N-piperidin-4-yl derivatives

Patent metadata

Field	Value
Publication number	US-8993757-B2
Application number	US-201214346241-A
Country	US
Kind code	B2
Filing date	Sep 14, 2012
Priority date	Sep 22, 2011
Publication date	Mar 31, 2015
Grant date	Mar 31, 2015

Abstract

The invention relates to a N-piperidin-4-yl derivative having the general Formula I or a pharmaceutically acceptable salt thereof, to pharmaceutical compositions comprising the same and to the use of said N-piperidin-4-yl derivatives for the treatment and prevention of endometriosis, for the treatment and prevention of pre-menopausal and peri-menopausal hormone-dependent breast cancer, for contraception, or for the treatment of uterine fibroids or other menstrual-related disorders.

First claim

The invention claimed is:

1. A N-piperidin-4-yl compound having the Formula I

wherein
W is C(O)NH or NH(CO);
Y is CHR 3 or a bond;
X is N, CH, CF or CR 8 ;
A is a (hetero)aromatic group selected from

R 1 is H, halogen, (C 1-4 )alkyl, halo(C 1-4 )alkyl, (C 1-4 )alkyloxy or halo(C 1-4 )alkyloxy;
R 2 is H, halogen, di(C 1-4 )alkylamino, (C 2-4 )alkenyl, (C 2-4 )alkynyl, halo(C 1-4 )alkyl or (C 1-6 )alkyloxy, optionally substituted with one or more halogens, hydroxy or (C 1-4 )alkyloxy; or
R 2 is OCH 2 R 7 ;
R 3 is H, (C 1-3 )alkyl or COOR 8 ;
R 4 is H, halogen or (C 1-3 )alkyl; or
R 4 forms together with R 3 and the carbon atoms to which they are bonded a (C 3-5 )cycloalkyl group;
R 5 is, halogen, (C 1-4 )alkyl, halo(C 1-4 )alkyl, hydroxy(C 1-4 alkyl, CN, COOH, CONR 9 , R 10 , pyridyl or a 5-membered heteroaryl group comprising 1, 2 or 3 nitrogen atoms and optionally an oxygen or a sulfur atom;
R 6 is H, hydroxy or halogen; or
R 6 forms together with R 5 and the carbon atoms to which they are bonded a fused 5-membered heteroaryl group comprising 1 or 2 nitrogen atoms and optionally an oxygen or a sulfur atom;
R 7 is vinyl, ethynyl, cyano, (C 3-6 )cycloalkyl, CONR 11 , R 12 , CH 2 NR 13 R 14 , phenyl or a 5 or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N and S;
each R 8 is independently (C 1-3 )alkyl;
R 9 is H or (C 1-6 )alkyl, optionally substituted with 1-3 halogens, hydroxyl or COOR 8 ;
R 10 is H, (C 1-3 )alkyl or a 5-membered heteroaryl group comprising 1-3 heteroatoms selected from N, S and O; or
R 9 and R 10 form together with the nitrogen atom to which they are bonded a saturated 5-7 membered ring;
R 11 , R 12 , R 13 and R 14 are independently selected from H or (C 1-3 )alkyl; or a pharmaceutically acceptable salt thereof.

2. The N-piperidin-4-yl compound of claim 1 , wherein W is C(O)NH.

3. The N-piperidin-4-yl compound of claim 2 , wherein R 4 is H.

4. The N-piperidin-4-yl compound of claim 3 , wherein A is

R 5 is CN or a 5-membered heteroaryl group comprising 2 nitrogen atoms; and R 6 is H.

5. The N-piperidin-4-yl compound of claim 4 , wherein R 5 is 1H-pyrazol-1-yl, 1H-pyrazol-5-yl or 1H-imidazol-2-yl.

6. The N-piperidinyl-4-yl compound of claim 5 , wherein R 1 is (C 1-4 )alkyloxy and R 2 is OCH 2 R 7 , wherein R 7 is (C 3-6 )cycloalkyl.

7. The N-piperidinyl-4-yl compound of claim 1 which is selected from
1-(2-(3-(1H-pyrazol-1-yl)phenyl)pyrimidin-4-yl)-N-(3-methoxy-5-((5-methylisoxazol-3-yl)methoxy)phenyl)piperidine-4-carboxamide;
N-((1-(2-(3-(1H-pyrazol-1-yl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methyl)-3-(cyclopropylmethoxy)-5-methoxybenzamide;
N-((1-(2-(3-(1H-pyrazol-1-yl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methyl)-3-methoxy-5-((5-methylisoxazol-3-yl)methoxy)benzamide;
N-((1-(4-(3-(1H-pyrazol-1-yl)phenyl)-1,3,5-triazin-2-yl)piperidin-4-yl)methyl)-3-(cyclopropylmethoxy)-5-methoxybenzamide;
N-((1-(4-(3-cyanophenyl)-1,3,5-triazin-2-yl)piperidin-4-yl)methyl)-3-methoxy-5-(2,2,2-trifluoroethoxy)benzamide;
N-((1-(2-(3-(1H-pyrazol-5-yl)phenyl)-5-fluoropyrimidin-4-yl)piperidin-4-yl)methyl)-3-(cyclopropylmethoxy)-5-methoxybenzamide;
3-(cyclopropylmethoxy)-5-methoxy-N-((1-(2-(3-(1-methyl-1H-pyrazol-3-ylcarbamoyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methyl)benzamide;
3-(cyclopropylmethoxy)-5-methoxy-N-((1-(2-(3-(4-methyl-1H-pyrazol-1-yl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methyl)benzamide;
N-(1-(1-(4-(3-(1H-pyrazol-3-yl)phenyl)-1,3,5-triazin-2-yl)piperidin-4-yl)ethyl)-3-(cyclopropylmethoxy)-5-methoxybenzamide;
N-(1-(1-(2-(3-cyanophenyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)-3-(cyclopropylmethoxy)-5-methoxybenzamide;
N-(1-(1-(2-(3-(1H-pyrazol-1-yl)phenyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)-3-(cyclopropyl methoxy)-5-methoxybenzamide;
N-((1-(4-(3-(1H-imidazol-2-yl)phenyl)-1,3,5-triazin-2-yl)piperidin-4-yl)methyl)-3-(cyclopropylmethoxy)-5-methoxybenzamide 2,2,2-trifluoroacetate;
1-(2-(3-(1H-pyrazol-1-yl)phenyl)pyrimidin-4-yl)-N-(3,5-dimethoxyphenyl) piperidine-4-carboxamide; and N-((1-(2-(3-(1H-imidazol-2-yl)phenyl)-5-fluoropyrimidin-4-yl)piperidin-4-yl)-methyl)-3-(cyclopropylmethoxy)-5-methoxybenzamide 2,2,2-trifluoroacetate; or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a N-piperidinyl-4-yl compound of claim 1 or a pharmaceutically acceptable salt thereof, in admixture with pharmaceutically acceptable auxiliaries.

Assignees

• Huisman Ines
• Van Der Stelt Marcelis
• Wiedenhof Wouter
• Baker-Glenn Charles Anthony Graham
• Blackaby Wesley Peter
• Trivedi Naimisha
• Merck Sharp & Dohme

Inventors

• Huisman Ines
• Van Der Stelt Marcelis
• Wiedenhof Wouter
• Baker-Glenn Charles Anthony Graham
• Blackaby Wesley Peter
• Trivedi Naimisha

Classifications

• A61P5/06

  of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P15/00

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

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D417/14 Primary

  containing three or more hetero rings · CPC title