Novel Spiro-benzo[c]chromene derivatives useful as modulators of the estrogen receptors

Abstract

The present invention is directed to novel spiro-benzo[C]chromene derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders mediated by one or more estrogen receptors. The compounds of the invention are useful in the treatment of disorders associated with the depletion of estrogen such as hot flashes, vaginal dryness, osteopenia and osteoporosis; hormone sensitive cancers and hyperplasia of the breast, endometrium, cervix and prostate; endometriosis, uterine fibroids, osteoarthritis and as contraceptive agents, alone or in combination with a progestogen or progestogen antagonist.

1 - 7 . (canceled) 
   
   
       8 . A method of treating a disorder mediated by an estrogen receptor, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) 
     
       
         
         
             
             
         
       
       wherein 
          represents a single or double bond, 
       X Y are selected from the group consisting of O, S, SO and SO 2 ; 
       Z is selected from the group consisting of O and S;
 R 1  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heteroaryl-alkyl; wherein the cycloalkyl, aryl, aralkyl, heteroaryl or heteroaryl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, —SH, —S(alkyl), SO 2 , NO 2 , CN, CO 2 H, R C , —OR C , —SO 2 —NR D R E , —NR D R E , NR D —SO 2 —R F , -(alkyl) 0-4 -C(O)NR D R E , (alkyl) 0-4 -NR D —C(O)—R F , -(alkyl) 0-4 -(Q) 0-1 -(alkyl) 0-4 -NR D R E , -(alkyl) 0-4 -(Q) 0-1 -(alkyl) 0-4 -C(O)—OR F , -(alkyl) 0-4 -(Q) 0-1 -(alkyl) 0-4 -C(O)—NR D R E  or -(alkyl) 0-4 -C(O)-(alkyl) 0-4 -C(O)—OR F ; 
 wherein R C  is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl; wherein the cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, —SH, —S(alkyl), SO 2 , NO 2 , CN, CO 2 H, R C , —SO 2 —NR D R E , NR D R E , NR D —SO 2 —R F , -(alkyl) 0-4 -C(O)—NR D R E , -(alkyl) 0-4 -NR D —C(O)—R F , -(alkyl) 0-4 -(Q) 0-1 -(alkyl) 0-4 -NR D R E , -(alkyl) 0-4 -(Q) 0-1 -(alkyl) 0-4 -C(O)—OR F , -(alkyl) 0-4 -(Q) 0-1 -(alkyl) 0-4 -C(O)—NR D R E  or -(alkyl) 0-4 -C(O)-(alkyl) 0-4 -C(O)—OR F ; 
 wherein Q is selected from the group consisting of O, S, NH, N(alkyl) and —CH═CH—; 
 wherein R D  and R E  are each independently selected from the group consisting of hydrogen and alkyl; alternatively R D  and R E  are taken together with the nitrogen atom to which they are bound to form a 4 to 8 membered ring selected from the group consisting of heteroaryl or heterocycloalkyl; wherein the heteroaryl or heterocycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano; 
 wherein R F  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl; wherein the cycloalkyl, aryl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano; 
 R 2  is selected from the group consisting of hydroxy, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heteroaryl-alkyl; wherein the cycloalkyl, aryl, aralkyl, heteroaryl or heteroaryl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, —SH, —S(alkyl), SO 2 , NO 2 , CN, CO 2 H, R C , —OR C , —SO 2 —NR D R E , —NR D R E , NR D —SO 2 —R F , -(alkyl) 0-4 -C(O)NR D R E , (alkyl) 0-4 -NR D —C(O)—R F , -(alkyl) 0-4 -(Q) 0-1 -(alkyl) 0-4 -NR D R E , -(alkyl) 0-4 -(Q) 0-1 -(alkyl) 0-4 -C(O)—OR F , -(alkyl) 0-4 -(Q) 0-1 -(alkyl) 0-4 -C(O)—NR D R E  or -(alkyl) 0-4 -C(O)-(alkyl) 0-4 -C(O)—OR F ; 
 alternatively R 1  and R 2  are taken together with the carbon atom to which they are bound to form C(O); 
 m is an integer selected from 0 to 4; 
 R 3  is independently selected from the group consisting of halogen, hydroxy, R C , amino, alkylamino, dialkylamino, nitro, cyano, SO 2 , —C(O)R G , —C(O)OR G , —OC(O)R G , —OC(O)OR G , —OC(O)N(R G ) 2 , —N(R G )C(O)R G , —OSi(R G ) 3 —OR G , —SO 2 N(R G ) 2 , —O-(alkyl) 1-4 -C(O)R G  and —O-(alkyl) 1-4 -C(O)OR G ; 
 
     
     wherein each R G  is independently selected from hydrogen, alkyl, aryl, aralkyl and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-3-one; wherein the alkyl, aryl or aralkyl group is optionally substituted with one or more substituents independently selected from alkyl, halogenated alkyl, alkoxy, halogen, hydroxy, nitro, cyano, —OC(O)-alkyl or —C(O)O-alkyl;
 alternatively two R G  groups are taken together with the nitrogen atom to which they are bound to form a heterocycloalkyl group; wherein the heterocycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano; 
 1 is an integer selected from 0, 1. 
 
   
   
       9 . The method of  claim 8 , wherein the disorder mediated by an estrogen receptor is selected from the group consisting of hot flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, loss of cognitive function, degenerative brain diseases, cardiovascular diseases, cerebrovascular diseases, cancer of the breast tissue, hyperplasia of the breast tissue, cancer of the endometrium, hyperplasia of the endometrium, cancer of the cervix, hyperplasia of the cervix, cancer of the prostate, hyperplasia of the prostate, endometriosis, uterine fibroids, osteoarthritis and contraception. 
   
   
       10 . The method of  claim 8 , wherein the disorder mediated by an estrogen receptor is selected from the group consisting of osteoporosis, hot flashes, vaginal dryness, breast cancer and endometriosis. 
   
   
       11 . A method of treating a disorder mediated by an estrogen receptor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the composition of claim  6 . 
   
   
       12 . A method of contraception comprising co-therapy with a therapeutically effective amount of a compound of formula (I) 
     
       
         
         
             
             
         
       
       wherein 
          represents a single or double bond, 
       X, Y are selected from the group consisting of O, S, SO and SO 2 ; 
       Z is selected from the group consisting of O and S;
 R 1  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heteroaryl-alkyl; wherein the cycloalkyl, aryl, aralkyl, heteroaryl or heteroaryl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, —SH, —S(alkyl), SO 2 , NO 2 , CN, CO 2 H, R C , —OR C , —SO 2 —NR D R E , —NR D R E , NR D —SO 2 —R F , -(alkyl) 0-4 -C(O)NR D R E , (alkyl) 0-4 -NR D —C(O)—R F , -(alkyl) 0-4 -(Q) 0-1 -(alkyl) 0-4 -NR D R E , -(alkyl) 0-4 -(Q) 0-1 -(alkyl) 0-4 -C(O)—OR F , -(alkyl) 0-4 -(Q) 0-1 -(alkyl) 0-4 -C(O)—NR D R E  or -(alkyl) 0-4 -C(O)-(alkyl) 0-4 -C(O)—OR F ; 
 wherein R C  is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl; wherein the cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, —SH, —S(alkyl), SO 2 , NO 2 , CN, CO 2 H, R C , —SO 2 —NR D R E , NR D R E , NR D —SO 2 —R F , -(alkyl) 0-4 -C(O)—NR D R E , -(alkyl) 0-4 -NR D —C(O)—R F , -(alkyl) 0-4 -(Q) 0-1 -(alkyl) 0-4 -NR D R E , -(alkyl) 0-4 -(Q) 0-1 -(alkyl) 0-4 -C(O)—OR F , -(alkyl) 0-4 -(Q) 0-1 -(alkyl) 0-4 -C(O)—NR D R E  or -(alkyl) 0-4 -C(O)-(alkyl) 0-4 -C(O)—OR F ; 
 wherein Q is selected from the group consisting of O, S, NH, N(alkyl) and —CH═CH—; 
 wherein R D  and R E  are each independently selected from the group consisting of hydrogen and alkyl; alternatively R D  and R E  are taken together with the nitrogen atom to which they are bound to form a 4 to 8 membered ring selected from the group consisting of heteroaryl or heterocycloalkyl; wherein the heteroaryl or heterocycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano; 
 wherein R F  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl; wherein the cycloalkyl, aryl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano; 
 R 2  is selected from the group consisting of hydroxy, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heteroaryl-alkyl; wherein the cycloalkyl, aryl, aralkyl, heteroaryl or heteroaryl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, —SH, —S(alkyl), SO 2 , NO 2 , CN, CO 2 H, R C , —OR C , —SO 2 —NR D R E , —NR D R E , NR D —SO 2 —R F , -(alkyl) 0-4 -C(O)NR D R E , (alkyl) 0-4 -NR D —C(O)—R F , -(alkyl) 0-4 -(Q) 0-1 -(alkyl) 0-4 NR D R E , -(alkyl) 0-4 -(Q) 0-1 -(alkyl) 0-4 -C(O)—OR F , -(alkyl) 0-4 -(Q) 0-1 -(alkyl) 0-4 -C(O)—NR D R E  or -(alkyl) 0-4 -C(O)-(alkyl) 0-4 -C(O)—OR F ; 
 alternatively, R 1  and R 2  are taken together with the carbon atom to which they are bound to form C(O); 
 m is an integer selected from 0 to 4; 
 R 3  is independently selected from the group consisting of halogen, hydroxy, R C , amino, alkylamino, dialkylamino, nitro, cyano, SO 2 , —C(O)R G , —C(O)OR G , —OC(O)R G , —OC(O)OR G , —OC(O)N(R G ) 2 , —N(R G )C(O)R G , —OSi(R G ) 3 —OR G , —SO 2 N(R G ) 2 , —O-(alkyl) 1-4 -C(O)R G  and —O-(alkyl) 1-4 -C(O)OR G ; 
 
     
     wherein each R G  is independently selected from hydrogen, alkyl, aryl, aralkyl, and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-3-one; wherein the alkyl, aryl or aralkyl group is optionally substituted with one or more substituents independently selected from alkyl, halogenated alkyl, alkoxy, halogen, hydroxy, nitro, cyano, —OC(O)-alkyl or —C(O)O-alkyl;
 alternatively two R G  groups are taken together with the nitrogen atom to which they are bound to form a heterocycloalkyl group; wherein the heterocycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano; 
 1 is an integer selected from 0, 1. 
 
     and a progestogen or a progestogen antagonist.