TRIAZOLONE COMPOUNDS AS mPGES-1 INHIBITORS

A compound of formula (II)

• or a pharmaceutically acceptable salt thereof, wherein
• X1, X2, X3 and X4 are each independently selected from CH and N;
• each occurrence of L is independently selected from —CH2NHC(O)— and —CH2NHS(O)2—;
• each occurrence of P is independently selected from —CH2NHC(O)— and —CH2NHS(O)2—;
• each occurrence of Q is independently selected from C1-8alkyl, haloC1-8alkyl, C1-8alkoxyC1-8alkyl, hydroxyC1-8alkyl, carboxylC1-8alkyl, C3-12cycloalkyl, C6-14aryl, 3-15 membered heterocyclyl, and 5-14 membered heteroaryl;
• each occurrence of W is independently selected from C1-8alkyl, haloC1-8alkyl, C1-8alkoxyC1-8alkyl, hydroxyC1-8alkyl, carboxylC1-8alkyl, C3-12cycloalkyl, C6-14aryl, 3-15 membered heterocyclyl, and 5-14 membered heteroaryl;
• each occurrence of R1 is independently selected from halogen, cyano, C1-8alkyl, C1-8alkoxy, haloC1-8alkoxyC1-8alkyl, haloC1-8alkyl, C3-6cycloalkyl, 5 membered heterocyclylC1-8alkyl, 5 membered heteroaryl, 5 membered heteroarylC1-8alkyl, and —C≡CR;
• each occurrence of R2 is independently selected from halogen, cyano, C1-8alkyl, C1-8alkoxy, haloC1-8alkyl, C3-6cycloalkyl, 5 membered heteroaryl, —C(O)NHR, —NHC(O)R, —S(O)2NHR and —C≡CR;
• each occurrence of R is independently selected from C1-8alkyl, C3-12cycloalkyl, and C6-14aryl;
• ‘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.

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.

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,
• X1, X2, X3 and X4 are each independently selected from CH and N;
• each occurrence of L is independently selected from —CH2NHC(O)— and —CH2NHS(O)2—;
• each occurrence of P is independently selected from —CH2NHC(O)— and —CH2NHS(O)2—;
• each occurrence of Q is independently selected from C1-8alkyl, haloC1-8alkyl, C1-8alkoxyC1-8alkyl, hydroxyC1-8alkyl, carboxylC1-8alkyl, C3-12cycloalkyl, C6-14aryl, 3-15 membered heterocyclyl, and 5-14 membered heteroaryl;
• each occurrence of W is independently selected from C1-8alkyl, haloC1-8alkyl, C1-8alkoxyC1-8alkyl, hydroxyC1-8alkyl, carboxylC1-8alkyl, C3-12cycloalkyl, C6-14aryl, 3-15 membered heterocyclyl, and 5-14 membered heteroaryl;
• each occurrence of R1 is independently selected from halogen, cyano, C1-8alkyl, C1-8alkoxy, haloC1-8alkoxyC1-8alkyl, haloC1-8alkyl, C3-6cycloalkyl, 5 membered heterocyclylC1-8alkyl, 5 membered heteroaryl, 5 membered heteroarylC1-8alkyl, and —C≡CR;
• each occurrence of R2 is independently selected from halogen, cyano, C1-8alkyl, C1-8alkoxy, haloC1-8alkyl, C3-6cycloalkyl, 5 membered heteroaryl, —C(O)NHR, —NHC(O)R, —S(O)2NHR and —C≡CR;
• each occurrence of R is independently selected from C1-8alkyl, C3-12cycloalkyl, and C6-14aryl;
• PG1 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.