Substituted thiohydantoin derivatives as androgen receptor antagonists

Patent metadata

Field	Value
Publication number	US-10000502-B2
Application number	US-201715403741-A
Country	US
Kind code	B2
Filing date	Jan 11, 2017
Priority date	Jan 11, 2016
Publication date	Jun 19, 2018
Grant date	Jun 19, 2018

Abstract

Disclosed are compounds, compositions and methods for treating of disorders that are affected by the antagonism of one or more androgen receptor types. Such compounds are represented by Formula (I) as follows:

wherein R 1 and G are defined herein.

First claim

We claim:

1. A compound of Formula (I)

wherein
R 1 is chloro, methyl, methoxy, difluoromethyl, or trifluoromethyl;
G is
i)

 wherein R 4 is selected from the group consisting of bromo, morpholin-2-yl, morpholin-4-yl, morpholin-4-ylmethyl, morpholin-2-ylmethoxy, 5-methylmorpholin-2-ylmethoxy, 4,4-difluoropyrrolidin-2-ylmethoxy, (1-methylcarbonyl)-4,4-difluoropyrrolidin-2-ylmethoxy, (1-t-butoxycarbonyl)-4,4-difluoropyrrolidin-2-ylmethoxy, (2-oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy, (6,6-difluoro-2-methyl-2-azaspiro[3.3]heptan-6-yl)ethoxy, 2-oxa-8-azaspiro[4.5]decan-8-yl)ethoxy, 1H-pyrazol-4-yl, 1H-pyrazol-3-yl, (1-aminocarbonyl)pyrazol-4-yl, (1-ethylaminocarbonyl)pyrazol-4-yl, methylaminocarbonylmethyl, 2-oxo-imidazolidin-1-yl, (5-methoxymethyl)furan-2-yl, 5-methylfuran-2-yl, tetrahydrofuran-2-yloxy, 4-methylmorpholin-2-yl, 1-methylpyrrolidin-3-yloxy, 8-azabicyclo[3.2.1]oct-3-en-3-yl, 8-methyl-8-azabicyclo[3.2.1]oct-3-en-3-yl, 8-azabicyclo[3.2.1]octan-3-yl, 8-methyl-8-azabicyclo[3.2.1]octan-3-yl, 5,8-diazaspiro[2.5]octan-5-ylmethyl, 1-azaspiro[3.3]heptan-6-yloxy, 2-azaspiro[3.3]heptan-6-yloxy, 2-azabicyclo[2.2.1]heptan-5-yloxy, (4-aminopiperidin-1-yl)methyl, (2S,3R,4S)-3,4-dihydroxy-2-methyl-3,4-dihydro-2H-pyran-6-yl, 3,4-dihydroxy-3,4-dihydro-2H-pyran-6-yl, 2-(hydroxymethyl)-3,4-dihydro-2H-pyran-6-yl, 2-methyl-2-azaspiro[3.3]heptan-6-yl)oxy, 1-methylpiperidin-4-ylcarbonyl, (1-methyl-1-azaspiro[3.3]heptan-6-yl)oxy, (2-methyl-2-azabicyclo[2.2.1]heptan-5-yl)oxy, (3-methyl-3-azaspiro[3.3]heptan-6-yl)oxy, 3-azabicyclo[3.2.1]octan-8-yloxy, (3-t-butoxycarbonyl-3-azaspiro[3.3]heptan-6-yl)oxy, (1R,5S)-8-azabicyclo[3.2.1]octan-3-yl]oxy, (1-methylazetidin-3-yl)methylaminocarbonyl, 1-methylpyrrolidin-3-ylaminocarbonyl, (1-methyl-1-oxido-piperidin-1-ium-4-yl)oxy, (3-methyl-3-azabicyclo[3.2.1]octan-8-yl)oxy, [(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]oxy, (1,2,3,5,6,7,8,8a-octahydroindolizin-7-yl)oxy, 9-azaspiro[3.5]nonan-6-yloxy, (9-methyl-9-azaspiro[3.5]nonan-6-yl)oxy, (1-methylpyrrolidin-3-yl)methylaminocarbonyl, (piperidin-3-yl)methylaminocarbonyl, (4-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy, (4-fluoro-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy, (4-fluoro-8-(t-butoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy, (1-methyl-piperidin-4-yl)methylaminocarbonyl, piperidin-4-ylmethylaminocarbonyl, (1-methyl-piperidin-3-yl)methylaminocarbonyl, 1-(methyl)piperidin-4-ylmethyl-N(methyl)aminocarbonyl, 1-(methylaminocarbonyl)piperidin-4-ylmethylaminocarbonyl, 1-(ethoxycarbonyl)piperidin-4-ylmethylaminocarbonyl, 1-(t-butoxycarbonyl)piperidin-4-ylmethylaminocarbonyl, 8-(t-butoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl, methylaminothiocarbonyl, 3-(t-butoxycarbonylamino)-2,2,4,4-tetramethylcyclobut-1-yloxy, and a substituent selected from a) to e);
a)

 wherein L a is absent or —(CH 2 ) r —, wherein r is an integer of 1 or 2; R a is a substituent selected from methyl, prop-2-yn-1-yl, 2-hydroxyethyl, 2-methoxyethyl, or cyanomethyl;
b)

 wherein V is absent or —OCH 2 —; and wherein R b is amino, dimethylamino, or t-butoxycarbonyl(N-methyl)amino;
c)

 wherein L c absent or selected from O, S, or —CH 2 —; and wherein W is selected from the group consisting of NH, N(methyl), N(cyclopropyl), N(2-hydroxyethyl), N(2-methoxyethyl), N(2-fluoroethyl), N(2,2,2-trifluoroethyl), N(cyanomethyl), N(allyl), N(1-prop-2-ynyl), N(3-fluoropropyl), N(methoxycarbonylmethyl), N(3-amino-2-hydroxy-prop-1-yl), N(3,3-dimethyl-butyl), CH(amino), CH(methylamino), CH(dimethylamino), S, and SO 2 ;
d) a substituent selected from the group consisting of 2-oxo-piperidin-4-yloxy, 4-methyl-piperidin-4-yloxy, 1-methyl-2-trifluoromethyl-piperidin-4-yloxy, 1-methyl-piperidin-3-yloxy, 2-trifluoromethyl-piperidin-4-yloxy, azepan-4-yloxy, azepan-3-yloxy, 1-methyl-azepan-4-yloxy, 1-methyl-2-oxo-piperidin-4-yloxy, 1,4-dimethyl-piperidin-4-yloxy, 2-hydroxymethyl-piperidin-4-yloxy, 2-hydroxymethyl-1-methyl-piperidin-4-yloxy, 3-fluoro-piperidin-4-yloxy, 3-fluoro-1-methyl-piperidin-4-yloxy, 3,3-difluoro-piperidin-4-yloxy, 3,3-difluoro-1-methyl-piperidin-4-yloxy, piperazin-1-ylmethyl, 4-methyl-piperazin-1-ylmethyl, 3-oxopiperazin-1-ylmethyl, 4-cyclopropyl-piperazin-1-ylmethyl, 3-hydroxymethyl-piperazin-1-ylmethyl, 4-(2-hydroxyethyl)piperazin-1-ylmethyl, 4-(methylaminocarbonyl)piperazin-1-ylmethyl, 4-(ethoxycarbonyl)piperazin-1-yl, 4-(ethoxycarbonyl)piperazin-1-ylmethyl, 4-(ethoxycarbonyl)piperazin-1-ylcarbonyl, 4-(pyrrolidin-1-ylcarbonyl)piperazin-1-yl, 4-(t-butoxycarbonyl)piperazin-1-ylmethyl, and 4-(t-butoxycarbonyl)piperazin-1-ylcarbonyl;
and R 3 is hydrogen, fluoro, or methoxy;

provided that when R 4 is bromo, R 3 is hydrogen or methoxy;
provided that when R 4 is

 R 1 is chloro, methoxy, or difluoromethyl;
provided that when R 4 is

 and R 3 is hydrogen or fluoro, R 1 is chloro, methoxy, or difluoromethyl;
provided that when R 4 is

 and R 3 is hydrogen, R 1 is chloro, methoxy, or difluoromethyl;
provided that when R 4 is

 or and R 3 is hydrogen, R 1 is chloro, methoxy, difluoromethyl, or trifluoromethyl;
provided that when R 4 is

 and R 3 is hydrogen, R 1 is chloro, methyl, methoxy, or difluoromethyl;

ii)

 wherein R 7 is selected from the group consisting of hydroxy, methoxy, cyanomethyl, 1,4-(dimethyl)piperidin-4-yl)oxy, tetrahydro-2H-thiopyran-4-yloxy, aminosulfonyl, 2-azabicyclo[2.2.1]heptan-5-yloxy, 2-methyl-2-azabicyclo[2.2.1]heptan-5-yloxy, (3-methyl-3-azaspiro[3.3]heptan-6-yl)oxy, 3-azabicyclo[3.2.1]octan-8-yloxy, (3-methyl-3-azabicyclo[3.2.1]octan-8-yl)oxy, 9-azaspiro[3.5]nonan-6-yloxy, (9-methyl-9-azaspiro[3.5]nonan-6-yl)oxy, 4-(ethoxycarbonyl)piperazin-1-yl, 3-(dimethylamino)propyloxy, 3-(t-butoxycarbonyl)-3-azaspiro[3.3]heptan-6-yloxy, and substituent f)

wherein W f is selected from the group consisting of NH, N(methyl), N(2-hydroxyethyl), N(2-methoxyethyl), N(2-fluoroethyl), N(2,2,2-trifluoroethyl), N(cyanomethyl), N(allyl), N(isopentyl), N(prop-2-yn-1-yl), N(3,3-dimethylbutyl), N(3-fluoropropyl), N(3,3,3-trifluoropropyl), N(methoxycarbonylmethyl),

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Bignan Gilles
• Connolly Peter J
• Hickson Ian
• Meerpoel Lieven
• Pande Vineet
• Zhang Zhuming
• Branch Jonathan
• Rocaboy Christian
• Trabalón Escolar Luis B

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title