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Last Updated: January 29, 2022

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Claims for Patent: 8,975,254


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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): Wohlfahrt; Gerd (Helsinki, FI), Tormakangas; Olli (Turku, FI), Salo; Harri (Turku, FI), Hoglund; Iisa (Turku, FI), Karjalainen; Arja (Espoo, FI), Knuuttila; Pia (Littoinen, FI), Holm; Patrik (Lielahti TL, FI), Rasku; Sirpa (Vantaa, FI), Vesalainen; Anniina (Paimio, FI)
Assignee: Orion Corporation (Espoo, FI)
Application Number:13/504,511
Patent Claims: 1. A compound of formula (III), (IV), or (V) ##STR00025## wherein R.sub.1 is hydrogen, halogen, cyano, nitro or optionally substituted 5- or 6-membered heterocyclic ring; R.sub.2 is hydrogen, halogen, cyano, nitro, amino, C.sub.1-7 alkyl, halo C.sub.1-7 alkyl, hydroxy C.sub.1-7 alkyl, thio C.sub.1-7 alkyl or C.sub.1-7 alkoxy; R.sub.3 is hydrogen, halogen or C.sub.1-7 alkyl, or R.sub.2 and R.sub.3 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 R.sub.1, R.sub.2 and R.sub.3 are not hydrogen; R.sub.4, R.sub.4', R.sub.5, R.sub.6 and R.sub.7 are, independently, hydrogen, C.sub.1-7 alkyl, halo C.sub.1-7 alkyl or hydroxy C.sub.1-7 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 ##STR00026## ##STR00027## ##STR00028## ##STR00029## R.sub.8 is hydrogen, hydroxy, halogen, nitro, amino, cyano, oxo, C.sub.1-7 alkyl, C.sub.1-7 alkoxy, halo C.sub.1-7 alkyl, hydroxy C.sub.1-7 alkyl, cyano C.sub.1-7 alkyl, amino C.sub.1-7 alkyl, oxo C.sub.1-7 alkyl, C.sub.1-7 alkoxy C.sub.1-7 alkyl, methylsulfonamido C.sub.1-7 alkyl, oxiran C.sub.1-7 alkyl, C.sub.1-7 alkylamino, hydroxy C.sub.1-7 alkylamino, C.sub.1-7 alkoxy C.sub.1-7 alkylamino, C.sub.1-7 alkylamino C.sub.1-7 alkyl, hydroxy C.sub.1-7 alkylamino C.sub.1-7 alkyl, hydroxyimino C.sub.1-7 alkyl, halo C.sub.1-7 alkylhydroxy C.sub.1-7 alkyl, --C(O)R.sub.10, --OC(O)R.sub.17, --NH--C(O)R.sub.18 or an optionally substituted 5-12 membered carbocyclic or heterocyclic ring, each group optionally linked to A-ring via C.sub.1-7 alkylene linker; R.sub.9 is hydrogen, halogen, C.sub.1-7 alkyl, oxo, hydroxy C.sub.1-7 alkyl, oxo C.sub.1-7 alkyl or an optionally substituted 5 or 6 membered carbocyclic or heterocyclic ring, each group optionally linked to A-ring via C.sub.1-7 alkylene linker; R.sub.10 is hydrogen, hydroxy, C.sub.1-7 alkyl, hydroxy C.sub.1-7 alkyl, halo C.sub.1-7 alkyl, C.sub.1-7 alkoxy, NR.sub.11R.sub.12, or an optionally substituted 5-12 membered carbocyclic or heterocyclic ring; R.sub.11 is hydrogen, C.sub.1-7 alkyl, hydroxy C.sub.1-7 alkyl, amino C.sub.1-7 alkyl, C.sub.1-7 alkyl amino C.sub.1-7 alkyl, R.sub.12 is hydrogen or C.sub.1-7 alkyl; R.sub.13 and R.sub.14 are, independently, hydrogen, C.sub.1-7 alkyl, halogen, cyano or hydroxy C.sub.1-7 alkyl; R.sub.17 is C.sub.1-7 alkyl, C.sub.1-7 alkoxy, amino C.sub.1-7 alkyl or C.sub.1-7 alkylamino C.sub.1-7 alkyl; R.sub.18 is C.sub.1-7 alkyl, amino C.sub.1-7 alkyl or C.sub.1-7 alkylamino C.sub.1-7 alkyl; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein ring atom E is C, R.sub.1 is halogen, C.sub.1-7 alkyl, cyano, nitro or halo C.sub.1-7 alkyl, R.sub.2 is cyano, halogen or nitro, R.sub.3 is hydrogen, halogen or C.sub.1-7 alkyl, A is any one of groups (5'), (6'), (7'), (8'), (12'), (20'), (21'), (27') and (28') or tautomers thereof, R.sub.13 and R.sub.14 are hydrogen, R.sub.4 (and R.sub.4' if applicable) is hydrogen or methyl, R.sub.5 is hydrogen or C.sub.1-7 alkyl, R.sub.6 (if applicable) is hydrogen, R.sub.8 is hydrogen, C.sub.1-7 alkyl, hydroxy C.sub.1-7 alkyl, halogen, hydroxyimino C.sub.1-7 alkyl, a 5 or 6 membered heterocyclic ring or --C(O)R.sub.10 wherein R.sub.10 is C.sub.1-7 alkyl, and R.sub.9 is hydrogen, halogen or C.sub.1-7 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)-1- H-pyrazole-5-carboxamide; (S/R)--N-(1-(5-(3,4-dichlorophenyl)furan-2-yl)propan-2-yl)-3-(pyridin-4-y- l)-1H-pyrazole-5-carboxamide; (S)--N-(1-(3-(4-cyano-3-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(fur- an-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-py- razol-4-yl)isoxazole-3-carboxamide; (S)--N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-m- ethyl-1H-pyrazol-4-yl)isoxazole-3-carboxamide; N-(2-(3-(3,4-dicyanophenyl)-1H-pyrazol-1-yl)ethyl)-3-(pyridin-3-yl)-1H-py- razole-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)thiazol- e-4-carboxamide; (S)--N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(pyr- idin-3-yl)-1H-pyrazole-5-carboxamide: (S)--N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazol- e-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)-1- H-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)pr- opan-2-yl)-1H-pyrazole-5-carboxamide; N--((S)-1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-y- l)-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-y- l)thiazole-4-carboxamide; (S)--N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-y- l)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide; (S)--N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-y- l)-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-y- l-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-m- ethyl-thiazol-4-yl)-1H-pyrazole-3-carboxamide; (S)--N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-meth- yl-1,2,4-oxadiazole-5-carboxamide; (R)--N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-morp- holinothiazole-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-meth- yl-1H-imidazole-4-carboxamide; N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-5-(1-hy- droxyethyl)isoxazole-3-carboxamide; (S)--N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-ethy- l-1,2,4-oxadiazole-5-carboxamide; N--((S)-1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-y- l)-2-(1-hydroxyethyl)thiazole-4-carboxamide; (R)--N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propyl)-2-(cyan- omethyl)thiazole-4-carboxamide, (S)--N-{1-[3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl]propan-2-y- l}-2-methyl-1H-imidazole-4-carboxamide: (S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y- l)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) ##STR00030## wherein R.sub.1 is halogen, methyl, cyano nitro or trifluoromethyl; R.sub.2 is cyano, halogen or nitro; R.sub.3 is hydrogen, halogen or methyl; R.sub.4 is hydrogen or methyl; and R.sub.5 is hydrogen or C.sub.1-3 alkyl.

8. The compound according to claim 7, wherein R.sub.1 is halogen, R.sub.2 is cyano; R.sub.3 is hydrogen, halogen or methyl; R.sub.4 is hydrogen, and R.sub.5 is methyl.

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