Estrogen receptor modulators

Abstract

The present invention relates to compounds and derivatives thereof, their synthesis, and their use as estrogen receptor modulators. The compounds of the instant invention are ligands for estrogen receptors and as such may be useful for treatment or prevention of a variety of conditions related to estrogen functioning including: bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorders, restinosis, gynacomastia, vascular smooth muscle cell proliferation, obesity, incontinence, and cancer, in particular of the breast, uterus and prostate.

1 - 21 . (canceled)  
     
     
         22 . A method of treating depression in a mammal in need thereof by administering to the mammal a therapeutically effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein X is selected from the group consisting of: O, N—OR a , N—NR a R b  and C 1-6 alkylidene, wherein said alkylidene group is unsubstituted or substituted with hydroxy, amino, O(C 1-4  alkyl), NH(C 1-4  alkyl), or N(C 1-4 alkyl) 2 ; 
 R 1  is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein said alkyl, alkenyl and alkynyl groups are either unsubstituted or substituted OR c , SR c , NR b R c , C(═O)R c , C(═O)CH 2 OH, or phenyl, wherein said phenyl group can either be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of C 1-4 alkyl, OH, O(C 1-4 alkyl), NH 2 , NH(C 1-4 alkyl), NH(C 1-4 alkyl) 2 , halo, CN, NO 2 , CO 2 H, CO 2 (C 1-4 alkyl), C(O)H, and C(O)(C 1-4 alkyl);  
 R 2  is selected from the group consisting of hydrogen, hydroxy, iodo, O(C═O)R c , C(═O)R c , CO 2 R c , C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein said alkyl, alkenyl and alkynyl groups are either unsubstituted or substituted with OR c , SR c , NR b R c , C(═O)R c , C(═O)CH 2 OH, or phenyl, wherein said phenyl group can either be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of C 1-4 alkyl, OH, O(C 1-4 alkyl), NH 2 , NH(C 1-4 alkyl), NH(C 1-4 alkyl) 2 , halo, CN, NO 2 , CO 2 H, CO 2 (C 1-4 alkyl), C(O)H, and C(O)(C 1-4 alkyl); 
 or R 1  and R 2 , when taken together with the carbon atom to which they are attached, form a carbonyl group;  
 or R 1  and R 2 , when taken together, form a C 1-6  alkylidene group, wherein said alkylidene group is either unsubstituted or substituted with a group selected from the group consisting of hydroxy, O(C 1-4 alkyl), N(C 1-4 alkyl) 2 , and phenyl, wherein said phenyl group can either be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of C 1-4 alkyl, OH, O(C 1-4 alkyl), NH 2 , NH(C 1-4 alkyl), NH(C 1-4 alkyl) 2 , halo, CN, NO 2 , CO 2 H, CO 2 (C 1-4 alkyl), C(O)H, and C(O)(C 1-4 alkyl);  
 
 R 3  is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, cyano, NR a R c , OR a , C(═O)R a , CO 2 R c , CONR a R c , SR a , S(═O)R a , SO 2 R a , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl groups are either unsubstituted or independently substituted with 1, 2 or 3 groups selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, OR a , NR a R c , O(C═O)R a , O(C═O)NR a R c , NR a  (C═O)R c , NR a  (C═O)OR c , C(═O)R a , CO 2 R a , CONR a R c , CSNR a R c , SR a , S(O)R a , SO 2 R a , SO 2 NR a R c , YR d , and ZYR d ;  
 R 4  is selected from the group consisting of hydrogen, hydroxy, amino, methyl, CF 3 , fluoro, chloro, and bromo;  
 R 5  and R 6  are each independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, amino, OR b , OR a , O(C═O)R c , O(C═O)OR c , and NH(C═O)R c ;  
 R 7  is selected from the group consisting of hydrogen, OR b , NR b R c , fluoro, chloro, bromo, iodo, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, CF 3 , and CHF 2 ;  
 R 8  and R 9  are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, 
 or R 8  and R 9 , when taken together with the carbon atom to which they are attached, form a 3-5 membered cycloalkyl ring,  
 
 or R 8  and R 9 , when taken together with the carbon atom to which they are attached, form a carbonyl group;  
 R 10  is selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl groups can be optionally substituted with chloro, bromo, iodo, OR b , SR b , C(═O)R b , or 1-5 fluoro, 
 or R 10  and R 1 , when taken together with the three intervening carbon atoms to which they are attached, form a 5-6 membered cycloalkyl ring which can be optionally substituted with C 1-6 alkyl;  
 
 R 11  is selected from the group consisting of hydrogen and C 1-4 alkyl;  
 R a  is selected from the group consisting of hydrogen, C 1-10 alkyl, and phenyl, 
 wherein said alkyl group can be optionally substituted with hydroxy, amino, O(C 1-4 alkyl), NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , phenyl, or 1-5 fluoro, and  
 
 wherein said phenyl groups can either be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of C 1-4 alkyl, OH, O(C 1-4 alkyl), NH 2 , NH(C 1-4 alkyl), NH(C 1-4 alkyl) 2 , halo, CN, NO 2 , CO 2 H, CO 2 (C 1-4 alkyl), C(O)H, and C(O)(C 1-4 alkyl);  
 R b  is selected from the group consisting of hydrogen, C 1-10 alkyl, benzyl and phenyl, wherein said phenyl group can either be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of C 1-4 alkyl, OH, O(C 1-4 alkyl), NH 2 , NH(C 1-4 alkyl), NH(C 1-4 alkyl) 2 , halo, CN, NO 2 , CO 2 H, CO 2 (C 1-4 alkyl), C(O)H, and C(O)(C 1-4 alkyl);  
 R c  is selected from the group consisting of hydrogen, C 1-10  alkyl and phenyl, 
 wherein said phenyl group can either be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of C 1-4 alkyl, OH, O(C 1-4 alkyl), NH 2 , NH(C 1-4 alkyl), NH(C 1-4 alkyl) 2 , halo, CN, NO 2 , CO 2 H, CO 2 (C 1-4 alkyl), C(O)H, and C(O)(C 1-4 alkyl);  
 or R a  and R c , whether or not on the same atom, can be taken together with any attached and intervening atoms to form a 4-7 membered ring;  
 
 R d  is selected from the group consisting of NR b R c , OR a , CO 2 R a , O(C═O)R a , CN, NR c (C═O)R b , CONR a R c , SO 2 NR a R c , and a 4-7 membered N-heterocycloalkyl ring that can be optionally interrupted by O, S, NR c , or C═O;  
 Y is selected from the group consisting of CR b R c , C 2-6 alkylene and C 2-6 alkenylene, wherein said alkylene and alkenylene linkers can be optionally interrupted by O, S, or NR c ;  
 Z is selected from the group consisting of O, S, NR c , C═O, O(C═O), (C═O)O, NR c (C═O) and (C═O)NR c ;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         23 . The method of  claim 22  wherein the compound is of the formula:  
       
         
           
           
               
               
           
         
       
       wherein X is selected from the group consisting of O and N—OR a ; 
 R 1  is selected from the group consisting of hydrogen and C 1-6 alkyl, wherein said alkyl group is either unsubstituted or substituted with OR c  or C(═O)R c ;  
 R 2  is selected from the group consisting of hydrogen, hydroxy, iodo, and C 1-6 alkyl, wherein said alkyl group is either unsubstituted or substituted with OR c  or C(═O)R c ;  
 R 3  is selected from the group consisting of hydrogen, chloro, bromo, iodo, cyano, C 1-10 alkyl, C 2-10 alkenyl, aryl and heteroaryl, wherein said alkyl, alkenyl, aryl and heteroaryl groups are either unsubstituted or independently substituted with 1, 2 or 3 groups selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, OR a , NR a R c , C(═O)R a , CO 2 R c , NR a C(═O)R c , CONR a R c , CSNR a R c , SR a , YR d , and ZYR d ;  
 R 4  is selected from the group consisting of hydrogen, fluoro, hydroxy and methyl;  
 R 5  and R 6  are each independently selected from the group consisting of hydrogen, fluoro, O(C═O)R c  and OR a ;  
 R 7  is selected from the group consisting of hydrogen, NR b R c , chloro, bromo, nitro and C 1-6 alkyl;  
 R 8  and R 9  are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; 
 or R 8  and R 9 , when taken together with the carbon atom to which they are attached, form a carbonyl group;  
 
 R 10  is selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-6 cycloalkyl and cycloalkylalkyl, wherein said alkyl, alkenyl, cycloalkyl and cycloalkylalkyl groups can be optionally substituted with OR b , SR b , C(═O)R b , or 1-5 fluoro; 
 or R 10  and R 1 , when taken together with the three intervening carbon atoms to which they are attached, form a 5-6 membered cycloalkyl ring which can be optionally substituted with C 1-6 alkyl;  
 
 R 11  is selected from the group consisting of hydrogen and C 1-4 alkyl;  
 R a  is selected from the group consisting of hydrogen, C 1-10 alkyl, and phenyl, 
 wherein said alkyl group can be optionally substituted with hydroxy, amino, O(C 1-4 alkyl), NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , phenyl, or 1-5 fluoro;  
 
 R b  is selected from the group consisting of hydrogen, C 1-10 alkyl, benzyl and phenyl;  
 R c  is selected from the group consisting of hydrogen and C 1-10 alkyl and phenyl; 
 or R a  and R c , whether or not on the same atom, can be taken together with any attached and intervening atoms to form a 4-7 membered ring;  
 
 R d  is selected from the group consisting of NR b R c , OR a , CO 2 R a , O(C═O)R a , CN, NR c (C═O)R b , CONR a R c , SO 2 NR a R c , and a 4-7 membered N-heterocycloalkyl ring that can be optionally interrupted by O, S, NR c , or C═O;  
 Y is selected from the group consisting of CR b R c , C 2-6 alkylene and C 2-6 alkenylene, wherein said alkylene and alkenylene linkers can be optionally interrupted by O, S, or NR c ;  
 Z is selected from the group consisting of O, S, NR c , C═O, O(C═O), (C═O)O, NR c (C═O) and (C═O)NR c ;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         24 . The method of  claim 23  wherein X is selected from the group consisting of O, N—OH and N—OCH 3 ; or a pharmaceutically acceptable salt thereof.  
     
     
         25 . The method of  claim 24  wherein R 6  is selected from the group consisting of OR a  and O(C═O)R c ; or a pharmaceutically acceptable salt thereof.  
     
     
         26 . The method of  claim 25  wherein R 3  is selected from the group consisting of hydrogen, chloro, bromo, iodo, cyano, C 1-10 alkyl, aryl and heteroaryl, wherein said alkyl, aryl and heteroaryl groups are either unsubstituted or independently substituted with 1, 2 or 3 groups selected from the group consisting of fluoro, chloro, bromo, cyano, NR a R c , C(═O)R a , CO 2 R c , CONR a R c , SR a , YR d , and ZYR d ; or a pharmaceutically acceptable salt thereof.  
     
     
         27 . The method of  claim 22  wherein the compound is selected from the group consisting of: 
 4-bromo-7-hydroxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (3E)-9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one oxime;    9a-[(1E)-1-butenyl]-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    4-bromo-9a-butyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    4-bromo-9a-butyl-3-methylene-2,3,9,9a-tetrahydro-1H-fluoren-7-ol;    9a-butyl-4-cyano-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    4-benzyl-9a-butyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a butyl-7-hydroxy-4-(2-thienyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-ene;    9a-butyl-7-hydroxy-4-{4-[2-(1-piperidinyl)ethoxy]phenyl}-1,2,9,9a-tetrahydro-3H-fluoren-3-one hydrochloride;    9a-butyl-7-hydroxy-4-(4-hydroxyphenyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (2E)-3-[4-(9a-butyl-7-hydroxy-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-4-yl)phenyl]-2-propenoic acid;    9a-butyl-7-hydroxy-8-methyl-1,2,9,9a-3H-tetrahydro-fluoren-3-one;    4-bromo-9a-butyl-7-hydroxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a butyl-4,8-dimethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-8-chloro-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (2SR,9aSR)-9a-butyl-2,4-dimethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (2SR,9aRS)-9a-butyl-2,4-dimethyl-7-hydroxy-2-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-7-hydroxy-2,2,4-trimethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (2SR,9aRS)-9a-butyl-7-hydroxy-2-iodo-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (2SR,9aRS)-9a-butyl-2,7-dihydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (2RS,9aSR)-9a-butyl-7-hydroxy-2-(2-hydroxyethyl)-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (2SR,9aSR)-2-allyl-9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (2RS,9aSR)-9a-butyl-7-hydroxy-2-(3-hydroxy-2-oxopropyl)-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (9SR,9aSR)-7-hydroxy-4-methyl-9-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-8-chloro-7-hydroxy-4-(trifluoromethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    4-acetyl-9a-butyl-8-chloro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-8-chloro-4-cyano-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-4-ethyl-6-fluoro-7-hydroxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-8-chloro-6-fluoro-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-8-chloro-4-ethyl-6-fluoro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    4-bromo-9a-butyl-8-chloro-6-fluoro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-8-chloro-6-fluoro-7-hydroxy-4-(trifluoromethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    2-hydroxy-5-methylgibba-1 (10a),2,4,4b-tetraen-6-one;    4-bromo-9a-butyl-3-oxo-2,3,9,9a-1H-fluoren-7-yl pivalate;    7-hydroxy-4,9a-dimethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-ethyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    7-hydroxy-4-methyl-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    7-hydroxy-9a-isobutyl-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-4-ethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-7-hydroxy-4-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    4,9a-dibutyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-4-chloro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-7-hydroxy-4-iodo-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-7-hydroxy-4-trifluoromethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-7-hydroxy-4-phenyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-4-(2-furyl)-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    7-hydroxy-9a-(3-iodopropyl)-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    7-hydroxy-4-methyl-9a-(2-methyl-1-propenyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-4-{4-[2-(dimethylamino)ethoxy]phenyl}-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one hydrochloride;    9a-butyl-4-{4-[2-(diethylamino)ethoxy]-phenyl}-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one hydrochloride;    9a-butyl-7-hydroxy-4-{4-[2-(1-pyrrolidinyl)ethoxy]phenyl}-1,2,9,9a-tetrahydro-3H-fluoren-3-one hydrochloride;    9a-butyl-7-hydroxy-4-{4-[2-(4-morpholinyl)ethoxy]phenyl}-1,2,9,9a-tetrahydro-3H-fluoren-3-one hydrochloride;    9a-butyl-4-{4-[3-(dimethylamino)propoxy]-phenyl}-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one hydrochloride;    9a-butyl-7-hydroxy-4-{4-[3-(1-piperidinyl)propoxy]phenyl}-1,2,9,9a-tetrahydro-3H-fluoren-3-one hydrochloride;    (3E)-9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one O-methyloxime;    (2SR,9aSR)-9a-butyl-2-ethyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (2SR,9aSR)-9a-butyl-7-hydroxy-2-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (2SR,9aSR)-9a-butyl-7-hydroxy-4-methyl-2-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (2SR,9aSR)-4,9a-dibutyl-7-hydroxy-2-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (2SR,9aSR)-4-bromo-9a-butyl-7-hydroxy-2-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (2RS,9aSR)-9a-butyl-7-hydroxy-2-(2-oxoethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (2SR,9aSR)-2,9a-dibutyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (2RS,9aRS)-9a-butyl-7-hydroxy-2,4-dimethyl-2-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-7-hydroxy-2,2-dipropyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-7-hydroxy-4-methyl-2,2-dipropyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (2SR,9aRS)-9a-butyl-2,7-dihydroxy-4-methyl-2-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    4-bromo-9a-butyl-2,2-diethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (2SR,9aSR)-7-hydroxy-2,4,9a-trimethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (2SR,9aSR)-7-hydroxy-4,9a-dimethyl-2-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    (2SR,9aSR)-9a-butyl-8-chloro-2-ethyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    8-chloro-9a-ethyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    8-bromo-9a-ethyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-ethyl-7-hydroxy-4,8-dimethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    8-chloro-7-hydroxy-4-methyl-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    8-bromo-7-hydroxy-4-methyl-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    7-hydroxy-4,8-dimethyl-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    8-chloro-7-hydroxy-4-methyl-9a-[(1 E)-1-propenyl]-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    8-bromo-9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-7-hydroxy-4,8-dimethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-7-hydroxy-4-methyl-8-nitro-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    8-amino-9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-7-hydroxy-4-(4-hydroxyphenyl)-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-7-hydroxy-8-methyl-4-{4-[2-piperidinyl)-ethoxy]phenyl}-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    4-bromo-7-hydroxy-9a-propyl-1H-fluorene-3,9(2H,9aH)-dione;    4,8-dibromo-7-hydroxy-9a-propyl-1H-fluorene-3,9(2H,9aH)-dione;    4-bromo-9a-butyl-7-hydroxy-6-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-8-chloro-4-methyl-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-7-yl pivalate;    9a-butyl-6,8-difluoro-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-4-ethyl-6,8-difluoro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    4-bromo-9a-butyl-6,8-difluoro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    8-bromo-9a-butyl-4-chloro-8-difluoro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-butyl-4,8-dibromo-6-fluoro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-ethyl-6-fluoro-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-ethyl-6,8-difluoro-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    8-chloro-9a-ethyl-6-fluoro-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    8-bromo-9a-ethyl-6-fluoro-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-ethyl-6-fluoro-7-hydroxy-4,8-dimethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    4,9a-diethyl-6,8-difluoro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    4-bromo-8-chloro-9a-ethyl-6-fluoro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    4-bromo-8-chloro-9a-(cyclopentylmethyl)-6-fluoro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-ethyl-5-fluoro-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    8-bromo-9a-ethyl-5-fluoro-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-ethyl-6,7-dihydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    8-bromo-9a-ethyl-6,7-dihydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-ethyl-6-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    9a-ethyl-6-hydroxy-4-vinyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    4-allyl-9a-ethyl-6-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    2-hydroxy-5-methyl-7,8,9,10-tetrahydro-7,10a-methanocycloocta[α]inden-6(11H)-one;    7-amino-4-bromo-9a-butyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    7-amino-4,8-dibromo-9a-ethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;    and the pharmaceutically acceptable salts thereof.    
     
     
         28 . The method of  claim 27  wherein the compound is 4-bromo-9a-butyl-8-chloro-6-fluoro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one, or a pharmaceutically acceptable salt thereof.  
     
     
         29 . The method of  claim 28  wherein the compound is 4-bromo-9a-butyl-8-chloro-6-fluoro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one.  
     
     
         30 . The method of  claim 22  further comprising an organic bisphosphonate or a cathepsin K inhibitor, or a pharmaceutically acceptable salt or mixture thereof.  
     
     
         31 . The method of  claim 30  wherein the bisphosphonate is selected from alendronate, clodronate, etidronate, ibandronate, incadronate, minodronate, neridronate, risedronate, piridronate, pamidronate, tiludronate, zoledronate, pharmaceutically acceptable salts, esters or mixtures thereof.  
     
     
         32 . The method of  claim 31  wherein the bisphosphonate is alendronate.