Compounds

Patent metadata

Field	Value
Publication number	US-9409870-B2
Application number	US-201514953183-A
Country	US
Kind code	B2
Filing date	Nov 27, 2015
Priority date	Dec 15, 2014
Publication date	Aug 9, 2016
Grant date	Aug 9, 2016

Abstract

Compounds of formula (I) described herein are imidazolone derivatives having human neutrophil elastase (HNE) inhibitory properties and are useful for the treatment of diseases and conditions in which HNE is implicated.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein
A is —CH or —N—;
B is —CH or —N—;
D is —CH or —N—;
X is —CH or —N—;
R 3 is —CF 3 , CHF 2 , or halogen;
W is a 5 or 6-membered heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of —CN, —NO 2 , —O(C 1 -C 6 )alkyl, —(C 1 -C 3 )alkyl-O—(C 1 -C 6 )alkyl, —(C 1 -C 3 )alkylamino, —(C 3 -C 8 )cycloalkyl, —OH, (C 1 -C 3 )alkyl, halo, —CF 3 , and —SO 2 (C 1 -C 4 )alkyl;
R 1 is H, —C(O)R 4 , —(CH 2 ) t —(CHR 6 ) n —R 4 , —(CH 2 ) t —(CHR 6 ) n S(O 2 )—NR 4 R 5 , —S(O 2 )—R 4 , —(CH 2 ) t -CHR 6 ) n —C(O)—NR 4 R 5 , or —(CH 2 ) t —(CHR 6 ) n —C(O)O—R 4 ,
R 4 is H or is selected from the group consisting of —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkyl-NR 7 R 8 , —(C 2 -C 6 )alkyl-N + R 7 R 8 R 9 , —(C 2 -C 6 )alkyl-O—(C 1 -C 4 )alkyl, —(C 2 -C 6 )alkyl-S(O 2 )(C 1 -C 4 )alkyl, —(CH 2 ) t -aryl, —(CH 2 ) t —(C 3 -C 8 )cycloalkyl, —(CH 2 ) t —(C 3 -C 8 )heterocycloalkyl, and —(CH 2 ) t -heteroaryl, optionally substituted with one or more substituents selected from the group consisting of —CN, —NO 2 , —O(C 1 -C 6 )alkyl, —(C 1 -C 3 )alkyl-O—(C 1 -C 6 )alkyl, —(C 1 -C 3 )alkylamino, —(C 3 -C 8 )cycloalkyl, —OH, (C 1 -C 3 )alkyl, halo, —CF 3 , and —SO 2 (C 1 -C 4 )alkyl;
n is 0 or an integer of 1, 2 or 3;
t is 0 or an integer of 1, 2 or 3;
R 5 is H or —(C 1 -C 6 )alkyl;
R 6 is H, —(C 1 -C 6 )alkyl, —CF 3 , or —CHF 2 ;
R 7 is H or —(C 1 -C 6 )alkyl;
R 8 is H or —(C 1 -C 6 )alkyl;
R 9 is H or —(C 1 -C 6 )alkyl;
or, alternatively, R 4 and R 5 , together with the nitrogen atom to which they are linked, form a (C 3 -C 8 )heterocycloalkyl or heteroaryl ring system, optionally substituted with one or more substituents selected from the group consisting of —CN, —NO 2 , —O(C 1 -C 6 )alkyl, —(C 1 -C 3 )alkyl-O—(C 1 -C 6 )alkyl, —(C 1 -C 3 )alkylamino, —(C 3 -C 8 )cycloalkyl, —OH, (C 1 -C 3 )alkyl, halo, —CF 3 , and —SO 2 (C 1 -C 4 )alkyl, wherein said (C 3 -C 8 )heterocycloalkyl or heteroaryl ring system contains a maximum of three hetero-atoms or hetero-groups selected from the group consisting of —N, —NH, —O, —S—, and —SO 2 ; and
R 2 is H, —SMe, —S(O)R 7 , —S(O 2 )R 7 , or halogen,
or a pharmaceutically acceptable salt thereof.

2. The compound or pharmaceutically acceptable salt according to claim 1 , wherein A, B, D and X are —CH.

3. The compound or pharmaceutically acceptable salt according claim 1 , wherein W is apyrazolyl, imidazolyl, or tiazolyl ring.

4. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is —CF 3 .

5. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 2 is H, halogen, or —S(O 2 )R 7 wherein R 7 is —(C 1 -C 6 )alkyl.

6. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 1 is —(CH 2 ) t —(CHR 6 ) n —C(O)—NR 4 R 5 wherein R 4 is H or —(C 1 -C 6 )alkyl, optionally substituted with one or more groups selected from the group consisting of —O(C 1 -C 6 )alkyl, —(C 1 -C 3 )alkylamino, —SO 2 (C 1 -C 4 )alkyl, and —OH or R 4 is —(CH 2 (C 3 -C 8 )cycloalkyl, —(CH 2 ) t —(C 3 -C 8 )heterocycloalkyl, —(C 2 -C 6 )alkyl-NR 7 R 8 , —(CH 2 ) t -aryl, —(CH 2 ) t -heteroaryl, and —(C 2 -C 6 )alkyl-N + R 7 R 8 R 9 , optionally substituted with one or more of —(C 1 -C 6 )alkyl or —SO 2 (C 1 -C 4 )alkyl; R 5 is H or —(C 1 -C 6 )alkyl; or alternatively R 4 and R 5 , together with the nitrogen atom to which they are linked, form a (C 3 -C 8 )heteocycloalkyl or heteroaryl ring system, optionally substituted with one or more substituents selected from the group consisting of —OH and (C 1 -C 3 )alkyl, wherein said (C 3 -C 8 )heteocycloalkyl or heteroaryl ring system contains a maximum of three hetero-atoms or hetero-groups selected from the group consisting of —N, —NH, —O, —S—, and —SO 2 ; R 6 is H, —(C 1 -C 6 )alkyl, —CF 3 or —CHF 2 ; R 7 is H or —(C 1 -C 6 )alkyl; R 8 is H or —(C 1 -C 6 )alkyl; t is 0 or an integer of 1, 2 or 3; and n is 0 or an integer selected from 1, 2 or 3.

7. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 1 is —(CH 2 ) t —(CHR 6 ) n —C(O)O—R 4 , R 4 is H or —(C 1 -C 6 )alkyl, optionally substituted with one or more substituents selected from the group consisting of —CN, —NO 2 , —O(C 1 -C 6 )alkyl, —OH, (C 1 -C 3 )alkyl, halo, and —CF 3 ; R 6 is H, —(C 1 -C 6 )alkyl, —CF 3 or —CHF 2 ; t is 0 or an integer selected from 1, 2 or 3; and n is 0 or an integer selected from 1, 2 or 3.

8. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 1 is —(CH 2 ) t —(CHR 6 ) n S(O 2 )—NR 4 R 5 wherein R 4 is H, —(C 1 -C 6 )alkyl, or —(C 3 -C 8 )cycloalkyl; R 5 is H or —(C 1 -C 6 )alkyl; t is 0 or an integer selected from 1, 2 or 3; and n is 0 or an integer selected from 1, 2 or 3.

9. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 1 is —S(O 2 )—R 4 , R 4 is H or —(CH 2 ) t —(C 3 -C 8 )cycloalkyl, or —(C 1 -C 6 )alkyl; and t is 0 or an integer selected from 1, 2 or 3.

10. The compound or pharmaceutically acceptable salt according to claim 1 , which is a compound selected from the group consisting of
4-(5-{5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile;
4-(5-{5-methyl-3-[3-(methylsulfonyl)propyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile;
4-(5-{3,5-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile;
ethyl-5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazole-1-carboxylate;
4-(5-{3-acetyl-5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile;
5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N-ethyl-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazole-1-carboxamide;
5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N-(2-hydroxyethyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazole-1-carboxamide;
5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N-(3-hydroxypropyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazole-1-carboxamide;
5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N-[3-(dimethylamino)propyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazole-1-carboxamide;
4-(5{-3-butanoyl-5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile;
5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N-(2-methoxyethyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazole-1-carboxamide;
5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N-[2-(dimethylamino)ethyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazole-1-carboxamide;
5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-N-[2-(methyl sulfonyl)ethyl]-2-oxo-3-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazole-1-carboxamide;
5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2-oxo-N-(tetrahydrofuran-3-yl)-3-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazole-1-carboxamide;
5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2-oxo-N-[(3S)-tetrahydrfuran-3-yl]-3-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazole-1-carboxamide;
5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2-oxo-N-[(3R)-tetrahydrofuran-3yl]-3-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazole-1-carboxamide;
5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-2-oxo-3-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazole-1-carboxamide;
methyl-5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-met

Assignees

• Chiesi Farm Spa

Inventors

• Armani Elisabetta
• Capaldi Carmelida
• Sutton Jonathan Mark
• Heald Robert Andrew

Classifications

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• A61P11/06

  Antiasthmatics · CPC title

• A61P11/08

  Bronchodilators · CPC title

• A61P11/02

  Nasal agents, e.g. decongestants · CPC title