Factor IXa inhibitors

Patent metadata

Field	Value
Publication number	US-9969724-B2
Application number	US-201515303310-A
Country	US
Kind code	B2
Filing date	Apr 10, 2015
Priority date	Apr 16, 2014
Publication date	May 15, 2018
Grant date	May 15, 2018

Abstract

In its many embodiments, the present invention provides a novel class of benzamide compounds represented by Formula (I) or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions comprising one or more said compounds or pharmaceutically acceptable salts or solvates thereof, and methods for using said compounds or pharmaceutically acceptable salts or solvates thereof for treating or preventing a thromboses, embolisms, hypercoagulability or fibrotic changes.

First claim

What is claimed is:

1. A compound of the Formula (I)

or a pharmaceutically acceptable salt thereof;
wherein: m is an integer of 1 to 2; n is an integer of 1 to 2; o is an integer of 0 or 1; p is an integer of 0 to 5; q is an integer of 0 to 4; r is an integer of 0 to 4; s is an integer of 0 to 4; X is a nitrogen atom or CH; Y is an oxygen atom, a sulfur atom or NH (when o=0), a nitrogen atom or CH (when o=1);
Z 1 , Z 2 , Z 3 , Z 4 are each independently a nitrogen atom or CH;
each R 1 is independently a halogen atom, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a hydroxyl C 1-6 alkyl group, a C 3-12 cycloalkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a C 2-7 alkanoyl group or a group of —NR A R B ;
R A and R B are each independently a hydrogen atom, a C 1-6 alkyl group or a C 2-7 alkanoyl group;
each R 2 is independently a hydroxyl group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a hydroxyl C 1-6 alkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a C 6-14 aryl group, a heteroaryl group or oxo;
each R 3 is independently a halogen atom, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 3-12 cycloalkyl group, a C 1-6 alkoxy group or a halogenated C 1-6 alkoxy group;
each R 4 is independently a halogen atom, a cyano group, a C 1-6 alkyl group, a C 3-12 cycloalkyl group, a halogenated C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a cyanated C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 alkyl group, a halogenated C 1-6 alkoxy group, a C 2-7 alkanoyl group, a C 1-6 alkylthio group, a C 1-6 alkylsulfonyl group, a group of —NR A R B or oxo;
a dotted line in a substructure of a bicycle represented by Formula (II):

represents a single bond when o is 0 or a double bond when o is 1;

is heteroaryl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein o is 1.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein o is 0.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is an integer of 0 to 2, q is an integer of 0 to 2, r is an integer of 0 to 2 and s is 0 or 1.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the substructure of Formula (V):

in Formula (I) is:

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the substructure of Formula (II):

in Formula (I) is:

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein a substructure of Formula (II):

in Formula (I) is:

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group or a halogenated C 1-6 alkyl group.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: R 2 is a hydroxyl group, a C 1-6 alkyl group or a C 6-14 aryl group.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: R 3 is a halogen atom or a C 1-6 alkyl group.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: R 4 is a cyano group, a C 1-6 alkyl group, a C 3-12 cycloalkyl group, a halogenated C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy group or oxo.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is:
N-(1-(3-Aminobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(4H-1,2,4-triazol-4-yl)benzamide;
N-(1-(3-Aminobenzo[d]isoxazol-7-yl)-3-methylpyrrolidin-3-yl)-2,6-dichloro-4-(4H-1,2,4-triazol-4-yl)benzamide;
N-(1-(3-Aminobenzo[d]isoxazol-7-yl)-3-phenylpyrrolidin-3-yl)-2,6-dichloro-4-(4H-1,2,4-triazol-4-yl)benzamide;
N-(1-(3-Aminobenzo[d]isothiazol-7-yl)pyrrolidin-3-yl)-2,6-dichloro-4-(4H-1,2,4-triazol-4-yl)benzamide;
N-(1-(3-Aminoisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(4H-1,2,4-triazol-4-yl)benzamide;
N-(1-(3-Amino-5-methylbenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2,6-dichloro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzamide;
N-((3R*,4S*)-1-(3-Aminobenzo[d]isoxazol-7-yl)-3,4-dimethylpyrrolidin-3-yl)-2,6-dichloro-4-(4H-1,2,4-triazol-4-yl)benzamide;
N-((3S*,4S*)-1-(3-Aminobenzo[d]isoxazol-7-yl)-4-hydroxypyrrolidin-3-yl)-2,6-dichloro-4-(4H-1,2,4-triazol-4-yl)benzamide;
(R)—N-(1-(3-Amino-4-chlorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(4H-1,2,4-triazol-4-yl)benzamide;
(R)—N-(1-(3-Amino-5-chlorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(4H-1,2,4-triazol-4-yl)benzamide;
(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzamide;
(R)—N-(1-(3-Amino-4-chloro-5-methylbenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(4H-1,2,4-triazol-4-yl)benzamide;
(R)—N-(1-(3-Amino-4-fluorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(4H-1,2,4-triazol-4-yl)benzamide;
(R)—N-(1-(3-Amino-4,5-dichlorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(4H-1,2,4-triazol-4-yl)benzamide;
N-(1-(3-Amino-5-chlorobenzo[d]isoxazol-7-yl)-3-methylpyrrolidin-3-yl)-2-chloro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzamide;
(R)—N-(1-(3-Amino-5-chlorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)benzamide;
(R)—N-(1-(3-Amino-5-chlorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)benzamide;
(R)—N-(1-(3-Amino-4-chlorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-fluoro-4-(1H-1,2,4-triazol-1-yl)benzamide;
(R)—N-(1-(3-Amino-4-chlorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)benzamide;
(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(pyrimidin-5-yl)benzamide;
(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(2-methoxypyrimidin-5-yl)benzamide;
(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(2-cyanopyrimidin-5-yl)benzamide;
(R)—N-(1-(3-Amino-4-chlorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(3-(2-hydroxyethyl)-1H-1,2,4-triazol-1-yl)benzamide;
(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(1H-1,2,4-triazol-1-yl)

Assignees

• Sakurada Isao
• Hirabayashi Tomokazu
• Maeda Yoshitaka
• Nagasue Hiroshi
• Mizuno Takashi
• Xu Jiayi
• Zhang Ting
• Smith Cameron
• Parker Dann
• Merck Sharp & Dohme
• Mochida Pharm Co Ltd

Inventors

• Sakurada Isao
• Hirabayashi Tomokazu
• Maeda Yoshitaka
• Nagasue Hiroshi
• Mizuno Takashi
• Xu Jiayi
• Zhang Ting
• Smith Cameron
• Parker Dann

Classifications

• A61K31/428

  condensed with carbocyclic rings · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title