Heterocyclic compound

Patent metadata

Field	Value
Publication number	US-10081634-B2
Application number	US-201515312192-A
Country	US
Kind code	B2
Filing date	Jun 23, 2015
Priority date	Jun 23, 2014
Publication date	Sep 25, 2018
Grant date	Sep 25, 2018

Abstract

The present invention relates to a compound represented by chemical formula 1, which can be used for the prevention and treatment of diseases caused by abnormality in a prolyl-tRNA synthetase (PRS) activity, or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition comprising the same.

First claim

The invention claimed is:

1. A compound represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof:

in Chemical Formula 1,
n is 1, or 2,
R 1 is hydrogen, or hydroxy,
R 1 ′ is hydrogen,
R 2 is hydroxy, halogen, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino or C 1-4 alkoxy; R 3 is hydrogen, halogen, C 1-4 alkyl, or C 1-4 haloalkyl; or R 2 and R 3 together form an oxo (═O), hydroxyimino (═N—OH), or C 1-4 alkoxyimino (═N—O—(C 1-4 alkyl));
Y is

Y1 is N, CH, or CR 4 ,
wherein R 4 is C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkyl substituted with C 1-4 alkoxy, C 1-4 haloalkyl, or —(CH 2 ) m NR 9 R 10 , wherein m is an integer of 1 to 4, and R 9 and R 10 are each independently hydrogen, or C 1-4 alkyl,
Y2 is N, or CH,
A is benzene, heteroaryl having 1 to 4 nitrogen atoms, or cyclohexene, as a six-membered ring,
k is an integer of 0 to 4, and
each of Ra is independently C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, halogen, cyano, or carboxy.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is hydroxy, fluoro, amino, methylamino, dimethylamino or methoxy; R 3 is hydrogen, fluoro, methyl, or trifluoromethyl; or R 2 and R 3 together form oxo (═O), hydroxyimino (═N—OH), or methoxyimino (═N—OCH 3 ).

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein A is benzene, pyridine, pyrimidine, or cyclohexene.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 4 is methyl, ethyl, hydroxymethyl, hydroxyethyl, 1-hydroxyethyl, trifluoromethyl, methoxymethyl, aminomethyl, or (dimethylamino)methyl.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein
Y is

Y3 is N, or C—R 5 ;
Y4 is N, or C—R 6 ;
Y5 is N, or C—R 7 ;
Y6 is N, or C—R 8 ,
R 5 is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, or halogen;
R 6 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, halogen, cyano, or carboxy;
R 7 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, halogen, or cyano; and
R 8 is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, or halogen.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 5 , wherein
R 5 is hydrogen, methyl, trifluoromethyl, fluoro, chloro, or bromo;
R 6 is hydrogen, methyl, trifluoromethyl, trifluoromethoxy, fluoro, chloro, bromo, cyano, or carboxy;
R 7 is hydrogen, methyl, trifluoromethyl, fluoro, chloro, or bromo; and
R 8 is hydrogen, methyl, trifluoromethyl, trifluoromethoxy, chloro, or bromo.

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

is selected from the group consisting of

and k is an integer of 0 to 2.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 7 , wherein each of Ra is independently C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, halogen, cyano, or carboxy.

9. The compound or a pharmaceutically acceptable salt thereof according to claim 8 , wherein each of Ra is independently methyl, trifluoromethyl, trifluoromethoxy, fluoro, chloro, bromo, cyano, or carboxy.

10. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein
n is an integer of 1 or 2,
R 1 is hydrogen or hydroxy,
R 1 ′ is hydrogen,
R 2 is hydroxy, halogen, C 1-4 alkylamino, or C 1-4 alkoxy;
R 3 is hydrogen, halogen, C 1-4 alkyl, or C 1-4 haloalkyl; or R 2 and R 3 together form an oxo (═O), hydroxyimino(=N—OH), or C 1-4 alkoxyimino (═N—O—(C 1-4 alkyl));
Y is

Y1 is CH, or CR 4 ,
wherein R 4 is C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkyl substituted with C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 alkyl substituted with amino, or C 1-4 alkyl substituted with di(C 1-4 alkyl)amino,
Y2 is N,
k is an integer of 0 to 2, and
each of Ra is independently C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, or halogen.

11. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein
n is 2,
R 1 is hydroxy,
R 1 ′ is hydrogen,
R 2 is hydroxy; R 3 is hydrogen; or R 2 and R 3 together form an oxo (═O);
Y is

Y1 is CH,
Y2 is N,
k is an integer of 0 to 2,
each of Ra is independently C 1-4 alkyl, C 1-4 haloalkyl, halogen, or cyano.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound represented by Chemical Formula 1 is any one selected from the group consisting of:
1) 1-(1H-benzo[d]imidazol-1-yl)-3-((2R,3S)-3-hydroxypiperidin-2-yl)propan-2-one,
2) 1-(5-chloro-1H-benzo[d]imidazol-1-yl)-3-((2R,3S)-3-hydroxypiperidin-2-yl)propan-2-one,
3) 1-(6-chloro-1H-benzo[d]imidazol-1-yl)-3-((2R,3S)-3-hydroxypiperidin-2-yl)propan-2-one,
4) 1-(5-bromo-1H-benzo[d]imidazol-1-yl)-3-((2R,3S)-3-hydroxypiperidin-2-yl)propan-2-one,
5) 1-(6-bromo-1H-benzo[d]imidazol-1-yl)-3-((2R,3S)-3-hydroxypiperidin-2-yl)propan-2-one,
6) 1-((2R,3S)-3-hydroxypiperidin-2-yl)-3-(5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)propan-2-one,
7) 1-((2R,3S)-3-hydroxypiperidin-2-yl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)propan-2-one,
8) 1-((2R,3S)-3-hydroxypiperidin-2-yl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)propan-2-one,
9) 1-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)-3-((2R,3S)-3-hydroxypiperidin-2-yl)propan-2-one,
10) 1-(5,6-difluoro-1H-benzo[d]imidazol-1-yl)-3-((2R,3S)-3-hydroxypiperidin-2-yl)propan-2-one,
11) 1-(4,5-difluoro-1H-benzo[d]imidazol-1-yl)-3-((2R,3S)-3-hydroxypiperidin-2-yl)propan-2-one,
12) 1-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)-3-((2R,3S)-3-hydroxypiperidin-2-yl)propan-2-one,
13) 1-(5-fluoro-4-methyl-1H-benzo[d]imidazol-1-yl)-3-((2R,3S)-3-hydroxypiperidin-2-yl)propan-2-one,
14) 1-(5-chloro-4-methyl-1H-benzo[d]imidazol-1-yl)-3-((2R,3S)-3-hydroxypiperidin-2-yl)propan-2-one,
15) 1-(5-bromo-4-methyl-1H-benzo[d]imidazol-1-yl)-3-((2R,3S)-3-hydroxypiperidin-2-yl)propan-2-one,
16) 1-(4,5-dimethyl-1H-benzo[d]imidazol-1-yl)-3-((2R,3S)-3-hydroxypiperidin-2-yl)propan-2-one,
17) 1-(5-fluoro-4-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-3-((2R,3S)-3-hydroxypiperidin-2-yl)propan-2-one,
18) 1-(5-bromo-4-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-3-((2R,3S)-3-hydroxypiperidin-2-yl)propan-2-one,
19) 1-(4-bromo-5-methyl-1H-benzo[d]imidazol-1-yl)-3-((2R,3S)-3-hydroxypiperidin-2-yl)propan-2-one,
20) 1-(5-bromo-4-fluoro-1H-benzo[d]imidazol-1-yl)-3-((2R,3S)-3-hydroxypiperidin-2-yl)propan-2-one,
21) 1-(4-chloro-5-fluoro-1H-benzo[d]imidazol-1-yl)-3-((2R,3S)-3-hydroxypiperidin-2-yl)propan-2-one,
22) 1-(5-bromo-4-chloro-1H-benzo[d]imidazol-1-yl)-3-((2R,3S)-3-

Assignees

• Dae Woong Pharma

Inventors

• Park Joon Seok
• Yoon Youn Jung
• Cho Min Jae
• Lee Ho Bin
• Yoo Ja Kyung
• Bong Yong Lee

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P19/04

  for non-specific disorders of the connective tissue · CPC title

• C07D235/04 Primary

  Benzimidazoles; Hydrogenated benzimidazoles · CPC title