Claims for Patent: 8,975,254

Summary for Patent: 8,975,254

Title:	Androgen receptor modulating compounds
Abstract:	The present disclosure relates to compounds of formula (I), and pharmaceutically acceptable salts thereof. The present disclosure also relates to compositions and methods of treating comprising compounds of formula (I), and pharmaceutically acceptable salts thereof.
Inventor(s):	Gerd Wohlfahrt, Olli Törmäkangas, Harri Salo, Iisa Höglund, Arja Karjalainen, Pia Knuuttila, Patrik Holm, Sirpa Rasku, Anniina Vesalainen
Assignee:	Orion Oyj
Application Number:	US13/504,511
Patent Claims:	1. A compound of formula (III), (IV), or (V) wherein R1 is hydrogen, halogen, cyano, nitro or optionally substituted 5- or 6-membered heterocyclic ring; R2 is hydrogen, halogen, cyano, nitro, amino, C1-7 alkyl, halo C1-7 alkyl, hydroxy C1-7 alkyl, thio C1-7 alkyl or C1-7 alkoxy; R3 is hydrogen, halogen or C1-7 alkyl, or R2 and R3 together with the carbon atoms to which they are attached form a optionally substituted 5- or 6-membered carbocyclic or heterocyclic ring; wherein at least two of R1, R2 and R3 are not hydrogen; R4, R4′, R5, R6 and R7 are, independently, hydrogen, C1-7 alkyl, halo C1-7 alkyl or hydroxy C1-7 alkyl; ring atom E is C or N; dashed line means an optional double bond; A is any one of the following groups or tautomers thereof R8 is hydrogen, hydroxy, halogen, nitro, amino, cyano, oxo, C1-7 alkyl, C1-7 alkoxy, halo C1-7 alkyl, hydroxy C1-7 alkyl, cyano C1-7 alkyl, amino C1-7 alkyl, oxo C1-7 alkyl, C1-7 alkoxy C1-7 alkyl, methylsulfonamido C1-7 alkyl, oxiran C1-7 alkyl, C1-7 alkylamino, hydroxy C1-7 alkylamino, C1-7 alkoxy C1-7 alkylamino, C1-7 alkylamino C1-7 alkyl, hydroxy C1-7 alkylamino C1-7 alkyl, hydroxyimino C1-7 alkyl, halo C1-7 alkylhydroxy C1-7 alkyl, —C(O)R10, —OC(O)R17, —NH—C(O)R18 or an optionally substituted 5-12 membered carbocyclic or heterocyclic ring, each group optionally linked to A-ring via C1-7 alkylene linker; R9 is hydrogen, halogen, C1-7 alkyl, oxo, hydroxy C1-7 alkyl, oxo C1-7 alkyl or an optionally substituted 5 or 6 membered carbocyclic or heterocyclic ring, each group optionally linked to A-ring via C1-7 alkylene linker; R10 is hydrogen, hydroxy, C1-7 alkyl, hydroxy C1-7 alkyl, halo C1-7 alkyl, C1-7 alkoxy, NR11R12, or an optionally substituted 5-12 membered carbocyclic or heterocyclic ring; R11 is hydrogen, C1-7 alkyl, hydroxy C1-7 alkyl, amino C1-7 alkyl, C1-7 alkyl amino C1-7 alkyl, R12 is hydrogen or C1-7 alkyl; R13 and R14 are, independently, hydrogen, C1-7 alkyl, halogen, cyano or hydroxy C1-7 alkyl; R17 is C1-7 alkyl, C1-7 alkoxy, amino C1-7 alkyl or C1-7 alkylamino C1-7 alkyl; R18 is C1-7 alkyl, amino C1-7 alkyl or C1-7 alkylamino C1-7 alkyl; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein ring atom E is C, R1 is halogen, C1-7 alkyl, cyano, nitro or halo C1-7 alkyl, R2 is cyano, halogen or nitro, R3 is hydrogen, halogen or C1-7 alkyl, A is any one of groups (5′), (6′), (7′), (8′), (12′), (20′), (21′), (27′) and (28′) or tautomers thereof, R13 and R14 are hydrogen, R4 (and R4′ if applicable) is hydrogen or methyl, R5 is hydrogen or C1-7 alkyl, R6 (if applicable) is hydrogen, R8 is hydrogen, C1-7 alkyl, hydroxy C1-7 alkyl, halogen, hydroxyimino C1-7 alkyl, a 5 or 6 membered heterocyclic ring or —C(O)R10 wherein R10 is C1-7 alkyl, and R9 is hydrogen, halogen or C1-7 alkyl. 3. A pharmaceutical composition comprising a compound of claim 1 together with a pharmaceutically acceptable carrier. 4. A method for the treatment of androgen receptor dependent conditions, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1. 5. A method according to claim 4, wherein the androgen receptor dependent condition is prostate cancer. 6. A compound according to claim 1 which is N-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethyl)-3-(morpholine-4-carbonyl)-1H-pyrazole-5-carboxamide; (S/R)—N-(1-(5-(3,4-dichlorophenyl)furan-2-yl)propan-2-yl)-3-(pyridin-4-yl)-1H-pyrazole-5-carboxamide; (S)—N-(1-(3-(4-cyano-3-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxamide; (S)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide; N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)ethyl)-5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxamide; (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxamide; N-(2-(3-(3,4-dicyanophenyl)-1H-pyrazol-1-yl)ethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxamide; (R)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide; N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide; (S)-2-amino-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide; (R)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)butan-2-yl)-1H-pyrazole-5-carboxamide; (R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide; (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxamide: (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide; N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)ethyl)-3-(furan-2-yl)-1H-pyrazole-5-carboxamide; 3-tert-butyl-N-(1-(5-(4-cyano-3-(trifluoromethyl)phenyl)furan-2-yl)propan-2-yl)-1-pyrazole-5-carboxamide; 3-tert-butyl-N-(2-(5-(3-chloro-4-cyano-2-methylphenyl)furan-2-yl)ethyl)-1H-pyrazole-5-carboxamide; N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)ethyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxamide; (S)-5-acetyl-N-(1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-H-pyrazole-3-carboxamide; (R)—N-(1-(3-(4-cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxamide; (S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide; N—((S)-1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide; (S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-yl)propan-2-yl)-5-methylisoxazole-3-carboxamide; (S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide; (S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide; (S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxamide; (R)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2H-yl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxamide; (R)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl-3-(furan-2-yl)-1H-pyrazole-5-carboxamide; (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-methyl-thiazol-4-yl)-1H-pyrazole-3-carboxamide; (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-methyl-1,2,4-oxadiazole-5-carboxamide; (R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-morpholinothiazole-4-carboxamide; (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; (S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1H-imidazole-4-carboxamide; N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-5-(1-hydroxyethyl)isoxazole-3-carboxamide; (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-ethyl-1,2,4-oxadiazole-5-carboxamide; N—((S)-1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-hydroxyethyl)thiazole-4-carboxamide; (R)—N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propyl)-2-(cyanomethyl)thiazole-4-carboxamide, (S)—N-{1-[3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1H-imidazole-4-carboxamide: (S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)imidazo[1,2-a]pyrimidine-2-carboxamide; (S)-3-acetyl-N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propyl)-1H-pyrazole-5-carboxamide; or (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxamide. 7. The compound according claim 1, which is a compound of formula (VI) wherein R1 is halogen, methyl, cyano nitro or trifluoromethyl; R2 is cyano, halogen or nitro; R3 is hydrogen, halogen or methyl; R4 is hydrogen or methyl; and R5 is hydrogen or C1-3 alkyl. 8. The compound according to claim 7, wherein R1 is halogen, R2 is cyano; R3 is hydrogen, halogen or methyl; R4 is hydrogen, and R5 is methyl.