Triazolone compounds as mPGES-1 inhibitors

Patent metadata

Field	Value
Publication number	US-9949955-B2
Application number	US-201615228681-A
Country	US
Kind code	B2
Filing date	Aug 4, 2016
Priority date	Jun 15, 2012
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

Abstract

The present disclosure is directed to compounds of formula (I), and pharmaceutically acceptable salts thereof, as mPGES-1 inhibitors. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme and are therefore useful in the treatment of pain and/or inflammation from a variety of diseases or conditions, such as asthma, osteoarthritis, rheumatoid arthritis, acute or chronic pain and neurodegenerative diseases.

First claim

What is claimed is:

1. A method of relieving a mPGES-1 mediated disease, disorder, syndrome or condition in a subject comprising administering an effective amount of a compound of formula (II)

or a pharmaceutically acceptable salt thereof, wherein
X 1 , X 2 , X 3 and X 4 are each independently selected from CH and N;
each occurrence of L is independently selected from —CH 2 NHC(O)— and —CH 2 NHS(O) 2 —;
each occurrence of P is independently selected from —CH 2 NHC(O)— and —CH 2 NHS(O) 2 —;
each occurrence of Q is independently selected from C 1-8 alkyl, haloC 1-8 alkyl, C 1-8 alkoxyC 1-8 alkyl, hydroxyC 1-8 alkyl, carboxylC 1-8 alkyl, C 3-12 cycloalkyl, C 6-14 aryl, 3-15 membered heterocyclyl, and 5-14 membered heteroaryl;
each occurrence of W is independently selected from C 1-8 alkyl, haloC 1-8 alkyl, C 1-8 alkoxyC 1-8 alkyl, hydroxyC 1-8 alkyl, carboxylC 1-8 alkyl, C 3-12 cycloalkyl, C 6-14 aryl, 3-15 membered heterocyclyl, and 5-14 membered heteroaryl;
each occurrence of R 1 is independently selected from halogen, cyano, C 1-8 alkyl, C 1-8 alkoxy, haloC 1-8 alkoxyC 1-8 alkyl, haloC 1-8 alkyl, C 3-6 cycloalkyl, 5 membered heterocyclylC 1-8 alkyl, 5 membered heteroaryl, 5 membered heteroarylC 1-8 alkyl, and —C≡CR;
each occurrence of R 2 is independently selected from halogen, cyano, C 1-8 alkyl, C 1-8 alkoxy, haloC 1-8 alkyl, C 3-6 cycloalkyl, 5 membered heteroaryl, —C(O)NHR, —NHC(O)R, —S(O) 2 NHR and —C≡CR;
each occurrence of R is independently selected from C 1-8 alkyl, C 3-12 cycloalkyl, and C 6-14 aryl;
‘m’ is an integer ranging from 0 to 3, both inclusive;
‘n’ is an integer ranging from 0 to 3, both inclusive;
‘s’ is an integer ranging from 0 to 1, both inclusive; and
‘t’ is an integer ranging from 0 to 1, both inclusive;

with the provisos that (i) ‘s’ and ‘t’ are not ‘0’ simultaneously, and (ii) ‘m’ and ‘n’ are not ‘0’simultaneously; and
wherein the mPGES-1 mediated disease, disorder, syndrome or condition is selected from inflammation, a brain tumor, breast cancer, a gastrointestinal carcinoid tumor, kidney cancer, thyroid cancer, colon cancer, adrenocortical carcinoma, basal cell carcinoma, carcinoma of unknown primary, cardiac (heart) tumors, ductal carcinoma in situ, lobular carcinoma in situ, merkel cell carcinoma, midline tract carcinoma involving NUT gene, squamous cell carcinoma, thymoma and thymic carcinoma, and carcinoma of ureter and renal pelvis.

2. The method according to claim 1 , wherein each occurrence of R 1 is independently cyano, Cl, F, CHF 2 , CF 3 , OCH 3 , CH 3 , (2,2,2-trifluoroethoxy)methyl, cyclopropyl, (pyrrolidin-1-yl)methyl, 4-methylthiophenyl, 5-isopropyl-1,3,4-oxadiazol-2-yl, (3,5-dimethyl -1H-pyrazol-1-yl)methyl, 3,3-dimethylbut-1-ynyl, 2-cyclopropylethynyl, (2,5-dichlorophenyl)ethynyl, (4-chloro-2-fluorophenyl)ethynyl, (3-chloro-2-fluorophenyl)ethynyl, (3-(trifluoromethyl)phenyl)ethynyl or (2-chloro-4-(trifluoromethyl)phenyl)ethynyl; and ‘n’ is 1 or 2.

3. The method according to claim 1 , wherein each occurrence of R 2 is independently cyano, Cl, F, CH 3 , CF 3 , OCH 3 , 3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl, cyclopropanecarboxamido, 3,3-dimethylbut-1-ynyl, 2-cyclopropylethynyl, —CONH-[3 -(trifluoromethyl)phenyl], —CONH-[3-(difluoromethyl)-4-fluorophenyl] or —CONH-[3-(difluoromethyl)phenyl]; and ‘m’ is 1 or 2.

4. The method according to claim 1 , wherein Q is isopropyl, tert-butyl, trifluoromethyl, 1-fluoro-2-methylpropan-2-yl, 1-methoxy-2-methylpropan-2-yl, 1-hydroxy-2-methylpropan-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, 2-fluorophenyl, tetrahydrofuranyl, tetrahydrofuranyl, tetrahydrofuran-2-yl, (S)-tetrahydrofuran-2-yl, (R)-tetrahydrofuran-2-yl, isoxazolyl or 1-methyl-1H-imidazole-2-yl; ‘s’ is 1; and ‘t’ is 0.

5. The method according to claim 1 , wherein W is isopropyl, tert-butyl, trifluoromethyl, 1-fluoro-2-methylpropan-2-yl, 1-hydroxy-2-methylpropan-2-yl or cyclopropyl; ‘t’ is 1; and ‘s’ is 0.

6. The method according to claim 1 , wherein the compound of formula (II) is selected from
4-(3-(2-Chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide;
N-(4-Chloro-3-(1-(4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-3-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)cyclopropanecarboxamide;
4-(3-(2-Chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)-4-fluorophenyl)-2-methoxybenzamide;
N-(4-Chloro-3-(1-(4-(cyclopropanecarboxamido)-3-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)cyclopropanecarboxamide;
4-(3-(2-Chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)phenyl)-2-methoxybenzamide;
4-(3-(2-Chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(trifluoromethyl)phenyl)benzamide;
N-(4-Chloro-3-(3-(4-((2,5-dichlorophenyl)ethynyl)-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide;
N-(4-Chloro-3-(3-(4-((4-chloro-2-fluorophenyl)ethynyl)-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide;
N-(4-Chloro-3-(3-(2-fluoro-4-((3-(trifluoromethyl)phenyl)ethynyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide;
N-(4-Chloro-3-(3-(4-((3-chloro-2-fluorophenyl)ethynyl)-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide;
N-(4-Chloro-3-(3-(4-((2-chloro-4-(trifluoromethyl)phenyl)ethynyl)-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide;
N-(4-Chloro-3-(1-(3,4-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide;
N-(4-Chloro-2-fluoro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro -1H-1,2,4-triazol-3-yl)benzyl)pivalamide;
N-(4-Chloro-3-(1-(2,4-difluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide;
N-(4-Chloro-2-fluoro-3-(1-(4-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;
N-(4-Chloro-2-fluoro-3-(3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)pivalamide;
N-(4-Chloro-3-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorobenzyl)pivalamide;
N-(4-Chloro-3-(1-(4-cyanophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide;
N-(4-Chloro-3-(3-(4-chloro-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorobenzyl)pivalamide;
N-(4-Chloro-3-(3-(4-chloro-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide;
N-(4-Chloro-3-(3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide;
N-(4-Chloro-2-fluoro-3-(5-oxo-3-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)pivalamide;
N-(4-Chloro-2-fluoro-3-(5-oxo-1-(5-(trifluoromethyl)pyridin-2-yl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;
N-(4-Chloro-2-fluoro-3-(5-oxo-1-(6-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;
N-(4-Chloro-3-(1-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide;
N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide;
N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;
(R)-N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)tetrahydrofuran-2-carboxamide;
N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)cyclopropanesulfonamide;
N-(4-Chloro-3-(5-ox

Assignees

• Glenmark Pharmaceuticals Sa

Inventors

• Gharat Laxmikant A
• Muthukaman Nagarajan
• Khairatkar-Joshi Neelima
• Kattige Vidya G

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/02

  Immunomodulators · CPC title