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Details for Patent: 6,127,404

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Details for Patent: 6,127,404

Title: Tissue selective compounds in the treatment of endometrial proliferation
Abstract:The present invention relates to new 2-Phenyl-1-[4-(2-Aminoethoxy)-Benzyl]-Indole compounds which are useful as estrogenic agents, as well as pharmaceutical compositions and methods of treatment utilizing these compounds, which have the general structures below: ##STR1##
Inventor(s): Miller; Chris P. (Strafford, PA), Collini; Michael D. (Clifton Heights, PA), Tran; Bach D. (Media, PA), Santilli; Arthur A. (Havertown, PA)
Assignee: American Home Products Corporation (Madison, NJ)
Filing Date:Sep 02, 1999
Application Number:09/388,580
Claims:1. A method of treating or preventing disease in a mammal which result from proliferation of abnormal development, actions or growth of endometrial or endometrial-like tissue, the method comprising administering to a mammal in need thereof an effective amount of a compound of the formulae: ##STR175## wherein:

R.sub.1 is selected from H, OH, --O--C(O)--C.sub.1 -C.sub.12 alkyl (straight chain or branched), --O--C.sub.1 -C.sub.12 alkyl (straight chain or branched or cyclic), or halogens; or C.sub.1 -C.sub.4 halogenated ethers.

R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently selected from H, OH, --O--C(O)--C.sub.1 -C.sub.12 (straight chain or branched), --O--C.sub.1 -C.sub.12 (straight chain or branched or cyclic), halogens, or C.sub.1 -C.sub.4 halogenated ethers, cyano, C.sub.1 -C.sub.6 alkyl (straight chain or branched), or trifluoromethyl, with the proviso that, when R.sub.1 is H, R.sub.2 is not OH;

X is selected from H, C.sub.1 -C.sub.6 alkyl, cyano, nitro, trifluoromethyl, halogen;

n is 2 or 3;

Y is the moiety; ##STR176## wherein: a) R.sub.7 and R.sub.8 are independently selected from the group of H, C.sub.1 -C.sub.6 alkyl, or phenyl optionally substituted by CN, C.sub.1 -C.sub.6 alkyl (straight chain or branched), C.sub.1 -C.sub.6 alkoxy (straight chain or branched), halogen, --OH, --CF.sub.3, or --OCF.sub.3 ; or

b) R.sub.7 and R.sub.8 are concatenated to form a five-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C.sub.1 -C.sub.4 alkyl, trihalomethyl, C.sub.1 -C.sub.4 alkoxy, trihlomethoxy, C.sub.1 -C.sub.4 acyloxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, hydroxy (C.sub.1 -C.sub.4)alkyl, --CO.sub.2 H, --CN--, --CONHR.sub.1, --NH.sub.2, --NH.sub.2, --NH (C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.4 alkyl).sub.2, --NHSO.sub.2 R.sub.1, --NHCOR.sub.1, --NO.sub.2, or phenyl optionally substituted with 1-3 (C.sub.1 -C.sub.4) alkyl; or

c) R.sub.7 and R.sub.8 are concatenated to form a six-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C.sub.1 -C.sub.4 alkyl, trihalomethyl, C.sub.1 -C.sub.4 alkoxy, trihalomethoxy, C.sub.1 -C.sub.4 acyloxy, C.sub.1 -C.sub.4 alkythio, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, hydroxy (C.sub.1 -C.sub.4)alkyl, --CO.sub.2 H, --CN, --NH.sub.2, --NH(C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.4 alkyl).sub.2, --NHSO.sub.2 R.sub.1, --NHCOR.sub.1, --NO.sub.2, or physical optionally substituted with 1--3 (C.sub.1 -C.sub.4)alkyl; or

d) R.sub.7 and R.sub.8 are concatenated to form a seven-membered saturated heterocycle containing one nitrogen, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C.sub.1 -C.sub.4 alkyl, trihalomethyl, C.sub.1 -C.sub.4 alkoxy, trihalomethoxy, C.sub.1 -C.sub.4 acyloxy, C.sub.1 -C.sub.4 alkythio, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, hydroxy (C.sub.1 -C.sub.4)alkyl, --CO.sub.2 H, --N, --CONHR.sub.1, --NH.sub.2, --NH(C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.4 alkyl).sub.2, --NHSO.sub.2 R.sub.1, --NHCOR.sub.1, --NO.sub.2, or phenyl optionally substituted with 1-3 (C.sub.1 -C.sub.4)alkyl; or

e) R.sub.7 and R.sub.8 are concatenated to form a eight-membered saturated heterocycle containing one nitrogen, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C.sub.1 -C.sub.4 alkyl, trihalomethyl, C.sub.1 -C.sub.4 alkoxy, trihalomethoxy, C.sub.1 -C.sub.4 acyloxy, C.sub.1 -C.sub.4 alkythio, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, hydroxy (C.sub.1 -C.sub.4)alkyl, --CO.sub.2 H, --N, --CONHR.sub.1, --NH.sub.2, --NH(C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.4 alkyl).sub.2, --NHSO.sub.2 R.sub.1, --NHCOR.sub.1, --NO.sub.2, or phenyl optionally substituted with 1-3 (C.sub.1 -C.sub.4)alkyl;

f) R.sub.7 and R.sub.8 are concatenated to form a saturated bicyclic heterocycle containing from 6-12 carbon atoms either bridged or fused and containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C.sub.1 -C.sub.4 alkyl, trihalomethyl, C.sub.1 -C.sub.4 alkoxy, trihalomethoxy, C.sub.1 -C.sub.4 acyloxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, hydroxy, (C.sub.1 -C.sub.4)alkyl, --CO.sub.2 H, --CN, --CONHR.sub.1, --NH.sub.2, --NH(C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.4 alkyl).sub.2, --NHSO.sub.2 R.sub.1, --NHCOR.sub.1, --NO.sub.2, or phenyl optionally substituted with 1-3 (C.sub.1 -C.sub.4)alkyl; or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 wherein the disease in a mammal which results from proliferation or abnormal development, actions or growth of endometrial or endometrial-like tissue is endometrial cancer.

3. The method of claim 1 wherein the disease in a mammal which results from proliferation or abnormal development, actions or growth of endometrial or endometrial-like tissue is endometriosis.

4. The method of claim 1 wherein the disease in a mammal which results from proliferation or abnormal development, actions or growth of endometrial or endometrial-like tissue is endometrial polyps.

5. The method of claim 1 wherein:

R.sub.1 is selected from Ho, OH, --O--C(O)--C.sub.1 -C.sub.4 alkyl or --O--C.sub.1 -C.sub.4 alkyl, halogen;

R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently selected from H, OH, --O--C(O)--(C.sub.1 -C.sub.4 alkyl), --O--(C.sub.1 -C.sub.4 alkyl), halogen, cyano, C.sub.1 -C.sub.6 alkyl, or trifluoromethyl, with the proviso that, when R.sub.1 is H, R.sub.2 is not OH;

X is selected from H, C.sub.1 -C.sub.6 alkyl, cyano, nitro, trifluoromethyl halogen;

Y is the moiety ##STR177## R.sub.7 and R.sub.8 are selected independently from H, C.sub.1 -C.sub.6 alkyl, or combined by --(CH.sub.2)--, wherein p is an integer of from 2 to 6, so as to form a saturated ring, the ring being optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, C.sub.1 -C.sub.4 alkyl, trihalomethyl, C.sub.1 -C.sub.4 alkoxy, trihalomethoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, hydroxy (C.sub.1 -C.sub.4)alkyl, --CO.sub.2 H, --CN, --CONH(C.sub.1 -C.sub.4), --NH.sub.2, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4)alkylamino, --NHSO.sub.2 (C.sub.1 -C.sub.4), --NHCO(C.sub.1 -C.sub.4), or --NO.sub.2 ; or a pharmaceutically acceptable salt thereof.

6. A method of treating or preventing disease in a mammal which result from proliferation or abnormal development, actions or growth of endometrial or endometrial-like tissue, the method comprising administering to a mammal in need thereof an effective amount of a compound of the formulae: ##STR178## wherein: R.sub.1 is selected from H, OH, --O--C(O)--C.sub.1 -C.sub.12 alkyl or --O--C.sub.1 -C.sub.4 alkyl (straight chain or branched), --O--C.sub.1 -C.sub.12 alkyl (straight chain or branched or cyclic), or halogens; or C.sub.1 -C.sub.4 halogenated ethers.

R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently selected from H, OH, --O--C(O)--C.sub.1 -C.sub.12 (straight chain or branched), --O--C.sub.1 -C.sub.12 (straight chain or branched or cyclic), halogens, or C.sub.1 -C.sub.4 halogenated ethers, cyano, C.sub.1 -C.sub.6 alkyl (straight chain or branched), or trifluoromethyl, with the proviso that, when R.sub.1 is H, R.sub.2 is not OH;

X is selected from H, C.sub.1 -C.sub.6 alkyl, cyano, nitro, trifluoromethyl halogen;

n is 2 or 3;

Y is the moiety ##STR179## wherein: a) R.sub.7 and R.sub.8 are independently selected from the group of H, C.sub.1 -CV.sub.6 alkyl, or phenyl optionally substituted by CN, C.sub.1 -C.sub.6 alkyl (straight chain or branched), C.sub.1 -C.sub.6 alkoxy (straight chain or branched), halogen, --OH, --CF.sub.3, or --OCF.sub.3 ; or

b) R.sub.7 and R.sub.8 are concatenated to form a pyrrolidine ring, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C.sub.1 -C.sub.4 alkyl, trihalomethyl, C.sub.1 -C.sub.4 alkoxy, trihalomethoxy, C.sub.1 -C.sub.4 acyloxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, hydroxy (C.sub.1 -C.sub.4)alkyl, --CO.sub.2 H, --CN--, --CONHR.sub.1, --NH.sub.2, --NH(C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.4 alkyl).sub.2, --NHSO.sub.2 R.sub.1, --NHOR.sub.1, or --NO.sub.2 ; or

c) R.sub.7 and R.sub.8 are concatenated to form a piperidine ring, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C.sub.1 -C.sub.4 alkyl, trihalomethyl, C.sub.1 -C.sub.4 alkoxy, trihalomethoxy, C.sub.1 -C.sub.4 acyloxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, hydroxy (C.sub.1 -C.sub.4)alkyl, --CO.sub.2 H, --CN, --CONHR.sub.1, --NH.sub.2, --NH(C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.4 alkyl).sub.2, --NHSO.sub.2 R.sub.1, --NHCOR.sub.1, or --NO.sub.2 ; or

d) R.sub.7 and R.sub.8 are concatenated to form an azepan ring, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C.sub.1 -C.sub.4 alkyl, trihalomethyl, C.sub.1 -C.sub.4 alkoxy, trihalomethoxy, C.sub.1 -C.sub.4 acyloxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, hydroxy (C.sub.1 -C.sub.4)alkyl, --CO.sub.2 H, --CN, --CONHR.sub.1, --NH.sub.2, --NH(C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.4 alkyl).sub.2, --NHSO.sub.2 R.sub.1, --NHCOR.sub.1, --NHCOR.sub.1, or --NO.sub.2 ; or

e) R.sub.7 and R.sub.8 are concatenated to form a bicyclic heterocycle containing from 6-12 carbon atoms either bridged or fused and containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C.sub.1 -C.sub.4 alkyl, trihalomethyl, C.sub.1 -C.sub.4 alkoxy, trihalomethoxy, C.sub.1 -C.sub.4 acyloxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, hydroxy (C.sub.1 -C.sub.4)alkyl, --CO.sub.2 H, --CN, --CONHR.sub.1 ; --NH.sub.2, --NH(C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.4 alkyl).sub.2 ; --NHSO.sub.2 R.sub.1, --NHCOR.sub.1, or --NO.sub.2 ;

or a pharmaceutically acceptable salt thereof.

7. A method of treating or preventing disease in a mammal which result from proliferation or abnormal development, actions or growth of endometrial or endometrial-like tissue, the method comprising administering to a mammal in need thereof an effective amount of a compound of the formulae: ##STR180## wherein: R.sub.1 is selected from H, OH, --O--C(O)--(C.sub.1 -C.sub.4 alkyl), --O--(C.sub.1 -C.sub.4 alkyl), halogen, or C.sub.1 -C.sub.4 halogenated ethers;

R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently selected from H, OH, --O--(O)--(C.sub.1 -C.sub.4 alkyl), --O--(C.sub.1 -C.sub.4 alkyl), halogen, or C.sub.1 -C.sub.4 halogenated ethers, cyano, C.sub.1 -C.sub.6 alkyl (straight chain or branched), or trifluoromethyl, with the proviso that, when R.sub.1 is H, R.sub.2 is not OH;

X is selected from H, C.sub.1 -C.sub.6 alkyl, cyano, nitro, trifluoromethyl, halogen;

n is 2 or 3;

Y is the moiety; ##STR181## wherein R.sub.7 and R.sub.8 are independently selected from the group of H, C.sub.1 -C.sub.6 alky, or phenyl, optionally substituted by CN, C.sub.1 -C.sub.6 alkyl (straight chain or branched), C.sub.1 -C.sub.6 alkoxy (Straight chain or branched), halogen, --OH, --CF.sub.3, or --OCF.sub.3 ; or R.sub.7 and R.sub.8 are concatenated to form a nitrogen containing heterocyclic moiety selected from the group of: ##STR182## the nitrogen containing heterocyclic moiety being optionally substituted by from 1 to 3 groups selected from hydrogen, hydroxy, halo, C.sub.1 -C.sub.4 alkyl, trihalomethyl, C.sub.1 -C.sub.4 alkoxy, trihalomethoxy, C.sub.1 -C.sub.4 alkylthio, --CN, --CO.sub.2 H, --CONHR.sub.1, --NH.sub.2, --NH(C.sub.1 -C.sub.4 alkyl), or --N(C.sub.1 -C.sub.4 alkyl).sub.2 or --NO.sub.2 ;

or a pharmaceutically acceptable salt thereof.

8. The method of claim 7 wherein R.sub.1 is selected from H, OH, --O--C(O)--(C.sub.1 -C.sub.4 alkyl), --O--(C.sub.1 -C.sub.4 alkyl), halogen, or C.sub.1 -C.sub.4 halogenated ethers;

R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently selected from H, OH, --O--C(O)--(C.sub.1 -C.sub.4 alkyl), --O--(C.sub.1 -C.sub.4 alkyl), halogen, or C.sub.1 -C.sub.4 halogenated ethers, cyano, C.sub.1 -C.sub.6 alkyl (straight chain or branched), or trifluoromethyl, with the proviso that, when R.sub.1 is H, R.sub.2 is not OH;

X is selected from H, C.sub.1 -C.sub.6 alkyl, cyano, nitro, trifluoromethyl, halogen;

n is 2 or 3;

Y is the moiety; ##STR183## wherein R.sub.7 and R.sub.8 are independently selected from the group of H or C.sub.1 -C.sub.6 alkyl; or R.sub.7 and R.sub.8 are concatenated to form a nitrogen containing heterocyclic moiety of the group; ##STR184## the nitrogen containing heterocyclic moiety being optionally substituted by from 1 to 3 groups selected from hydrogen, hydroxy, halo, C.sub.1 -C.sub.4 alkyl, trihalomethyl, C.sub.1 -C.sub.4 alkoxy, trihalomethoxy, C.sub.1 -C.sub.4 alkylthio, --CN, --CO.sub.2 H, --CONHR.sub.1, --NH.sub.2, --NH(C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.4 alkyl).sub.2 or --NO.sub.2 ;

or a pharmaceutically acceptable salt thereof.

9. The method of claim 1 in which the compound is is 5-Benzyloxy-2)4-ethoxy-phenyl)3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benz yl]-1H-indole or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 in which the compound is is 5-Benzyloxy-2)phenyl -3-methoxy-1-[4-(2-azepan-1-yl-ethoxy-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof.

11. The method of claim 1 in which the compound is is 5-Benzyloxy-2)4-benzyloxy-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-ben zyl]-1H-indole or pharmaceutically acceptable salt thereof.

12. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-diisopropylamino-1-yl- ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-butyl-methylamino-1-yl -ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof.

14. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-dimethylamino)-ethoxy}-1H -indole or a pharmaceutically acceptable salt thereof.

15. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-[2-(3-methyl-piperidin-1- yl)-ethoxy]-benzyl}-1H-indole or a pharmaceutically acceptable salt thereof.

16. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-[2-(3-methyl-piperidin-1- yl)-ethoxy]-benzyl}-1H-indole or a pharmaceutically acceptable salt thereof.

17. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{(4-[2-(4-methyl-piperidin-1 -yl)-ethoxy]-benzyl}-1H-indole or a pharmaceutically acceptable salt thereof.

18. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-[2-((cis)-2,6-Dimethyl-pi peridin-1-yl)-ethoxy]-benzyl}-1H-indole or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-{4-[2-(1,3,3-trimethyl-6-aza-b icyclo[3.2.1]oct-6-yl)-ethoxy]-benzyl}-1H-indole or a pharmaceutically acceptable salt thereof.

20. The method of claim 1 in which the compound is is (1S, 4R)-5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-{4-2-(2-Aza-bicyclo [2.2.1]hept-2-yl)-ethoxy]-benzyl}-1H-indole or a pharmaceutically acceptable salt thereof.

21. The method of claim 1 in which the compound is is is 5-Benzyloxy-2-(4-fluoro-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzy l]-1H-indole or a pharmaceutically acceptable salt thereof.

22. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-fluoro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-be nzyl}-1H-indole or a pharmaceutically acceptable salt thereof.

23. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-chloro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-be nzyl]-1H-indole or a pharmaceutically acceptable salt thereof.

24. The method of claim 1 in which the compound is is 5-Benzyloxy-2-[3,4-methylenedioxy-phenyl]-3-methyl-1-[4-(2-piperidin-1-yl- ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof.

25. The method of claim 1 in which the compound is is 5-Benzyloxy-2-[4-isopropoxy-phenyl]-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy )-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof.

26. The method of claim 1 in which the compound is is 5-Benzyloxy-2-[4-methyl-phenyl]-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-be nzyl]-1H-indole or a pharmaceutically acceptable salt thereof.

27. The method of claim 1 in which the compound is is 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(3-benzyloxy-phenyl)-3-m ethyl-1H-indole or a pharmaceutically acceptable salt thereof.

28. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-benzyloxy-3-fluoro-phenyl)-3-methyl-1-[4-(2-piperidin-1-y l-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof.

29. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-benzyloxy-3-fluoro-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-e thoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof.

30. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(3-methoxy-phenyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-3-m ethyl-1H-indole or a pharmaceutically acceptable salt thereof.

31. The method of claim 1 in which the compound i is 5-Benzyloxy-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-(4-trifluoro methoxy-phenyl)-1H-indole or a pharmaceutically acceptable salt thereof.

32. The method of claim 1 in which the compound is (2-{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-yl-methyl]-phen oxy}-ethyl)-cyclohexyl-amine or a pharmaceutically acceptable salt thereof.

33. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-(4-methylpiperazin-1-yl)-eth oxy]-benzyl{-1H-indole or a pharmaceutically acceptable salt thereof.

34. The method of claim 1 in which the compound is is 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(3-methoxy-phenyl)-3-met hyl-1H-indole or a pharmaceutically acceptable salt thereof.

35. The method of claim 1 in which the compound is is 4-{3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol} (HCl).

36. The method of claim 1 in which the compound is is 4-[3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-2-yl}-phenol hydrochloride (HCl).

37. The method of claim 1 in which the compound is is 3-Methyl-2-phenyl-1-[4-(2-piperidine-1-yl-ethoxy)-benzyl]-1H-indol-5-ol (HCl).

38. The method of claim 1 in which the compound is is 4-{5-Methoxy-3-methyl-1-{4-[2-(piperidin-1-yl)-ethoxy]-benzyl}-1H-indol-2- yl}-phenol or a pharmaceutically acceptable salt thereof.

39. The method of claim 1 in which the compound is is 2-(4-methoxy-phenyl)-3-methyl-1-{4-[2-(piperidin-1-yl)-ethoxy]-benzyl}-1H- indol-5-ol or a pharmaceutically acceptable salt thereof.

40. The method of claim 1 in which the compound is is 5-Methoxy-2-(4-methoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-ben zyl]-1H-indole (HCl).

41. The method of claim 1 in which the compound is is 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-methoxy-2-(4-methoxy-phenyl)-3-methy l-1H-indole (HCl).

42. The method of claim 1 in which the compound is is 2-(4-Ethoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-ind ol-5-ol or a pharmaceutically acceptable salt thereof.

43. The method of claim 1 in which the compound is is 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-ethoxy-phenyl)-3-methyl-1H-indol- 5-ol or a pharmaceutically acceptable salt thereof.

44. The method of claim 1 in which the compound is is 4-{5-Fluoro-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-2-yl} -phenol (HCl).

45. The method of claim 1 in which the compound is is 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-3-methyl-2-phenyl-1H-indol-5-ol (HCl).

46. The method of claim 1 in which the compound is is 2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-pyrollidin-1-yl-ethoxy)-benzyl]-1H-i ndol-5-ol or a pharmaceutically acceptable salt thereof.

47. The method of claim 1 in which the compound is is 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol -5-ol (HCl).

48. The method of claim 1 in which the compound is is 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol -5-ol Acetate Salt.

49. The method of claim 1 in which the compound is is 1-[4-(2-Azocan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol -5-ol or a pharmaceutically acceptable salt thereof.

50. The method of claim 1 in which the compound is is 2-(4-Hydroxy-phenyl)3-methyl-1-[4-(2-dimethyl-1-yl-ethoxy)-benzyl]-1H-indo l-5-ol or a pharmaceutically acceptable salt thereof.

51. The method of claim 1 in which the compound is is 2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-diethyl-1-yl-ethoxy)-benzyl]-1H-indo l-5-ol or a pharmaceutically acceptable salt thereof.

52. The method of claim 1 in which the compound is is 1-[4-(2-Dipropylamino-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-ind ol-5-ol or a pharmaceutically acceptable salt thereof.

53. The method of claim 1 in which the compound is is 1-[4-(2-Dibutylamino-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indo l-5-ol or a pharmaceutically acceptable salt thereof.

54. The method of claim 1 in which the compound is is 1-[4-(2-Diisopropylamino-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H- indol-5-ol or a pharmaceutically acceptable salt thereof.

55. The method of claim 1 in which the compound is is 1-{4-[2-Butyl-methyl-amino)-ethoxy]-benzyl}-2-(4-hydroxy-phenyl)-3-methyl- 1H-indol-5-ol or a pharmaceutically acceptable salt thereof.

56. The method of claim 1 in which the compound is is 2-(4-Hydroxy-phenyl)-3-methyl-1-{4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-be nzyl}-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.

57. The method of claim 1 in which the compound is is 2-(4-Hydroxy-phenyl)-3-methyl-1-{4-[2-(3-methyl-piperdin-1-yl)-ethoxy]-ben zyl}-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.

58. The method of claim 1 in which the compound is is 2-(4-Hydroxy-phenyl)-3-methyl-1-{4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-be nzyl}-1H-indol-5-ol (HCl).

59. The method of claim 1 in which the compound is is 1-{4-[2-(3,3-Dimethyl-piperidin-1-yl)-ethoxy]-benzyl}-2-(4-hydroxy-phenyl) -3-methyl-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.

60. The method of claim 1 in which the compound is is 1-{4-[2-((cis)-2,6-Dimethyl-piperidin-1-yl)-ethoxy]-benzyl}-2-(4-hydroxy-p henyl)-3-methyl-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.

61. The method of claim 1 in which the compound is is 2-(4-Hydroxy-phenyl)-1-{4-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-benzyl}-3- methyl-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.

62. The method of claim 1 in which the compound is is (1S, 4R)-1-{4-[2-(2-Aza-bicyclo [2.2.1] hept-2-yl)-ethoxy]-benzyl}-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.

63. The method of claim 1 in which the compound is is 2-(4-Hydroxy-phenyl)-3-methyl-1-{4-[2-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)-ethoxy]-benzyl}-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.

64. The method of claim 1 in which the compound is is 2-(4-Fluoro-phenyl)-3-methyl-1-[4-(2-piperidine-1-yl-ethoxy)-benzyl]-1H-in dol-5-ol (HCl).

65. The method of claim 1 in which the compound is is 1-[4-(2-Azepan-1-yl-ethoxy]-2-(4-fluoro-phenyl)-3-methyl-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.

66. The method of claim 1 in which the compound is is 2-(3-Methoxy-4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy]-1H- indol-5-ol (HCl).

67. The method of claim 1 is which the compound is is 2-Benzo[1,3]dioxol-5-yl-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H -indol-5-ol (HCl).

68. The method of claim 1 in which the compound is is 2-(4-Isopropoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H -indol-5-ol (HCl).

69. The method of claim 1 in which the compound is is 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-isopropoxy-phenyl)-3-methyl-1H-in dol-5-ol (HCl).

70. The method of claim 1 in which the compound is is 2-(4-Cyclopenyloxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl] -1H-indol-5-ol or a pharmaceutically acceptable salt thereof.

71. The method of claim 1 in which the compound is is 3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-(4-trifluoromethyl-pheny l)-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.

72. The method of claim 1 in which the compound is is 3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-p-tolyl-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.

73. The method of claim 1 in which the compound is is 2-(4-Chloro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-ind ol-5-ol (HCl).

74. The method of claim 1 in which the compound is is 2-(2,4-Dimethoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1 H-indol-5-ol or a pharmaceutically acceptable salt thereof.

75. The method of claim 1 in which the compound is is 2-(3-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-in dol-5-ol or a pharmaceutically acceptable salt thereof.

76. The method of claim 1 in which the compound is is 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(3-hydroxy-phenyl)-3-methyl-1H-indol e-5-ol or a pharmaceutically acceptable salt thereof.

77. The method of claim 1 in which the compound is is 2-(3-Fluoro-4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benz yl]-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.

78. The method of claim 1 in which the compound is is 2-(3-Fluoro-4-hydroxy-phenyl)-3-methyl-1-[4-(azepan-1-yl-ethoxy]-1H-indol- 5-ol or a pharmaceutically acceptable salt thereof.

79. The method of claim 1 in which the compound is is 2-(3-Methoxy-phenyl)-3-methyl-1-[4-2-piperidin-1-yl-ethoxy]-1H-indole-5-ol or a pharmaceutically acceptable salt thereof.

80. The method of claim 1 in which the compound is is 3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-(4-trifluoromethoxy-phen yl)-1H-indole-5-ol or a pharmaceutically acceptable salt thereof.

81. The method of claim 1 in which the compound is is 3-Chloro-2-(4-hydroxy-phenyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)-benzyl]-1H-i ndol-5-ol (HCl).

82. The method of claim 1 in which the compound is is 3-Chloro-2-(4-hydroxy-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-in dol-5-ol (HCl).

83. The method of claim 1 in which the compound is is 3-Chloro-2-(4-hydroxy-phenyl)-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indol -5-ol (HCl).

84. The method of claim 1 in which the compound is is 3-Chloro-2-(4-hydroxy-2-methyl-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benz yl]-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.

85. The method of claim 1 in which the compound is is 2-(4-Hydroxy-phenyl)-3-ethyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-ind ol-5-ol (HCl).

86. The method of claim 1 in which the compound is is 5-Hydroxy-2-(4-Hydroxy-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-i ndole-3-carbonitrile (HCl).

87. The method of claim 1 in which the compound is is 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-hydroxy-2-(4-hydroxy-phenyl)-1H-indo le-3-carbonitrile (HCl).

88. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-chloro-1-[4-(2-piperidin-1-yl-ethoxy) -benzyl]-1H-indole or a pharmaceutically acceptable salt thereof.

89. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-chloro-1-[4-(2-azepan-1-yl-ethoxy)-be nzyl]-1H-indole or a pharmaceutically acceptable salt thereof.

90. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(2-methyl-4-benzyloxy-phenyl)-3-chloro-1-[4-(2-piperidin-1-y l-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof.

91. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-ethyl-1-4-(2-piperidin-1-yl-ethoxy)-b enzyl]-1H-indole or a pharmaceutically acceptable salt thereof.

92. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-cyano-1-[4-(2-piperidin-1-yl-ethoxy)- benzyl]-1H-indole or a pharmaceutically acceptable salt thereof.

93. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-cyano-1-[4-(2-azepan-1-yl-ethoxy)-ben zyl]-1H-indole or a pharmaceutically acceptable salt thereof.

94. The method of claim 1 in which the compound is is Di-propionate of 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol -5-ol.

95. The method of claim 1 in which the compound is is Di-pivalate of 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol -5-ol.

96. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(3-piperidin-1-yl-propoxy)-benzyl] -3-methyl-1H-indole or a pharmaceutically acceptable salt thereof.

97. The method of claim 1 in which the compound is is 2-(4-Hydroxy-phenyl)-3-methyl-1-{4-[3-(piperidin-1-yl-propoxy]-benzyl}-1H- indol-5-ol or a pharmaceutically acceptable salt thereof.

98. The method of claim 1 in which the compound is is 2-(4-Hydroxy-phenyl)-1-[3-methoxy-4-(2-piperidin-1-yl-ethoxy)-benzyl]-3-me thyl-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.

99. The method of claim 1 in which the compound is is 2-(4-Hydroxy-phenyl)-1-[3-methoxy-4-(2-azepan-1-yl-ethoxy)-benzyl]-3-methy l-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.

100. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[3-Methoxy-4-(2-piperidin-1- yl-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof.

101. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[2-Methoxy-4-(2-azepan-1-yl- ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof.

102. The method of claim 1 in which the compound is is Di-pivalate ester of 2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-in dol-5-ol.

103. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy) -benzyl]-1H-indole or a pharmaceutically acceptable salt thereof.

104. The method of claim 1 in which the compound is is 5-Benzyloxy-2-(3-benzyloxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy) -benzyl]-1H-indole or a pharmaceutically acceptable salt thereof.

105. The method of claim 1 in which the compound is is 2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-in dol-5-ol or a pharmaceutically acceptable salt thereof.

106. The method of claim 1 in which the compound is is 2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-in dol-5-ol methiodide.

107. The method of claim 1 in which the compound is is 2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-dimethyl-1-yl-ethoxy)-1H-indol-5-ol methiodide.
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