LXR agonists and uses thereof

Abstract

This invention features compounds that modulate the activity of liver X receptors, pharmaceutical compositions including the compounds of the invention, and methods of utilizing those compositions for modulating the activity of liver X receptors in the treatment of cancer.

Claims

1. A compound of Formula I: ##STR00262## wherein A is: ##STR00263## wherein e is 0, 1, 2, 3, or 4; R.sup.A is optionally substituted C.sub.1-C.sub.6 acyl, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.4-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.12 cycloalkynyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, 8F optionally substituted C.sub.2-C.sub.9 heterocyclyl C.sub.1-C.sub.6 alkyl; each R.sup.B is independently hydroxyl, optionally substituted amino, halo, thiol, optionally substituted amino acid, optionally substituted C.sub.1-C.sub.6 acyl, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.8-C.sub.12 cycloalkenyl, optionally substituted C.sub.4-C.sub.10 cycloalkynyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl C.sub.1-C.sub.6 alkyl; and L is O; a is 2 or 3; b is 1; c is 0; d is 1; each R.sup.1, R.sup.2, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently hydrogen or optionally substituted C.sub.1-C.sub.6 alkyl; R.sup.3 is hydrogen, halo, or optionally substituted C.sub.1-C.sub.6 alkyl; R.sup.4 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, or optionally substituted C.sub.6-C.sub.10 aryl; R.sup.5 is optionally substituted C.sub.6-C.sub.10 aryl; and B is optionally substituted C.sub.6-C.sub.10 aryl; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein each R.sup.6 and R.sup.7 is hydrogen.

3. The compound of claim 1, wherein R.sup.3 is hydrogen.

4. The compound of claim 1, wherein R.sup.4 is hydrogen, phenyl, cyclohexyl, or methyl.

5. The compound of claim 1, wherein R.sup.5 is phenyl.

6. The compound of claim 1, wherein each R.sup.8 and R.sup.9 is hydrogen.

7. The compound of claim 1, wherein (CR.sup.1R.sup.2).sub.a has the structure: ##STR00264##

8. The compound of claim 7, wherein (CR.sup.1R.sup.2).sub.3 has the structure: ##STR00265##

9. The compound of claim 1, wherein said compound has the structure: ##STR00266##

10. The compound of claim 1, wherein said optionally substituted C.sub.6-C.sub.10 aryl is 2-chloro-3-trifluoromethyl-phenyl, 2-fluoro-3-trifluoromethyl-phenyl, 3-(1,1,2,2-tetrafluoroethoxy)-phenyl, 3-trifluoromethyl-phenyl, 3-trifluoromethyl-4-fluoro-phenyl, or 3-trifluoromethoxy-phenyl.

11. The compound of claim 10, wherein B is 2-chloro-3-trifluoromethyl-phenyl, 2-fluoro-3-trifluoromethyl-phenyl, or 3-trifluoromethyl-phenyl.

12. The compound of claim 11, wherein B is 2-chloro-3-trifluoromethyl-phenyl.

13. A compound, or pharmaceutically acceptable salt thereof, selected from: ##STR00267## ##STR00268## ##STR00269## ##STR00270## ##STR00271## ##STR00272## ##STR00273## (2-fluoro-6-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)methanol, (2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl) methanol, (2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl) methanol, (4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl) methanol, (4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl) methanol, [2-fluoro-4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]methanol, [2-fluoro-4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]methanol, [2-fluoro-4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]methanol, [2-fluoro-4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]methanol, {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4-fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methanol, [4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6-methanesulfonylphenyl]methanol, [4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6-methanesulfonylphenyl]methanol, {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methanol, {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methanol, {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methanol, {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methanol, {2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}methanol, {2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-6-methanesulfonylphenyl}methanol, {2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}methanol, {2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-6-methanesulfonylphenyl}methanol, {2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-6-methanesulfonylphenyl}methanol, {2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-6-methanesulfonylphenyl}methanol, {2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-6-methanesulfonylphenyl}methanol, (2-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl) methanol, (2-methanesulfonyl-4-{3-[(2-phenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)methanol, (2-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)methanol, {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-methanesulfonylphenyl}methanol, (4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl) methanol, (4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl) methanol, (4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl) methanol, (4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl) methanol, (4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl) methanol, [4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]methanol, [4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]methanol, [4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]methanol, [4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]methanol, {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}methanol, [4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]methanol, [4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]methanol, {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}methanol, {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-methanesulfonylphenyl}methanol, {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}methanol, {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}methanol, {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}methanol, {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}methanol, {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}methanol, {4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}methanol, {4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-methanesulfonylphenyl}methanol, {4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}methanol, {4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}methanol, {4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}methanol, {4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}methanol, {4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl) propyl]amino)propoxy]-2-methanesulfonylphenyl}methanol, [3-(3-methanesulfonylphenoxy)propyl](2-methyl-2-phenylpropyl){[3-(trifluoromethyl)phenyl]methyl}amine, [3-(3-methanesulfonylphenoxy)propyl](2-phenylethyl){[3-(trifluoromethyl)phenyl]methyl}amine, [3-(3-methanesulfonylphenoxy)propyl](2-phenylpropyl){[3-(trifluoromethyl)phenyl]methyl}amine, (2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})[3-(3-methanesulfonylphenoxy)propyl]amine, (2,2-diphenylethyl)[3-(3-methanesulfonylphenoxy)propyl]{[3-(trifluoromethyl)phenyl]methyl}amine, benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})[3-(3-methanesulfonylphenoxy)propyl]amine, benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})[3-(3-methanesulfonylphenoxy)propyl]amine, benzyl[3-(3-methanesulfonylphenoxy)propyl]{[3-(trifluoromethyl)phenyl]methyl}amine, [(4-fluorophenyl)methyl][3-(3-methanesulfonylphenoxy)propyl]{[3-(trifluoromethyl)phenyl]methyl}amine, [2-(4-fluorophenyl)-2-methylpropyl][3-(3-methanesulfonylphenoxy)propyl]{[3-(trifluoromethyl)phenyl]methyl}amine, [2-(4-fluorophenyl)ethyl][3-(3-methanesulfonylphenoxy)propyl]{[3-(trifluoromethyl)phenyl]methyl}amine, [2-(4-fluorophenyl) propyl][3-(3-methanesulfonylphenoxy)propyl]{[3-(trifluoromethyl)phenyl]methyl}amine, {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4-fluorophenyl)ethyl][3-(3-methanesulfonylphenoxy)propyl]amine, [2,2-difluoro-2-(4-fluorophenyl) ethyl]({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})[3-(3-methanesulfonylphenoxy)propyl]amine, [2,2-difluoro-2-(4-fluorophenyl) ethyl][3-(3-methanesulfonylphenoxy)propyl]{[3-(trifluoromethyl)phenyl]methyl}amine, {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[3-(3-methanesulfonylphenoxy)propyl](2-methyl-2-phenylpropyl)amine, {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[3-(3-methanesulfonylphenoxy)propyl](2-phenylethyl)amine, {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[3-(3-methanesulfonylphenoxy)propyl](2-phenylpropyl)amine, {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl][3-(3-methanesulfonylphenoxy)propyl]amine, {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl][3-(3-methanesulfonylphenoxy)propyl]amine, {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl][3-(3-methanesulfonylphenoxy)propyl]amine, {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl) propyl][3-(3-methanesulfonylphenoxy)propyl]amine, {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[3-(3-methanesulfonylphenoxy)propyl](2-methyl-2-phenylpropyl)amine, {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[3-(3-methanesulfonylphenoxy)propyl](2-phenylethyl)amine, {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[3-(3-methanesulfonylphenoxy)propyl](2-phenylpropyl)amine, {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl][3-(3-methanesulfonylphenoxy)propyl]amine, {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl][3-(3-methanesulfonylphenoxy)propyl]amine, {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl][3-(3-methanesulfonylphenoxy)propyl]amine, {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl][3-(3-methanesulfonylphenoxy)propyl]amine, 1-(2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol, 1-(2-fluoro-6-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol, 1-(2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylpropyl) ({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol, 1-(4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)ethan-1-ol, 1-(4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)ethan-1-ol, 1-(4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)ethan-1-ol, 1-(4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)ethan-1-ol, 1-(4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)ethan-1-ol, 1-[2-fluoro-4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]ethan-1-ol, 1-[2-fluoro-4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]ethan-1-ol, 1-[2-fluoro-4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]ethan-1-ol, 1-[2-fluoro-4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]ethan-1-ol, 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4-fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol, 1-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6-methanesulfonylphenyl]ethan-1-ol, 1-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6-methanesulfonylphenyl]ethan-1-ol, 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol, 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol, 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol, 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol, 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol, 1-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol, 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol, 1-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol, 1-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol, 1-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol, 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol, 1-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol, 1-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol, 1-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol, 1-(2-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol, 1-(2-methanesulfonyl-4-{3-[(2-phenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol, 1-(2-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol, 1-(4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)ethan-1-ol, 1-(4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)ethan-1-ol, 1-(4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)ethan-1-ol, 1-(4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)ethan-1-ol, 1-(4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)ethan-1-ol, 1-[4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]ethan-1-ol, 1-[4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]ethan-1-ol, 1-[4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]ethan-1-ol, 1-[4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]ethan-1-ol, 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 1-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]ethan-1-ol, 1-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]ethan-1-ol, 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 1-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 1-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 1-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 1-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 1-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 1-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 1-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}benzaldehyde, 4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylbenzaldehyde, 2-fluoro-6-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}benzaldehyde, 4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylbenzaldehyde, 4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylbenzaldehyde, 4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylbenzaldehyde, 4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylbenzaldehyde, 2-fluoro-4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylbenzaldehyde, 2-fluoro-4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylbenzaldehyde, 2-fluoro-4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylbenzaldehyde, 2-fluoro-4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylbenzaldehyde, 4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6-methanesulfonylbenzaldehyde, 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4-fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylbenzaldehyde, 4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6-methanesulfonylbenzaldehyde, 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylbenzaldehyde, 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylbenzaldehyde, 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylbenzaldehyde, 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-fluoro-6-methanesulfonylbenzaldehyde, 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-fluoro-6-methanesulfonylbenzaldehyde, 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-6-methanesulfonylbenzaldehyde, 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-fluoro-6-methanesulfonylbenzaldehyde, 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-6-methanesulfonylbenzaldehyde, 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-6-methanesulfonylbenzaldehyde, 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-6-methanesulfonylbenzaldehyde, 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-6-methanesulfonylbenzaldehyde, 2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}benzaldehyde, 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-6-methanesulfonylbenzaldehyde, 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-6-methanesulfonylbenzaldehyde, 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylbenzaldehyde, 2-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}benzaldehyde, 2-methanesulfonyl-4-{3-[(2-phenylethyl) ({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}benzaldehyde, 2-methanesulfonyl-4-{3-[(2-phenylpropyl) ({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}benzaldehyde, 4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylbenzaldehyde, 4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylbenzaldehyde, 4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylbenzaldehyde, 4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylbenzaldehyde, 4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylbenzaldehyde, 4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzaldehyde, 4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzaldehyde, 4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzaldehyde, 4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzaldehyde, 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylbenzaldehyde, 4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzaldehyde, 4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzaldehyde, 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-methanesulfonylbenzaldehyde, 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-methanesulfonylbenzaldehyde, 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-methanesulfonylbenzaldehyde, 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-methanesulfonylbenzaldehyde, 4-[3({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylbenzaldehyde, 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-methanesulfonylbenzaldehyde, 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylbenzaldehyde, 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylbenzaldehyde, 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-methanesulfonylbenzaldehyde, 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-methanesulfonylbenzaldehyde, 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-methanesulfonylbenzaldehyde, 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylbenzaldehyde, 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-methanesulfonylbenzaldehyde, 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylbenzaldehyde, 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylbenzaldehyde, methyl 2-fluoro-6-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}benzoate, methyl 2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}benzoate, methyl 4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylbenzoate, methyl 2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}benzoate, methyl 4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylbenzoate, methyl 4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylbenzoate, methyl 4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylbenzoate, methyl 4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylbenzoate, methyl 2-fluoro-4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylbenzoate, methyl 2-fluoro-4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylbenzoate, methyl 2-fluoro-4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylbenzoate, methyl 2-fluoro-4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylbenzoate, methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4-fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylbenzoate, methyl 4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6-methanesulfonylbenzoate, methyl 4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6-methanesulfonylbenzoate, methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylbenzoate, methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylbenzoate, methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-fluoro-6-methanesulfonylbenzoate, methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-fluoro-6-methanesulfonylbenzoate, methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylbenzoate, methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-fluoro-6-methanesulfonylbenzoate, methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylbenzoate, methyl 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-6-methanesulfonylbenzoate, methyl 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-6-methanesulfonylbenzoate, methyl 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-6-methanesulfonylbenzoate, methyl 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-6-methanesulfonylbenzoate, methyl 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-6-methanesulfonylbenzoate, methyl 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-6-methanesulfonylbenzoate, methyl 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-6-methanesulfonylbenzoate, methyl 2-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}benzoate, methyl 2-methanesulfonyl-4-{3-[(2-phenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}benzoate, methyl 2-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}benzoate, methyl 4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylbenzoate, methyl 4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylbenzoate, methyl 4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylbenzoate, methyl 4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylbenzoate, methyl 4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylbenzoate, methyl 4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzoate, methyl 4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzoate, methyl 4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzoate, methyl 4-(3-{[2-(4-fluorophenyl) propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzoate, methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylbenzoate, methyl 4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzoate, methyl 4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzoate, methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-methanesulfonylbenzoate, methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-methanesulfonylbenzoate, methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-methanesulfonylbenzoate, methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-methanesulfonylbenzoate, methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylbenzoate, methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-methanesulfonylbenzoate, methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylbenzoate, methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylbenzoate, methyl 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-methanesulfonylbenzoate, methyl 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-methanesulfonylbenzoate, methyl 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-methanesulfonylbenzoate, methyl 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylbenzoate, methyl 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-methanesulfonylbenzoate, methyl 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylbenzoate, methyl 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylbenzoate, 2-(2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol, 2-(2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol, 2-(2-fluoro-6-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol, 2-(4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)ethan-1-ol, 2-(4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)ethan-1-ol, 2-(4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)ethan-1-ol, 2-(4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)ethan-1-ol, 2-[2-fluoro-4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]ethan-1-ol, 2-[2-fluoro-4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]ethan-1-ol, 2-[2-fluoro-4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]ethan-1-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4-fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol, 2-[2-fluoro-4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]ethan-1-ol, 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6-methanesulfonylphenyl]ethan-1-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol, 2-(4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)ethan-1-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol, 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6-methanesulfonylphenyl]ethan-1-ol, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol, 2-(2-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol, 2-(2-methanesulfonyl-4-{3-[(2-phenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol, 2-(2-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol, 2-(4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)ethan-1-ol, 2-(4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)ethan-1-ol, 2-(4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)ethan-1-ol, 2-(4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)ethan-1-ol, 2-(4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)ethan-1-ol, 2-[4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]ethan-1-ol, 2-[4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]ethan-1-ol, 2-[4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]ethan-1-ol, 2-[4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]ethan-1-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]ethan-1-ol, 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]ethan-1-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol, 2-(2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)acetic acid, 2-(2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)acetic acid, 2-(4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)acetic acid, 2-(4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)acetic acid, 2-(4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)acetic acid, 2-(4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)acetic acid, 2-[2-fluoro-4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]acetic acid, 2-[2-fluoro-4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]acetic acid, 2-[2-fluoro-4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]acetic acid, 2-[2-fluoro-4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]acetic acid, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4-fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}acetic acid, 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6-methanesulfonylphenyl]acetic acid, 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6-methanesulfonylphenyl]acetic acid, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}acetic acid, 2-(4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)acetic acid, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}acetic acid, 2-(2-fluoro-6-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)acetic acid, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}acetic acid, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-6-methanesulfonylphenyl}acetic acid, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-6-methanesulfonylphenyl}acetic acid, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-6-methanesulfonylphenyl}acetic acid, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-6-methanesulfonylphenyl}acetic acid, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-6-methanesulfonylphenyl}acetic acid, 2-(2-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)acetic acid, 2-(2-methanesulfonyl-4-{3-[(2-phenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)acetic acid, 2-(2-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)acetic acid, 2-(4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)acetic acid, 2-(4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)acetic acid, 2-(4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)acetic acid, 2-(4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)acetic acid, 2-(4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)acetic acid, 2-[4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]acetic acid, 2-[4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]acetic acid, 2-[4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]acetic acid, 2-[4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]acetic acid, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}acetic acid, 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]acetic acid, 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]acetic acid, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}acetic acid, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}acetic acid, N-[(2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)methyl]acetamide, N-[(4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)methyl]acetamide, N-[(2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)methyl]acetamide, N-[(2-fluoro-6-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl) methyl]acetamide, N-[(4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)methyl]acetamide, N-[(4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)methyl]acetamide, N-[(4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)methyl]acetamide, N-{[2-fluoro-4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]methyl}acetamide, N-{[2-fluoro-4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]methyl}acetamide, N-{[2-fluoro-4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]methyl}acetamide, N-{[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6-methanesulfonylphenyl]methyl}acetamide, N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4-fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methyl)acetamide, N-{[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6-methanesulfonylphenyl]methyl}acetamide, N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methyl)acetamide, N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methyl)acetamide, N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methyl)acetamide, N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methyl)acetamide, N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methyl)acetamide, N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methyl)acetamide, N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methyl)acetamide, N-({2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}methyl)acetamide, N-({2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-6-methanesulfonylphenyl}methyl)acetamide, N-({2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}methyl)acetamide, N-{[2-fluoro-4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]methyl}acetamide, N-[(4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)methyl]acetamide, N-({2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-6-methanesulfonylphenyl}methyl)acetamide, N-({2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-6-methanesulfonylphenyl}methyl)acetamide, N-({2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-6-methanesulfonylphenyl}methyl)acetamide, N-({2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-6-methanesulfonylphenyl}methyl)acetamide, N-[(2-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl) ({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)methyl]acetamide, N-[(2-methanesulfonyl-4-{3-[(2-phenylethyl) ({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl) methyl]acetamide, N-[(2-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)methyl]acetamide, N-[(4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)methyl]acetamide, N-[(4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)methyl]acetamide, N-[(4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)methyl]acetamide, N-[(4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)methyl]acetamide, N-[(4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)methyl]acetamide, N-{[4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]methyl}acetamide, N-{[4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]methyl}acetamide, N-{[4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]methyl}acetamide, N-{[4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]methyl}acetamide, N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide, N-{[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]methyl}acetamide, N-{[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]methyl}acetamide, N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide, N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide, N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide, N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide, N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide, N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide, N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide, N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide, N-({4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide, N-({4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide, N-({4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide, N-({4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide, N-({4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide, N-({4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide, N-({4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide, 2-(2-fluoro-6-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)propan-2-ol, 2-(2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)propan-2-ol, 2-(2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)propan-2-ol, 2-(4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl) propan-2-ol, 2-(4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)propan-2-ol, 2-(4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)propan-2-ol, 2-(4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)propan-2-ol, 2-(4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)propan-2-ol, 2-[2-fluoro-4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]propan-2-ol, 2-[2-fluoro-4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]propan-2-ol, 2-[2-fluoro-4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]propan-2-ol, 2-[2-fluoro-4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]propan-2-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4-fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}propan-2-ol, 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6-methanesulfonylphenyl]propan-2-ol, 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6-methanesulfonylphenyl]propan-2-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}propan-2-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}propan-2-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}propan-2-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}propan-2-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}propan-2-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}propan-2-ol, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}propan-2-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}propan-2-ol, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-6-methanesulfonylphenyl}propan-2-ol, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}propan-2-ol, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-6-methanesulfonylphenyl}propan-2-ol, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-6-methanesulfonylphenyl}propan-2-ol, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-6-methanesulfonylphenyl}propan-2-ol, 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-6-methanesulfonylphenyl}propan-2-ol, 2-(2-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)propan-2-ol, 2-(2-methanesulfonyl-4-{3-[(2-phenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)propan-2-ol, 2-(2-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)propan-2-ol, 2-(4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)propan-2-ol, 2-(4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)propan-2-ol, 2-(4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)propan-2-ol, 2-(4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)propan-2-ol, 2-(4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylphenyl)propan-2-ol, 2-[4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]propan-2-ol, 2-[4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]propan-2-ol, 2-[4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]propan-2-ol, 2-[4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]propan-2-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol, 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]propan-2-ol, 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]propan-2-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol, 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol, 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol, and 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol.

14. The compound of claim 1, wherein at least one of R.sup.A or R.sup.B is optionally substituted C.sub.1-C.sub.6 heteroalkyl, wherein the optionally substituted C.sub.1-C.sub.6 heteroalkyl is OR.sup.V, wherein R.sup.V is: ##STR00274## wherein each R and R is independently hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl.

15. A method of ameliorating one or more symptoms of cancer comprising administering an effective amount of a compound of claim 1, or pharmaceutically acceptable salts thereof to a subject in need thereof.

16. A method of ameliorating one or more symptoms of cancer comprising contacting a cell with an effective amount of a compound of claim 1, or pharmaceutically acceptable salts thereof.

17. The method of claim 15, wherein said cancer is breast cancer, colon cancer, renal cell cancer, non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, ovarian cancer, pancreatic cancer, esophageal cancer, prostate cancer, sarcoma, glioblastoma, diffuse large B-cell lymphoma, acute myeloid leukemia, multiple myeloma, or melanoma.

18. The method of claim 15, wherein said method further comprises administration of an additional anticancer therapy.

19. The method of ameliorating one or more symptoms of a neurological disorder comprising administering an effective amount of a compound of claim 1, or pharmaceutically acceptable salts thereof to a subject in nee thereof, wherein said neurological disorder is Alzheimer's disease.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The present invention features methods for preventing or reducing aberrant proliferation, differentiation, or survival of cells. For example, compounds of the invention may be useful in reducing the risk of, or preventing, tumors from increasing in size or from reaching a metastatic state. The subject compounds may be administered to halt the progression or advancement of cancer. In addition, the instant invention includes use of the subject compounds to reduce the risk of, or prevent, a recurrence of cancer.

(2) Compounds

(3) The invention features compounds useful in the treatment of cancer. Exemplary compounds described herein include compounds having a structure according to Formula I as described herein:

(4) ##STR00117##
wherein A is:

(5) ##STR00118##

(6) wherein e, f, g, h, and i are independently 0, 1, 2, 3, or 4;

(7) j is 0, 1, 2, or 3;

(8) k is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

(9) l is 0, 1, or 2;

(10) R.sup.A, R.sup.C, R.sup.I, R.sup.L, R.sup.M, and R.sup.T are independently hydrogen, hydroxyl, optionally substituted C.sub.1-C.sub.6 acyl, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.4-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.12 cycloalkynyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl C.sub.1-C.sub.6 alkyl;

(11) R.sup.D, R.sup.E, R.sup.G, R.sup.O, R.sup.P, R.sup.Q, and R.sup.R are independently hydrogen, hydroxy, optionally substituted amino, azido, halo, thiol, optionally substituted amino acid, optionally substituted C.sub.1-C.sub.6 acyl, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.4-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.12 cycloalkynyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl C.sub.1-C.sub.6 alkyl;

(12) each R.sup.B, R.sup.F, R.sup.H, R.sup.K, R.sup.N, and R.sup.S are independently hydroxyl, optionally substituted amino, halo, thiol, optionally substituted amino acid, optionally substituted C.sub.1-C.sub.6 acyl, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.8-C.sub.12 cycloalkenyl, optionally substituted C.sub.4-C.sub.10 cycloalkynyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl C.sub.1-C.sub.6 alkyl;

(13) R.sup.J is hydrogen, optionally substituted C.sub.1-C.sub.6 acyl, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.4-C.sub.10 cycloalkenyl, optionally substituted C.sub.9-C.sub.12 cycloalkynyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl C.sub.1-C.sub.6 alkyl; or R.sup.I and R.sup.J combine to form an optionally substituted C.sub.2-C.sub.9 heterocyclyl or R.sup.J and R.sup.K combine to form an optionally substituted C.sub.2-C.sub.9 heterocyclyl;

(14) R.sup.U is hydroxyl, oxo, optionally substituted amino, halo, thiol, optionally substituted amino acid, optionally substituted C.sub.1-C.sub.6 acyl, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.8-C.sub.12 cycloalkenyl, optionally substituted C.sub.4-C.sub.10 cycloalkynyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl C.sub.1-C.sub.6 alkyl; and

(15) L is absent, O, S, N(R.sup.12), or C(R.sup.4)(R.sup.5);

(16) a is 2, 3, 4, 5, 6, 7, or 8;

(17) b, c, and d are independently 0 or 1;

(18) each R.sup.1, R.sup.2, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently hydrogen, hydroxyl, halo, optionally substituted amino, thiol, optionally substituted amino acid, optionally substituted C.sub.1-C.sub.6 acyl, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted

(19) C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.4-C.sub.10 cycloalkenyl, optionally substituted C.sub.4-C.sub.10 cycloalkynyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl C.sub.1-C.sub.6 alkyl; or R.sup.1 and R.sup.2 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl; or R.sup.6 and R.sup.7 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl; or R.sup.8 and R.sup.9 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl;

(20) R.sup.3 is hydrogen, hydroxyl, optionally substituted amino, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl;

(21) R.sup.4 and R.sup.5 are independently hydrogen, hydroxyl, halo, optionally substituted amino, thiol, optionally substituted amino acid, optionally substituted C.sub.1-C.sub.6 acyl, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.4-C.sub.10 cycloalkenyl, optionally substituted C.sub.4-C.sub.10 cycloalkynyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl C.sub.1-C.sub.6 alkyl; and

(22) B is optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl;

(23) or a pharmaceutically acceptable salt thereof and/or a prodrug thereof.

(24) In some embodiments, the compound is a prodrug or a pharmaceutically acceptable salt of a prodrug (e.g., A includes a moiety OR.sup.V, wherein R.sup.V is:

(25) ##STR00119##

(26) wherein each R and R is independently hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, such as methyl or t-butyl, or optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl, such as benzyl).

(27) For example, in some embodiments A is:

(28) ##STR00120## ##STR00121##

(29) Other embodiments (e.g., any compound described herein), as well as exemplary methods for the synthesis of these compounds, are described herein.

(30) Utility and Administration

(31) The compounds described herein (e.g., a compound according to Formula I or any of compound of Table 1 or Table 4) are useful in the methods of the invention and, while not bound by theory, are believed to exert their desirable effects through their ability to act as LXR agonists. The compounds described herein (e.g., a compound according to Formula I or any of Table 1 or Table 4) can also be used for the treatment of certain conditions such as cancer.

(32) While nuclear hormone receptors have emerged as key therapeutic targets in hormonally driven cancers, their potential for therapeutic benefit in non-hormonally induced epithelial cancers has not been explored. Melanoma, a non-hormonally driven carcinoma with steeply increasing incidence, represents the most aggressive type of skin cancer that incurs 48,000 deaths annually worldwide (Lucas et al., 2006). Presently, there are no effective therapies for the prevention of melanoma metastasis, with interferon alpha (IFN-), the only FDA-approved adjuvant therapy in melanoma, conferring a 5-year overall survival benefit of an inappreciable 1-3% (Garbe et al., Oncologist, 2011, 16(1):5-24). The poor clinical prognosis and the lack of curative and preventative therapies for patients with advanced (stages IV) melanoma necessitate the development and implementation of novel approaches that prevent metastatic relapse rates in this cancer. LXR is the major LXR isoform expressed by melanoma cells and pharmacologic modulation of LXR strongly inhibits melanoma progression phenotypescell invasion, endothelial recruitment, tumor progression, and metastasis. LXR targeting mediates melanoma suppression through the transcriptional induction of cancer-derived and systemic ApoEa potent metastasis suppressor in melanoma.

(33) LXR and LXR, initially discovered by multiple groups at roughly the same time, belong to a family of nuclear hormone receptors that are endogenously activated by cholesterol and its oxidized derivatives to mediate transcription of genes involved in maintaining glucose, cholesterol, and fatty acid metabolism. Given the intricate link between lipid metabolism and cancer cell growth (Cairns et al., Nat Rev Cancer, 2011 February; 11(2):85-95), the ubiquitous expression of LXR in melanoma is unlikely to be coincidental, allowing melanoma cells to synthesize lipids and lipoprotein particles to sustain their growth. At the same time, however, such stable basal expression levels make LXR an ideal therapeutic target, as exemplified by the broad-ranging responsiveness of melanoma cells to LXR activation therapy.

(34) Compounds have been shown to have selectivity for LXR or LXR. This selectivity may allow for increased activity and/or decreased off target effects. Examples of compounds with selectivity towards LXR or LXR are shown in Table 2.

(35) TABLE-US-00002 TABLE 2 EC.sub.50 values for selected compounds against LXR and LXR Compound EC.sub.50 LXR (nM) EC.sub.50 LXR (nM) GW3965 200 40 SB742881 74 25 TO901317 20 50 LXR-623 179 24

(36) As used herein, reference to the activity of an LXR agonist at LXR and LXR refer to the activity as measured using the ligand sensing assay (LiSA) described in Spencer et al. J. Med. Chem. 2001, 44, 886-897, incorporated herein by reference. In some embodiments, the LXR agonist has an EC.sub.50 of less than 1 M in the ligand sensing assay (e.g., 0.5 nm to 500 nM, 10 nM to 100 nM). For example, the methods of the invention can be performed using an LXR agonist having activity for LXR that is at least 3-fold greater than the activity of the agonist for LXR, or having activity for LXR that is at least 10-fold greater than the activity of the agonist for LXR, or having activity for LXR that is at least 100-fold greater than the activity of the agonist for LXR, or having activity for LXR that is at least within 3-fold of the activity of the agonist for LXR. The term greater activity in the LiSA assay assay refers to a lower EC.sub.50. For example, GW3965 has approximately 6-fold greater activity for LXR (EC.sub.50=40) compared to LXR (EC.sub.50=200).

(37) As used herein, the term increases the level of ApoE expression in vitro refers to certain LXR agonists capable of increasing the level of ApoE expression 2.5-fold in the qPCR assay of Example 1 at a concentration of less than 5 M (e.g., at a concentration of 100 nM to 2 M, at a concentration of less than or equal to 1 M). The LXR agonists exhibiting this in vitro effect can be highly efficacious for use in the methods of the invention.

(38) As used herein, the term increases the level of ApoE expression in vivo refers to certain LXR agonists capable of increasing the level of ApoE expression 2.5-fold in the whole blood gene expression analysis assay of Example 4 at a concentration of less than 5 M (e.g., at a concentration of 100 nM to 2 M, at a concentration of less than or equal to 1 M). The LXR agonists exhibiting this in vivo effect can be highly efficacious for use in the methods of the invention.

(39) Treatment Methods

(40) As disclosed herein, and known in the art (e.g., as disclosed in Pencheva et al. Cell 151(5): 1068-1082, 2012 incorporated herein by reference) ApoE and LXR function as metastasis suppressors or inhibitors of the same process. Cancer-secreted ApoE suppresses invasion and endothelial recruitment by activating melanoma cell LRP1 and endothelial LRP8 receptors, respectively. Accordingly, this invention provides methods for treating cancer via increasing in the subject the expression level or activity level of ApoE.

(41) Compounds that increase expression of ApoE or are LXR agonists have been shown to be effective in the treatment of murine models of atherosclerosis, diabetes, anti-inflammation, and Alzheimer's disease as disclosed in Li et al. Expert Opin. Ther. Pat. 20(4):535-562, 2010, herein incorporated by reference.

(42) The invention also provides methods for treating in a subject an angiogenic disorder or a disorder of angiogenesis. The terms angiogenic disorder, disorder of angiogenesis, and angiogenesis disorder are used interchangeably herein, and refer to a disorder characterized by pathological angiogenesis. A disorder characterized by pathological angiogenesis refers to a disorder where abnormal or aberrant angiogenesis, alone or in combination with others, contributes to causation, origination, or symptom of the disorder. Examples of this disorder include various cancers (e.g., vascularized tumors), eye disorders, inflammatory disorders, and others.

(43) Typical vascularized tumors that can be treated with the method include solid tumors, particularly carcinomas, which require a vascular component for the provision of oxygen and nutrients. Exemplary solid tumors include, but are not limited to, carcinomas of the lung, breast, bone, ovary, stomach, pancreas, larynx, esophagus, testes, liver, parotid, biliary tract, colon, rectum, cervix, uterus, endometrium, kidney, bladder, prostate, thyroid, squamous cell carcinomas, adenocarcinomas, small cell carcinomas, melanomas, gliomas, glioblastomas, neuroblastomas, Kaposi's sarcoma, and sarcomas.

(44) A number of disorders or conditions, other than cancer, also can be treated with the above-described method. Examples include arthritis, rheumatoid arthritis, psoriasis, atherosclerosis, diabetic retinopathy, age-related macular degeneration, Grave's disease, vascular restenosis (including restenosis following angioplasty), arteriovenous malformations (AVM), meningioma, hemangioma, neovascular glaucoma, chronic kidney disease, diabetic nephropathy, polycystic kidney disease, interstitial lung disease, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), emphysema, autoimmune hepatitis, chronic inflammatory liver disease, hepatic cirrhosis, cutaneous T-cell lymphoma, rosacea, and basal cell carcinoma.

(45) Other treatment targets include those described in, e.g., US Applications 2009004297, 20090175791, and 20070161553, such as angiofibroma, atherosclerotic plaques, corneal graft neovascularization, hemophilic joints, hypertrophic scars, Osler-Weber syndrome, pyogenic granuloma retrolental fibroplasia, scleroderma, trachoma, vascular adhesions, synovitis, dermatitis, various other inflammatory diseases and disorders, and endometriosis.

(46) Treating cancer can result in a reduction in size or volume of a tumor. For example, after treatment, tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to its size prior to treatment. Size of a tumor may be measured by any reproducible means of measurement. The size of a tumor may be measured as a diameter of the tumor or by any reproducible means of measurement.

(47) Treating cancer may further result in a decrease in number of tumors. For example, after treatment, tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment. Number of tumors may be measured by any reproducible means of measurement. The number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2, 3, 4, 5, 10, or 50).

(48) Treating cancer can result in a decrease in number of metastatic nodules in other tissues or organs distant from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment. The number of metastatic noduless may be measured by any reproducible means of measurement. The number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2, 10, or 50).

(49) Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound of the invention. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with the compound of the invention.

(50) Treating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with the compound of the invention. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with the compound of the invention.

(51) Treating cancer can also result in an increased average progression-free survival time of a population of treated subjects in comparison to an untreated population. For example the average progression-free survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average progression-free survival time of a population may be measured by any reproducible means. An increase in average progression-free survival time of a population may be measured, for example, by calculating for a population the average length of progression-free survival following initiation of treatment with the compound of the invention. An increase in average progression-free survival time of a population may also be measured, for example, by calculating for a population the average length of progression-free survival following completion of a first round of treatment with the compound of the invention.

(52) An increase in ApoE levels has also been shown to be effective for the treatment of neurological disorders. For example, Jiang et al., Neuron, 2008, 58(5):681-693, herein incorporated by reference, have shown brain ApoE induction by GW3965 leads to therapeutic reduction of amyloid-beta plaques in a mouse model of Alzheimer's disease resulting in improved memory deficits. Other references which establish a link between increased ApoE expression by LXR agonists and the treatment of Alzheimers disease include Donkin et al., J Biol Chem, 2010, 285:34144-34154; Fitz et al., J Neurosci. 2010, 30:6862-6872; Koldamova et al., J Biol Chem 2008, 280:4079-4088; and Riddell et al. Mol Cell Neurosci, 2007, 34:621-628, each of which is incorporated herein by reference. Accordingly, this invention provides methods for treating neurological disorders such as Alzheimers disease via increasing in the subject the expression level or activity level of ApoE.

(53) As is known in the art, LXR activation is associated with inflammation, hyperproliferation, and/or disordered skin barrier differentiation, e.g., see International Patent Publication Nos.: WO2013/130892 and WO2013/138565, each of which is herein incorporated by reference. Further LXR activation also modulates several pathways underlying etiology and pathology of skin aging. Accordingly, this invention provides methods for treating dermal diseases, disorders, or conditions (e.g., skin aging, scarring, psoriasis, atopic dermatitis, eczema, urticaria, rosacea, burns, or acne) including administering an effective amount of a compound of the invention.

(54) The liver X receptors (LXR alpha and LXR beta) are highly expressed in the epidermis and LXR activators stimulate keratinocyte proliferation and differentiation. Activation of LXRs also improves permeability barrier homeostasis by a number of mechanisms, including stimulating epidermal lipid synthesis, increasing lamellar body formation and secretion, and increasing the activity of enzymes required for the extracellular processing of lipids in the stratum corneum, leading to the formation of lamellar membranes that mediate permeability barrier function. LXR activation is also anti-inflammatory, reducing inflammation in animal models of allergic and irritant contact dermatitis. (Schmuth et al. 2008, Journal of Lipid Research, 49, 499-509).

(55) Examples of conditions that involve or give rise to a disrupted or dysfunctional epidermal barrier are: inflammation to mucous membranes, such as cheilitis, chapped lips, nasal irritation and vulvovaginitis; eczematous dermnatitides, such as atopic and seborrheic dermatitis, allergic or irritant contact dermatitis, eczema craquelee, photo allergic dermatitis, phototoxic dermatitis, phytophotodermatitis, radiation dermatitis, and stasis dermatitis; ulcers and erosions resulting from trauma, burns, bullous disorders, or ischemia of the skin or mucous membranes; several forms of ichthyoses; epidermolysis bullosae; psoriasis; hypertrophic scars and keloids and cutaneous changes of intrinsic aging and photoaging.

(56) Topical formulations containing LXR activators or activators described herein are applied to beneficial effect to skin and/or mucus membranes. The activators are formulated as lotions, solutions, gels, creams, emollient creams, unguents, sprays, or any other form that will permit topical application. The formulation may also contain one or more agents that promote the spreading of the formulation over the affected area, but are otherwise biologically inactive. Examples of these agents are surfactants, humectants, wetting agents, emulsifiers, or propellants.

(57) Amounts that are referred to herein as effective in enhancing barrier development are any amount that will cause a substantial relief of the symptoms of a disrupted or dysfunctional epidermal permeability barrier when applied repeatedly over time. The optimum amounts in any given instance will be readily apparent to those skilled in the art or are capable of determination by routine experimentation.

(58) Examples of skin conditions that are susceptible to topical treatment with LXR activators are: atopic and seborrheic dermatitis; inflammation to mucous membranes, such as cheilitis, chapped lips, nasal irritation and vulvovaginitis; eczematous dermatitis resulting from allergic and irritant contact, eczema craquelee, radiation and stasis dermatitis; ulcers and erosions due to chemical or thermal burns, bullous disorders, or vascular compromise or ischemia including venous, arterial, embolic or diabetic ulcers; ichthyoses, with or without an associated barrier abnormality; epidermolysis bullosa; psoriasis; hypertrophic scars and keloids; intrinsic aging, photoaging and/or dermatoheliosus; melanoma and non-melanoma skin cancer, including lignin melanoma, basal cell carcinoma, squamous cell carcinoma, actinic keratoses, and virally induced neoplasia (warts and condylomata accuminata).

(59) Compositions

(60) Within the scope of this invention is a composition that contains a suitable carrier and one or more of the therapeutic agents described above. The composition can be a pharmaceutical composition that contains a pharmaceutically acceptable carrier, a dietary composition that contains a dietarily acceptable suitable carrier, or a cosmetic composition that contains a cosmetically acceptable carrier.

(61) The term pharmaceutical composition refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo. A pharmaceutically acceptable carrier, after administered to or upon a subject, does not cause undesirable physiological effects. The carrier in the pharmaceutical composition must be acceptable also in the sense that it is compatible with the active ingredient and can be capable of stabilizing it. One or more solubilizing agents can be utilized as pharmaceutical carriers for delivery of an active compound. Examples of a pharmaceutically acceptable carrier include, but are not limited to, biocompatible vehicles, adjuvants, additives, and diluents to achieve a composition usable as a dosage form. Examples of other carriers include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.

(62) As used herein, the term pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, or allergic response, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977), incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting a free base or free acid function with a suitable reagent, as described generally below. For example, a free base function can be reacted with a suitable acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts, include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

(63) As described above, the pharmaceutical compositions of the present invention additionally include a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; natural and synthetic phospholipids, such as soybean and egg yolk phosphatides, lecithin, hydrogenated soy lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearoyl lecithin, dioleoyl lecithin, hydroxylated lecithin, lysophosphatidylcholine, cardiolipin, sphingomyelin, phosphatidylcholine, phosphatidyl ethanolamine, diastearoyl phosphatidylethanolamine (DSPE) and its pegylated esters, such as DSPE-PEG750 and, DSPE-PEG2000, phosphatidic acid, phosphatidyl glycerol and phosphatidyl serine. Commercial grades of lecithin which are preferred include those which are available under the trade name Phosal or Phospholipon and include Phosal 53 MCT, Phosal 50 PG, Phosal 75 SA, Phospholipon 90H, Phospholipon 90G and Phospholipon 90 NG; soy-phosphatidylcholine (SoyPC) and DSPE-PEG2000 are particularly preferred; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

(64) The above-described composition, in any of the forms described above, can be used for treating melanoma, or any other disease or condition described herein. An effective amount refers to the amount of an active compound/agent that is required to confer a therapeutic effect on a treated subject. Effective doses will vary, as recognized by those skilled in the art, depending on the types of diseases treated, route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatment.

(65) A pharmaceutical composition of this invention can be administered parenterally, orally, nasally, rectally, topically, or buccally. The term parenteral as used herein refers to subcutaneous, intracutaneous, intravenous, intrmuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection, as well as any suitable infusion technique.

(66) A sterile injectable composition can be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Such solutions include, but are not limited to, 1,3-butanediol, mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides). Fatty acid, such as, but not limited to, oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as, but not limited to, olive oil or castor oil, polyoxyethylated versions thereof. These oil solutions or suspensions also can contain a long chain alcohol diluent or dispersant such as, but not limited to, carboxymethyl cellulose, or similar dispersing agents. Other commonly used surfactants, such as, but not limited to, Tweens or Spans or other similar emulsifying agents or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms also can be used for the purpose of formulation.

(67) A composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions. In the case of tablets, commonly used carriers include, but are not limited to, lactose and corn starch. Lubricating agents, such as, but not limited to, magnesium stearate, also are typically added. For oral administration in a capsule form, useful diluents include, but are not limited to, lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.

(68) Pharmaceutical compositions for topical administration according to the described invention can be formulated as solutions, ointments, creams, suspensions, lotions, powders, pastes, gels, sprays, aerosols, or oils. Alternatively, topical formulations can be in the form of patches or dressings impregnated with active ingredient(s), which can optionally include one or more excipients or diluents. In some preferred embodiments, the topical formulations include a material that would enhance absorption or penetration of the active agent(s) through the skin or other affected areas.

(69) A topical composition contains a safe and effective amount of a dermatologically acceptable carrier suitable for application to the skin. A cosmetically acceptable or dermatologically-acceptable composition or component refers a composition or component that is suitable for use in contact with human skin without undue toxicity, incompatibility, instability, or allergic response. The carrier enables an active agent and optional component to be delivered to the skin at an appropriate concentration(s). The carrier thus can act as a diluent, dispersant, solvent, or the like to ensure that the active materials are applied to and distributed evenly over the selected target at an appropriate concentration. The carrier can be solid, semi-solid, or liquid. The carrier can be in the form of a lotion, a cream, or a gel, in particular one that has a sufficient thickness or yield point to prevent the active materials from sedimenting. The carrier can be inert or possess dermatological benefits. It also should be physically and chemically compatible with the active components described herein, and should not unduly impair stability, efficacy, or other use benefits associated with the composition.

(70) Combination Therapies

(71) In some embodiments, the pharmaceutical composition may further include an additional compound having antiproliferative activity. The additional compound having antiproliferative activity can be selected from a group of antiproliferative agents including those shown in Table 3.

(72) It will also be appreciated that the compounds and pharmaceutical compositions of the present invention can be formulated and employed in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated with or administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder, or they may achieve different effects (e.g., control of any adverse effects).

(73) By antiproliferative agent is meant any antiproliferative agent, including those antiproliferative agents listed in Table 3, any of which can be used in combination with a LXR agonist to treat the medical conditions recited herein. Antiproliferative agents also include organo-platine derivatives, naphtoquinone and benzoquinone derivatives, chrysophanic acid and anthroquinone derivatives thereof.

(74) TABLE-US-00003 TABLE 3 Alkylating agents Busulfan Chlorambucil dacarbazine procarbazine ifosfamide altretamine hexamethylmelamine estramustine phosphate thiotepa mechlorethamine lomustine streptozocin cyclophosphamide temozolomide Semustine Platinum agents spiroplatin lobaplatin (Aeterna) tetraplatin satraplatin (Johnson Matthey) ormaplatin BBR-3464 (Hoffmann-La Roche) iproplatin SM-11355 (Sumitomo) ZD-0473 (AnorMED) AP-5280 (Access) oxaliplatin cisplatin carboplatin Antimetabolites azacytidine trimetrexate Floxuridine deoxycoformycin 2-chlorodeoxyadenosine pentostatin 6-mercaptopurine hydroxyurea 6-thioguanine decitabine (SuperGen) cytarabine clofarabine (Bioenvision) 2-fluorodeoxy cytidine irofulven (MGI Pharma) methotrexate DMDC (Hoffmann-La Roche) tomudex ethynylcytidine (Taiho) fludarabine gemcitabine raltitrexed capecitabine Topoisomerase amsacrine exatecan mesylate (Daiichi) inhibitors epirubicin quinamed (ChemGenex) etoposide gimatecan (Sigma-Tau) teniposide or mitoxantrone diflomotecan (Beaufour-Ipsen) 7-ethyl-10-hydroxy-camptothecin TAS-103 (Taiho) dexrazoxanet (TopoTarget) elsamitrucin (Spectrum) pixantrone (Novuspharma) J-107088 (Merck & Co) rebeccamycin analogue (Exelixis) BNP-1350 (BioNumerik) BBR-3576 (Novuspharma) CKD-602 (Chong Kun Dang) rubitecan (SuperGen) KW-2170 (Kyowa Hakko) irinotecan (CPT-11) hydroxycamptothecin (SN-38) topotecan Antitumor antibiotics valrubicin azonafide therarubicin anthrapyrazole idarubicin oxantrazole rubidazone losoxantrone plicamycin MEN-10755 (Menarini) porfiromycin GPX-100 (Gem Pharmaceuticals) mitoxantrone (novantrone) Epirubicin amonafide mitoxantrone doxorubicin Antimitotic colchicine E7010 (Abbott) agents vinblastine PG-TXL (Cell Therapeutics) vindesine IDN 5109 (Bayer) dolastatin 10 (NCI) A 105972 (Abbott) rhizoxin (Fujisawa) A 204197 (Abbott) mivobulin (Warner-Lambert) LU 223651 (BASF) cemadotin (BASF) D 24851 (ASTAMedica) RPR 109881A (Aventis) ER-86526 (Eisai) TXD 258 (Aventis) combretastatin A4 (BMS) epothilone B (Novartis) isohomohalichondrin-B (PharmaMar) T 900607 (Tularik) ZD 6126 (AstraZeneca) T 138067 (Tularik) AZ10992 (Asahi) cryptophycin 52 (Eli Lilly) IDN-5109 (Indena) vinflunine (Fabre) AVLB (Prescient NeuroPharma) auristatin PE (Teikoku Hormone) azaepothilone B (BMS) BMS 247550 (BMS) BNP-7787 (BioNumerik) BMS 184476 (BMS) CA-4 prodrug (OXiGENE) BMS 188797 (BMS) dolastatin-10 (NIH) taxoprexin (Protarga) CA-4 (OXiGENE) SB 408075 (GlaxoSmithKline) docetaxel Vinorelbine vincristine Trichostatin A paclitaxel Aromatase inhibitors aminoglutethimide YM-511 (Yamanouchi) atamestane (BioMedicines) formestane letrozole exemestane anastrazole Thymidylate pemetrexed (Eli Lilly) nolatrexed (Eximias) synthase inhibitors ZD-9331 (BTG) CoFactor (BioKeys) DNA antagonists trabectedin (PharmaMar) edotreotide (Novartis) glufosfamide (Baxter International) mafosfamide (Baxter International) albumin + 32P (Isotope Solutions) apaziquone (Spectrum thymectacin (NewBiotics) Pharmaceuticals) O6 benzyl guanine (Paligent) Farnesyltransferase arglabin (NuOncology Labs) tipifarnib (Johnson & Johnson) inhibitors lonafarnib (Schering-Plough) perillyl alcohol (DOR BioPharma) BAY-43-9006 (Bayer) Pump inhibitors CBT-1 (CBA Pharma) zosuquidar trihydrochloride (Eli Lilly) tariquidar (Xenova) biricodar dicitrate (Vertex) MS-209 (Schering AG) Histone tacedinaline (Pfizer) pivaloyloxymethyl butyrate (Titan) acetyltransferase SAHA (Aton Pharma) depsipeptide (Fujisawa) inhibitors MS-275 (Schering AG) Metalloproteinase Neovastat (Aeterna Laboratories) CMT-3 (CollaGenex) inhibitors marimastat (British Biotech) BMS-275291 (Celltech) Ribonucleoside gallium maltolate (Titan) tezacitabine (Aventis) reductase inhibitors triapine (Vion) didox (Molecules for Health) TNF alpha virulizin (Lorus Therapeutics) revimid (Celgene) agonists/antagonists CDC-394 (Celgene) Endothelin A atrasentan (Abbott) YM-598 (Yamanouchi) receptor antagonist ZD-4054 (AstraZeneca) Retinoic acid fenretinide (Johnson & Johnson) alitretinoin (Ligand) receptor agonists LGD-1550 (Ligand) Immuno-modulators interferon dexosome therapy (Anosys) oncophage (Antigenics) pentrix (Australian Cancer GMK (Progenics) Technology) adenocarcinoma vaccine (Biomira) ISF-154 (Tragen) CTP-37 (AVI BioPharma) cancer vaccine (Intercell) IRX-2 (Immuno-Rx) norelin (Biostar) PEP-005 (Peplin Biotech) BLP-25 (Biomira) synchrovax vaccines (CTL Immuno) MGV (Progenics) melanoma vaccine (CTL Immuno) -alethine (Dovetail) p21 RAS vaccine (GemVax) CLL therapy (Vasogen) MAGE-A3 (GSK) Ipilimumab (BMS), nivolumab (BMS) CM-10 (cCam Biotherapeutics) abatacept (BMS) MPDL3280A (Genentech) pembrolizumab (Merck) Hormonal and estrogens dexamethasone antihormonal agents conjugated estrogens prednisone ethinyl estradiol methylprednisolone chlortrianisen prednisolone idenestrol aminoglutethimide hydroxyprogesterone caproate leuprolide medroxyprogesterone octreotide testosterone mitotane testosterone propionate; P-04 (Novogen) fluoxymesterone 2-methoxyestradiol (EntreMed) methyltestosterone arzoxifene (Eli Lilly) diethylstilbestrol tamoxifen megestrol toremofine bicalutamide goserelin flutamide Leuporelin nilutamide bicalutamide Photodynamic talaporfin (Light Sciences) Pd-bacteriopheophorbide (Yeda) agents Theralux (Theratechnologies) lutetium texaphyrin (Pharmacyclics) motexafin gadolinium hypericin (Pharmacyclics) Kinase Inhibitors imatinib (Novartis) EKB-569 (Wyeth) leflunomide (Sugen/Pharmacia) kahalide F (PharmaMar) ZD1839 (AstraZeneca) CEP-701 (Cephalon) erlotinib (Oncogene Science) CEP-751 (Cephalon) canertinib (Pfizer) MLN518 (Millenium) squalamine (Genaera) PKC412 (Novartis) SU5416 (Pharmacia) Phenoxodiol (Novogen) SU6668 (Pharmacia) C225 (ImClone) ZD4190 (AstraZeneca) rhu-Mab (Genentech) ZD6474 (AstraZeneca) MDX-H210 (Medarex) vatalanib (Novartis) 2C4 (Genentech) PKI166 (Novartis) MDX-447 (Medarex) GW2016 (GlaxoSmithKline) ABX-EGF (Abgenix) EKB-509 (Wyeth) IMC-1C11 (ImClone) trastuzumab (Genentech) Tyrphostins OSI-774 (Tarceva) Gefitinib (Iressa) CI-1033 (Pfizer) PTK787 (Novartis) SU11248 (Pharmacia) EMD 72000 (Merck) RH3 (York Medical) Emodin Genistein Radicinol Radicinol Vemurafenib (B-Raf enzyme Met-MAb (Roche) inhibitor, Daiichi Sankyo) SR-27897 (CCK A inhibitor, Sanofi-Synthelabo) ceflatonin (apoptosis promotor, ChemGenex) tocladesine (cyclic AMP agonist, Ribapharm) BCX-1777 (PNP inhibitor, BioCryst) alvocidib (CDK inhibitor, Aventis) ranpirnase (ribonuclease stimulant, Alfacell) CV-247 (COX-2 inhibitor, Ivy Medical) galarubicin (RNA synthesis inhibitor, Dong-A) P54 (COX-2 inhibitor, Phytopharm) tirapazamine (reducing agent, SRI CapCell (CYP450 stimulant, Bavarian Nordic) International) GCS-100 (gal3 antagonist, GlycoGenesys) N-acetylcysteine (reducing agent, Zambon) G17DT immunogen (gastrin inhibitor, Aphton) R-flurbiprofen (NF-kappaB inhibitor, Encore) efaproxiral (oxygenator, Allos Therapeutics) 3CPA (NF-kappaB inhibitor, Active Biotech) PI-88 (heparanase inhibitor, Progen) seocalcitol (vitamin D receptor agonist, Leo) tesmilifene (histamine antagonist, YM 131-I-TM-601 (DNA antagonist, BioSciences) TransMolecular) histamine (histamine H2 receptor agonist, Maxim) eflornithine (ODC inhibitor, ILEX Oncology) tiazofurin (IMPDH inhibitor, Ribapharm) minodronic acid (osteoclast inhibitor, cilengitide (integrin antagonist, Merck KGaA) Yamanouchi) SR-31747 (IL-1 antagonist, Sanofi-Synthelabo) indisulam (p53 stimulant, Eisai) CCI-779 (mTOR kinase inhibitor, Wyeth) aplidine (PPT inhibitor, PharmaMar) exisulind (PDE V inhibitor, Cell Pathways) gemtuzumab (CD33 antibody, Wyeth Ayerst) CP-461 (PDE V inhibitor, Cell Pathways) PG2 (hematopoiesis enhancer, AG-2037 (GART inhibitor, Pfizer) Pharmagenesis) WX-UK1 (plasminogen activator inhibitor, Wilex) Immunol (triclosan oral rinse, Endo) PBI-1402 (PMN stimulant, ProMetic LifeSciences) triacetyluridine (uridine prodrug, Wellstat) bortezomib (proteasome inhibitor, Millennium) SN-4071 (sarcoma agent, Signature SRL-172 (T cell stimulant, SR Pharma) BioScience) TLK-286 (glutathione S transferase inhibitor, TransMID-107 (immunotoxin, KS Biomedix) Telik) PCK-3145 (apoptosis promotor, Procyon) PT-100 (growth factor agonist, Point doranidazole (apoptosis promotor, Pola) Therapeutics) CHS-828 (cytotoxic agent, Leo) midostaurin (PKC inhibitor, Novartis) trans-retinoic acid (differentiator, NIH) bryostatin-1 (PKC stimulant, GPC Biotech) MX6 (apoptosis promotor, MAXIA) CDA-II (apoptosis promotor, Everlife) apomine (apoptosis promotor, ILEX Oncology) SDX-101 (apoptosis promotor, Salmedix) urocidin (apoptosis promotor, Bioniche) rituximab (CD20 antibody, Genentech Ro-31-7453 (apoptosis promotor, La Roche) carmustine brostallicin (apoptosis promotor, Pharmacia) Mitoxantrone -lapachone Bleomycin gelonin Absinthin cafestol Chrysophanic acid kahweol Cesium oxides caffeic acid BRAF inhibitors, Tyrphostin AG PDL1 inhibitors PD-1 inhibitors MEK inhibitors CTLA-4 inhibitors bevacizumab sorafenib angiogenesis inhibitors BRAF inhibitors dabrafenib rindopepimut ramucirumab vedotin glembatumumab ANG4043 ANG1005 Demcizumab Revlimid pertuzumab Thalidomide Olaparib Optune Vintafolide Cobimetinib Cabozantinib Talimogene laherparepvec Crizotinib

EXAMPLES

Example 1: General Synthesis Methods

(75) The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein. As a guide the following synthetic methods may be utilized.

(76) Names of all compounds were generated using ChemAxon's Instant JChem v6.1 for Desktop and IUPAC Naming Plugin.

(77) A comprehensive list of abbreviations utilized by organic chemists appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled Standard List of Abbreviations, provides definitions for abbreviations not found in the following list of abbreviations: ACN acetonitrile AcOH acetic acid DCM or CH.sub.2Cl.sub.2 dichloromethane or methylene chloride DIPEA diisopropylethylamine DMAP 4-dimethylaminopyridine or N,N-dimethylaminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethylsulfoxide EtOAc ethyl acetate EtOH ethanol HPLC high performance liquid chromatography h hour(s) H.sub.2O.sub.2 hydrogen peroxide INT intermediate IBX 2-iodoxybenzoic acid LDA lithium diisopropylamide LiHMDS lithuim bis(trimethylsilyl)amide mCPBA meta-chloroperbenzoic acid MeOH methanol min minute(s) mL milliliter mmol millimole MS mass spectrometry MTBE methyl tert-butyl ether NaHMDS sodium bis(trimethylsilyl)amide Pd(dppf)Cl.sub.2 [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdCl.sub.2(PPh.sub.3).sub.2 bis(triphenylphosphine)palladium(II) dichloride Pd/C palladium on carbon RT room temperature S.E.M. standard error of the mean S.D. standard deviation TBAF 3H.sub.2O tetrabutylammonium fluoride trihydrate TEA triethylamine TFA trifluoroacetic acid THF THF TLC thin layer chromatography

(78) Compounds of the present invention can be prepared using methods illustrated in general synthetic schemes and experimental procedures detailed below. These general synthetic schemes and experimental procedures are presented for purposes of illustration and are not intended to be limiting. Starting materials used to prepare compounds of the present invention are commercially available or can be prepared using routine methods known in the art. Three methodologies described below are used to make compounds described herein.

(79) In Scheme 1, an aldehyde A is reacted with an amine B under standard reductive amination conditions using a reducing agent such as borohydride (e.g. sodium cyanoborohydride or sodium triacetoxyborohydride), an acid (e.g. acetic acid or TFA), and a solvent (e.g. THF, DCM, ACN) to afford secondary amines C. These amines are alkylated with various optionally substituted carbon linkers (e.g. 1,3-dibromopropane, 3-bromopropanol, 1,4-dibromobutane, etc.) in polar solvent (e.g. DMF, THF, ACN) to afford tertiary amines D. X represents a leaving group (i.e. chloride, bromide, iodide, methanesulfonate, para-toluenesulfoneate, trifluoromethanesulfonate), if not already part of the original carbon linker reagent, it is installed after the linker is attached, for example through mesylate formation from an alcohol. Finally, the leaving group X is displaced with the appropriate nucleophile (R4OH) using base (e.g. potassium carbonate, cesium carbonate) in polar solvent (e.g. DMF, THF, ACN) to afford the final products E.

(80) ##STR00126##

(81) In Scheme 2, amines B are reacted with silyl-protect carbinols F via displacement of the leaving group X (e.g. chloride, bromide, iodide, methanesulfonate, para-toluenesulfoneate, trifluoromethanesulfonate) in a polar solvent (e.g. DMF, THF, ACN) to afford secondary amines G. These amines are alkylated with various substituted benzyl reagents (e.g. 2-chloro-3-trifluoromethylbenzyl bromide) in polar solvent (e.g. DMF, THF, ACN) to afford tertiary amines H. The silyl-protecting group is removed under standard conditions (e.g. TBAF, HF) in polar solvent (e.g. DMF, THF, ACN) and the resulting alcohol is converted to a leaving group X (e.g. chloride, bromide, iodide, methanesulfonate, para-toluenesulfoneate, trifluoromethanesulfonate) to afford intermediates D. Finally, the leaving group X is displaced with the appropriate nucleophile (R4OH) using base (e.g. potassium carbonate, cesium carbonate) and polar solvent (e.g. DMF, THF, ACN) to afford final products E.

(82) ##STR00127##

Example 2: Synthesis of Compound 1

(83) Step 1: Synthesis of INT-01

(84) ##STR00128##

(85) Intermediate INT-01 was made as previously described in Bioorg. Med. Chem. Lett. 2009, 19, 5617-5621. 2,2-Diphenethylamine and 2-chloro-3-trifluoromethylbenzaldehyde were reacted via reductive amination using sodium triacetoxyborohydride in dichloromethane and acetic acid. The resulting benzyl amine was reacted with 1,3-dibromopropane in refluxing acetonitrile overnight to afford bromide (3-bromopropyl)({[2-chloro-3-(trifluoromethyl)phenyl]methyl})(2,2-diphenylethyDamine (INT-01).

(86) Step 2: Synthesis of INT-02

(87) ##STR00129##

(88) To a solution of bromide INT-01 (0.30 g, 0.59 mmol) in acetonitrile (5 mL) was added methyl 3-hydroxyphenylacetic acid (107 mg, 0.65 mmol) and potassium carbonate (0.12 g, 0.9 mmol). The reaction was heated to 70-80 C. overnight. The mixture was cooled, filtered, and the solid was washed with acetonitrile (1 mL) and the combined filtrates were concentrated and purified by silica gel column chromatography to yield methyl-2-{3-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}-(2,2-diphenylethyl)-amino)-propoxy]phenyl}acetate (INT-02) (0.27 g, 76% yield); TLC=20% ethyl acetate/hexanes (0.5 Rf).

(89) Step 3: Synthesis of Compound 1

(90) ##STR00130##

(91) INT-02 (190 mg, 0.319 mmol) was dissolved in dry methanol (5 mL). Addition of hydroxylamine hydrochloride (89 mg, 1.27 mmol) and sodium hydroxide (90 mg, 1.60 mmol) was followed by stirring at room temperature for 18 h or until TLC control showed completed conversion. The reaction mixture was poured into ethyl acetate (100 mL) and extracted with water (2100 mL), dried over magnesium sulfate, filtrated, solvent was evaporated under reduced pressure, and purified by silica gel preparative TLC to afford 2-{3-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethy)amino)propoxy]phenyl}-N-hydroxyacetamide (1) as a glassy oil (125 mg, 66%). ES(pos)MS m/z 597.21 (M+H.sup.+).

Example 3: Synthesis of Compound 2

(92) ##STR00131##

(93) GW3965 was made from INT-02 using aqueous base hydrolysis as previously described (U.S. Pat. No. 7,247,748). 1,1-Carbonyldiimidazole (0.1 g, 0.67 mmol) was added to a stirring solution of GW3965 (0.3 g, 0.52 mmol) in THF (5 mL) and the solution was stirred under argon for 3 h. To this solution was added methane sulfonamide (74 mg, 0.78 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 g, 0.78 mmol) and the reaction was stirred at RT overnight. The mixture was concentrated, dissolved in EtOAc (1 mL), washed with water and brine, and concentrated under reduced pressure. The residue was purified by silica gel preparative TLC to afford 2-{3-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino) propoxy]phenyl}-N-methanesulfonylacetamide (2) as a colorless liquid (0.19 mg, 55% yield); TLC=60% EtOAc/hexanes (0.4 Rf); MS (ESI) 659.2 (M+H.sup.+).

Example 4: Synthesis of Compound 3

(94) Step 1: Synthesis of INT-03

(95) ##STR00132##

(96) To a solution of bromide INT-01 (0.20 g, 0.39 mmol) in ACN (3 mL) was added methyl 3-hydroxybenzoate (60 mg, 0.39 mmol) and potassium carbonate (0.27 g, 1.95 mmol). The reaction was heated to 70-80 C. overnight. The mixture was cooled, filtered, and the solid was washed with ACN (1 mL) and the combined filtrates were concentrated and purified by silica gel column chromatography to yield methyl 3-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]benzoate (INT-03) as a syrup (0.21 g, 91% yield); TLC=10% EtOAc/hexanes (0.4 Rf).

(97) Step 2: Synthesis of Compound 3

(98) ##STR00133##

(99) To a solution of ester INT-03 (0.2 g, 0.34 mmol) in a 1:1 mixture of MeOH/THF (3 mL) was added 2N sodium hydroxide (3 mL) drop-wise at 0 C. The resulting solution was stirred at RT overnight. The reaction mixture was acidified with 3N hydrochloric acid (pH 4) and volatiles were removed under reduced pressure. The reaction mixture was extracted with EtOAc (210 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield 3-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]benzoic acid (3) as a syrup (0.15 g, 89% yield); TLC=30% EtOAc/hexanes (0.2 Rf); MS (ESI) 597.21 (M+H.sup.+).

Example 5: Synthesis of Compound 4

(100) Step 1: Synthesis of INT-04

(101) ##STR00134##

(102) To a 1M solution of methyl magnesium chloride in THF (30 mL, 30.6 mmol) at RT was added a solution of methyl 3-hydroxybenzoate (2.0 g, 13.3 mmol) in THF (10 mL) drop-wise at RT under argon atmosphere. After 2 h the reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with EtOAc (215 mL). The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to yield 3-(2-hydroxypropan-2-yl)phenol (INT-04) as a liquid (1.45 g, 72.5% yield); TLC=20% EtOAc/hexanes (0.5 Rf).

(103) Step 2: Synthesis of compound 4

(104) ##STR00135##

(105) The bromide INT-01 (0.2 g, 0.32 mmol) was reacted with phenol INT-04 (50 mg, 0.38 mmol) in ACN (3 mL) using potassium carbonate (66 mg, 0.48 mmol) as base as described above for compound 3 to yield 2-{3-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]phenyl}propan-2-ol (4) as an oil (0.14 g, 63% yield); TLC=15% EtOAc/hexanes (0.3 Rf); MS (ESI) 582.24 (M+H.sup.+).

Example 6: Synthesis of Compound 5

(106) Step 1: Synthesis of INT-05

(107) ##STR00136##

(108) Bromide INT-01 (0.30 mmol) is reacted with 3-bromophenol (0.30 mmol) in ACN (3 mL) using potassium carbonate (0.40 mmol) as base as described above for compound 3 to yield [3-(3-bromophenoxy)propyl]({[2-chloro-3-(trifluoromethyl)phenyl]methyl})(2,2-diphenylethyl)amine (INT-05).

(109) Step 2: Synthesis of Compound 5

(110) ##STR00137##

(111) INT-05 (0.2 mmol) is dissolved in THF, cooled to 78 C., and treated with n-butyllithium (0.22 mmol, 1.6 M in hexanes). After 30 min, hexafluoroacetone is bubbled into the solution and the mixture is stirred for an additional 30 min at 78 C. The reaction is quenched with saturated aqueous ammonium chloride solution, extracted with EtOAc (350 mL), the combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography to afford 2-{3-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl) amino)-propoxy]phenyl}-1,1,1,3,3,3-hexafluoropropan-2-ol (5).

Example 7: Synthesis of Compound 6

(112) Step 1: Synthesis of INT-06

(113) ##STR00138##

(114) 6-Methoxy-3,4-dihydro-1H-2-benzopyran-3-one was prepared as described previously (WO2009005998 and J. Org. Chem. 1997, 42, 2989).

(115) Step 2: Synthesis of Compound 6

(116) ##STR00139##

(117) The bromide INT-01 (0.3 mmol) was reacted with phenol INT-06 (0.3 mmol) in ACN (3 mL) using potassium carbonate (0.40 mmol) as base as described above for compound 3 to yield 6-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-3,4-dihydro-1H-2-benzopyran-3-one (6) as a viscous oil (85 mg, 48%). ES(pos)MS m/z 594.20 (M+H.sup.+).

Example 8: Synthesis of Compound 7

(118) ##STR00140##

(119) To a solution of bromide INT-01 (500 mg, 0.98 mmol) in acetonitrile (10 mL) was added 3-(methylsulfonyl) phenol (168 mg, 0.98 mmol, prepared according to procedures described in J. Am. Chem. Soc. 1957, 79, 717-722) and potassium carbonate (202 mg, 1.47 mmol) at RT. The solution was heated to 70 C. for 6 h. The mixture was worked-up as described above for compound 3, and purified by silica gel column chromatography to afford {[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)[3-(3-methane sulfonylphenoxy)propyl]amine (7) as a thick syrup (459 mg, 78%); TLC=30% EtOAc/hexanes (0.3 Rf); ES (pos) MS m/z 602.18 (M+H.sup.+).

Example 9: Synthesis of Compound 8

(120) Step 1: Synthesis of INT-07

(121) ##STR00141##

(122) INT-07 was made as previously described (WO20100138598). (4-Bromo-2-fluoro-6-methanesulfonyl phenyl)methanol (300 mg, 1.06 mmol), potassium acetate (2.44 mmol, 2.49 mmol), and bis(pinacolato) diborane (350 mg, 1.38 mmol) were suspended in dry DMSO (10 mL). After degassing with argon for 5 min, dichloro((1,1-biphenylphosphino)ferrocene)palladium (II) dichloromethane complex (43.3 mg, 5 mol %) was added the mixture was degassed for another 5 min. The reaction was heated to 90 C. for 3 h. The cooled reaction mixture was poured into water (100 mL) and extracted with MTBE (2100 mL). The combined organic layers were washed with water (350 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford [2-fluoro-6-methanesulfonyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (INT-07) as crude material that was used directly in the next step without further purification.

(123) Step 2: Synthesis of INT-08

(124) ##STR00142##

(125) The crude mixture of the previous step was dissolved in MeOH (15 mL) and treated with 30% aqueous hydrogen peroxide (5 mL). After addition of iodine (5 mg, catalytic), the mixture was stirred at RT for 3 h or until all starting material had disappeared judged by TLC. The resulting mixture was poured into EtOAc (100 mL) and washed with water (2100 mL). The combined aqueous layers were re-extracted with EtOAc (100 mL) and this second organic phase was washed with water (100 mL). All organic layers were combined, dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (EtOAc/hexanes) to yield 3-fluoro-4-(hydroxymethyl)-5-methanesulfonyl-phenol (INT-08) as an off-white solid (200 mg, 85% yield).

(126) Step 3: Synthesis of Compound 8

(127) ##STR00143##

(128) Bromide INT-01 (200 mg, 0.392 mmol), phenol INT-08 (112 mg, 0.509 mmol), and potassium carbonate (325 mg, 2.35 mmol) were suspended in dry ACN (5 mL) and heated to 90 C. for 16 h. The resulting mixture was poured into EtOAc (100 mL) and then washed with water (2100 mL). The combined aqueous layers were re-extracted with EtOAc (100 mL) and this second organic layer was washed with water (100 mL) again. All organic layers were combined, dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by prep-TLC (MeOH/DCM) to yield {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methanol (8) as a glassy oil (98 mg, 38% yield); ES(pos)MS m/z 650.2 (M+H.sup.+).

Example 10: Synthesis of Compound 84

(129) Step 1: Synthesis of INT-09

(130) ##STR00144##

(131) INT-09 was made using a modified protocol previously described for [4-bromo-2-fluoro-6-(methylsulfanyl)phenyl]methanol (see WO20100138598) by replacing sodium borohydride with sodium borodeuteride for the reduction of the acid.

(132) Sodium borodeuteride (483 mg, 11.54 mmol) was suspended to dry THF (10 mL) and to this slurry was added 4-bromo-2-fluoro-6-(methylsulfanyl)benzoic acid (1.53 g, 5.77 mmol) dissolved in dry THF (10 mL) over 5 min. After gas evolution was complete, iodine (2.56 g, 10.07 mmol) dissolved in dry THF (15 mL) was slowly added over 30 min. The reaction mixture was then refluxed for 6 h and most of the solvent was removed under reduced pressure. The residue was taken up in EtOAc (100 mL), washed with saturated sodium bicarbonate (100 mL), water (100 mL), and the combined aqueous layers were re-extracted with EtOAc (100 mL). The second organic layer was washed with water (100 mL) and the combined organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM/MeOH=100/1) to afford INT-09 as a white solid (1.25 g, 86%).

(133) Step 2: Synthesis of INT-10

(134) ##STR00145##

(135) Synthesis of INT-10 followed the protocol outlined for compound INT-08 substituting [4-bromo-2-fluoro-6-(methylsulfanyl)phenyl]methanol with INT-09.

(136) Step 3: Synthesis of Compound 84

(137) ##STR00146##

(138) The synthesis of 84 followed the previously described synthesis of compound 8. Bromide INT-01 (260 mg. 0.51 mmol) and INT-10 (130 mg, 0.585 mmol) were reacted in presence of potassium carbonate (210 mg, 1.5 mmol) to afford {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino) propoxy]-2-fluoro-6-methanesulfonylphenyl}(.sup.2H.sub.2)methanol (84) as a white solid (284 mg, 86%). ES(pos)MS m/z 652.18 (M+H.sup.+).

Example 11: Synthesis of Compound 78

(139) Step 1: Synthesis of INT-11

(140) ##STR00147##

(141) 2-Cyclohexyl-2-phenylethylamine (0.5 g, 2.5 mmol) and 2-chloro-3-trifluoromethyl benzaldehyde (0.52 g, 2.5 mmol) were dissolved in DCM (12 mL) and reacted under reductive amination conditions using sodium triacetoxyborohydride (0.53 g, 2.5 mmol) and acetic acid (0.5 mL) as described in Bioorg. Med. Chem. Lett. 2009, 19, 5617-5621 for INT-01 to yield {[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-cyclohexyl-2-phenylethyl)amine (INT-11) (0.75 g, 76%); TLC=30% EtOAc/hexanes (0.3 Rf).

(142) Step 2: Synthesis of INT-12

(143) ##STR00148##

(144) The amine INT-11 (0.5 g, 1.26 mmol) was reacted with 1,3-dibromopropane (2.5 g, 10 eq) in refluxing acetonitrile (25 mL) overnight as described for INT-01 to afford (3-bromopropyl)({[2-chloro-3-(trifluoromethyl)phenyl]methyl})(2-cyclohexyl-2-phenylethyl)amine (INT-12) (0.46 g, 70%); TLC=5% EtOAc/hexanes (0.8 Rf).

(145) Step 3: Synthesis of Compound 78

(146) ##STR00149##

(147) Bromide INT-12 (250 mg, 0.48 mmol), phenol INT-08 (105 mg, 0.48 mmol), and potassium carbonate (132 mg, 0.96 mmol) were suspended in dry ACN (5 mL) and heated to reflux for 12 h. The resulting mixture was poured into EtOAc (50 mL), washed with water (250 mL), and the combined aqueous layers were re-extracted with EtOAc (25 mL). The second organic layer was washed with water (100 mL) and the combined organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel preparative TLC (30% EtOAc/hexanes) to afford {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-cyclohexyl-2-phenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methanol (78) as a glassy oil (250 mg, 80% yield); TLC=30% EtOAc/hexanes (0.6 Rf); ES(pos)MS m/z 656.6 (M+H.sup.+).

Example 12: Synthesis of Compound 79

(148) Step 1: Synthesis of INT-13

(149) ##STR00150##

(150) (R)-2-Phenylpropan-1-amine (200 mg, 1.48 mmol) was reacted with 2-chloro-3-trifluoromethyl benzaldehyde (308 mg, 1.48 mmol) as described above for INT-11 to afford {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(2R)-2-phenylpropyl]amine (INT-13) (300 mg, 62%).

(151) Step 2: Synthesis of INT-14

(152) ##STR00151##

(153) INT-13 (150 mg, 0.46 mmol) was reacted with 1,3-dibromopropane (920 mg, 10 eq) in refluxing acetonitrile as described above for INT-12 to (3-bromopropyl)({[2-chloro-3-(trifluoromethyl)phenyl]methyl})[(2R)-2-phenylpropyl]amine (INT-14) as colorless oil (137 mg, 67%); TLC=5% EtOAc/hexanes (0.8 Rf).

(154) Step 3: Synthesis of Compound 79

(155) ##STR00152##

(156) Bromide INT-14 (125 mg, 0.28 mmol) was reacted with phenol INT-08 (62 mg, 0.28 mmol) as described above for compound 78 and purified by silica gel preparative TLC (30% EtOAc/hexanes) to afford {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(2R)-2-phenylpropyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methanol (79) as colorless oil (128 mg, 78% yield); TLC=30% EtOAc/hexanes (0.6 Rf); ES(pos) MS m/z 588.5 (M+H.sup.+).

Example 13: Synthesis of Compound 80

(157) Step 1: Synthesis of INT-15

(158) ##STR00153##

(159) (S)-2-Phenylpropan-1-amine (100 mg, 0.74 mmol) was reacted with 2-chloro-3-trifluoromethyl benzaldehyde (153 mg, 0.74 mmol) as described above for INT-13 to yield {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(2S)-2-phenylpropyl]amine (150 mg, 62%). This amine (150 mg, 0.46 mmol) was reacted with 1,3-dibromopropane (920 mg, 10 eq) in refluxing acetonitrile as described above for INT-14 to afford (3-bromopropyl)({[2-chloro-3-(trifluoromethyl)phenyl]methyl})[(2S)-2-phenylpropyl]amine (INT-15) as colorless oil (137 mg, 68%); TLC=5% EtOAc/hexanes (0.8 Rf).

(160) Step 2: Synthesis of compound 80

(161) ##STR00154##

(162) Bromide INT-15 (125 mg, 0.28 mmol) was reacted with phenol INT-08 (62 mg, 0.28 mmol) as described above for compound 78 and purified by silica gel preparative TLC (30% EtOAc/hexanes) to afford {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(2S)-2-phenylpropyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methanol (80) as colorless oil (128 mg, 78% yield); TLC=30% EtOAc/hexanes (0.6 Rf); ES(pos) MS m/z 588.5 (M+H.sup.+).

Example 14: Synthesis of Compound 81

(163) Step 1: Synthesis of INT-16

(164) ##STR00155##

(165) 2-Phenylethanamine (150 mg, 1.23 mmol) was reacted with 2-chloro-3-trifluoromethyl benzaldehyde (0.26 g, 1.23 mmol) as described above for INT-11 to yield {[2-chloro-3-(trifluoromethyl) phenyl]methyl}(2-phenylethyl)amine (223 mg, 58%). This amine (150 mg, 0.48 mmol) was reacted with 1,3-dibromopropane (970 mg, 10 eq) in refluxing acetonitrile as described above for INT-12 to afford (3-bromopropyl)({[2-chloro-3-(trifluoromethyl)phenyl]methyl})(2-phenylethyl)amine (INT-16) as thick syrup (150 mg, 72%); TLC=5% EtOAc/hexanes (0.8 Rf).

(166) Step 2: Synthesis of Compound 81

(167) ##STR00156##

(168) Bromide INT-16 (160 mg, 0.37 mmol) was reacted with phenol INT-08 (82 mg, 0.37 mmol) as described above for compound 78 and purified by silica gel preparative TLC (30% EtOAc/hexanes) to afford {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methanol (81) as colorless oil (161 mg, 76% yield); TLC=30% EtOAc/hexanes (0.55 Rf); ES(pos) MS m/z 574.5 (M+H.sup.+).

Example 15: Synthesis of Compound 82

(169) Step 1: Synthesis of INT-17

(170) ##STR00157##

(171) 2-Methyl-2-phenylpropan-1-amine (150 mg, 1.0 mmol) was reacted with 2-chloro-3-trifluoromethyl benzaldehyde (207 mg, 1.0 mmol) as described above for INT-11 to yield {[2-chloro-3-(trifluoromethyl) phenyl]methyl}(2-methyl-2-phenylpropyl)amine (184 mg, 54%). The amine (150 mg, 0.43 mmol) was reacted with 1,3-dibromopropane (869 mg, 10 eq) in refluxing acetonitrile as described above for INT-12 to afford (3-bromopropyl)({[2-chloro-3-(trifluoromethyl)phenyl]methyl})(2-methyl-2-phenylpropyl)amine (INT-17) as colorless oil (147 mg, 74%); TLC=5% EtOAc/hexanes (0.85 Rf).

(172) Step 2: Synthesis of Compound 82

(173) ##STR00158##

(174) Bromide INT-17 (100 mg, 0.22 mmol) was reacted with phenol INT-08 (48 mg, 0.22 mmol) as described above for compound 78 and purified by silica gel preparative TLC (30% EtOAc/hexanes) to afford {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methanol (82) as colorless thick syrup (99 mg, 75% yield); TLC=30% EtOAc/hexanes (0.6 Rf); ES(pos) MS m/z 602.5 (M+H.sup.+).

Example 16: Synthesis of Compound 83

(175) Step 1: Synthesis of INT-18

(176) ##STR00159##

(177) Benzylamine (200 mg, 1.87 mmol) was reacted with 2-chloro-3-trifluoromethyl benzaldehyde (0.38 g, 1.87 mmol) as described above for INT-11 to yield benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amine (381 mg, 68%). The amine (200 mg, 0.67 mmol) was reacted with 1,3-dibromopropane (1.4 g, 10 eq) in refluxing acetonitrile as described above for INT-12 to afford benzyl(3-bromopropyl){[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (INT-18) as colorless oil (205 mg, 73%); TLC=5% EtOAc/hexanes (0.85 Rf).

(178) Step 2: Synthesis of Compound 83

(179) ##STR00160##

(180) Bromide INT-18 (150 mg, 0.36 mmol) was reacted with phenol INT-08 (78 mg, 0.36 mmol) as described above for compound 78 and purified by silica gel preparative TLC (30% EtOAc/hexanes) to afford (4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl) methanol (83) as colorless oil (156 mg, 78% yield); TLC=30% EtOAc/hexanes (0.6 Rf); ES(pos)MS m/z 560.5 (M+H.sup.+).

Example 17: Synthesis of Compound 9

(181) Step 1: Synthesis of INT-21

(182) ##STR00161##

(183) Crude (2S)-4-[(tert-butyldimethylsilyl)oxy]butan-2-ol was made as described WO0166534A2 using (S)-1,3-butanediol (2.1 g, 23.3 mmol). The crude product was dissolved in dry dichloromethane (40 mL) and then reacted with methanesulfonyl chloride (1.81 mL, 23.4 mmol) and triethylamine (3.5 mL, 25.1 mmol) at 0 C. The mixture was allowed to warm to RT over 1 h and then stirred an additional 2 h. Upon completion, judged by TLC, the reaction mixture was poured into EtOAc and washed with 1N hydrochloric acid (2100 mL), water (100 mL), and brine (50 mL). The mixture was dried over magnesium sulfate, filtrated, and concentrated under reduced pressure to yield crude (2S)-4-[(tert-butyldimethylsilyl)oxy]-butan-2-yl methanesulfonate (INT-21) as a yellowish oil in quantitative yield.

(184) Step 2: Synthesis of INT-22

(185) ##STR00162##

(186) Crude INT-21 (1.0 g, 3.54 mmol) and 2,2-diphenylethylamine (770 mg, 3.89 mmol) were dissolved in dry ACN (10 mL), followed by addition of potassium carbonate (2.93 g, 21.2 mmol). The mixture was heated at 90 C. for 48 h until TLC showed very little starting material remaining. The heterogeneous reaction mixture was poured into EtOAc (100 mL) and washed with water (2100 mL).

(187) The combined aqueous layers were extracted with EtOAc (100 mL) and this second organic layer was in turn washed with water (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/hexane) to afford [(2R)-4-[(tert-butyldimethylsilyl)oxy]butan-2-yl](2,2-diphenylethyl)amine (INT-22) as a slightly yellowish oil (1.06 g, 78% yield).

(188) Step 3: Synthesis of INT-23

(189) ##STR00163##

(190) Amine INT-22 (1.3 g, 3.39 mmol), 2-chloro-3-(trifluoromethyl)benzyl bromide (1.18 g, 4.31 mmol), and potassium carbonate (1.87 g, 13.6 mmol) were suspended in dry acetonitrile (13 mL). After 12 h at 90 C., the reaction was deemed complete by TLC and poured into MTBE (100 mL). The organic mixture was washed with water (2100 mL). The combined aqueous layers were extracted with MTBE (100 mL) and this second organic layer was in turn washed with water (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford [(2R)-4-[(tert-butyldimethylsilyl)oxy]butan-2-yl]({[2-chloro-3-(trifluoromethyl)phenyl]methyl})(2,2-diphenylethyl)amine (INT-23) as a brownish oil which was used directly in the following step without further purification.

(191) Step 4: Synthesis of INT-24

(192) ##STR00164##

(193) Crude INT-23 (3.39 mmol) was dissolved in dry THF (15 mL) and subsequently treated with tetrabutylammonium fluoride (1.0 M in THF, 6.8 mL, 6.8 mmol). After stirring for 20 h at RT, TLC showed no starting material remaining. The homogeneous mixture was poured into EtOAc (100 mL) and washed with water (2100 mL). The combined aqueous layers were extracted with EtOAc (100 mL) and this second organic layer was in turn washed with water (100 mL). The combined organic layers were then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/hexane) to afford (3R)-3-({[2-chloro-3-(trifluoromethyl) phenyl]methyl}(2,2-diphenylethyl)amino)butan-1-ol (INT-24) as a viscous oil (1.33 g, 68% yield over 2 steps).

(194) Step 5: Synthesis of INT-25

(195) ##STR00165##

(196) INT-24 (1.30 g, 2.81 mmol) and triethylamine (1.18 mL, 8.44 mmol) were dissolved in dry DCM (20 mL). The mixture was cooled to 0 C. and then treated with methanesulfonyl chloride (0.326 mL, 4.22 mmol). The reaction mixture was allowed to warm to RT overnight and then poured into EtOAc (100 mL) and washed with water (2100 mL). The combined aqueous layers were extracted with EtOAc (100 mL) and this second organic layer was in turn washed with water (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield (3R)-3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)butyl methanesulfonate (INT-25) as a crude oil in quantitative yield which was used directly in the following step without further purification.

(197) Step 6: Synthesis of Compound 9

(198) ##STR00166##

(199) INT-08 (183 mg, 0.832 mmol), crude mesylate INT-25 (0.693 mmol), and potassium carbonate (575 mmol, 4.16 mmol) were heated in dry ACN (3 mL) for 16 h at 90 C. After cooling to RT, the mixture was poured into EtOAc (100 mL) and washed with water (2100 mL). The combined aqueous layers were re-extracted with EtOAc (100 mL) and this second organic layer was washed with water (100 mL) again. All organic layers were combined, dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (EtOAc/hexanes) to yield a mixture of isomers as an off-white solid (256 mg, 56% yield). The two isomers were separated by silica preparative TLC purification by running the plates multiple times with EtOAc/hexanes. The isolation of the bottom spot afforded {4-[(3R)-3-({[2-chloro-3-(trifluoromethyl) phenyl]methyl}(2,2-diphenylethyl)amino)butoxy]-2-fluoro-6-methanesulfonylphenyl}methanol (9) as a white solid (6 mg, 30% yield); ES(pos)MS m/z 664.2 (M+H.sup.+).

Example 18: Synthesis of Compound 59

(200) ##STR00167##

(201) Preparative TLC purification to isolate compound 10 also afforded a pure top spot (4-{[4-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)butan-2-yl]oxy}-2-fluoro-6-methanesulfonylphenyl)methanol (59); ES(pos)MS m/z 664 (M+H.sup.+).

Example 19: Synthesis of Compound 71

(202) ##STR00168##

(203) The synthesis of 71 follows the same sequence of procedures described for the synthesis of compound 9 but starting from (2R)-4-[(tert-butyldimethylsilyl)oxy]butan-2-ol to afford the opposite enantiomer {4-[(3S)-3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)butoxy]-2-fluoro-6-methanesulfonylphenyl}methanol (71).

Example 20: Synthesis of Compound 10

(204) Step 1: Synthesis of INT-26

(205) ##STR00169##

(206) 4-Bromo-2,6-difluorobenzoic acid (4.23 g, 17.85 mmol) was converted into the corresponding methylsulfide as described previously (WO20100138598). A portion of the crude residue (3.0 g of 4.7 g) was suspended in dry DCM (50 mL), oxalyl chloride (1.15 mL, 13.6 mmol) and a catalytic amount of dry DMF were added resulting in a bubbling suspension that was stirred for 1 h at RT. The clear solution was concentrated under reduced pressure and the brown oil was dissolved in dry DCM (50 mL). Triethylamine (6.27 mL, 45 mmol) was added and the mixture was cooled to 0 C. followed by slow addition of dry MeOH (5 mL, large excess). The reaction was warmed to RT over 30 min and then stirred for 1 h. The reaction was poured into water (200 mL), the pH was adjusted to pH 1 with 1N hydrochloric acid, extracted with EtOAc (200 mL), the organic layer was washed with water (100 mL), and the combined aqueous layers were extracted with EtOAc (100 mL). The second organic layer was also washed with water (100 mL). All organic layers were combined, dried over magnesium sulfate, filtrated, and concentrated under reduced pressure to yield crude methyl 4-bromo-2-fluoro-6-(methylsulfanyl)-benzoate (INT-26) that was used directly in the next step without further purification.

(207) Step 2: Synthesis of INT-27

(208) ##STR00170##

(209) The crude mixture of INT-26 in DCM (100 mL) was treated with mCPBA (77%, 5.07 g, 22.6 mmol). The resulting biphasic mixture was stirred overnight at RT. The organic solvent was removed under reduced pressure and the resulting slurry was dissolved in EtOAc (200 mL). The light yellowish solution was washed with 1N sodium hydroxide (2200 mL) and water (2100 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and the yellow residue was purified by silica gel chromatography (MeOH/DCM) to yield methyl 4-bromo-2-fluoro-6-methanesulfonylbenzoate (INT-27) as an off-white solid (1.35 g, 38% over 4 steps).

(210) Step 3: Synthesis of INT-28

(211) ##STR00171##

(212) Bromide INT-27 (1.0 g, 3.21 mmol) was converted to methyl 2-fluoro-6-methanesulfonyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-benzoate (INT-28) as described for INT-07, which was used in the next step without further purification.

(213) Step 4: Synthesis of INT-28

(214) ##STR00172##

(215) The crude boronic ester INT-28 was dissolved in MeOH (20 mL) and treated with hydrogen peroxide (30% in water, 10 mL). The mixture was stirred overnight at RT and poured into EtOAc (100 mL) and then washed with water (2100 mL). The combined aqueous layers were re-extracted with EtOAc (100 mL) and this second organic phase was washed with water (100 mL). All organic layers were combined and dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by silica gel chromatography (MeOH/DCM) to yield a brown oil. This residue was suspended in DCM (10 mL), hexanes (10 mL) were added and the mixture was stirred overnight at RT. The slurry was filtrated and washed with DCM/hexanes (1:1) to afford methyl 2-fluoro-4-hydroxy-6-methanesulfonylbenzoate (INT-28) as an off-white solid (256 mg, 58% 2 steps).

(216) Step 5: Synthesis of Compound 10

(217) ##STR00173##

(218) The mesylate INT-25 (0.3 mmol) is reacted with phenol INT-28 (0.3 mmol) in ACN (3 mL) using potassium carbonate (0.40 mmol) as base as described above for compound 9. The resulting product is hydrolyzed as described for compound 3 to afford 4-[(3R)-3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)butoxy]-2-fluoro-6-methanesulfonylbenzoic acid (10).

Example 21: Synthesis of Compound 37

(219) ##STR00174##

(220) The synthesis of 37 is accomplished using procedures described in Bioorg. Med. Chem. Lett. 2009, 19, 5617-5621 by replacing methyl 3-hydroxyphenylacetic acid with INT-28 to afford methyl 4-[(2R)-3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)-2-methylpropoxy]-2-fluoro-6-methanesulfonylbenzoate (37).

Example 22: Synthesis of Compound 70

(221) ##STR00175##

(222) Compound 37 is hydrolyzed as described for compound 3 and subsequent benzoic acid reduction is accomplished as described for the synthesis of INT-09 using sodium borohydride and catalytic iodine. Work-up and purification affords {4-[(2R)-3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)-2-methylpropoxy]-2-fluoro-6-methanesulfonylphenyl}methanol (70).

Example 23: Synthesis of Compound 39

(223) ##STR00176##

(224) The synthesis of 39 is accomplished using procedures described in Bioorg. Med. Chem. Lett. 2009, 19, 5617-5621 by replacing methyl 3-hydroxyphenylacetic acid with INT-28 and using chiral (S)-1,3-butanediol to afford methyl 4-{[(2R)-4-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl) amino)butan-2-yl]oxy}-2-fluoro-6-methanesulfonylbenzoate (39).

Example 24: Synthesis of Compound 69

(225) ##STR00177##

(226) Compound 39 is hydrolyzed as described for compound 3 and subsequent benzoic acid reduction is accomplished as described for the synthesis of INT-09 using sodium borohydride and catalytic iodine. Work-up and purification affords (4-{[(2R)-4-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)butan-2-yl]oxy}-2-fluoro-6-methanesulfonylphenyl)methanol (69).

Example 25: Synthesis of Compound 68

(227) ##STR00178##

(228) The synthesis of 68 is accomplished as described for compound 69 but using (R)-1,3-butanediol as the starting material to afford (4-{[(2S)-4-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)butan-2-yl]oxy}-2-fluoro-6-methanesulfonylphenyl)methanol (68).

Example 26: Synthesis of Compound 64

(229) ##STR00179##

(230) To a solution of bromide INT-01 (374 mg, 0.81 mmol) in ACN (8 mL) were added phenol INT-28 (200 mg, 0.73 mmol) and potassium carbonate (607 mg, 4.39 mmol). The reaction was heated to 90 C. overnight, cooled, and diluted with EtOAc (100 mL). The organic layer was washed with water (2100 mL), and the combined aqueous layers were re-extracted with EtOAc (100 mL). The second organic layer was washed with water (100 mL) and the combined organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc/hexanes=1/3) to afford methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylbenzoate (64) as a colorless solid foam (315 mg, 63%). ES(pos)MS m/z 678.13 (M+H.sup.+).

Example 27: Synthesis of Compound 35

(231) ##STR00180##

(232) Ester 64 (80 mg, 0.118 mmol) was dissolved in THF (10 mL) and treated with a solution of 2.0 N lithium hydroxide (2 mL). After stirring for 16 h, the reaction mixture was quenched with water (100 mL) and 2N aqueous hydrochloric acid to adjust the pH to between 2-3. The mixture was extracted with EtOAc (3100 mL), dried over magnesium sulfate, and purified by silica gel column chromatography (DCM/MeOH=10/1) to afford 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino) propoxy]-2-fluoro-6-methanesulfonylbenzoic acid (35) as a white solid (51 mg, 65% yield). ES(pos)MS m/z 664.15 (M+H.sup.+).

Example 28: Synthesis of Compound 60

(233) ##STR00181##

(234) Ester 64 (100 mg, 0.148 mmol) was dissolved in dry THF (5 mL) and treated with 3.0 M methylmagnesium bromide solution in diethyl ether (0.45 mL, 1.35 mmol). The reaction was heated for 2 days at 60 C. HPLC analysis showed 60-70% conversion. The reaction was cooled and the mixture was poured into diethyl ether (100 mL), washed with half-saturated sodium bicarbonate solution (100 mL) and water (100 mL). The combined aqueous layers were re-extracted with diethyl ether (100 mL). The second organic layer was washed with water (100 mL) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield an inseparable mixture of starting material and product. This mixture was dissolved in THF (5 mL), treated with 2N lithium hydroxide solution (0.5 mL, 1.0 mmol), and the reaction was stirred at RT overnight. The reaction was diluted with EtOAc (100 mL), washed with water (2100 mL), and the combined aqueous layers were re-extracted with EtOAc (100 mL). The second organic layer was washed with water (100 mL) and the combined organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc/hexanes=1/3) to afford 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}propan-2-ol (60) as a slightly yellow oil (31 mg, 31%). ES(pos)MS m/z 678.16 (M+H.sup.+).

Example 29: Synthesis of Compound 65

(235) ##STR00182##

(236) Chromium trioxide (75 mg, 0.75 mmol) was slurried in concentrated sulfuric acid (0.075 mL) for 5 min. Water (0.225 mL) was then added to the mixture resulting in a bright red solution. Silica gel (1.0 g) was added followed by stirring the orange powder for 10 min. Compound 8 (325 mg, 0.50 mmol) was added in DCM (15 mL) and the slurry was stirred for 30 min at RT or until TLC indicated consumption of starting materials. The remaining oxidant was quenched with MeOH (5 mL) and the mixture was stirred for 10 min (the slurry becomes dark green). The solids were filtered off, the filtrate was diluted with EtOAc (100 mL), washed with water (2100 mL), and the combined aqueous layers were re-extracted with EtOAc (100 mL). The second organic layer was washed with water (100 mL) and the combined organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc/hexanes=1/5 to 1/2) to afford 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonyl-benzaldehyde (65) as a colorless solid foam (90%). ES(pos)MS m/z 648.16 (M+H.sup.+).

Example 30: Synthesis of Compound 85

(237) ##STR00183##

(238) Compound 65 (150 mg, 0.231 mmol) was dissolved in dry THF (10 mL) and treated with 3.0 M methylmagnesium bromide solution in diethyl ether (0.31 mL, 0.93 mmol). After stirring at RT for 1 h, an additional amount of methylmagnesium bromide (0.31 mL, 0.93 mmol) was added and the reaction was stirred overnight. The mixture was quenched with saturated sodium bicarbonate solution (5 mL), diluted with EtOAc (100 mL), washed with water (2100 mL), and the combined aqueous layers were re-extracted with EtOAc (100 mL). The second organic layer was washed with water (100 mL) and the combined organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel preparative TLC (22000 micron plates, EtOAc/hexanes=1/1 and then again with DCM/MeOH=50/1) to afford 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol (85) as a colorless foam (35 mg, 22%). ES(pos)MS m/z 664.19 (M+H.sup.+).

Example 31: Synthesis of Compound 87

(239) ##STR00184##

(240) Silica gel supported Jones Reagent was synthesized as described for compound 65 (0.5 mmol).

(241) The resulting orange powder was slurried in DCM (3 mL) and alcohol 85 (25 mg, 0.038 mmol) was added. After stirring for 10 min at RT or until TLC indicated consumption of starting materials, the excess oxidant was quenched with MeOH (5 mL) and the mixture was stirred for 10 min (slurry becomes dark green). The solids were filtered off, the filtrate was diluted with EtOAc (100 mL), washed with water (2100 mL), and the combined aqueous layers were re-extracted with EtOAc (100 mL). The second organic layer was washed with water (100 mL) and the combined organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel preparative TLC (2000 micron plate, EtOAc/hexanes=1/1) to afford 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-one (87) as a colorless solid foam (15 mg, 60%). ES(pos)MS m/z 662.17 (M+H.sup.+).

Example 32: Synthesis of Compound 88

(242) Step 1: Synthesis of INT-29

(243) ##STR00185##

(244) Alcohol 8 (325 mg, 0.50 mmol) was dissolved in dry DCM (10 mL) and treated with triethylamine (0.21 mL, 3.0 mmol) and methanesulfonyl chloride (0.058 mL, 1.5 mmol). The reaction was stirred overnight, diluted with EtOAc (100 mL), washed with water (2100 mL), and the combined aqueous layers were re-extracted with EtOAc (100 mL). The second organic layer was washed with water (100 mL) and the combined organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure to yield the crude mesylate INT-29, which was used in the next step without further purification.

(245) Step 2: Synthesis of INT-30

(246) ##STR00186##

(247) Crude mesylate INT-29 was dissolved in dry DMF (5 mL) and treated with potassium phthalate (278 mg, 1.5 mmol). The reaction was heated at 90 C. for 3 h until TLC indicated complete consumption of the starting material. The mixture was cooled, diluted with EtOAc (100 mL), washed with water (2100 mL), and the combined aqueous layers were re-extracted with EtOAc (100 mL). The second organic layer was washed with water (100 mL) and the combined organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM/MeOH=200/1) to afford the desired phthalate (INT-30) as a white solid (72% over 2 steps).

(248) Step 3: Synthesis of Compound 88

(249) ##STR00187##

(250) Phthalate INT-30 (280 mg, 0.359 mmol) was suspended in ethanol (5 mL) and treated with hydrazine monohydrate (1.0 mL). The mixture was heated at 70 C. for 3 h resulting in a clear solution, followed by precipitate formation at which point TLC showed complete consumption of the starting material. The reaction was diluted with EtOAc (100 mL), washed with water (2100 mL), and the combined aqueous layers were then re-extracted with EtOAc (100 mL). The second organic layer was washed with water (100 mL) and the combined organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM/MeOH (7.0 N ammonia)=50/1) to afford {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methanamine (88) as a white colorless oil (185 mg, 79%). ES(pos)MS m/z 649.19 (M+H.sup.+).

Example 33: Synthesis of Compound 89

(251) ##STR00188##

(252) Primary amine 88 (73 mg, 0.112 mmol) was dissolved in dry DCM (3 mL) and treated with triethylamine (0.063 mL, 0.45 mmol) and acetyl chloride (0.017 mL, 0.225 mmol). After stirring for 2 h, the reaction mixture was diluted with EtOAc (100 mL), washed with water (2100 mL), and the combined aqueous layers were re-extracted with EtOAc (100 mL). The second organic layer was washed with water (100 mL) and the combined organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc/hexanes=5/1) to afford N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methyl)acetamide (89) as a white solid foam (70 mg, 90%). ES(pos)MS m/z 691.20 (M+H.sup.+).

Example 34: Synthesis of Compound 91

(253) Step 1: Synthesis of INT-31

(254) ##STR00189##

(255) (Methoxymethyl)triphenylphosphonium chloride (68.6 mg, 0.20 mmol) was suspended in dry THF (1.0 mL) and cooled to 0 C. A solution of 1.0 M LiHMDS in THF (0.186 mg, 0.185 mmol) was added to the reaction and the mixture was stirred for 30 min at the same temperature. The resulting bright orange solution was cooled to 78 C. and aldehyde 65 (120 mg, 0.185 mmol) dissolved in dry THF (2 mL) was slowly added to the reaction over 5 min. The mixture was warmed to RT over 1 h and stirred at this temperature for an additional 2 h. The yellow mixture was quenched with saturated sodium bicarbonate solution, diluted with EtOAc (100 mL), washed water (2100 mL), and the combined aqueous layers were re-extracted with EtOAc (100 mL). The second organic layer was washed with water (100 mL) and the combined organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc/hexanes=1/1) to afford INT-31 as a mixture of E/Z-isomers and as a colorless solid foam (120 mg, 96%).

(256) Step 2: Synthesis of Compound 91

(257) ##STR00190##

(258) INT-31 (115 mg, 0.17 mmol) was dissolved in THF (3 mL) and treated with 6N hydrochloric acid (2 mL). The reaction was stirred for 3.5 h at RT, or until TLC showed complete consumption of starting material. The mixture was carefully quenched with saturated potassium carbonate solution to adjust the pH to 8-9. The mixture was diluted with EtOAc (100 mL), washed with water (2100 mL), and the combined aqueous layers were re-extracted with EtOAc (100 mL). The second organic layer was washed with water (100 mL) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude aldehyde.

(259) The crude residue was dissolved in MeOH (5 mL) and treated with solid sodium borohydride (13 mg, 0.34 mmol). After stirring for 15 min at RT, TLC showed no starting material remained. The mixture was diluted with EtOAc (100 mL), washed with water (2100 mL), and the combined aqueous layers were re-extracted with EtOAc (100 mL). The second organic layer was washed with water (100 mL) and the combined organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc/hexanes=1/1) to afford semi-pure product. This lower spot was re-purified by silica gel preparative TLC (2000 micron plate, DCM/MeOH=50/1) to yield 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl} ethan-1-ol (91) as a white foam (31 mg, 27%). ES(pos)MS m/z 664.19 (M+H.sup.+).

Example 35: Synthesis of Compound 95

(260) ##STR00191##

(261) The reaction was performed according to J. Med. Chem. 2009, 52 (19) 6097-6106. To a solution of aldehyde 65 (0.3 g, 0.46 mmol) in anhydrous THF (5 mL) under nitrogen atmosphere was added trifluoromethyltrimethylsilane (78 mg, 0.55 mmol) and cesium fluoride (10 mg, 0.06 mmol). The resulting solution was sonicated for 15 min to initiate the reaction and then stirred at RT for 6 h. Aqueous 1 M hydrochloric acid (2 mL) was added and the mixture was stirred for an additional 2 h. The reaction was poured into EtOAc (25 mL), washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel preparative TLC (30% EtOAC/hexanes) to afford 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino) propoxy]-2-fluoro-6-methanesulfonylphenyl}-2,2,2-trifluoroethan-1-ol (95) as a white solid (171 mg, 52%); TLC=30% EtOAc/hexanes (0.5 Rf); ES(pos)MS m/z 718.5 (M+H.sup.+).

Example 36: Synthesis of Compound 93

(262) ##STR00192##

(263) Compound 95 (200 mg, 0.28 mmol) was oxidized as described for compound 65 and purified by silica gel preparative TLC to afford 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl) amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}-2,2,2-trifluoroethan-1-one (93) as a semi solid (70 mg, 35%); TLC=30% EtOAc/hexanes (0.65 Rf); ES (pos) MS m/z 716.5 (M+H.sup.+).

Example 37: Synthesis of Compound 94

(264) ##STR00193##

(265) To a solution of aldehyde 93 (0.2 mmol) in anhydrous THF (2 mL) under nitrogen atmosphere is added trifluoromethyltrimethylsilane (0.25 mmol) and cesium fluoride (0.02 mmol). The resulting solution is sonicated for 15 min to initiate the reaction and then stirred at RT for 6 h. Aqueous 1 M hydrochloric acid (2 mL) is added and the mixture is stirred for an additional 2 h. The reaction is poured into EtOAc (25 mL), washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel preparative TLC (30% EtOAC/hexanes) to afford 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}-1,1,1,3,3,3-hexafluoropropan-2-ol (94).

Example 38: Synthesis of Compound 97

(266) Step 1: Synthesis of INT-64

(267) ##STR00194##

(268) 1-Bromo-4-methoxy-2-(methylsulfanyl)benzene is prepared as described in Organic Process Research & Development 2004, 8(1), 33-44. 1-Bromo-4-methoxy-2-(methylsulfanyl)benzene (5.0 mmol) is dissolved in THF (50 mL), cooled to 78 C., and treated with n-butyllithium (5.3 mmol, 1.6 M in hexanes). After 30 min, hexafluoroacetone is bubbled into the solution and the mixture is stirred for an additional 30 min at 78 C. The reaction is quenched with saturated aqueous ammonium chloride solution, extracted with EtOAc (3100 mL), the combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography to afford 1,1,1,3,3,3-hexafluoro-2-[4-methoxy-2-(methylsulfanyl)phenyl]propan-2-ol (INT-64).

(269) Step 2: Synthesis of INT-65

(270) ##STR00195##

(271) To a suspension of INT-64 (2.0 mmol) and sodium iodide (20.0 mmol) in acetonitrile (15 mL) is added trimethylsilyl chloride (10 mmol) at RT. The mixture is heated to reflux for 48 h, cooled to RT, diluted with water (100 mL) and extracted into EtOAc (2100 mL). The combined EtOAc extracts are washed with saturated sodium thiosulfate solution (100 mL) to remove the iodine color, washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue is purified by silica gel chromatography to afford 4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-3-(methylsulfanyl)phenol (INT-65).

(272) Step 3: Synthesis of INT-66

(273) ##STR00196##

(274) INT-65 (1.0 mmol) is dissolved in DCM (10 mL) and treated with mCPBA (77%, 3.0 mmol). The resulting mixture is stirred overnight at RT. The organic solvent is removed under reduced pressure and the residue is dissolved in EtOAc (50 mL). The solution is washed with 1N sodium hydroxide (250 mL) and water (250 mL). The organic layer is dried over magnesium sulfate, filtered, concentrated under reduced pressure, and the residue is purified by silica gel chromatography (MeOH/DCM) to yield 4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-3-methanesulfonylphenol (INT-66).

(275) Step 4: Synthesis of Compound 97

(276) ##STR00197##

(277) Bromide INT-01 (0.50 mmol) and INT-66 (0.55 mmol) are dissolved in DMF (2 mL) and potassium carbonate (1.5 mmol) is added. After 6 h at RT the reaction is poured into EtOAc (25 mL), washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel preparative TLC to afford 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-methanesulfonylphenyl}-1,1,1,3,3,3-hexafluoropropan-2-ol (97).

Example 39: Synthesis of Compound 90

(278) Step 1: Synthesis of INT-32

(279) ##STR00198##

(280) To benzoic acid 35 (850 mg, 1.28 mmol) in DCM (10 mL) was added oxalyl chloride (131 L, 1.54 mmol) and a catalytic amount of DMF under nitrogen atmosphere. The reaction mixture was stirred for 1 h and concentrated under reduced pressure and the residue 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylbenzoyl chloride (INT-32) (840 mg, crude) was used in the next step without further purification.

(281) Step 2: Synthesis of Compound 90

(282) ##STR00199##

(283) To a solution of acid chloride INT-32 (150 mg, 0.22 mmol) in DCM (5 mL) at 0 C. was added methanolic ammonia (5 mL, 17%) in large excess and the solution was slowly warmed to RT. After 1 h, the volatiles were removed under reduced pressure and the residue was purified by silica gel preparative TLC (40% EtOAc/hexanes) to afford 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl) amino)-propoxy]-2-fluoro-6-methanesulfonylbenzamide (90) as a white solid (90 mg, 63%). TLC=30% EtOAc/hexanes (0.2 Rf); ES (pos) MS m/z 663.5 (M+H.sup.+).

Example 40: Synthesis of Compound 92

(284) ##STR00200##

(285) To a solution of acid chloride INT-32 (150 mg, 0.22 mmol) in DCM (5 mL) at 0 C. was added methanolic methylamine (8 mL, 10%) in large excess and the solution was slowly warmed to RT. After 1 h, the volatiles were removed and the residue was purified by silica gel preparative TLC (30% EtOAc/hexanes) to afford 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)-propoxy]-2-fluoro-6-methanesulfonyl-N-methylbenzamide (92) as a thick syrup (90 mg, 64%). TLC=30% EtOAc/hexanes (0.25 Rf); ES(pos)MS m/z 677.5 (M+H.sup.+).

Example 41: Synthesis of Compound 96

(286) ##STR00201##

(287) To a solution of acid chloride INT-32 (150 mg, 0.22 mmol) in DCM (5 mL) at 0 C. was added triethylamine (140 L, 1.0 mmol) and dimethylamine hydrochloride (82 mg, 1.0 mmol). The solution was slowly warmed to RT and stirred for 1 h. The reaction mixture was concentrated under reduced pressure and EtOAc (15 mL) and water were added. The organic layer was separated and the water layer was back extracted with EtOAc (10 mL) The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure and the residue was purified by silica gel preparative TLC (30% EtOAc/hexanes) to afford 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino) propoxy]-2-fluoro-6-methanesulfonyl-N,N-dimethylbenzamide (96) as a thick syrup (62 mg, 41%). TLC=30% EtOAc/hexanes (0.3 Rf); ES (pos) MS m/z 691.6 (M+H.sup.+).

Example 42: Synthesis of Compound 11

(288) Step 1: Synthesis of INT-33

(289) ##STR00202##

(290) To a solution of compound 9 (2.0 mmol) in DCM (2 mL) is added di-tert-butyl diisopropylphosphoramidite (1.35 g, 2.5 mmol) in DCM (2 mL) and tetrazole (5.0 mmol). The resulting suspension is stirred at RT for 16 h. Hydrogen peroxide (30%, 4.0 mmol) is added drop-wise and the resulting mixture is stirred for 2 h. The reaction mixture is diluted with DCM (10 mL), washed with brine, dried, concentrated under reduced pressure, and purified by silica gel chromatography to afford di-tert-butyl {4-[(3R)-3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)-butoxy]-2-fluoro-6-methanesulfonylphenyl} methyl phosphate (INT-33).

(291) Step 2: Synthesis of Compound 11

(292) ##STR00203##

(293) INT-33 (1.0 mmol) is dissolved in toluene (5 mL), TFA (10 mmol) is added, and the reaction is stirred for 2.5 h at RT. The mixture is concentrated under reduced pressure, and purified by preparatory reverse phase preparative HPLC to afford ({4-[(3R)-3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)butoxy]-2-fluoro-6-methanesulfonylphenyl}methoxy)phosphonic acid (11).

Example 43: Synthesis of Compound 12

(294) Step 1: Synthesis of INT-34

(295) ##STR00204##

(296) 2-(4-(Bis(benzyloxy)phosphoryloxy)phenyl)acetic acid (1.0 mmol) is prepared as previously described (WO20120135082) and added to a solution of compound 9 (0.5 mmol) and DMAP (1.0 mmol) in DCM (5 mL). N,N-dicyclohexylcarbodiimide (1.2 mmol) in DCM (5 mL) is added to the reaction and the mixture is stirred at RT for 30 min. The solution is filtered and concentrated under reduced pressure to yield crude product. The residue is purified by silica gel chromatography to afford {4-[(3R)-3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)-butoxy]-2-fluoro-6-methanesulfonylphenyl} methyl 2-(4-{[bis(benzyloxy)phosphoryl]oxy}phenyl)acetate (INT-34).

(297) Step 2: Synthesis of Compound 12

(298) ##STR00205##

(299) To a solution of INT-34 (0.25 mmol) in MeOH (5 mL) is added Pd/C (10% w/w) under an atmosphere of hydrogen at RT for 15 min. The mixture is filtered, concentrated under reduced pressure, and purified by reverse phase preparative HPLC to afford {4-[2-({4-[(3R)-3-({[2-chloro-3-(trifluoromethyl)-phenyl]methyl}-(2,2-diphenylethyl)amino)butoxy]-2-fluoro-6-methanesulfonylphenyl}methoxy)-2-oxoethyl]phenoxy} phosphonic acid (12).

Example 44: Synthesis of Compound 13

(300) Step 1: Synthesis of INT-35

(301) ##STR00206##

(302) To a solution of compound 9 (1 mmol) in DME (5 mL) is added sodium hydride (60% in mineral oil, 1.5 mmol) at 0 C. and then the reaction is cooled to 60 C. Chloromethylditertiarybutylphosphate (1.5 mmol) is prepared as previously described (WO20120135082) and sodium iodide (1.5 mmol) are added to the reaction. The temperature is maintained at 60 C. for 2 hours, and then the reaction is warmed to RT. The reaction is stirred for 2 h, poured into cold water (10 mL), extracted with EtOAc (315 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford crude di-tert-butyl ({4-[(3R)-3-({[2-chloro-3-(trifluoromethyl)-phenyl]-methyl}-(2,2-diphenylethyl)amino)-butoxy]-2-fluoro-6-methanesulfonylphenyl}methoxy)methyl phosphate (INT-35).

(303) Step 2: Synthesis of Compound 13

(304) ##STR00207##

(305) A stirred solution INT-35 (0.5 mmol) in 1:1 acetone/water (4 mL) is heated to 60 C. for 16 h. Solvent is removed under reduced pressure and the crude product is purified by reverse phase preparative HPLC to afford [({4-[(3R)-3-({[2-chloro-3-(trifluoromethyl)-phenyl]methyl}-(2,2-diphenylethyl)amino)-butoxy]-2-fluoro-6-methanesulfonylphenyl}-methoxy)methoxy]phosphonic acid (13).

Example 45: Synthesis of Compound 14

(306) Step 1: Synthesis of INT-36

(307) ##STR00208##

(308) To a solution of compound 9 (1.0 mmol), mono-tert-butylfumerate ester (1.0 mmol), and DMAP (0.5 mmol) in DCM (5 mL) is added N,N-dicyclohexylcarbodiimide (1.2 mmol) in DCM (5 mL). The mixture is stirred at RT overnight, diluted with DCM (10 mL), washed with water (33 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography to afford 1-tert-butyl 4-{4-[(3R)-3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}-(2,2-diphenylethyl)amino)butoxy]-2-fluoro-6-methanesulfonylphenyl}methyl (2E)-but-2-enedioate (INT-36).

(309) Step 2: Synthesis of Compound 14

(310) ##STR00209##

(311) INT-36 (0.50 mmol) in DCM (2 mL) is added TFA (0.2 mL) drop-wise over a period of 10 min at 0 C. The mixture is warmed to RT, stirred for 4 h, and the solvent removed under reduced pressure. The residue is purified by reverse phase preparative HPLC to afford (2E)-4-({4-[(3R)-3-({[2-chloro-3-(trifluoromethyl)-phenyl]methyl}-(2,2-diphenylethyl)amino)butoxy]-2-fluoro-6-methanesulfonylphenyl)-methoxy)-4-oxobut-2-enoic acid (14).

Example 46: Synthesis of Compound 15

(312) ##STR00210##

(313) To a stirred solution of compound 9 (0.50 mmol) in pyridine (1 mL) is added DMAP (0.05 mmol) and succinic anhydride (0.5 mmol) at RT. The reaction is stirred at RT overnight, solvent is removed under reduced pressure, and the crude product is purified by reverse phase preparative HPLC to afford 4-({4-[(3R)-3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)butoxy]-2-fluoro-6-methanesulfonylphenyl}methoxy)-4-oxobutanoic acid (15).

Example 47: Synthesis of Compound 16

(314) ##STR00211##

(315) Using a similar procedure to prepare compound 11, starting material compound 9 is replaced with compound 8 to afford ({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}-(2,2-diphenylethyl)amino)-propoxy]-2-fluoro-6-methanesulfonylphenyl}methoxy)phosphonic acid (16).

Example 48: Synthesis of Compound 17

(316) ##STR00212##

(317) Using a similar procedure to prepare compound 12, starting material compound 9 is replaced with compound 8 to afford {4-[2-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}-(2,2-diphenylethyl)amino)-propoxy]-2-fluoro-6-methanesulfonylphenyl}methoxy)-2-oxoethyl]phenoxy}phosphonic acid (17).

Example 49: Synthesis of Compound 18

(318) ##STR00213##

(319) Using a similar procedure to prepare compound 13, starting material compound 9 is replaced with compound 8 to afford [({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}-(2,2-diphenylethyl)amino)-propoxy]-2-fluoro-6-methanesulfonylphenyl}methoxy)methoxy]phosphonic acid (18).

Example 50: Synthesis of Compound 19

(320) ##STR00214##

(321) Using a similar procedure to prepare compound 14, starting material compound 9 is replaced with compound 8 to afford (2E)-4-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl) amino)-propoxy]-2-fluoro-6-methanesulfonylphenyl}methoxy)-4-oxobut-2-enoic acid (19).

Example 51: Synthesis of Compound 20

(322) ##STR00215##

(323) Using a similar procedure to prepare compound 15, starting material compound 9 is replaced with compound 8 to afford 4-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)-propoxy]-2-fluoro-6-methanesulfonylphenyl}methoxy)-4-oxobutanoic acid (20).

Example 52: Synthesis of Compound 21

(324) ##STR00216##

(325) Ethyl (3-hydroxyphenyl)methylphosphinate (0.5 mmol) is prepared as previously described (WO2010036613) and dissolved in ACN (3 mL). Bromide INT-01 (0.5 mmol) and potassium carbonate (0.60 mmol) are added as described above for compound 9. The resulting product is isolated and purified by chromatography and then the ester is hydrolyzed in dioxane (0.5 mL) with 5N sodium hydroxide (0.2 mL) at reflux temperature overnight. The reaction is concentrated under reduced pressure, treated with TFA (0.5 mL), and concentrated. The residue is purified by reverse phase preparative HPLC to afford {3-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-phenyl}(methyl)-phosphinic acid (21).

Example 53: Synthesis of Compound 22

(326) Step 1: Synthesis of INT-37

(327) ##STR00217##

(328) Methods to make benzoxaphosphol-1-ones have been previously described (Tetrahedron Lett. 1985, 26(39), 4771; J. Org. Chem. 1982, 47(9), 1677; and J. Org. Chem. 1981, 46(17), 3486). Using similar protocols, 6-hydroxy-1-methyl-1,3-dihydro-2,1-benzoxaphosphol-1-one (INT-37) is made from 3-bromo-4-methyl-phenol (U.S. Pat. No. 6,414,002).

(329) Step 2: Synthesis of Compound 22

(330) ##STR00218##

(331) INT-37 (0.5 mmol) and bromide INT-01 (0.5 mmol) are dissolved in ACN (3 mL) and potassium carbonate (0.60 mmol) is added as base as described above for compound 9. The resulting product is isolated and purified by chromatography to afford 6-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)-amino)-propoxy]-1-methyl-1,3-dihydro-2,1-benzoxaphosphol-1-one (22).

Example 54: Synthesis of Compound 23

(332) ##STR00219##

(333) Compound 22 is hydrolyzed in dioxane (0.5 mL) with 5N sodium hydroxide (0.2 mL) at reflux temperature overnight. The reaction is concentrated under reduced pressure, treated with TFA (0.5 mL), and concentrated. The residue is purified by reverse phase preparative HPLC to afford {5-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-(hydroxymethyl)phenyl}-(methyl)-phosphinic acid (23).

Example 55: Synthesis of Compound 24

(334) Step 1: Synthesis of INT-38

(335) ##STR00220##

(336) 3-(Trifluoromethoxy)benzaldehyde (975 mg, 5.13 mmol) and 2,2-diphenylethylamine (920 mg, 4.66 mmol) were dissolved in dry DCM (10 mL). Subsequent addition of sodium triacetoxyborohydride (988 mg, 4.66 mmol) and acetic acid (1 mL) was followed by stirring at RT overnight or until TLC showed no starting material remained. The reaction mixture was poured into saturated sodium bicarbonate solution (150 mL) and then extracted with EtOAc (3100 mL). The organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (MeOH/DCM/7N ammonium hydroxide) to afford the desired (2,2-diphenylethyl)({[3-(trifluoromethoxy)-phenyl]methyl})amine (INT-38) as a viscous oil (1.13 g, 65% yield).

(337) Step 2: Synthesis of INT-39

(338) ##STR00221##

(339) INT-38 (1.1 g, 2.96 mmol) and 1,3-dibromopropane (5.98 g, 29.6 mmol) were dissolved in dry ACN (24 mL). Potassium carbonate (613 mg, 4.44 mmol) was added and the reaction was heated to 90 C. for 16 h. The reaction mixture was poured into saturated sodium bicarbonate solution (100 mL) and then extracted with EtOAc (3100 mL). The organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (DCM/hexanes) to afford (3-bromopropyl)(2,2-diphenylethyl){[3-(trifluoromethoxy)phenyl]methyl}amine

(340) (INT-39) as a slightly yellowish oil (1.5 g, 76% yield) contaminated with 1,3-dibromopropane according to .sup.1H-NMR.

(341) Step 3: Synthesis of INT-40

(342) ##STR00222##

(343) INT-39 (270 mg, 0.406 mmol), methyl 3-hydroxyphenyl acetate (202 mg, 1.22 mmol), and potassium carbonate (561 mg, 4.06 mmol) were suspended in dry ACN and heated to 90 C. for 18 h. The reaction mixture was poured into saturated sodium bicarbonate solution (75 mL) and extracted with EtOAc (375 mL). The organic layers were dried over magnesium sulfate, filtered, concentrated, under reduced pressure, and the residue was purified by silica gel chromatography (EtOAc/hexanes) to afford the desired coupled ester methyl 2-(3-{3-[(2,2-diphenylethyl)({[3-(trifluoromethoxy)phenyl]methyl})-amino]propoxy}phenyl)acetate (INT-40) as a glassy oil (165 mg, 67% yield).

(344) Step 4: Synthesis of Compound 24

(345) ##STR00223##

(346) INT-40 (150 mg, 0.260 mmol) was dissolved in MeOH (30 mL) and then treated with 2.5 N sodium hydroxide (2.5 mL). Stirring at RT for 18 h resulted in completed conversion to the acid as judged by TLC. The solvent was removed under reduced pressure, the residue was dissolved in water (20 mL), the pH of the solution was adjusted to pH 2 with 1N hydrochloric acid, and the mixture was extracted with EtOAc (350 mL). The combined organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by prep-TLC (MeOH/DCM) to yield 2-(3-{3(2,2-diphenylethyl)({[3-(trifluoromethoxy)phenyl]methyl})amino]propoxy}phenyl)acetic acid (24) as a glassy oil (98 mg, 67% yield); ES(pos)MS m/z 564.23 (M+H.sup.+).

Example 56: Synthesis of Compound 25

(347) ##STR00224##

(348) Using a similar protocol to make compound 24, 3-(trifluoromethoxy)benzaldehyde was replaced with 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde to make 2-(3-{3[(2,2-diphenylethyl)({[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl})amino]propoxy}phenyl)acetic acid (25) as a glassy oil (115 mg, 56% yield); ES(pos)MS m/z 596.24 (M+H.sup.+).

Example 57: Synthesis of Compound 26

(349) ##STR00225##

(350) Using a similar protocol to make compound 24, 3-(trifluoromethoxy)benzaldehyde was replaced with 2,2-difluoro-2H-1,3-benzodioxole-4-carbaldehyde to make 2[3-(3-{[(2,2-difluoro-2H-1,3-benzodioxol-4-yl)methyl](2,2-diphenylethyl)amino}propoxy)phenyl]acetic acid (26) as a viscous oil (105 mg, 49% yield); ES(pos)MS m/z 560.23 (M+H.sup.+).

Example 58: Synthesis of Compound 27

(351) Step 1: Synthesis of INT-41

(352) ##STR00226##

(353) To a solution of 1-chloro-2-(trifluoromethoxy)benzene (2.5 mmol) in THF (10 mL) is added 2.5 M n-butyllithium in hexanes (1.4 mmol) at 78 C. After 40 min, a solution of DMF (2.8 mmol) in THF (2.5 mL) is added and the mixture is stirred to room overnight. The reaction is quenched with water at 0 C., extracted with EtOAc (350 mL), the combined organic layers are dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography provides 2-chloro-3-(trifluoromethoxy)benzaldehyde (INT-41).

(354) Step 2: Synthesis of Compound 27

(355) ##STR00227##

(356) Using a similar protocol to make compound 24, 3-(trifluoromethoxy)benzaldehyde is replaced with INT-41 to make 2-{3-[3-({[2-chloro-3-(trifluoromethoxy)phenyl]methyl}(2,2-diphenylethyl)amino)-propoxy]-phenyl}-acetic acid (27).

Example 59: Synthesis of Compound 28

(357) Step 1: Synthesis of INT-42

(358) ##STR00228##

(359) Using a similar protocol to make INT-41, 1-chloro-2-(trifluoromethoxy)benzene is replaced with 1-chloro-2-[(trifluoromethyl)sulfanyl]benzene to make 2-chloro-3-[(trifluoromethyl)sulfanyl]benzaldehyde (INT-42).

(360) Step 2: Synthesis of Compound 28

(361) ##STR00229##

(362) Using a similar protocol to make compound 24, 3-(trifluoromethoxy)benzaldehyde is replaced with INT-42 to make 2-(3-{3-[({2-chloro-3-[(trifluoromethyl)sulfanyl]phenyl}methyl)(2,2-diphenylethyl)amino]propoxy}-phenyl)-acetic acid (28).

Example 60: Synthesis of Compound 72

(363) Step 1: Synthesis of INT-43

(364) ##STR00230##

(365) Phenol INT-08 (50 mg, 0.227 mmol) and 1,3-dibromopropane (0.23 mL, 2.27 mmol) were dissolved in dry ACN (2 mL). Potassium carbonate (94 mg, 0.681 mmol) was added followed by heating at 40 C. overnight or until TLC showed complete consumption of the starting material. The reaction was diluted with EtOAc (100 mL), washed with water (2100 mL), and the combined aqueous layers were re-extracted with EtOAc (100 mL). The second organic layer was washed with water (100 mL) and the combined organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM/MeOH=50/1) to afford [4-(3-bromopropoxy)-2-fluoro-6-methanesulfonylphenyl]methanol (INT-43) as a white solid (55 mg, 71%).

(366) Step 2: Synthesis of INT-44

(367) ##STR00231##

(368) 2-2-Diphenylethylamine (500 mg, 2.6 mmol) and 2-fluoro-3-trifluoromethylbenzaldehyde (467 mg, 2.37 mmol) were dissolved in dry DCM (11 mL). Sodium triacetoxyborohydride (703 mg, 3.32 mmol) and acetic acid (0.136 mL, 2.37 mmol) were added and the reaction was stirred at RT overnight or until TLC showed consumption of the starting material. The reaction was diluted with EtOAc (100 mL), washed with half-saturated potassium carbonate solution (100 mL), water (100 mL), and the combined aqueous layers were re-extracted with EtOAc (100 mL). The second organic layer was washed with water (100 mL) and the combined organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc/hexanes=1/3) to afford (2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amine (INT-44) as a yellow viscous oil (736 mg, 83%).

(369) Step 3: Synthesis of 72

(370) ##STR00232##

(371) Secondary amine INT-44 (98 mg, 0.264 mmol) and bromide INT-43 (60 mg, 0.176 mmol) were dissolved in dry ACN (2 mL). Potassium carbonate (73 mg, 0.53 mmol) was added and the reaction was heated at 90 C. overnight. The mixture was diluted with EtOAc (100 mL), washed with water (2100 mL), and the combined aqueous layers were re-extracted with EtOAc (100 mL). The second organic layer was washed with water (100 mL) and the combined organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel preparative TLC (2000 micron plate, EtOAc/hexanes=1/2 then a second purification using DCM/MeOH 50/1) to afford (4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)methanol (72) as a slightly yellow foam (59 mg, 53%). ES(pos)MS m/z 634.21 (M+H.sup.+).

Example 61: Synthesis of Compound 73

(372) ##STR00233##

(373) Synthesis of 73 followed the protocol outlined for compound 72 substituting 3-trifluromethylbenzaldehyde for 2-fluoro-3-trifluromethylbenzaldehyde. The reaction sequence yielded (4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)methanol (73) as a viscous oil (65 mg, 60%). ES(pos)MS m/z 616.21 (M+H.sup.+).

Example 62: Synthesis of Compound 74

(374) ##STR00234##

(375) Synthesis of compound 74 followed the protocol outlined for compound 72 substituting 3-trifluromethoxybenzaldehyde for 2-fluoro-3-trifluromethylbenzaldehyde. The reaction sequence yielded (4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethoxy)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)methanol (74) as a viscous oil (70 mg, 63%). ES(pos)MS m/z 632.21 (M+H.sup.+).

Example 63: Synthesis of Compound 75

(376) ##STR00235##

(377) Synthesis of compound 75 followed the protocol outlined for compound 72 substituting 4-fluoro-3-trifluoromethylbenzaldehyde for 2-fluoro-3-trifluoromethylbenzaldehyde. The reaction sequence yielded (4-{3-[(2,2-diphenylethyl)({[4-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylphenyl)methanol (75) as a viscous oil (68 mg, 61%). ES(pos)MS m/z 634.21 (M+H.sup.+).

Example 64: Synthesis of Compound 29

(378) Step 1: Synthesis of INT-45

(379) ##STR00236##

(380) To a solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (0.24 g, 1.17 mmol) in DMF (3 mL) was added sodium hydride (0.05 mg, 1.17 mg) in portions at 0 C. over 30 min. A solution of bromide INT-01 (0.5 g, 0.98 mmol) was added and the solution was stirred at RT for 3 h. The reaction mixture was quenched with ice and extracted into diethyl ether (210 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to yield tert-butyl 3-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]piperidine-1-carboxylate (INT-45) as a colorless liquid (0.3 g, 55% yield); TLC=30% EtOAc/hexanes (0.4 Rf).

(381) Step 2: Synthesis of INT-46

(382) ##STR00237##

(383) To a solution of INT-45 (0.25 g, 0.39 mmol) in DCM (2.5 mL) was added TFA (0.045 mL, 0.59 mmol) and the solution was stirred at RT for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was re-dissolved in fresh DCM (5 mL) and re-concentrated under reduced pressure. The process was repeated 3 times and the residue {[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)[3-(piperidin-3-yloxy)propyl]amine (INT-46) was used in the next step without further purification.

(384) Step 3: Synthesis of Compound 29

(385) ##STR00238##

(386) To amine INT-46 (0.2 g, 0.38 mmol) in DCM (3 mL) was added triethylamine (79 L, 0.56 mmol) and methanesulfonyl chloride (28 L, 0.38 mmol) at 0 C. After 2 h stirring at RT, the reaction mixture was diluted with DCM (5 mL), washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC to yield {[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl){3-[(1-methanesulfonylpiperidin-3-yl)oxy]propyl}amine (29) as thick syrup (0.16 g, 72% yield); MS (ESI) 609.1 (M+H.sup.+).

Example 65: Synthesis of Compound 30

(387) ##STR00239##

(388) Using a similar protocol to make compound 29, tert-butyl 3-hydroxypiperidine-1-carboxylate was replaced with (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate and INT-01 was replaced with INT-25 to make {[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)[(2R)-4-{[(3R)-1-methanesulfonylpiperidin-3-yl]oxy}butan-2-yl]amine (30) as a glassy oil (56 mg, 48% yield); MS (ESI) 623.23 (M+H.sup.+).

Example 66: Synthesis of Compound 31

(389) ##STR00240##

(390) Using a similar protocol to make compound 29, tert-butyl 3-hydroxypiperidine-1-carboxylate was replaced with (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate and INT-01 was replaced with INT-25 to make {[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)[(2R)-4-{[(3S)-1-methanesulfonylpiperidin-3-yl]oxy}butan-2-yl]amine (31) as a glassy oil (63 mg, 51% yield); MS (ESI) 623.22 (M+H.sup.+).

Example 67: Synthesis of Compound 32

(391) ##STR00241##

(392) Using a similar protocol to make compound 29, tert-butyl 3-hydroxypiperidine-1-carboxylate is replaced with (3S)-1-methanesulfonylpyrrolidin-3-ol and INT-01 is replaced with INT-25 to make {[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)[(2R)-4-{[(3S)-1-methanesulfonylpyrrolidin-3-yl]oxy}butan-2-yl]amine (32).

Example 68: Synthesis of Compound 33

(393) ##STR00242##

(394) Using a similar protocol to make compound 29, tert-butyl 3-hydroxypiperidine-1-carboxylate is replaced with (3R)-1-methanesulfonylpyrrolidin-3-ol and INT-01 is replaced with INT-25 to make {[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)[(2R)-4-{[(3R)-1-methanesulfonylpyrrolidin-3-yl]oxy}butan-2-yl]amine (33).

Example 69: Synthesis of Compound 34

(395) Step 1: Synthesis of INT-47

(396) ##STR00243##

(397) (2R,4S)-4-Hydroxypyrrolidine-2-carboxylic acid (0.5 mmol) is dissolved in DCM (2.5 mL) and triethylamine (1.0 mmol) is added followed by methanesulfonyl chloride (0.5 mmol). After stirring for 2 h at RT the reaction is poured into 1N aqueous hydrochloric acid (25 mL), and extracted with EtOAc (325 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered, concentrated under reduced pressure to afford crude (2R,4S)-4-hydroxy-1-methanesulfonylpyrrolidine-2-carboxylic acid (INT-47) which is used in the next reaction without further purification.

(398) Step 2: Synthesis of Compound 34

(399) ##STR00244##

(400) To a solution of INT-47 (0.25 mmol) in DMF (3 mL) is added sodium hydride (0.5 mmol) in portions at 0 C. over 30 min. A solution of INT-25 (0.25 mmol) is added and the solution is stirred at RT for 3 h. The reaction mixture is quenched with ice, the pH is adjusted to pH 3 using 1N aqueous hydrochloric acid, and the mixture is extracted into EtOAc (225 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography to yield (2R,4S)-4-[3R)-3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}-(2,2-diphenylethyl)amino)butoxy]-1-methanesulfonylpyrrolidine-2-carboxylic acid (34).

Example 70: Synthesis of Compound 36

(401) ##STR00245##

(402) Using a similar protocol to make compound 34, (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid is replaced with (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid to make (2S,4S)-4-[3R)-3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)butoxy]-1-methanesulfonylpyrrolidine-2-carboxylic acid (36).

Example 71: Synthesis of Compound 38

(403) ##STR00246##

(404) Using a similar protocol to make compound 34, (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid is replaced with (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid to make (2S,4R)-4-[(3R)-3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)-butoxy]-1-methanesulfonylpyrrolidine-2-carboxylic acid (38).

Example 72: Synthesis of Compound 40

(405) ##STR00247##

(406) Using a similar protocol to make compound 34, (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid is replaced with (2R,4R)-4-hydroxypyrrolidine-2-carboxylic acid to make (2R,4R)-4-[(3R)-3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)-butoxy]-1-methanesulfonylpyrrolidine-2-carboxylic acid (40).

Example 73: Synthesis of Compound 61

(407) Step 1: Synthesis of INT-48

(408) ##STR00248##

(409) Bromide INT-01 (200 mg, 0.395 mmol) and (S)N-Boc-3-pyrrolidinol (147 mg, 0.783 mmol) were dissolved in dry DMF (3 mL). Sodium hydride (60% in mineral oil, 28.2 mg, 0.706 mmol) was added and the reaction was stirred at 45 C. overnight or until TLC showed the bromide was mostly consumed. The reaction was quenched by addition of saturated sodium bicarbonate solution, extracted with 1:1 EtOAc/hexanes (3100 mL), dried over magnesium sulfate, the solvent was concentrated under reduced pressure, and the material was purified by silica gel column chromatography (EtOAc/hexanes=1/5 to 1/3) to afford INT-48 as a slightly yellow oil (206 mg, 52%).

(410) Step 2: Synthesis of INT-49

(411) ##STR00249##

(412) Protected amine INT-48 (127 mg, 0.206 mmol) was dissolved in dry DCM (10 mL) and treated with trifluoroacetic acid (0.80 mL). The mixture was stirred at RT for 3 h or until TLC confirmed full removal of the protecting group. The reaction was carefully quenched with saturated potassium carbonate solution (100 mL), extracted with DCM (3100 mL), dried over magnesium sulfate, and solvent was concentrated under reduced pressure to afford the crude amine INT-49 that was used in the next step without further purification.

(413) Step 3: Synthesis of 61

(414) ##STR00250##

(415) INT-49 was dissolved in dry DCM (5 mL), and treated with triethylamine (0.142 mL, 1.01 mmol) and methanesulfonyl chloride (0.039 mL, 0.5 mmol). The reaction was stirred at RT overnight or until TLC showed complete consumption of the starting material. The mixture was diluted with EtOAc (100 mL), washed with 10:1 water/saturated sodium bicarbonate solution (100 mL) and water (100 mL), and the combined aqueous layers were re-extracted with EtOAc (100 mL). The second organic layer was washed with water (100 mL) and the combined organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel preparative TLC (22000 micron plates, EtOAc/hexanes=2/3) to afford {[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)(3-{[(3S)-1-methanesulfonylpyrrolidin-3-yl]oxy}propyl)amine (61) as a slightly yellow foam (86 mg, 70% over two steps). ES(pos)MS m/z 595.20 (M+H.sup.+).

Example 74: Synthesis of Compound 62

(416) ##STR00251##

(417) Synthesis of 62 followed the protocol outlined for compound 61 substituting 1-N-Boc-3-hydroxyazetidine for (S)N-Boc-3-pyrrolidinol. The reaction sequence yielded {[2-chloro-3-(trifluoromethyl)phenyl]methyl} (2,2-diphenylethyl){3-[(1-methanesulfonylazetidin-3-yl)oxy]propyl}amine (62) as a viscous oil (215 mg, 63% over three steps). ES(pos)MS m/z 581.18 (M+H.sup.+).

Example 75: Synthesis of Compound 63

(418) ##STR00252##

(419) Synthesis of compound 63 followed the protocol outlined for compound 61 substituting (R)N-Boc-3-piperidinol for (S)N-Boc-3-pyrrolidinol. The reaction sequence yielded {[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)(3-{[(3R)-1-methanesulfonylpiperidin-3-yl]oxy}propyl)amine (63) as a viscous oil (105 mg, 33% over three steps). ES(pos)MS m/z 609.21 (M+H.sup.+).

Example 76: Synthesis of Compound 66

(420) ##STR00253##

(421) Synthesis of compound 66 followed the protocol outlined for compound 61 substituting (S)N-Boc-3-piperidinol for (S)N-Boc-3-pyrrolidinol. The reaction sequence yielded {[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)(3-{[(3S)-1-methanesulfonylpiperidin-3-yl]oxy}propyl)amine (66) as a viscous oil (91 mg, 29% over three steps). ES(pos)MS m/z 609.21 (M+H.sup.+).

Example 77: Synthesis of Compound 67

(422) ##STR00254##

(423) Synthesis of compound 67 followed the protocol outlined for compound 61 substituting NBoc-cis-4-hydroxy-L-proline for (S)N-Boc-3-pyrrolidinol. The reaction sequence yielded (2S,4S)-4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-1-methanesulfonylpyrrolidine-2-carboxylic acid (67) as a viscous oil (163 mg, 26% over three steps). ES(pos)MS m/z 653.17 (M+H.sup.+).

Example 78: Synthesis of Compound 42

(424) Step 1: Synthesis of INT-50

(425) ##STR00255##

(426) To a solution of INT-46 (0.2 g, 0.37 mmol) in DCM (5 mL) was added DIPEA (96 L, 0.55 mmol) and ethyl bromoacetate (49 L, 0.44 mmol) at 0 C. The reaction was stirred at RT for 4 h, concentrated under reduced pressure, and purified by silica gel chromatography to yield ethyl 2-{3-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-piperidin-1-yl}acetate (INT-50) as syrup (0.19 g, 83% yield); TLC=30% EtOAc/hexanes (0.6 Rf).

(427) Step 2: Synthesis of Compound 42

(428) ##STR00256##

(429) INT-50 (0.15 g, 0.24 mmol) was dissolved in 1:1 MeOH and THF (3 mL) and treated with 2N sodium hydroxide (0.5 mL) at 0 C. The mixture was stirred at RT overnight and then concentration under reduced pressure. The residue was dissolved in DCM (5 mL) and water (5 mL), carefully neutralized with 1N hydrochloric acid to pH 7, transferred into a separating funnel, and the organic layer was separated. The water layer was re-extracted with DCM (25 mL). The combined DCM layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC to yield 2-{3-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}-(2,2-diphenylethyl)amino)propoxy]piperidin-1-yl}acetic acid (42) as a syrup (0.12 g, 86% yield); TLC=5% MeOH/DCM (0.3 Rf); MS (ESI) 589.1 (M+H.sup.+).

Example 79: Synthesis of Compound 43

(430) ##STR00257##

(431) To a solution of hydroxylamine hydrochloride (0.05 g, 0.68 mmol) in MeOH (2.5 mL) is added potassium hydroxide (0.04 g, 0.68 mmol) in an ice-bath for 1 h. The salts are filtered off and the filtrate containing free hydroxylamine in MeOH is collected. INT-50 (0.2 mmol) in THF (2 mL) is added to the above solution and stirred at RT for 3 h. The reaction is concentrated under reduced pressure, the residue is diluted with water (10 mL) and acidified with 2N aqueous hydrochloric acid to pH 4. The mixture is extracted with EtOAc (210 mL). The organic layers are separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by preparative TLC to yield 2-{3-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-piperidin-1-yl}-N-hydroxyacetamide (43).

Example 80: Synthesis of Compound 44

(432) ##STR00258##

(433) Using a similar protocol to make compound 42, tert-butyl 3-hydroxypiperidine-1-carboxylate is replaced with tert-butyl 3-hydroxypyrrolidine-1-carboxylate to make 2-{3[3-({[2-chloro-3-(trifluoromethyl)-phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]pyrrolidin-1-yl}acetic acid (44).

Example 81: Synthesis of Compound 45

(434) ##STR00259##

(435) Using a similar protocol to make compound 43, reaction of compound 44 with hydroxylamine affords 2-{3-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]pyrrolidin-1-yl}-N-hydroxyacetamide (45).

Example 82: Synthesis of Compound 77

(436) ##STR00260##

(437) INT-31 (0.15 mmol) is dissolved in THF (3 mL) and treated with 6N hydrochloric acid (2 mL). The reaction is stirred for 3.5 h at RT, or until TLC showed complete consumption of starting material. The reaction is carefully quenched with saturated potassium carbonate solution to adjust the pH to 8-9. The mixture is diluted with EtOAc (50 mL), washed with water (250 mL), and the combined aqueous layers are re-extracted with EtOAc (50 mL). The second organic layer is washed with water (50 mL) and the combined organic layers are dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude aldehyde which is oxidized directly to the carboxylic acid without further purification and using known literature protocols (e.g. Org. Lett. 2003, 5, 1031-1034).

(438) The crude aldehyde (0.15 mmol) is dissolved in DMF (3 mL) and treated with methanesulfonic acid (0.15 mmol) and Oxone (0.15 mmol). The reaction is stirred for 3 h at RT, the mixture is diluted with EtOAc (50 mL), washed with water (250 mL), and the combined aqueous layers are extracted with EtOAc (50 mL). The second organic layer is washed with water (50 mL) and the combined organic layers are dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to afford 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}acetic acid (77).

Example 83: Selected LXR Agonists of the Invention

(439) Exemplary LXR agonists of the invention that are synthesized by combining intermediates and methods described herein are listed in Table 4.

(440) To make certain fluoridated compounds, starting materials for described syntheses are replaced as follows: 2-(phenyl)propan-1-amine is replaced by 2-(4-fluorophenyl)propan-1-amine [456-01-9]; phenethylamine is replaced with 2-(4-fluorophenyl)ethylamine [1583-88-6]; benzylamine is replaced with 4-fluorobenzylamine [140-75-0]; 2-phenyl-2-methylpropan-1-amine is replaced with 2-(4-fluorophenyl)-2-methylpropan-1-amine [40377-35-3]; and phenethylamine is replaced 2,2-difluoro-2-(4-fluorophenyl)ethan-1-amine which is made by standard lithium aluminum hydride reduction of 2,2-difluoro-2-(4-fluorophenyl)acetamide (Enamine #EN300-96772).

(441) To make certain desfluoridated compounds, INT-08 is replaced by INT-67 which is made from 4-bromo-2-(methylsulfonyl)benzaldehyde [849035-77-4] by standard sodium borohydride reduction and following a similar sequence of steps described for INT-08.

(442) ##STR00261##

(443) TABLE-US-00004 TABLE 4 Additional LXR agonists of the Invention. # Name 98 (2-fluoro-6-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)methanol 99 (2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylethyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)methanol 100 (2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)methanol 101 (4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylphenyl)methanol 102 (4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylphenyl)methanol 103 [2-fluoro-4-(3-{[(4-fluorophenyl)methyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]methanol 104 [2-fluoro-4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]methanol 105 [2-fluoro-4-(3-{[2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]methanol 106 [2-fluoro-4-(3-{[2-(4-fluorophenyl)propyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]methanol 107 {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4- fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methanol 108 [4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6- methanesulfonylphenyl]methanol 109 [4-(3-{[2,2-difluoro-2-(4-fluoropheny)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6- methanesulfonylphenyl]methanol 110 {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methanol 111 {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methanol 112 {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluoropheny)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methanol 113 {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methanol 114 {2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}methanol 115 {2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2- phenylethyl)amino)propoxy]-6-methanesulfonylphenyl}methanol 116 {2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2- phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}methanol 117 {2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-6-methanesulfonylphenyl}methanol 118 {2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-6-methanesulfonylphenyl}methanol 119 {2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluoropheny)ethyl]amino)propoxy]-6-methanesulfonylphenyl}methanol 120 {2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-6-methanesulfonylphenyl}methanol 121 (2-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)methanol 122 (2-methanesulfonyl-4-{3-[(2-phenylethyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)methanol 123 (2-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)methanol 124 {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2- methanesulfonylphenyl}methanol 125 (4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)methanol 126 (4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)methanol 127 (4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)methanol 128 (4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)methanol 129 (4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)methanol 130 [4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylphenyl]methanol 131 [4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]methanol 132 [4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylphenyl]methanol 133 [4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylphenyl]methanol 134 {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}methanol 135 [4-(3-{[2,2-difluoro-2-(4-fluoropheny)ethyl]({[2-fluoro-3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]methanol 136 [4-(3-{[2,2-difluoro-2-(4-fluoropheny)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]methanol 137 {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}methanol 138 {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2- methanesulfonylphenyl}methanol 139 {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2- methanesulfonylphenyl}methanol 140 {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}methanol 141 {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}methanol 142 {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}methanol 143 {4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}methanol 144 {4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}methanol 145 {4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2- methanesulfonylphenyl}methanol 146 {4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2- methanesulfonylphenyl}methanol 147 {4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}methanol 148 {4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}methanol 149 {4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}methanol 150 {4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}methanol 151 [3-(3-methanesulfonylphenoxy)propyl](2-methyl-2-phenylpropyl){[3- (trifluoromethyl)phenyl]methyl}amine 152 [3-(3-methanesulfonylphenoxy)propyl](2-phenylethyl){[3- (trifluoromethyl)phenyl]methyl}amine 153 [3-(3-methanesulfonylphenoxy)propyl](2-phenylpropyl){[3- (trifluoromethyl)phenyl]methyl}amine 154 (2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})[3-(3- methanesulfonylphenoxy)propyl]amine 155 (2,2-diphenylethyl)[3-(3-methanesulfonylphenoxy)propyl]{[3- (trifluoromethyl)phenyl]methyl}amine 156 benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})[3-(3- methanesulfonylphenoxy)propyl]amine 157 benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})[3-(3- methanesulfonylphenoxy)propyl]amine 158 benzyl[3-(3-methanesulfonylphenoxy)propyl]{[3-(trifluoromethyl)phenyl]methyl}amine 159 [(4-fluorophenyl)methyl][3-(3-methanesulfonylphenoxy)propyl]{[3- (trifluoromethyl)phenyl]methyl}amine 160 [2-(4-fluorophenyl)-2-methylpropyl][3-(3-methanesulfonylphenoxy)propyl]{[3- (trifluoromethyl)phenyl]methyl}amine 161 [2-(4-fluorophenyl)ethyl][3-(3-methanesulfonylphenoxy)propyl]{[3- (trifluoromethyl)phenyl]methyl}amine 162 [2-(4-fluorophenyl)propyl][3-(3-methanesulfonylphenoxy)propyl]{[3- (trifluoromethyl)phenyl]methyl}amine 163 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4-fluoropheny)ethyl][3-(3- methanesulfonylphenoxy)propyl]amine 164 [2,2-difluoro-2-(4-fluoropheny)ethyl]({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})[3-(3- methanesulfonylphenoxy)propyl]amine 165 [2,2-difluoro-2-(4-fluoropheny)ethyl][3-(3-methanesulfonylphenoxy)propyl]{[3- (trifluoromethyl)phenyl]methyl}amine 166 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[3-(3-methanesulfonylphenoxy)propyl](2- methyl-2-phenylpropyl)amine 167 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[3-(3-methanesulfonylphenoxy)propyl](2- phenylethyl)amine 168 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[3-(3-methanesulfonylphenoxy)propyl](2- phenylpropyl)amine 169 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl][3-(3- methanesulfonylphenoxy)propyl]amine 170 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl][3-(3- methanesulfonylphenoxy)propyl]amine 171 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluoropheny)ethyl][3-(3- methanesulfonylphenoxy)propyl]amine 172 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl][3-(3- methanesulfonylphenoxy)propyl]amine 173 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[3-(3-methanesulfonylphenoxy)propyl](2- methyl-2-phenylpropyl)amine 174 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[3-(3-methanesulfonylphenoxy)propyl](2- phenylethyl)amine 175 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[3-(3-methanesulfonylphenoxy)propyl](2- phenylpropyl)amine 176 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl][3-(3- methanesulfonylphenoxy)propyl]amine 177 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl][3-(3- methanesulfonylphenoxy)propyl]amine 178 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluoropheny)ethyl][3-(3- methanesulfonylphenoxy)propyl]amine 179 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl][3-(3- methanesulfonylphenoxy)propyl]amine 180 1-(2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylethyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol 181 1-(2-fluoro-6-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol 182 1-(2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol 183 1-(4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}- 2-fluoro-6-methanesulfonylphenyl)ethan-1-ol 184 1-(4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro- 6-methanesulfonylphenyl)ethan-1-ol 185 1-(4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylphenyl)ethan-1-ol 186 1-(4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylphenyl)ethan-1-ol 187 1-(4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylphenyl)ethan-1-ol 188 1-[2-fluoro-4-(3-{[(4-fluorophenyl)methyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]ethan-1-ol 189 1-[2-fluoro-4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]ethan-1-ol 190 1-[2-fluoro-4-(3-{[2-(4-fluoropheny)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]ethan-1-ol 191 1-[2-fluoro-4-(3-{[2-(4-fluorophenyl)propyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]ethan-1-ol 192 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4- fluoropheny)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol 193 1-[4-(3-{[2-difluoro-2-(4-fluoropheny)ethyl]({[2-fluoro-3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6- methanesulfonylphenyl]ethan-1-ol 194 1-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6- methanesulfonylphenyl]ethan-1-ol 195 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol 196 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2- fluoro-6-methanesulfonylphenyl}ethan-1-ol 197 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol 198 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol 199 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol 200 1-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol 201 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol 202 1-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2- phenylethyl)amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol 203 1-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2- phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol 204 1-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol 205 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2- fluoro-6-methanesulfonylphenyl}ethan-1-ol 206 1-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol 207 1-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol 208 1-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol 209 1-(2-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol 210 1-(2-methanesulfonyl-4-{3-[(2-phenylethyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol 211 1-(2-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol 212 1-(4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}- 2-methanesulfonylphenyl)ethan-1-ol 213 1-(4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)ethan-1-ol 214 1-(4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)ethan-1-ol 215 1-(4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)ethan-1-ol 216 1-(4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)ethan-1-ol 217 1-[4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylphenyl]ethan-1-ol 218 1-[4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]ethan-1-ol 219 1-[4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylphenyl]ethan-1-ol 220 1-[4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylphenyl]ethan-1-ol 221 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 222 1-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]ethan-1-ol 223 1-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]ethan-1-ol 224 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 225 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2- methanesulfonylphenyl}ethan-1-ol 226 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2- methanesulfonylphenyl}ethan-1-ol 227 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 228 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 229 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 230 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 231 1-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 232 1-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2- methanesulfonylphenyl}ethan-1-ol 233 1-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2- methanesulfonylphenyl}ethan-1-ol 234 1-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 235 1-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 236 1-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 237 1-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 238 1-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2- methanesulfonylphenyl}ethan-1-ol 239 2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylethyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}benzaldehyde 240 4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- fluoro-6-methanesulfonylbenzaldehyde 241 2-fluoro-6-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}benzaldehyde 242 4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylbenzaldehyde 243 4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylbenzaldehyde 244 4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylbenzaldehyde 245 4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylbenzaldehyde 246 2-fluoro-4-(3-{[(4-fluorophenyl)methyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylbenzaldehyde 247 2-fluoro-4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylbenzaldehyde 248 2-fluoro-4-(3-{[2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylbenzaldehyde 249 2-fluoro-4-(3-{[2-(4-fluorophenyl)propyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylbenzaldehyde 250 4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6- methanesulfonylbenzaldehyde 251 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4- fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylbenzaldehyde 252 4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6- methanesulfonylbenzaldehyde 253 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylbenzaldehyde 254 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2-fluoro- 6-methanesulfonylbenzaldehyde 255 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2- fluoro-6-methanesulfonylbenzaldehyde 256 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-fluoro-6-methanesulfonylbenzaldehyde 257 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-fluoro-6-methanesulfonylbenzaldehyde 258 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-6-methanesulfonylbenzaldehyde 259 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-fluoro-6-methanesulfonylbenzaldehyde 260 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]- 6-methanesulfonylbenzaldehyde 261 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2- phenylpropyl)amino)propoxy]-6-methanesulfonylbenzaldehyde 262 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-6-methanesulfonylbenzaldehyde 263 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-6-methanesulfonylbenzaldehyde 264 2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}benzaldehyde 265 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-6-methanesulfonylbenzaldehyde 266 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-6-methanesulfonylbenzaldehyde 267 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylbenzaldehyde 268 2-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}benzaldehyde 269 2-methanesulfonyl-4-{3-[(2-phenylethyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}benzaldehyde 270 2-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}benzaldehyde 271 4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylbenzaldehyde 272 4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylbenzaldehyde 273 4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylbenzaldehyde 274 4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylbenzaldehyde 275 4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylbenzaldehyde 276 4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylbenzaldehyde 277 4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzaldehyde 278 4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylbenzaldehyde 279 4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylbenzaldehyde 280 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylbenzaldehyde 281 4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzaldehyde 282 4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzaldehyde 283 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-methanesulfonylbenzaldehyde 284 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2- methanesulfonylbenzaldehyde 285 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2- methanesulfonylbenzaldehyde 286 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2- methanesulfonylbenzaldehyde 287 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylbenzaldehyde 288 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-methanesulfonylbenzaldehyde 289 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylbenzaldehyde 290 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylbenzaldehyde 291 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-methanesulfonylbenzaldehyde 292 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2- methanesulfonylbenzaldehyde 293 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2- methanesulfonylbenzaldehyde 294 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]- 2-methanesulfonylbenzaldehyde 295 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-methanesulfonylbenzaldehyde 296 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]- 2-methanesulfonylbenzaldehyde 297 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylbenzaldehyde 298 methyl 2-fluoro-6-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}benzoate 299 methyl 2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}benzoate 300 methyl 4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- fluoro-6-methanesulfonylbenzoate 301 methyl 2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylethyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}benzoate 302 methyl 4-{3-[(2,2-diphenylethyl)({[2-fluoro-3- (trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6-methanesulfonylbenzoate 303 methyl 4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- fluoro-6-methanesulfonylbenzoate 304 methyl 4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro- 6-methanesulfonylbenzoate 305 methyl 4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylbenzoate 306 methyl 2-fluoro-4-(3-{[(4-fluorophenyl)methyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylbenzoate 307 methyl 2-fluoro-4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylbenzoate 308 methyl 2-fluoro-4-(3-{[2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylbenzoate 309 methyl 2-fluoro-4-(3-{[2-(4-fluorophenyl)propyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylbenzoate 310 methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4- fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylbenzoate 311 methyl 4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6-methanesulfonylbenzoate 312 methyl 4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6-methanesulfonylbenzoate 313 methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylbenzoate 314 methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]- 2-fluoro-6-methanesulfonylbenzoate 315 methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-fluoro-6-methanesulfonylbenzoate 316 methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-fluoro-6-methanesulfonylbenzoate 317 methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2- phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylbenzoate 318 methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-fluoro-6-methanesulfonylbenzoate 319 methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylbenzoate 320 methyl 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-6-methanesulfonylbenzoate 321 methyl 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2- phenylethyl)amino)propoxy]-6-methanesulfonylbenzoate 322 methyl 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2- phenylpropyl)amino)propoxy]-6-methanesulfonylbenzoate 323 methyl 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-6-methanesulfonylbenzoate 324 methyl 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-6-methanesulfonylbenzoate 325 methyl 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-6-methanesulfonylbenzoate 326 methyl 2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-6-methanesulfonylbenzoate 327 methyl 2-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}benzoate 328 methyl 2-methanesulfonyl-4-{3-[(2-phenylethyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}benzoate 329 methyl 2-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}benzoate 330 methyl 4-{3-[(2,2-diphenylethyl)({[2-fluoro-3- (trifluoromethyl)phenyl]methyl})amino]propoxy}-2-methanesulfonylbenzoate 331 methyl 4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylbenzoate 332 methyl 4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylbenzoate 333 methyl 4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylbenzoate 334 methyl 4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylbenzoate 335 methyl 4-(3-{[(4-fluorophenyl)methyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzoate 336 methyl 4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzoate 337 methyl 4-(3-{[2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzoate 338 methyl 4-(3-{[2-(4-fluorophenyl)propyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzoate 339 methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylbenzoate 340 methyl 4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzoate 341 methyl 4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylbenzoate 342 methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-methanesulfonylbenzoate 343 methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]- 2-methanesulfonylbenzoate 344 methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2- phenylpropyl)amino)propoxy]-2-methanesulfonylbenzoate 345 methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2- diphenylethyl)amino)propoxy]-2-methanesulfonylbenzoate 346 methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylbenzoate 347 methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-methanesulfonylbenzoate 348 methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylbenzoate 349 methyl 4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylbenzoate 350 methyl 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-methanesulfonylbenzoate 351 methyl 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]- 2-methanesulfonylbenzoate 352 methyl 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]- 2-methanesulfonylbenzoate 353 methyl 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylbenzoate 354 methyl 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-methanesulfonylbenzoate 355 methyl 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylbenzoate 356 methyl 4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylbenzoate 357 2-(2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol 358 2-(2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylethyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol 359 2-(2-fluoro-6-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol 360 2-(4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}- 2-fluoro-6-methanesulfonylphenyl)ethan-1-ol 361 2-(4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylphenyl)ethan-1-ol 362 2-(4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylphenyl)ethan-1-ol 363 2-(4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylphenyl)ethan-1-ol 364 2-[2-fluoro-4-(3-{[2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]ethan-1-ol 365 2-[2-fluoro-4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]ethan-1-ol 366 2-[2-fluoro-4-(3-{[2-(4-fluorophenyl)propyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]ethan-1-ol 367 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4- fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol 368 2-[2-fluoro-4-(3-{[(4-fluorophenyl)methyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]ethan-1-ol 369 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6- methanesulfonylphenyl]ethan-1-ol 370 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol 371 2-(4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro- 6-methanesulfonylphenyl)ethan-1-ol 372 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2- fluoro-6-methanesulfonylphenyl}ethan-1-ol 373 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2- fluoro-6-methanesulfonylphenyl}ethan-1-ol 374 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol 375 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol 376 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol 377 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}ethan-1-ol 378 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol 379 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6- methanesulfonylphenyl]ethan-1-ol 380 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2- phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol 381 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol 382 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2- phenylethyl)amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol 383 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol 384 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol 385 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-6-methanesulfonylphenyl}ethan-1-ol 386 2-(2-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol 387 2-(2-methanesulfonyl-4-{3-[(2-phenylethyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol 388 2-(2-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)ethan-1-ol 389 2-(4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}- 2-methanesulfonylphenyl)ethan-1-ol 390 2-(4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)ethan-1-ol 391 2-(4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)ethan-1-ol 392 2-(4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)ethan-1-ol 393 2-(4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)ethan-1-ol 394 2-[4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylphenyl]ethan-1-ol 395 2-[4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]ethan-1-ol 396 2-[4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylphenyl]ethan-1-ol 397 2-[4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylphenyl]ethan-1-ol 398 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 399 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]ethan-1-ol 400 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]ethan-1-ol 401 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 402 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2- methanesulfonylphenyl}ethan-1-ol 403 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2- methanesulfonylphenyl}ethan-1-ol 404 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2- methanesulfonylphenyl}ethan-1-ol 405 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 406 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 407 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 408 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 409 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 410 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2- methanesulfonylphenyl}ethan-1-ol 411 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2- methanesulfonylphenyl}ethan-1-ol 412 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 413 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 414 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 415 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}ethan-1-ol 416 2-(2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylethyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)acetic acid 417 2-(2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)acetic acid 418 2-(4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}- 2-fluoro-6-methanesulfonylphenyl)acetic acid 419 2-(4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylphenyl)acetic acid 420 2-(4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylphenyl)acetic acid 421 2-(4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylphenyl)acetic acid 422 2-[2-fluoro-4-(3-{[(4-fluorophenyl)methyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]acetic acid 423 2-[2-fluoro-4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]acetic acid 424 2-[2-fluoro-4-(3-{[2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]acetic acid 425 2-[2-fluoro-4-(3-{[2-(4-fluorophenyl)propyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]acetic acid 426 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4- fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}acetic acid 427 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6-methanesulfonylphenyl]acetic acid 428 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6-methanesulfonylphenyl]acetic acid 429 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}acetic acid 430 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2- fluoro-6-methanesulfonylphenyl}acetic acid 431 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2- fluoro-6-methanesulfonylphenyl}acetic acid 432 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2- fluoro-6-methanesulfonylphenyl}acetic acid 433 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}acetic acid 434 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}acetic acid 435 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}acetic acid 436 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}acetic acid 437 2-(4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro- 6-methanesulfonylphenyl)acetic acid 438 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}acetic acid 439 2-(2-fluoro-6-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)acetic acid 440 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2- phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}acetic acid 441 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-6-methanesulfonylphenyl}acetic acid 442 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-6-methanesulfonylphenyl}acetic acid 443 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-6-methanesulfonylphenyl}acetic acid 444 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2- phenylethyl)amino)propoxy]-6-methanesulfonylphenyl}acetic acid 445 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-6-methanesulfonylphenyl}acetic acid 446 2-(2-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)acetic acid 447 2-(2-methanesulfonyl-4-{3-[(2-phenylethyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)acetic acid 448 2-(2-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)acetic acid 449 2-(4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}- 2-methanesulfonylphenyl)acetic acid 450 2-(4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)acetic acid 451 2-(4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)acetic acid 452 2-(4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)acetic acid 453 2-(4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)acetic acid 454 2-[4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylphenyl]acetic acid 455 2-[4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]acetic acid 456 2-[4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylphenyl]acetic acid 457 2-[4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylphenyl]acetic acid 458 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}acetic acid 459 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]acetic acid 460 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]acetic acid 461 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}acetic acid 462 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2- methanesulfonylphenyl}acetic acid 463 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2- methanesulfonylphenyl}acetic acid 464 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2- methanesulfonylphenyl}acetic acid 465 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}acetic acid 466 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}acetic acid 467 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}acetic acid 468 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}acetic acid 469 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2-phenylpropyl)amino)propoxy]-2- methanesulfonylphenyl}acetic acid 470 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2- methanesulfonylphenyl}acetic acid 471 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2- methanesulfonylphenyl}acetic acid 472 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}acetic acid 473 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}acetic acid 474 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}acetic acid 475 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}acetic acid 476 N-[(2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylethyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)methyl]acetamide 477 N-[(4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}- 2-fluoro-6-methanesulfonylphenyl)methyl]acetamide 478 N-[(2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)methyl]acetamide 479 N-[(2-fluoro-6-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)methyl]acetamide 480 N-[(4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro- 6-methanesulfonylphenyl)methyl]acetamide 481 N-[(4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylphenyl)methyl]acetamide 482 N-[(4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylphenyl)methyl]acetamide 483 N-{[2-fluoro-4-(3-{[(4-fluorophenyl)methyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6- methanesulfonylphenyl]methyl}acetamide 484 N-{[2-fluoro-4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6- methanesulfonylphenyl]methyl}acetamide 485 N-{[2-fluoro-4-(3-{[2-(4-fluorophenyl)propyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6- methanesulfonylphenyl]methyl}acetamide 486 N-{[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6- methanesulfonylphenyl]methyl}acetamide 487 N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4- fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methyl)acetamide 488 N-{[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6- methanesulfonylphenyl]methyl}acetamide 489 N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methyl)acetamide 490 N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2- fluoro-6-methanesulfonylphenyl}methyl)acetamide 491 N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2- fluoro-6-methanesulfonylphenyl}methyl)acetamide 492 N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-fluoro-6- methanesulfonylphenyl}methyl)acetamide 493 N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methyl)acetamide 494 N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}methyl)acetamide 495 N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-fluoro-6- methanesulfonylphenyl}methyl)acetamide 496 N-({2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}methyl)acetamide 497 N-({2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2- phenylethyl)amino)propoxy]-6-methanesulfonylphenyl}methyl)acetamide 498 N-({2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2- phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}methyl)acetamide 499 N-{[2-fluoro-4-(3-{[2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6- methanesulfonylphenyl]methyl}acetamide 500 N-[(4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylphenyl)methyl]acetamide 501 N-({2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-6-methanesulfonylphenyl}methyl)acetamide 502 N-({2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-6-methanesulfonylphenyl}methyl)acetamide 503 N-({2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-6-methanesulfonylphenyl}methyl)acetamide 504 N-({2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-6-methanesulfonylphenyl}methyl)acetamide 505 N-[(2-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)methyl]acetamide 506 N-[(2-methanesulfonyl-4-{3-[(2-phenylethyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)methyl]acetamide 507 N-[(2-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)methyl]acetamide 508 N-[(4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}- 2-methanesulfonylphenyl)methyl]acetamide 509 N-[(4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)methyl]acetamide 510 N-[(4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)methyl]acetamide 511 N-[(4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)methyl]acetamide 512 N-[(4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)methyl]acetamide 513 N-{[4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylphenyl]methyl}acetamide 514 N-{[4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylphenyl]methyl}acetamide 515 N-{[4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylphenyl]methyl}acetamide 516 N-{[4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)- 2-methanesulfonylphenyl]methyl}acetamide 517 N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide 518 N-{[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylphenyl]methyl}acetamide 519 N-{[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylphenyl]methyl}acetamide 520 N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide 521 N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2- methanesulfonylphenyl}methyl)acetamide 522 N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2- methanesulfonylphenyl}methyl)acetamide 523 N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]- 2-methanesulfonylphenyl}methyl)acetamide 524 N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide 525 N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide 526 N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide 527 N-({4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide 528 N-({4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide 529 N-({4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2- methanesulfonylphenyl}methyl)acetamide 530 N-({4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2- methanesulfonylphenyl}methyl)acetamide 531 N-({4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide 532 N-({4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide 533 N-({4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide 534 N-({4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}methyl)acetamide 535 2-(2-fluoro-6-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)propan-2-ol 536 2-(2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylethyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)propan-2-ol 537 2-(2-fluoro-6-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)propan-2-ol 538 2-(4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro- 6-methanesulfonylphenyl)propan-2-ol 539 2-(4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylphenyl)propan-2-ol 540 2-(4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylphenyl)propan-2-ol 541 2-(4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2-fluoro-6- methanesulfonylphenyl)propan-2-ol 542 2-(4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}- 2-fluoro-6-methanesulfonylphenyl)propan-2-ol 543 2-[2-fluoro-4-(3-{[(4-fluorophenyl)methyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]propan-2-ol 544 2-[2-fluoro-4-(3-{[2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]propan-2-ol 545 2-[2-fluoro-4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]propan-2-ol 546 2-[2-fluoro-4-(3-{[2-(4-fluorophenyl)propyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-6-methanesulfonylphenyl]propan-2-ol 547 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4- fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}propan-2-ol 548 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6- methanesulfonylphenyl]propan-2-ol 549 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-fluoro-6- methanesulfonylphenyl]propan-2-ol 550 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}propan-2-ol 551 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2- fluoro-6-methanesulfonylphenyl}propan-2-ol 552 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}propan-2-ol 553 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2- fluoro-6-methanesulfonylphenyl}propan-2-ol 554 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}propan-2-ol 555 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}propan-2-ol 556 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}propan-2-ol 557 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-fluoro-6-methanesulfonylphenyl}propan-2-ol 558 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2- phenylethyl)amino)propoxy]-6-methanesulfonylphenyl}propan-2-ol 559 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2- phenylpropyl)amino)propoxy]-6-methanesulfonylphenyl}propan-2-ol 560 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-6-methanesulfonylphenyl}propan-2-ol 561 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-6-methanesulfonylphenyl}propan-2-ol 562 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-6-methanesulfonylphenyl}propan-2-ol 563 2-{2-fluoro-4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-6-methanesulfonylphenyl}propan-2-ol 564 2-(2-methanesulfonyl-4-{3-[(2-methyl-2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)propan-2-ol 565 2-(2-methanesulfonyl-4-{3-[(2-phenylethyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)propan-2-ol 566 2-(2-methanesulfonyl-4-{3-[(2-phenylpropyl)({[3- (trifluoromethyl)phenyl]methyl})amino]propoxy}phenyl)propan-2-ol 567 2-(4-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}- 2-methanesulfonylphenyl)propan-2-ol 568 2-(4-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)propan-2-ol 569 2-(4-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)propan-2-ol 570 2-(4-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)propan-2-ol 571 2-(4-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-2- methanesulfonylphenyl)propan-2-ol 572 2-[4-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylphenyl]propan-2-ol 573 2-[4-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]propan-2-ol 574 2-[4-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylphenyl]propan-2-ol 575 2-[4-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-2- methanesulfonylphenyl]propan-2-ol 576 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol 577 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]propan-2-ol 578 2-[4-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-2-methanesulfonylphenyl]propan-2-ol 579 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol 580 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2- methanesulfonylphenyl}propan-2-ol 581 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2- methanesulfonylphenyl}propan-2-ol 582 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol 583 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol 584 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol 585 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol 586 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol 587 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-2- methanesulfonylphenyl}propan-2-ol 588 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-2- methanesulfonylphenyl}propan-2-ol 589 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol 590 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol 591 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol 592 2-{4-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-2-methanesulfonylphenyl}propan-2-ol 593 2-{4-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]-2- methanesulfonylphenyl}propan-2-ol 594 6-(3-{[(4-fluorophenyl)methyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-3,4- dihydro-1H-2-benzopyran-3-one 595 6-(3-{[2-(4-fluorophenyl)-2-methylpropyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-3,4-dihydro-1H-2-benzopyran-3-one 596 6-(3-{[2-(4-fluorophenyl)ethyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-3,4- dihydro-1H-2-benzopyran-3-one 597 6-(3-{[2-(4-fluorophenyl)propyl]({[3-(trifluoromethyl)phenyl]methyl})amino}propoxy)-3,4- dihydro-1H-2-benzopyran-3-one 598 6-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4- fluorophenyl)ethyl]amino)propoxy]-3,4-dihydro-1H-2-benzopyran-3-one 599 6-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-3,4-dihydro-1H-2-benzopyran-3-one 600 6-(3-{[2,2-difluoro-2-(4-fluorophenyl)ethyl]({[3- (trifluoromethyl)phenyl]methyl})amino}propoxy)-3,4-dihydro-1H-2-benzopyran-3-one 601 6-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-3,4-dihydro-1H-2-benzopyran-3-one 602 6-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-3,4- dihydro-1H-2-benzopyran-3-one 603 6-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-3,4- dihydro-1H-2-benzopyran-3-one 604 6-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4- fluorophenyl)methyl]amino)propoxy]-3,4-dihydro-1H-2-benzopyran-3-one 605 6-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-3,4-dihydro-1H-2-benzopyran-3-one 606 6-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)ethyl]amino)propoxy]-3,4-dihydro-1H-2-benzopyran-3-one 607 6-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-3,4-dihydro-1H-2-benzopyran-3-one 608 6-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-methyl-2- phenylpropyl)amino)propoxy]-3,4-dihydro-1H-2-benzopyran-3-one 609 6-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylethyl)amino)propoxy]-3,4- dihydro-1H-2-benzopyran-3-one 610 6-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}(2-phenylpropyl)amino)propoxy]-3,4- dihydro-1H-2-benzopyran-3-one 611 6-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]amino)propoxy]- 3,4-dihydro-1H-2-benzopyran-3-one 612 6-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2- methylpropyl]amino)propoxy]-3,4-dihydro-1H-2-benzopyran-3-one 613 6-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]amino)propoxy]- 3,4-dihydro-1H-2-benzopyran-3-one 614 6-[3-({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4- fluorophenyl)propyl]amino)propoxy]-3,4-dihydro-1H-2-benzopyran-3-one 615 6-{3-[(2-methyl-2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-3,4- dihydro-1H-2-benzopyran-3-one 616 6-{3-[(2-phenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-3,4-dihydro-1H- 2-benzopyran-3-one 617 6-{3-[(2-phenylpropyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-3,4-dihydro- 1H-2-benzopyran-3-one 618 6-{3-[(2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}- 3,4-dihydro-1H-2-benzopyran-3-one 619 6-{3-[(2,2-diphenylethyl)({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-3,4-dihydro- 1H-2-benzopyran-3-one 620 6-{3-[benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-3,4-dihydro- 1H-2-benzopyran-3-one 621 6-{3-[benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-3,4-dihydro-1H- 2-benzopyran-3-one 622 6-{3-[benzyl({[3-(trifluoromethyl)phenyl]methyl})amino]propoxy}-3,4-dihydro-1H-2- benzopyran-3-one 623 {3-[(1-methanesulfonylpiperidin-3-yl)oxy]propyl}(2-methyl-2-phenylpropyl){[3- (trifluoromethyl)phenyl]methyl}amine 624 {3-[(1-methanesulfonylpiperidin-3-yl)oxy]propyl}(2-phenylethyl){[3- (trifluoromethyl)phenyl]methyl}amine 625 {3-[(1-methanesulfonylpiperidin-3-yl)oxy]propyl}(2-phenylpropyl){[3- (trifluoromethyl)phenyl]methyl}amine 626 (2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}){3-[(1- methanesulfonylpiperidin-3-yl)oxy]propyl}amine 627 (2,2-diphenylethyl)({3-[(1-methanesulfonylpiperidin-3-yl)oxy]propyl}){[3- (trifluoromethyl)phenyl]methyl}amine 628 benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl}){3-[(1-methanesulfonylpiperidin-3- yl)oxy]propyl}amine 629 benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}){3-[(1-methanesulfonylpiperidin-3- yl)oxy]propyl}amine 630 benzyl({3-[(1-methanesulfonylpiperidin-3-yl)oxy]propyl}){[3- (trifluoromethyl)phenyl]methyl}amine 631 [(4-fluorophenyl)methyl]({3-[(1-methanesulfonylpiperidin-3-yl)oxy]propyl}){[3- (trifluoromethyl)phenyl]methyl}amine 632 [2-(4-fluorophenyl)-2-methylpropyl]({3-[(1-methanesulfonylpiperidin-3-yl)oxy]propyl}){[3- (trifluoromethyl)phenyl]methyl}amine 633 [2-(4-fluorophenyl)ethyl]({3-[(1-methanesulfonylpiperidin-3-yl)oxy]propyl}){[3- (trifluoromethyl)phenyl]methyl}amine 634 [2-(4-fluorophenyl)propyl]({3-[(1-methanesulfonylpiperidin-3-yl)oxy]propyl}){[3- (trifluoromethyl)phenyl]methyl}amine 635 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4-fluorophenyl)ethyl]{3-[(1- methanesulfonylpiperidin-3-yl)oxy]propyl}amine 636 [2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}){3-[(1- methanesulfonylpiperidin-3-yl)oxy]propyl}amine 637 [2,2-difluoro-2-(4-fluorophenyl)ethyl]({3-[(1-methanesulfonylpiperidin-3- yl)oxy]propyl}){[3-(trifluoromethyl)phenyl]methyl}amine 638 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}({3-[(1-methanesulfonylpiperidin-3- yl)oxy]propyl})(2-methyl-2-phenylpropyl)amine 639 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}({3-[(1-methanesulfonylpiperidin-3- yl)oxy]propyl})(2-phenylethyl)amine 640 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}({3-[(1-methanesulfonylpiperidin-3- yl)oxy]propyl})(2-phenylpropyl)amine 641 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]{3-[(1- methanesulfonylpiperidin-3-yl)oxy]propyl}amine 642 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]{3-[(1- methanesulfonylpiperidin-3-yl)oxy]propyl}amine 643 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]{3-[(1- methanesulfonylpiperidin-3-yl)oxy]propyl}amine 644 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]{3-[(1- methanesulfonylpiperidin-3-yl)oxy]propyl}amine 645 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}({3-[(1-methanesulfonylpiperidin-3- yl)oxy]propyl})(2-methyl-2-phenylpropyl)amine 646 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}({3-[(1-methanesulfonylpiperidin-3- yl)oxy]propyl})(2-phenylethyl)amine 647 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}({3-[(1-methanesulfonylpiperidin-3- yl)oxy]propyl})(2-phenylpropyl)amine 648 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]{3-[(1- methanesulfonylpiperidin-3-yl)oxy]propyl}amine 649 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]{3-[(1- methanesulfonylpiperidin-3-yl)oxy]propyl}amine 650 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]{3-[(1- methanesulfonylpiperidin-3-yl)oxy]propyl}amine 651 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]{3-[(1- methanesulfonylpiperidin-3-yl)oxy]propyl}amine 652 {3-[(1-methanesulfonylazetidin-3-yl)oxy]propyl}(2-methyl-2-phenylpropyl){[3- (trifluoromethyl)phenyl]methyl}amine 653 {3-[(1-methanesulfonylazetidin-3-yl)oxy]propyl}(2-phenylethyl){[3- (trifluoromethyl)phenyl]methyl}amine 654 {3-[(1-methanesulfonylazetidin-3-yl)oxy]propyl}(2-phenylpropyl){[3- (trifluoromethyl)phenyl]methyl}amine 655 (2,2-diphenylethyl)({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}){3-[(1- methanesulfonylazetidin-3-yl)oxy]propyl}amine 656 (2,2-diphenylethyl)({3-[(1-methanesulfonylazetidin-3-yl)oxy]propyl}){[3- (trifluoromethyl)phenyl]methyl}amine 657 benzyl({[2-chloro-3-(trifluoromethyl)phenyl]methyl}){3-[(1-methanesulfonylazetidin-3- yl)oxy]propyl}amine 658 benzyl({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}){3-[(1-methanesulfonylazetidin-3- yl)oxy]propyl}amine 659 benzyl({3-[(1-methanesulfonylazetidin-3-yl)oxy]propyl}){[3- (trifluoromethyl)phenyl]methyl}amine 660 [(4-fluorophenyl)methyl]({3-[(1-methanesulfonylazetidin-3-yl)oxy]propyl}){[3- (trifluoromethyl)phenyl]methyl}amine 661 [2-(4-fluorophenyl)-2-methylpropyl]({3-[(1-methanesulfonylazetidin-3-yl)oxy]propyl}){[3- (trifluoromethyl)phenyl]methyl}amine 662 [2-(4-fluorophenyl)ethyl]({3-[(1-methanesulfonylazetidin-3-yl)oxy]propyl}){[3- (trifluoromethyl)phenyl]methyl}amine 663 [2-(4-fluorophenyl)propyl]({3-[(1-methanesulfonylazetidin-3-yl)oxy]propyl}){[3- (trifluoromethyl)phenyl]methyl}amine 664 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2,2-difluoro-2-(4-fluorophenyl)ethyl]{3-[(1- methanesulfonylazetidin-3-yl)oxy]propyl}amine 665 [2,2-difluoro-2-(4-fluorophenyl)ethyl]({[2-fluoro-3-(trifluoromethyl)phenyl]methyl}){3-[(1- methanesulfonylazetidin-3-yl)oxy]propyl}amine 666 [2,2-difluoro-2-(4-fluorophenyl)ethyl]({3-[(1-methanesulfonylazetidin-3-yl)oxy]propyl}){[3- (trifluoromethyl)phenyl]methyl}amine 667 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}({3-[(1-methanesulfonylazetidin-3- yl)oxy]propyl})(2-methyl-2-phenylpropyl)amine 668 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}({3-[(1-methanesulfonylazetidin-3- yl)oxy]propyl})(2-phenylethyl)amine 669 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}({3-[(1-methanesulfonylazetidin-3- yl)oxy]propyl})(2-phenylpropyl)amine 670 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]{3-[(1- methanesulfonylazetidin-3-yl)oxy]propyl}amine 671 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]{3-[(1- methanesulfonylazetidin-3-yl)oxy]propyl}amine 672 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]{3-[(1- methanesulfonylazetidin-3-yl)oxy]propyl}amine 673 {[2-chloro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]{3-[(1- methanesulfonylazetidin-3-yl)oxy]propyl}amine 674 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}({3-[(1-methanesulfonylazetidin-3- yl)oxy]propyl})(2-methyl-2-phenylpropyl)amine 675 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}({3-[(1-methanesulfonylazetidin-3- yl)oxy]propyl})(2-phenylethyl)amine 676 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}({3-[(1-methanesulfonylazetidin-3- yl)oxy]propyl})(2-phenylpropyl)amine 677 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[(4-fluorophenyl)methyl]{3-[(1- methanesulfonylazetidin-3-yl)oxy]propyl}amine 678 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)-2-methylpropyl]{3-[(1- methanesulfonylazetidin-3-yl)oxy]propyl}amine 679 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)ethyl]{3-[(1- methanesulfonylazetidin-3-yl)oxy]propyl}amine 680 {[2-fluoro-3-(trifluoromethyl)phenyl]methyl}[2-(4-fluorophenyl)propyl]{3-[(1- methanesulfonylazetidin-3-yl)oxy]propyl}amine

Example 84: ApoE Gene Expression Analysis by qRT-PCR

(444) Cancer cells (MeWo) were treated in presence of drug or control (DMSO) at indicated concentrations for 48 h. RNA was extracted from whole cell lysates using the Total RNA Purification Kit (17200, Norgen, Thorold, Canada). 600 ng of total RNA was then reverse transcribed into cDNA using the Verso cDNA Synthesis Kit (AB-1453/B, Fisher Scientific). 6 ng of the resulting cDNA was then mixed with SYBR green PCR Master Mix (4309155, Applied Biosystems) and the appropriate primers. Each reaction was performed in quadruplicate, and mRNA expression was quantified by performing real-time PCR amplification using a StepOne Plus Real-Time PCR System (Applied Biosystems). GAPDH was used as an endogenous control for normalization. EC.sub.50 values were calculated using Prism6 software and plotting expression values versus drug concentration.

(445) The following primers were used:

(446) TABLE-US-00005 ApoEForward: (SEQIDNO:1) 5-TGGGTCGCTTTTGGGATTAC-3 ApoEReverse: (SEQIDNO:2) 5-TTCAACTCCTTCATGGTCTCG-3 GAPDHForward: (SEQIDNO:3) 5-AGCCACATCGCTCAGACAC-3 GAPDHReverse: (SEQIDNO:4) 5-GCCCAATACGACCAAATCC-3

(447) Results: The results of ApoE gene expression analysis are shown in Table 5. The results are shown in relation to GW3965 ApoE expression at 1 M (i.e. 100%). EC.sub.50 values for selected compounds are shown in Table 6.

(448) TABLE-US-00006 TABLE 5 Results of ApoE gene expression analysis Compound 1 M 10 M GW3965 100% ++ SB742881 ++ ++ WO2007002563 Tb. 1 Ex. 19 ++ ++ WO20100138598 Ex. 9 ++ ++ WO2013138565 Racemic Ex. E2a ++ ++ 1 +++ + 2 ++ ++ 3 ++ + 4 ++ ++ 6 +++ ++ 7 +++ ++ 8 +++ +++ 9 ++ +++ 24 ++ ++ 25 ++ + 26 + + 29 ++ +++ 30 ++ +++ 31 ++ +++ 35 + ++ 59 ++ ++ 60 ++ +++ 61 ++ +++ 62 +++ +++ 63 +++ +++ 64 +++ +++ 65 +++ +++ 66 +++ +++ 67 + + 71 + ND 72 +++ +++ 73 +++ +++ 74 ++ ++ 75 ++ +++ 78 ++ ND 79 +++ +++ 80 +++ +++ 81 ++ ++ 82 ++ ND 83 +++ ND 84 ++ ++ 85 +++ ND 87 ++ ND 88 +++ ND 89 +++ +++ 90 +++ ND 91 +++ ++ 92 ++ ND 93 + + 95 ++ ND 96 ++ ND +++ > 80% ApoE induction, ++ > 40% induction, and + < 40% induction, ND = Not Determined

(449) TABLE-US-00007 TABLE 6 EC.sub.50 values for ApoE expression for selected compounds Compound EC.sub.50 (M) GW3965 <0.3 SB742881 <1.0 WO20100138598 Ex. 9 <1.0 WO2013138565 Racemic <0.3 Ex. E2a 1 <1.0 4 <1.0 6 <0.3 7 <1.0 8 <1.0 9 <0.3 29 <0.3 31 <1.0 35 <3.0 59 <0.3 60 <0.3 62 <1.0 63 <3.0 64 <1.0 65 <1.0 66 <3.0 79 <1.0 80 <1.0 81 <0.3 83 <1.0 85 <1.0 89 <1.0 90 <1.0

Example 85: Matrigel Invasion Assay

(450) Cancer cells (MeWo) were pre-treated in presence of 1 M drug or control (DMSO) for 72 h after which cancer cells were switched to serum-starvation in 0.2% FBS DMEM-based media for 16 h in the presence of the drug or control, respectively. Trans-well invasion chambers (354480, BD Biosciences, Bedford, Mass.) were pre-equilibrated in DMEM-based media prior to the beginning of the assay by adding 0.5 ml of starvation media to the top and bottom chambers. After 30 min, the media in the top chamber was removed, and 0.5 ml of media containing 110.sup.5 cancer cells in the presence of the drug, was added into each matrigel-coated trans-well insert. Cells were allowed to invade through the matrigel-coated inserts for 24 h at 37 C.

(451) Results: The results of the invasion assay with select compounds are shown in Table 7.

(452) TABLE-US-00008 TABLE 7 Invasion assay results % of Cells Migrated Compared Compound to Control GW3965 <70% SB742881 <70% WO20100138598 Ex. 9 <90% DMSO Control 100% 1 <95% 8 <50% 9 <50% 29 <50% 31 <70%

Example 86: Whole Blood Gene Expression Analysis of ApoE

(453) Six drops of blood are collected from BL6 mice by Submandibular Sampling into serum blood sample collection tubes, inverted 8-10 times before centrifugation at 2,000 g for 10 min. Blood serum is removed and RNA was extracted from whole cell lysates using the Total RNA Purification Kit (17200, Norgen, Thorold, Canada). 600 ng of total RNA is then reverse transcribed into cDNA using the Verso cDNA Synthesis Kit (AB-1453/B, Fisher Scientific). 6 ng of the resulting cDNA is then mixed with SYBR green PCR Master Mix (4309155, Applied Biosystems) and the appropriate primers. Each reaction is performed in quadruplicate, and mRNA expression is quantified by performing real-time PCR amplification using a StepOne Plus Real-Time PCR System (Applied Biosystems). GAPDH is used as an endogenous control for normalization.

(454) The following primers were used:

(455) TABLE-US-00009 ApoEForward: (SEQIDNO:5) 5-GACCCTGGAGGCTAAGGACT-3 ApoEReverse: (SEQIDNO:6) 5-AGAGCCTTCATCTTCGCAAT-3 GAPDHForward: (SEQIDNO:7) 5-GCACAGTCAAGGCCGAGAAT-3 GAPDHReverse: (SEQIDNO:8) 5-GCCTTCTCCATGGTGGTGAA-3

Example 87: In Vivo Primary Tumor Growth Assay

(456) For primary tumor growth studies, 510.sup.4 B16F10 melanoma cells were mixed 1:1 with matrigel and subcutaneously injected into the lower flanks of 6-week old C57B16 mice. Upon the formation of palpable tumors, 4-5 days after tumor cell injection, 10 mice were randomly assigned to groups eating a control diet or a diet supplemented with compound 8 (5 and 25 mg/kg). Tumor volume was calculated as (small diameter).sup.2(large diameter)/2 and tumor growth inhibition was measured relative to vehicle control.

(457) Results: The result of in vivo tumor growth inhibition of compound 8 is shown in Table 8. Compound 8 demonstrated 39% tumor growth inhibition of B16F10 melanoma cells in vivo at 25 mpk.

(458) TABLE-US-00010 TABLE 8 In vivo tumor growth inhibition assay results for compound 8. 5 mg/kg 25 mg/kg Control Cmpd 8 Cmpd 8 Mean tumor 784 (+/77) 686 (+/97) 475 (+/56) volume (mm3) (+/S.E.M.) Tumor growth 0% (+/10%) 13% (+/12%) 39% (+/7%) inhibition % of control (+/S.E.M.)

Example 88: Pharmacodynamic Analysis of ApoE

(459) In Vivo Dosing and Sample Collection: 6-7 week old B16F10 mice received a single dose of Compound 8 at 52.6 mg/kg, formulated in 2% DMSO/20% Propylene Glycol/78% 0.5% Methylcellulose (400 cp) at a final concentration of 4.62 mg/mL by oral gavage. Bleeds were taken at 0.5 h, 2 h, 4 h, 8 h, 16 h, 24 h and 48 h. Mice were bled twice, the first bleed was drawn submandibular and the second through intracardiac puncture. Blood was collected in Dipotassium EDTA Microtainer tubes (02-669-38, Fisher). To isolate peripheral blood lymphocytes, blood samples were centrifuged at 2000 g for 5 min. After separation of the plasma, Erythrocytes were lysed in 1 mL Erythrocyte Lysis (EL) buffer (79217, Qiagen) and incubation at room temperature for 20 min. Samples were centrifuged at 400 g for 10 min, and peripheral blood lymphocytes washed once in EL buffer, followed by one wash in PBS.

(460) ApoE Gene Expression Analysis by qRT-PCR: RNA was extracted from peripheral blood lymphocytes using the Total RNA Purification Micro Kit (35300, Norgen, Thorold, Canada). 200-300 ng of total RNA was then reverse transcribed into cDNA using the Verso cDNA synthesis Kit (AB-1453B, Fisher Scientific) and 6 ng of the resulting cDNA was mixed with SYBR Green PCR Mater Mix (4385612, Applied Biosystems) and quantitative real-time PCR amplification was performed using an ABI Prism 7900HT Real-Time PCR System (Applied Biosystems, Austin, Tex.). Each PCR reaction was carried out in quadruplicates. Gene expression was normalized to GAPDH, which was used as an endogenous control. Primers used as described in Example 86.

(461) Results: The results of ApoE induction in vivo by compound 8 is shown in Table 9 where Pre-Dose represents endogenous levels of ApoE induction prior to dosing, n is the number of samples analyzed, and values are expressed as fold induction over pre-dose endogenous ApoE levels (normalized to 1.0). Peak induction of compound 8 is >6-fold over background at 4 h.

(462) TABLE-US-00011 TABLE 9 Pharmacodynamic assay results in vivo ApoE induction Time Fold ApoE Induction Over Sampling n Pre-Dose Level (+/S.D.) Pre-Dose 3 1.0 (+/0.2) 0.5 h 2 1.3 (+/0.3) 2 h 2 2.7 (+/0.5) 4 h 3 6.3 (+/1.8) 8 h 4 3.8 (+/2.4) 16 h 4 0.3 (+/0.4) 24 h 5 0.4 (+/0.6) 48 h 4 0.1 (+/0.3)

Example 89: Immunohistochemistry Analysis of ApoE

(463) Human primary melanoma skin samples are resected from melanoma patients, formalin-fixed, embedded in paraffin, and sectioned into 5-m-thick increments. To determine ApoE protein expression, the samples are first de-paraffinized by two consecutive xylene washes (5-min each), and rehydrated in a series of ethanol washes (100%, 95%, 80%, and 70% EtOH). ApoE antigen is retrieved by incubating the samples in the presence of proteinase K (5 g/mL) for 20 min at room temperature. To quench endogenous peroxidase activity, the slides are incubated in 3% H.sub.2O.sub.2 solution. The slides are then blocked in three consecutive Avidin, Biotin, and horse serum block solutions for 15 min each at room temperature (SP-2001, Vector Laboratories, Burlingame, Calif.). ApoE is detected by staining with D6E10 anti-ApoE antibody (ab1908, Abcam), which is used at a 1:100 dilution in PBS at 4 C. overnight. The primary antibody is then recognized by incubating the slides in a peroxidase-conjugated secondary antibody (PK-4002, Vector Laboratories) and exposed by DAB (SK-4105, Vector Laboratories) oxidation reaction. The slides are imaged at 10 magnification and analyzed in a double-blinded manner. ApoE expression is quantified by counting the number of DAB-positive cells and measuring the area of extracellular ApoE staining. Total ApoE staining signal is expressed as the percentage staining area per given tumor area, determined based on matched H&E-stained slides for each sample.

Example 90: Western Blot Analysis of ApoE in Plasma Samples

(464) For analysis of ApoE protein levels in plasma samples, 8 g of plasma is separated by SDS-PAGE and transferred to a PVDF membrane. The membrane is blocked in 5% milk in PBS/0.1% Tween-20 (PBS-T) for 1 h at room temperature (RT), washed three times in PBS-T before incubation with primary antibodies against mouse ApoE (ab20874, Abcam), or human ApoE (ab1906, Abcam) and transferrin (ab82411). Transferrin is used to normalize the ApoE signal. The membrane is washed three times in PBS-T and blotted with secondary antibody (65612, Invitrogen) for 1 h at RT. Following three washes in PBS-T, the membrane is developed using ECL substrate (32106, Pierce) according to the manufacturers instructions.

Example 91: Gene Expression Analysis in Human Peripheral Blood Mononuclear Cells (PBMCs)

(465) Purified PBMC are suspended in culture medium (RPMI+10% FBS+1% penicillin/streptomycin/amphotericin B with 1% L-glutamine) and transferred into 6-well culture dishes at 510.sup.6 cells/well. After one hour, drug or control (DMSO) is added and incubation is continued for 48 h. The conditioned media is removed and centrifuged at 450 g for 5 min. The cell pellet is washed once in PBS before resuspending in lysis buffer (17200, Norgen, Thorold, Canada). The remaining adherent cells are washed once in PBS and directly lysed by the addition of lysis buffer. The fractions are pooled and RNA extracted (17200, Norgen, Thorold, Canada). 600 ng of total RNA is then reverse transcribed into cDNA using the Verso cDNA Synthesis Kit (AB-1453/B, Fisher Scientific). 6 ng of the resulting cDNA is mixed with SYBR green PCR Master Mix (4309155, Applied Biosystems) and the appropriate primers. Each reaction is performed in quadruplicate, and mRNA expression is quantified by performing real-time PCR amplification using a StepOne Plus Real-Time PCR System (Applied Biosystems). GAPDH is used as an endogenous control for normalization.

(466) The following primers are used:

(467) TABLE-US-00012 ApoEForward: (SEQIDNO:1) 5-TGGGTCGCTTTTGGGATTAC-3 ApoEReverse: (SEQIDNO:2) 5-TTCAACTCCTTCATGGTCTCG-3 GAPDHForward: (SEQIDNO:3) 5-AGCCACATCGCTCAGACAC-3 GAPDHReverse: (SEQIDNO:4) 5-GCCCAATACGACCAAATCC-3 ABCG1Forward: (SEQIDNO:9) 5-GCCACTTTCGTGGGCCCAGTGA-3 ABCG1Reverse: (SEQIDNO:10) 5-TCTCATCACCAGCTGTGTTGCA-3 ABCA1Forward: (SEQIDNO:11) 5-TGCTGCATAGTCTTGGGACTC-3 ABCA1Reverse: (SEQIDNO:12) 5-ACCTCCTGTCGCATGTCACT

Example 92: LXR / Agonist Activity and Selectivity Profiling

(468) DiscoveRx PathHunter cells (NR1H2 for ; NR1H3 for ) are seeded in a total volume of 20 L in white-walled, 384-well microplates and incubated at 37 C. for the appropriate time prior to testing. Assay media contains charcoal-dextran-filtered serum to reduce the level of hormones present. Serial dilution of drug is performed to generate 5 sample in assay buffer and 3.5 L of each 5 sample is added to cells in the appropriate well. The plate is incubated at 37 C. or RT for 3-16 hours. Final assay vehicle concentration is 1%. Assay signal is generated through a single addition of 12.5 L or 15 L (50% v/v) of PathHunter Detection reagent cocktail, followed by incubation for 1 h at RT. Microplates are analyzed by chemiluminescent using a PerkinElmer Envision instrument. Compound activity is calculated using CBIS data analysis suite (Chem Innovation, Calif.). Percentage agonist activity is calculated using the following formula:
Actvity=100%(mean of test samplemean of vehicle control)/(mean control ligandmean of vehicle control)

Example 93: Allergic Contact Dermatitis of the Mouse Ear

(469) The mouse contact dermatitis model (ear edema model) has been previously used for the characterization of topical application of LXR activators for their effect on skin inflammation (Fowler et al. J. Invest. Dermatol. 2003, 120, 246).

(470) Briefly, phorbol 12-myristate-13-acetate (PMA) is applied topically to both the inner and outer surface (10 L each surface, 20 L total) of the left ears of the mice to induce irritant contact dermatitis. Acetone alone (vehicle) is applied to the right ears. Test compounds (20 L/side) are applied 30 min prior and 15 min after PMA application to both surfaces of left ear (40 L total). Identical treatments are performed with 20 L of the positive control (0.05% clobetasol) and the vehicle group (acetone application alone). Blood samples (approximately 60 L) are collected from retro-orbital plexus of 5 mice (from each group), at the 6 h time point, into labeled micro-tubes containing K.sub.2EDTA solution as an anticoagulant. Plasma is immediately harvested by centrifugation at 4000 rpm for 10 min at 42 C. and stored below 70 C. until bioanalysis. The inflammatory insult induced by PMA is assessed as the percentage increase in ear thickness and/or ear weight in the treated left ear versus the vehicle-treated right ear. Ear thickness is measured with a digital caliper followed by whole ear weight to ascertain changes in ear weights. The extent of inflammation is quantitated according to the following equation:
ear swelling (%)=100(ab)/b
where a is the thickness/weight of the left (treated) ear and b is the thickness/weight of the right (untreated control) ear. After obtaining the samples for assessment of ear thickness/weight, biopsies are obtained from adjacent sites for routine histopathology fixation in 4% freshly prepared paraformaldehyde in phosphate-buffered saline. Ear swelling and ear weight for test compounds are compared to Clobetasol (corticosteroid used to treat various skin disorders).

Example 94: Alzheimer's Disease Mouse Model

(471) A mouse model of Alzheimer's disease has been previously described for the characterization of LXR agonist's ability to reduce A levels and ameliorates plaque burden in Tg2576 mice (Neuron 2008, 58 (5), 681-693).

(472) In Vivo Dosing and Sample Collection: Tg2576 mice or wild type littermates (5 animals/group), 12 months of age, are fed AIN-76A standard rodent diet alone or supplemented with test compound (e.g., at 120 mg/kg; 33 mg/kg/day) ad libitum for 4 months. The animals are sacrificed, and the right hemispheres are fixed and processed for immunohistochemical analysis. The left hemispheres are snap-frozen on dry ice and subject to serial extraction of total RNA, DNA and protein. Wild type mice (C57BL/6), Apoe null mice (B6129P2-Apoe.sup.tm1Unc/J) and Abca1 heterozygote mice (DBA/1-Abca1.sup.tm1Jdm/J) are obtained from Jackson Laboratory (Bar Harbor, Me.). Abca1 +/+, +/ and / mice are bred from Abca1 heterozygote mice (DBA/1-Abca1.sup.tm1Jdm/J). Tg2576 mice are maintained by crossing to B6SJLF1/J animals. A plaque burden is monitored by 6E10 staining in the hippocampus by quantifying plaque number and plaque area for treated groups vs control. Levels of full-length APP, C99 C-terminal fragment, total A, ABCA1 and ApoE are monitored by Western blot analysis. The results are normalized to -actin.

(473) Immunohistochemistry and Image Analysis: Post-fixed hemispheres are sectioned sagittally into 10 m sections using a cryostat. Sections are mounted, air-dried, and then stored at 4 C. until use. For A immunohistochemistry, sections (3 per mouse, about 1.2 mm-1.5 mm from the midline, spaced 0.1 mm apart from each other) are incubated in 70% formic acid for 3 min and the endogenous tissue peroxidase activity is quenched by incubation with 1% peroxide in methanol for 10 min. Sections are then microwaved in distilled water for 3 min, and then incubated with blocking solution (5% normal goat serum and 0.1% Triton X-100 in PBS) for 1 h. Sections are incubated with primary antibody in the blocking solution overnight at 4 C. The antigens are detected by secondary antibodies using standard ABC-DAB methods. Sections are counterstained with hematoxylin. The 6E10 antibody against human A is used to stain A plaques. Images are analyzed using Image Pro-Plus software (Media Cybernetics, Silver Spring, Md.).

Example 95: Gene Expression Analysis in Whole Tissue

(474) Organs (e.g. liver, lung, small intestine, brain, tumor, etc.) are removed from control or drug-treated animals (See Example 99) are snapfrozen in liquid nitrogen until further processing. Frozen tissue (10 mg) is homogenized in 600 l lysis buffer (17200, Norgen, Thorold, Canada) using a scalpel followed by passing the lysate 5-10 times through a 25G needle attached to a syringe. The lysate is transferred to a microcentrifuge tube and centrifuged for 2 min at 14,000 g. The supernatant is transferred to a new microcentrifuge tube and an equal amount of 70% ethanol is added and mixed by vortexing. 650 l of the lysate is loaded onto a RNA extraction column and processed according to the manufacturers protocol (17200, Norgen, Thorold, Canada). 600 ng of total RNA is then reverse transcribed into cDNA using the Verso cDNA Synthesis Kit (AB-1453/B, Fisher Scientific). 6 ng of the resulting cDNA is mixed with SYBR green PCR Master Mix (4309155, Applied Biosystems) and the appropriate primers (see Example 98). Each reaction is performed in quadruplicate, and mRNA expression quantified by performing real-time PCR amplification using a StepOne Plus Real-Time PCR System (Applied Biosystems). GAPDH is used as an endogenous control for normalization.

(475) Alternatively, ApoE levels are determined by W-blot analysis, in which case mouse lung and brain tissues are homogenized on ice in RIPA buffer (Sigma-Aldrich). Mouse adipose tissue is homogenized in TNET buffer (1.5 mM Tris [pH 7.5], 150 mM NaCl, 2 mM EDTA, 1% triton, protease inhibitors). Total protein lysates are separated by SDS-PAGE and processed as described in Example 102, with the exception that tubulin (2148, Cell Signaling Technology) is used as an internal loading control.

(476) The following primers were used:

(477) TABLE-US-00013 ApoEForward: 5-GACCCTGGAGGCTAAGGACT-3 ApoEReverse: 5-AGAGCCTTCATCTTCGCAAT-3 GAPDHForward: 5-GCACAGTCAAGGCCGAGAAT-3 GAPDHReverse: 5-GCCTTCTCCATGGTGGTGAA-3 ABCA1Forward: 5-ATGGAGCAGGGAAGACCAC-3 ABCA1Reverse: 5-GTAGGCCGTGCCAGAAGTT-3 ABCG1Forward: 5-TTTCCCAGAGATCCCTTTCA-3 ABCG1Reverse: 5-ATCGAATTCAAGGACCTTTCC-3

Other Embodiments

(478) All literature and similar material cited in this application, including, but not limited to, patents, patent applications, articles, books, treatises, and web pages, regardless of the format of such literature and similar materials, are expressly incorporated by reference in their entirety. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.

(479) While the methods have been described in conjunction with various embodiments and examples, it is not intended that the methods be limited to such embodiments or examples. On the contrary, the present disclosure encompasses various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art.

(480) While the methods have been particularly shown and described with reference to specific illustrative embodiments, it should be understood that various changes in form and detail may be made without departing from the spirit and scope of the present disclosure. Therefore, all embodiments that come within the scope and spirit of the present disclosure, and equivalents thereto, are intended to be claimed. The claims, descriptions and diagrams of the methods, systems, and assays of the present disclosure should not be read as limited to the described order of elements unless stated to that effect.