Androgen receptor modulators and method of treating disease using the same
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Abstract
Disclosed herein are bicycloaryl compounds of Formula (I) that selectively modulate nuclear receptors, preferably the androgen receptor, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, and methods of treating disease comprising administering a compound of Formula (I) to a patient in need thereof.
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Citations
10 Claims
- 1. A compound represented by the Formula (I):
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8. A compound selected from the group consisting of:
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4-(3-endo-Hydroxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, 4-(3-Oxo-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, 4-{3-[2-(1H-Imidazol-4-yl)ethylamino]-8-azabicyclo[3.2.1]oct-8-yl}naphthalene-1-carbonitrile, dihydrochioride, 4-[3-(Cyclohexylmethylamino)-8-azabicyclo[3.2.1]oct-8-yl]naphthalene-1-carbonitrile, hydrochloride, 4-[3-(2-Morpholin-4-ylethylamino)-8-azabicyclo[3.2.1]oct-8-yl]naphthalene-1-carbonitrile, dihydrochioride, Methoxyacetic acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, 3-Morpholin-4-ylpropionic acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, hydrochloride, 3-(4-Ethylpiperazin-1-yl)propionic acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, hydrochloride, 3-Diethylaminopropionic acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, hydrochloride, Chioroacetic acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, Morpholin-4-ylacetic acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, hydrochloride, Imidazol-1-ylacetic acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, hydrochloride, (4-Ethylpiperazin-1-yl)acetic acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, dihydrochioride, Diethylaminoacetic acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, hydrochloride, Succinic acid mono endo-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]ester, Trifluoroacetic acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, 4-(endo-3-Methoxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, N-[8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-2-(4-ethylpiperazin-1-yl)acetamide, dihydrochioride, 4-(3-Endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, 4-(3-endo-hydroxy-3-exo-propyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, 4-(endo-Spiro[8-azabicyclo[3.2.1]octane-3,2′
-oxiran]-8-yl)naphthalene-1-carbonitrile,4-(3-exo-Cyanomethyl-3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, 4-Nitrobenzoic acid exo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, 4-(3-exo-Hydroxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, 4-(3-exo-Methoxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, 4-(8-Azabicyclo[3.2.1]oct-2-en-8-yl)naphthalene-1-carbonitrile, 4-(8-Azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, 3-Pyrrolidin-1-yl-propionic acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, fumarate, 3-Imidazol-1-yl-propionic acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, fumarate, 3-Pyrazol-1-yl-propionic acid endo-8-(4-cyano-naphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, fumarate, 4-(2-Methyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, Endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl dihydrogen phosphate, 4-(7-Azabicyclo[2.2.1]hept-7-yl)naphthalene-1-carbonitrile hydrochloride, 2-exo-[8-(4-Cyanonaphthalen-1-yl)-3-endo-hydroxy-8-azabicyclo[3.2.1]oct-3-yl]-N,N-dimethylethanesulfonamide, 4-(3-Endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, hydrochloride, 4-(3-Methyl-8-azabicyclo[3.2.1]oct-2-en-8-yl)naphthalene-1-carbonitrile, 3-Piperazin-1-ylpropionic acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, dihydrochioride, 3-[Bis(2-hydroxyethyl)amino]propionic acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, fumarate, 3-(3-Dimethylaminopyrrolidin-1-yl)propionic acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, difumarate, 3-(4-Methylpiperazin-1-yl)propionic acid endo-8-(4-cyanonaphthalen-1-yl)-8-aza-bicyclo[3.2.1]oct-3-yl ester, difumarate, and 4-(3-Diethylaminomethyl-3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, hydrochloride.
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9. A compound selected from the group consisting of:
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4-(3-endo-Hydroxy-8-azabicyclol[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, 3-(4-Ethylpiperazin-1-yl)propionic acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, hydrochloride, 3-Diethylaminopropionic acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, hydrochloride, 4-(3-Endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, 4-(3-endo-hydroxy-3-exo-propyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, 4-(endo-Spiro[8-azabicyclo[3.2.1]octane-3 ,2′
-oxiran]-8-yl)naphthalene-1-carbonitrile,4-(8-Azabicyclo[3.2.1]oct-2-en-8-yl)naphthalene-1-carbonitrile, 4-(8-Azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, 4-(2-Methyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, 4-(3-Endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, hydrochloride, and 4-(3-Methyl-8-azabicyclo[3.2.1]oct-2-en-8-yl)naphthalene-1-carbonitrile.
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10. A compound selected from the group consisting of:
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4-(3-Propylamino-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, hydrochloride, 4-(3-Dimethylamino-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, hydrochloride, 4-[3-(3-Hydroxypropylamino)-8-azabicyclo[3.2.1]oct-8-yl]naphthalene-1-carbonitrile, hydrochloride, 4-[3-(2-Ethoxyethylamino)-8-azabicyclo[3.2.1]oct-8-yl]naphthalene-1-carbonitrile, hydrochloride, 4-(3-Cyclopropylamino-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, hydrochloride, 4-[3-(2-Dimethylaminoethylamino)-8-azabicyclo[3.2.1]oct-8-yl]naphthalene-1-carbonitrile, dihydrochloride, 4-{3-[(Furan-2-ylmethyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}naphthalene-1-carbonitrile, hydrochloride, 4-{3-[(Pyridin-2-ylmethyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}naphthalene-1-carbonitrile, dihydrochioride, 4-[3-(2-Isopropoxyethylamino)-8-azabicyclo[3.2.1]oct-8-yl]naphthalene-1-carbonitrile, hydrochloride, 4-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)naphthalene-1-carbonitrile, 4-(3-Hydroxyimino-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, 3-Chloropropionic acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, 4-(3-exo-Ethynyl-3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, 4-[3-(2-[1,3]Dioxan-2-ylethyl)-3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl]naphthalene-1-carbonitrile, 4-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, hydrochloride, 2-Chloro-N-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]acetamide, hydrochloride, N-[8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-2-diethylaminoacetamide, hydrochloride, 2-Cyanoethyl endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl N,N-diisopropylamidophosphate, Endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl hydrogen N,N-diisopropylamidophosphate, [8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]urea, Dimethylcarbamic acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, 4-[3-exo-(4-ethylpiperazin-1-yl methyl)-3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl]naphthalene-1-carbonitrile, 4-(3-endo-hydroxy-3-exo-hydroxymethyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, 4-(3-endo-Hydroxy-3-exo-{[2-(1H-imidazol-4yl)ethylamino]methyl}-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, 4-(3-endo-Hydroxy-3-exo-methoxymethyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, Acrylic acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester, 4-(2-Methyl-3-oxo-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, 4-(3-exo-Benzyl-3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, 8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylic acid methyl ester, 8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester, 4-(2-Hydroxymethyl-8-azabicyclo[3.2.1]oct-2-en-8-yl)naphthalene-1-carbonitrile, (1R,2R,3S,5S)-3-Benzoyloxy-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester, (1R,2R,3S,5S)-4-(3-Hydroxy-2-hydroxymethyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile, 2-Cyanoethyl endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl N,N-diisopropylamidophosphite, 2-Cyanoethyl endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl diisopropylamidophosphate, 2-Cyanoethyl ethyl endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl phosphate, Ethyl endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl hydrogen phosphate, Bis(2-cyanoethyl) endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl phosphate, 2-Cyanoethyl endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl phenyl phosphate, Endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl phenyl hydrogen phosphate, N-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]acetamide, 3-Chloro-N-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]propanamide, N-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-3-(4-ethylpiperazin-1-yl)propanamide, dihydrochioride, N-[8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-3-diethylaminopropionamide, hydrochloride, N-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-3-(1H-imidazol-1-yl)propanamide hydrochloride, N-[8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-2-(ethoxyethoxy)acetamide, N′
-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-4-methylbenzenesulfonylhydrazone, and3-exo-[8-(4-Cyanonaphthalen-1-yl)-3-endo-hydroxy-8-azabicyclo[3.2.1]oct-3-yl]-N,N-dimethylpropanamide.
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Specification