IP Library Granted Patent US 9,096,545
Granted Patent B2
US 9,096,545 · App. 14/123,409 · Granted Aug 4, 2015

Triazolone compounds as mPGES-1 inhibitors

Inventors: Laxmikant Atmaram Gharat (Thane, IN); Nagarajan Muthukaman (Erode, IN); Neelima Khairatkar-Joshi (Thane, IN); Vidya Ganapati Kattige (Thane, IN)
Assignee: GLENMARK PHARMACEUTICALS S.A.
C07D249/12C07D401/04C07D401/10C07D403/04C07D403/10C07D403/12C07D405/12C07D409/14C07D413/10C07D413/12C07D417/10C07D417/12
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 9,096,545
App. No.
14/123,409
Granted
Aug 4, 2015
Kind
B2
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.

Claims (197)

1. 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.

2. The compound according to claim 1 , wherein X 1 , X 2 , X 3 and X 4 are CH.

3. The compound 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.

4. The compound 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.

5. The compound 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.

6. The compound 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.

7. The compound according to claim 1 of the formula (III)

or a pharmaceutically acceptable salt thereof, wherein

X 1 , X 2 and X 3 are each independently selected from CH and N;

P is selected from —CH 2 NHC(O)— and —CH 2 NHS(O) 2 —;

Q is 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 alkyl and C 3-6 cycloalkyl;

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; and

‘n’ is an integer ranging from 0 to 3, both inclusive; with the proviso that ‘m’ and ‘n’ are not ‘0’ simultaneously.

8. The compound according to claim 7 , wherein X 1 , X 2 , and X 3 are CH.

9. The compound according to claim 7 , wherein each occurrence of R 1 is independently cyano, Cl, F, CHF 2 , CF 3 , OCH 3 , CH 3 or cyclopropyl and ‘n’ is 1 or 2.

10. The compound according to claim 7 , 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.

11. The compound according to claim 7 , wherein P is —CH 2 NHC(O)—.

12. The compound according to claim 7 , 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.

13. The compound according to claim 1 of the formula (IV)

or a pharmaceutically acceptable salt thereof, wherein

L is selected from —CH 2 NHC(O)— and —CH 2 NHS(O) 2 —;

W is 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 and haloC 1-8 alkyl;

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; and

‘n’ is an integer ranging from 0 to 3, both inclusive; with the proviso that ‘m’ and ‘n’ are not ‘0’ simultaneously.

14. The compound according to claim 13 , wherein each occurrence of R 1 is independently cyano, Cl, F, CHF 2 , CF 3 , OCH 3 , CH 3 , (2,2,2-trifluoroethoxy)methyl, (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.

15. The compound according to claim 13 , wherein each occurrence of R 2 is independently cyano, Cl, F, CH 3 , CF 3 or OCH 3 ; and ‘m’ is 1 or 2.

16. The compound according to claim 13 , wherein L is —CH 2 NHC(O)—.

17. The compound according to claim 13 , wherein W is isopropyl, tert-butyl, trifluoromethyl, 1-fluoro-2-methylpropan-2-yl, 1-hydroxy-2-methylpropan-2-yl or cyclopropyl.

18. The compound according to claim 1 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-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2-fluorobenzamide;

N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)isoxazole-5-carboxamide;

N-(3-(1-(4-(Trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)-2,2,2-trifluoroacetamide;

(R)—N-(2,4-Dimethyl-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)tetrahydrofuran-2-carboxamide;

N-(3-(1-(4-(Trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)pivalamide;

(S)—N-(4-Chloro-3-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-tetrahydrofuran-2-carboxamide;

N-(4-Chloro-3-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-1-methyl-1H-imidazole-2-carboxamide;

N-(4-Chloro-2-fluoro-3-(4,5-dihydro-3-(4-(3,3-dimethylbut-1-ynyl)phenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide;

N-(4-Chloro-3-(3-(4-(2-cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)-2-fluorobenzyl)pivalamide;

N-(4-Chloro-2-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide;

N-(4-Chloro-2-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;

N-(4-Chloro-3-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-3-hydroxy-2,2-dimethylpropanamide;

N-(4-Chloro-3-(1-(4-chloro-3-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide;

(R)—N-(4-chloro-2-fluoro-5-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)tetrahydrofuran-2-carboxamide;

N-(4-Chloro-3-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-3-methoxy-2,2-dimethylpropanamide;

N-(4-Chloro-3-(1-(4-chloro-3-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;

N-(4-Chloro-5-(1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide;

N-(4-Chloro-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-methoxybenzyl)pivalamide;

N-(4-Chloro-2-fluoro-5-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;

N-(4-Chloro-2-fluoro-5-(1-(6-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;

N-(2,4-Dichloro-5-(3-(4-(2-cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide;

N-(4-Chloro-5-(1-(3-chloro-4-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide;

N-(4-Chloro-5-(1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)-2-fluorobenzamide;

N-(4-Chloro-2-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)isobutyramide;

N-(4-Chloro-5-(1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)-3-fluoro-2,2-dimethylpropanamide;

N-(4-Chloro-5-(1-(3-chloro-4-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide;

N-(4-Chloro-5-(3-(4-(2-cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)-2-fluorobenzyl)pivalamide;

N-(4-Chloro-2-fluoro-5-(4,5-dihydro-3-(4-(3,3-dimethylbut-1-ynyl)phenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide;

N-(4-Chloro-3-(1-(6-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;

N-(4-Chloro-3-(1-(3-chloro-4-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;

N-(4-Chloro-3-(1-(3-chloro-4-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;

N-(4-Chloro-3-(3-(4-(2-cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide;

N-(4-Chloro-3-(1-(3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;

N-(4-Chloro-3-(4,5-dihydro-3-(4-(3,3-dimethylbut-1-ynyl)phenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide;

N-(4-Chloro-3-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)isobutyramide;

N-(4-Chloro-3-(3-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide;

N-(4-Chloro-3-(3-(3-fluoro-4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide;

N-(4-Chloro-3-(3-(4-chloro-3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide;

N-(4-Chloro-3-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide;

N-(4-Chloro-3-(3-(3-fluoro-4-(3,3-dimethylbut-1-ynyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide;

N-(4-Chloro-3-(3-(4-(2-cyclopropylethynyl)-3-fluorophenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide;

N-(4-Chloro-3-(4,5-dihydro-5-oxo-3-(4-((pyrrolidin-1-yl)methyl)phenyl)-1,2,4-triazol-1-yl)benzyl)pivalamide;

N-(3-(3-(4-((2,2,2-Trifluoroethoxy)methyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)-4-chlorobenzyl)pivalamide;

N-(4-Chloro-3-(4,5-dihydro-3-(4-(5-isopropyl-1,3,4-oxadiazol-2-yl)phenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide;

N-(4-Chloro-3-(1-(4-chloro-3-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;

N-(4-Chloro-3-(1-(4-chloro-3-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)isobutyramide;

N-(4-Chloro-3-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;

N-(4-Chloro-3-(1-(4-chloro-3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;

N-(4-Chloro-3-(1-(3-(trifluoromethyl)-4-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;

N-(4-Chloro-3-(1-(4-(trifluoromethyl)-2-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;

N-(4-Chloro-3-(1-(3-fluoro-4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;

N-(4-Chloro-3-(1-(3-fluoro-4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)isobutyramide;

N-(4-Chloro-3-{5-oxo-1-[4-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}benzyl)propane-2-sulfonamide;

N-(4-Chloro-3-(1-(2-fluoro-4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;

N-(3-(4,5-Dihydro-1-(4-(3,3-dimethylbut-1-ynyl)phenyl)-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)isobutyramide;

N-(3-(1-(4-(2-Cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)pivalamide;

N-(4-Chloro-3-(3-(4-(2-cyclopropylethynyl)-3-fluorophenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide;

N-(4-Chloro-3-(1-(4-(2-cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;

N-(4-Chloro-3-(3-(4-(2-cyclopropylethynyl)-2-fluorophenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide;

N-(3-(1-(4-(2-Cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)-3-fluoro-2,2-dimethylpropanamide;

N-(3-(1-(3-Fluoro-4-(3,3-dimethylbut-1-ynyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)isobutyramide;

N-(4-Chloro-3-(4,5-dihydro-3-(4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)phenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide;

N-(4-Chloro-2-fluoro-3-(1-(3-fluoro-4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;

N-(4-Chloro-3-(1-(4-chloro-3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide;

N-(4-Chloro-3-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-3-fluoro-2,2-dimethylpropanamide;

N-((6-Cyclopropyl-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)pivalamide;

N-(4-Chloro-3-(1-(4-(2-cyclopropylethynyl)-2-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide;

N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2-methylpropane-2-sulfonamide;

N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)cyclobutanecarboxamide;

N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)cyclopentanecarboxamide;

N-((6-(Difluoromethyl)-5-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)pivalamide;

N-((6-(Difluoromethyl)-5-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)isobutyramide;

N-((6-(Difluoromethyl)-5-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)propane-2-sulfonamide;

N-((6-(Difluoromethyl)-5-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclobutanecarboxamide;

N-(4-Chloro-3-(3-(4-(cyclopropylethynyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)-2,2,2-trifluoroacetamide;

N-(4-Chloro-3-(3-(4-(cyclopropylethynyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)-3-hydroxy-2,2-dimethylpropanamide;

3-Fluoro-N-((6-(difluoromethyl)-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)-2,2-dimethylpropanamide;

and pharmaceutically acceptable salts thereof.

19. A compound of the formula

or a pharmaceutically acceptable salt thereof.

20. A compound of the formula

or a pharmaceutically acceptable salt thereof.

21. A compound of the formula

or a pharmaceutically acceptable salt thereof.

22. A compound selected from

3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one;

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-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide;

and pharmaceutically acceptable salts thereof.

23. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable excipient.

24. The pharmaceutical composition according to claim 23 , wherein the pharmaceutically acceptable excipient is a carrier or diluent.

25. A method of relieving a mPGES-1 mediated disease, disorder or syndrome in a subject comprising administering to a subject having said disease, disorder or syndrome an effective amount of a compound according to claim 1 .

26. A pharmaceutical composition comprising a compound according to claim 19 , and one or more pharmaceutically acceptable excipients, carriers, diluents or mixture thereof.

27. A pharmaceutical composition comprising a compound according to claim 20 , and one or more pharmaceutically acceptable excipients, carriers, diluents or mixture thereof.

28. A process for preparing a compound of formula (II)

or a pharmaceutically acceptable salt thereof, which comprises: reacting a compound of formula (Intermediate-IIA*) with a compound of formula (Intermediate-IIB*) to form a compound of formula (Intermediate-IIC*); and converting the compound of formula (Intermediate-IIC*) to a compound of formula (II):

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;

PG 1 represents an amine protecting group;

‘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) that ‘m’ and ‘n’ are not ‘0’ simultaneously.

29. The process according to claim 28 , wherein the isocyanate of formula (Intermediate-IIA*) is obtained from the corresponding acid, amide or acid halide derivative.

30. The process according to claim 28 , wherein a compound of formula (Intermediate-IIA*) is reacted with a compound of formula (Intermediate-IIB*) in DCM, toluene or EDC.

31. The process according to claim 28 , wherein Intermediate-IIC* is not isolated.

32. The process according to claim 28 , wherein Intermediate-IIC* is isolated.

33. The process according to claim 28 , wherein PG 1 is tert-butoxycarbonyl.

34. The process according to claim 28 , wherein a compound of formula (Intermediate-IIC*) is converted to compound of formula (II) using an acid.

35. The process according to claim 34 , wherein the acid is an organic acid.

36. A method of relieving a mPGES-1 mediated disease, disorder or syndrome in a subject comprising administering to a subject having such disease, disorder or syndrome an effective amount of a compound according to claim 19 .

Assignments (2)
CHANGE OF NAME Recorded Mar 26, 2020
From: GLENMARK PHARMACEUTICALS S.A.
To: ICHNOS SCIENCES SA
Reel/Frame 052232/0474 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 29, 2014
From: GHARAT, LAXMIKANT A; MUTHUKAMAN, NAGARAJAN; KHAIRATKAR-JOSHI, NEELIMA; KATTIGE, VIDYA G
To: GLENMARK PHARMACEUTICALS S.A.
Reel/Frame 034593/0108 →
Priority Claims (3)
IN 1733/MUM/2012 · Jun 15, 2012 · national
IN 3319/MUM/2012 · Nov 19, 2012 · national
IN 387/MUM/2013 · Feb 8, 2013 · national
Continuity (4)
Provisional Application 61668146 · Jul 5, 2012
Provisional Application 61735679 · Dec 11, 2012
Provisional Application 61792225 · Mar 15, 2013
Related Publication 20150087646A1 · Mar 26, 2015