)-5′-yl-2-thiophenecarbonitrile; 4-(Spiro[cyclohexane-1,3′-[3H]indole]-2′-(hydroxyimino)-5′-yl)-2-thiophenecarbonitrile; 5-(spiro[cyclohexane-1,3′-[3H]indole]-2′-(hydroxyimino)-5′-yl)-1H-pyrrole-1-methyl-2-carbonitrile; 5-(spiro[cyclohexane-1,3′-[3H]indol]-2′-(hydroxyimino)-5′-yl)-1H-pyrrole-2-carbonitrile; 4-(spiro[cyclohexane-1,3′-[3H]indole]-2′-(acetoxyimino)-5′-yl)-2-thiophenecarbonitrile; 3-Fluoro-N′-hydroxy-5-[2′-(hydroxyamino)spiro[cyclohexane-1,3′-[3H]indol]-5′-yl]benzenecarboximidamide; N′-hydroxy-5-(spiro[cyclohexane-1,3′-[3H]indole]-2′-(hydroxyimino)-5′-yl)-4-methyl-2-thiophenecarboximidamide; N′-Hydroxy-4-(spiro[cyclohexane-1,3′-[3H]indole]-2′-(hydroxyimino)-5′-yl-2-thiophenecarboximidamide; N′-Hydroxy-5-spiro[cyclohexane-1,3′-[3H]indol]2′-(hydroxyimino)-5′-yl)-2-thiophenecarboximidamide; 5′-(3-Chlorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide; 5′-(3-Cyano-5-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide; 5-(3-chlorophenyl)-3,3-dimethyl-1,3-dihydro-2H-indole-2-thione; 3-benzyl-5-(3-chlorophenyl)-3-methyl-1,3-dihydro-2H-indole-2-thione; 4-(3,3-dimethyl-2-thioxo-2,3-dihydro-1H-indol-5-yl)-2-furonitrile; 5-(3-methoxyphenyl)-3,3-dimethyl-1,3-dihydro-2H-indole-2-thione; and 5-(3-chlorophenyl)-3,3-diethyl-1,3-dihydro-2H-indole-2-thione; or a pharmaceutically acceptable salt thereof.  
     
     
         21 . A method of providing hormone replacement therapy or treating the symptoms of menopause, comprising the step of delivering to a female a composition comprising a compound of formula I and an estrogen receptor agonist to said female, wherein formula I is:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  and R 2  are independently selected from the group consisting of H, alkyl, substituted alkyl, OH, O(alkyl), O(substituted alkyl), O(Acetyl), aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, alkylaryl, substituted alkylaryl, alkylheteroaryl, substituted alkylheteroaryl, 1-propynyl, substituted 1-propynyl, 3-propynyl, and substituted 3-propynyl;  
 or R 1  and R 2  form a double bond to C(CH 3 ) 2 , C(cycloalkyl), O, or C(cycloether);  
 R 3  is selected from the group consisting of H, OH, NH 2 , C 1  to C 6  alky, substituted C 1  to C 6  alkyl, C 3  to C 6  alkenyl, substituted C 3  to C 6  alkenyl, alkynyl, substituted alkynyl, and CORA;  
 R A  is selected from the group consisting of H, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, and substituted C 1  to C 3  aminoalkyl;  
 R 4  is selected from the group consisting of H, halogen, CN, NH 2 , C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 1  to C 6  alkoxy, substituted C 1  to C 6  alkoxy, C 1  to C 6  aminoalkyl, and substituted C 1  to C 6  aminoalkyl;  
 R 5  is selected from the group consisting of a), b) and c):  
 a) a substituted benzene ring having the structure:  
                     X is selected from the group consisting of halogen, OH, CN, C 1  to C 3  ally, substituted C 1  to C 3  alkyl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  thioalkyl, substituted C 1  to C 3  thioalkyl, C 1  to C 3  thioalkoxy, substituted C 1  to C 3  thioalkoxy, S(O)alkyl, S(O) 2 alkyl, C 1  to C 3  aminoalkyl, substituted C 1  to C 3  aminoalkyl, NO 2 , C 1  to C 3  perfluoroalkyl, substituted C 1  to C 3  perfluoroalkyl, 5 or 6 membered heterocyclic ring having in its backbone 1 to 3 heteroatoms, CONH 2 , CSNH 2 , CNHNHOH, CNH 2 NOH, CNHNOH, COR B , CSR B , OCOR B , and NR C COR B ;    R B  is selected from the group consisting of H, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, aryl, substituted aryl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, and substituted C 1  to C 3  aminoalkyl;    R C  is H, C 1  to C 3  alkyl, or substituted C 1  to C 3  alkyl;    Y and Z are independently selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 4  alkyl, substituted C 1  to C 4  alkyl, C 1  to C 3  thioalkyl, and substituted C 1  to C 3  thioalkyl;    
 b) a five or six membered heterocyclic ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2  and NR 6  and having one or two independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 4  alkyl, substituted C 1  to C 4  alkyl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, substituted C 1  to C 3  aminoalkyl, COR D , CSR D , and NR E COR D ; 
 R D  is H, NH 2 , C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, aryl, substituted aryl, C 1  to C 3  alkoxy, substituted C 1  to C 3  alkoxy, C 1  to C 3  aminoalkyl, or substituted C 1  to C 3  aminoalkyl;  
 R E  is H, C 1  to C 3  alkyl, or substituted C 1  to C 3  alkyl;  
 R 6  is H, C 1  to C 3  alkyl, substituted C 1  to C 3  alkyl, or C 1  to C 4  CO 2 alkyl; or  
 
 c) an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, wherein said moiety is optionally substituted by from 1 to 3 substituents selected from the group consisting of halogen, alkyl, substituted alkyl, CN, NO 2 , alkoxy, substituted alkoxy, and CF 3 ;  
 Q 1  is S, NR 7 , or CR 8 R 9 ;  
 R 7  is selected from the group consisting of CN, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 8  cycloalkyl, substituted C 3  to CS cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, SO 2 CF 3 , OR 11 , and NR 11 R 12 ;  
 R 8  and R 9  are independently selected from the group consisting of H, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 8  cycloalkyl, substituted C 3  to C 8  cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, NO 2 , CN, and CO 2 R 10 ;  
 R 10  is C 1  to C 3  alkyl or substituted C 1  to C 3  alkyl;  
 or CR 8 R 9  comprise a six membered ring having the structure:  
                     
 R 11  and R 12  are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and substituted sulfonyl; or a tautomer or a pharmaceutically acceptable salt thereof.  
 
     
     
         22 . The method according to  claim 21 , wherein R 5  is the substituted benzene ring of the structure:  
       
         
           
           
               
               
           
         
         X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CONalkyl 2 , CSNalkyl 2 , C 1  to C 3  alkoxy, C 1  to C 3  alkyl, NO 2 , C 1  to C 3  perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 heteroatoms, and C 1  to C 3  thioalkoxy; and  
         Y is a substituent on the 4′ or 5′ position selected from the group consisting of H, halogen, CN, NO 2 , C 1  to C 3  alkoxy, C 1  to C 4  alkyl, and C 1  to C 3  thioalkyl; and  
         Q 1  is S, NR 7 , or CR 8 R 9 ; or a pharmaceutically acceptable salt thereof.  
       
     
     
         23 . The method according to  claim 21 , wherein R 5  is a five membered ring of the structure:  
       
         
           
           
               
               
           
         
         wherein:  
         U is O, S, or NR 6 ;  
         R 6  is H, or C 1  to C 3  alkyl, or C 1  to C 4  CO 2 alkyl;  
         X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CNHNHOH, CNH 2 NOH, CSNH 2 , CONHalkyl, CSNHalkyl, CONalkyl 2 , CSNalkyl 2 , C 1  to C 3  alkyl, and C 1  to C 3  alkoxy;  
         Y′ is selected from the group consisting of H, F and C 1  to C 4  alkyl;  
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         24 . The method according to  claim 21 , wherein R 5  is a thiophene or furan ring.  
     
     
         25 . The method according to  claim 21 , wherein R 5  is a six membered ring of the structure:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X 1  is N or CX 2 ;  
 X 2  is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CONalkyl 2 , CSNalkyl 2  or NO 2 ;  
 R 7  is selected from the group consisting of CN, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 3  to C 8  cycloalkyl, substituted C 3  to C 8  cycloalkyl, aryl, substituted aryl, -heterocyclic, substituted heterocyclic, and SO 2 CF 3 ;  
 R 10  is C 1  to C 3  alkyl; or pharmaceutically acceptable salt thereof.  
 
     
     
         26 . The method according to  claim 21 , wherein the compound is selected from the group consisting of 3-(1′,2′-Dihydro-2′-thioxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzonitrile; 5′-(5-Cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide; 5-(1,2-Dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5′-yl)-1H-pyrrole-2-carbonitrile; 5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-(tert-butoxycarbonyl)-pyrrole-2-carbonitrile; 5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-H-pyrrole-2-carbonitrile; 5-(2′-thioxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1-methyl-pyrrole-2-carbonitrile; 5-(1,2-Dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-3-thiophenecarbonitrile; 5-(1,2-Dihydro-thioxospiro(cyclopentane-1,3-[3H]indol)-5-yl)-2-thiophenecarbonitrile; 5-(3-Fluoro-4-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(2-Amino-5-pyrimidinyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 3-(1,2-Dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-5-fluorobenzonitrile; 3-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-2-yl)-4-fluorobenzonitrile; 5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-2-yl)-3-pyridinecarbonitrile; 5-(3,4-Difluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(5-Chloro-2-thienyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-3-furancarbonitrile; 5-(3-Chloro-4-fluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(3-Chloro-5-fluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(3,5-Difluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-propyl-2-thiophenecarbonitrile; 5-(3-Fluoro-4-nitrophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 4-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-furancarbonitrile;  5″-(3 -Chlorophenyl)spiro[cyclobutane-1,3″-[3H]indole]-2″(1″H)-thione;  5″-(2 -Chlorophenyl)spiro[cyclohexane-1,3″-[3H]indole]-2″(1″H)-thione; 5″-(4-Chlorophenyl)spiro[cyclohexane-1,3″-[3H]indole]-2″(1″H)-thione; 5-(1″,2″-Dihydro-2″thioxospiro[cyclohexane-1,3″-[3H]indol]-5″-yl)-4-methyl-2-thiophenecarbonitrile; 5′-(1″,2″-Dihydro-2″-thioxospiro[cyclohexane-1,3″-[3H]indol]-5″-yl)-2-thiophenecarbonitrile; 5″-(3-Fluorophenyl)spiro[cyclohexane-1,3″-[3H]indole]-2″(1″H)-thione; 5-(3-Hydroxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-[4-Fluoro-3-(trifluoromethyl)phenyl]spiro[cyclohexane-1,3-[3H]indol]-2(1H)-thione; 4-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-fluorobenzonitrile; 5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-n-butyl-2-thiophenecarbonitrile; 5-(3-Fluoro-5-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione; 5-(3-Chlorophenyl)-N-hydroxyspiro[cyclohexane-1,3′-[3H]indol]-2-amine; N-(Acetyloxy)-5′-(3-chlorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2″-amine; 5″-(3-Fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 5′-(2-Fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 5′-(4-Fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 5′-(3,4-Difluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 5′(3-methoxyphenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 5′(3-nitrophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 5′(3-cyanophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime; 3-[1′,2′-Dihydro-2′-(hydroxyimino)spiro[cyclohexane-1,3′-[3H]indol]-5′-yl]-5-fluorobenzonitrile; 5-(spiro[cyclohexane-1,3′-[3H]indol]-2′-(hydroxyimino)-5′-yl)-4-methyl-2-thiophenecarbonitrile; 5-(spiro[cyclohexane-1,3′-[3H]indole]-2′-(hydroxyimino)-5′-yl-2-thiophenecarbonitrile; 4-(Spiro[cyclohexane-1,3′-[3H]indole]-2′-(hydroxyimino)-5′-yl)-2-thiophenecarbonitrile; 5-(spiro[cyclohexane-1,3′-[3H]indole]-2′-(hydroxyimino)-5′-yl)-1H-pyrrole-1-methyl-2-carbonitrile; 5-(spiro[cyclohexane-1,3′-[3H]indol]-2′-(hydroxyimino)-5′-yl)-1H-pyrrole-2-carbonitrile; 4-(spiro[cyclohexane-1,3′-[3H]indole]-2′-(acetoxyimino)-5′-yl)-2-thiophenecarbonitrile; 3-Fluoro-N′-hydroxy-5-[2′-(hydroxyamino)spiro[cyclohexane-1,3′-[3H]indol]-5′-yl]benzenecarboximidamide; N′-hydroxy-5-(spiro[cyclohexane-1,3′-[3H]indole]-2′-(hydroxyimino)-5′-yl)-4-methyl-2-thiophenecarboximidamide; N′-Hydroxy-4-(spiro[cyclohexane-1,3′-[3H]indole]-2′-(hydroxyimino)-5′-yl-2-thiophenecarboximidamide; N′-Hydroxy-5-(spiro[cyclohexane-1,3′-[3H]indol]-2′-(hydroxyimino)-5′-yl)-2-thiophenecarboximidamide; 5′-(3-Chlorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide; 5′-(3-Cyano-5-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide; 5-(3-chlorophenyl)-3,3-dimethyl-1,3-dihydro-2H-indole-2-thione; 3-benzyl-5-(3-chlorophenyl)-3-methyl-1,3-dihydro-2H-indole-2-thione; 4-(3,3-dimethyl-2-thioxo-2,3-dihydro-1H-indol-5-yl)-2-furonitrile; 5-(3-methoxyphenyl)-3,3-dimethyl-1,3-dihydro-2H-indole-2-thione; and 5-(3-chlorophenyl)-3,3-diethyl-1,3-dihydro-2H-indole-2-thione; or a pharmaceutically acceptable salt thereof.