3H-imidazo [4, 5-C] pyridine-6-carboxamides as anti-inflammatory agents
This invention relates to compounds of formula I their use as inhibitors of the microsomal prostaglandin E 2 synthase-1 (mPGES-1), pharmaceutical compositions containing them, and their use as medicaments for the treatment and/or prevention of inflammatory diseases and associated conditions. A, M, W, R 1 , R 2 , R 6 , R 7 , R 8 have meanings given in the description.
1. A compound of formula I
in which
R 1 and R 2 independently represent halo;
W represents —C(O)—, or —C(O)O—, which groups are bound to the nitrogen of the —NH— moiety via the carbon atom;
M represents
—C 1-6 alkyl, or —C 3-7 cycloalkyl, both of which groups are optionally substituted by one or more groups selected from —F, —OH, —CN, —NH 2 , —NH(C 1-2 alkyl), —N(C 1-2 alkyl) 2 , —OC 1-3 alkyl, —C 1-5 alkyl, or —C 3-4 cycloalkyl, in which latter three groups the alkyl or cycloalkyl groups are optionally substituted by one or more fluorine atoms;
or
oxetanyl-, tetrahydrofuranyl-, tetrahydropyranyl-, azetidinyl-, pyrrolidinyl-, or piperidinyl-, all of which groups are optionally substituted by one or more substituents selected from fluoro, —CN, or —C 1-3 alkyl, which latter alkyl group is optionally substituted by one or more fluorine atoms;
or
phenyl-, pyridyl-, thienyl-, pyrrolyl-, pyrazolyl-, imidazolyl-, thiazolyl-, oxazolyl-, or isoxazolyl-, all of which groups are optionally substituted by one or more substituents selected from halo, —CN or —C 1-3 alkyl, which latter alkyl group is optionally further substituted by one or more fluorine atoms;
R 8 represents —H, halogen, or —C 1-3 alkyl, which latter alkyl group is optionally substituted by one or more fluorine atoms;
R 6 represents —H, —C 1-5 alkyl, or —C 3-5 cycloalkyl-C 0-2 alkyl, in which latter two groups the alkyl or cycloalkyl fragments are optionally substituted by one or more fluorine atoms;
R 7 represents halo, C 1-5 alkyl-O—, C 3-7 cycloalkyl-C 0-2 alkyl-O—, or 4-7-membered heterocycloalkyl-C 0-2 alkyl-O—, in which latter three groups the alkyl, cycloalkyl or heterocycloalkyl fragments are optionally substituted by one or more substituents selected from —F and —OC 1-3 alkyl which latter alkyl group is optionally further substituted by one or more fluorine atoms;
represents C 1-8 alkyl-, phenyl-, indanyl-, naphthyl-, 1,2,3,4-tetrahydronaphthyl-, pyridyl-, thienyl-, benzothienyl-, pyrrolyl-, indolyl-, pyrazolyl-, indazolyl-, thiazolyl-, benzothiazolyl-, oxazolyl-, benzooxazolyl-, isoxazolyl-, benzisoxazolyl-, phenyl-C 1-3 alkyl-, thienyl-C 1-3 alkyl-, pyridyl-C 1-3 alkyl-, C 3-7 cycloalkyl-C 0-3 alkyl-, oxetanyl-C 0-3 alkyl-, tetrahydrofuranyl-C 0-3 alkyl, or tetrahydropyranyl-C 0-3 alkyl, in which groups the alkyl-, cycloalkyl- and heterocycloalkyl fragments are optionally substituted by one or more substituents selected from R 9a and the aryl and heteroaryl fragments are optionally substituted by one or more substituents selected from R 9b ;
each R 9a independently represents —F, —Cl, or —C 1-3 alkyl which is optionally substituted by one or more substituents selected from —F, or —OC 1-3 alkyl;
each R 9b represents independently -halo, —CN; or —C 1-3 alkyl which is optionally substituted by one or more fluorine atoms;
or a salt thereof.
2. A compound according to claim 1 , wherein
R 8 represents —H or fluoro;
or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 , wherein
R 6 represents —H, —CH 3 , or cyclopropyl;
or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 1 , wherein
R 1 and R 2 independently represent chloro, or fluoro;
or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 1 , wherein
R 7 represents fluoro, —OCHF 2 , —OCF 3 , —OCH 2 CH 2 F, —OCH 2 CHF 2 , —OCH 2 CF 3 , —O-tetrahydrofuran-3-yl, or —O—CH 2 -cyclopropyl;
or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 1 , wherein
A represents C 1-4 alkyl-, C 3-7 cycloalkyl-C 0-2 alkyl-, tetrahydrofuranyl-methyl-, phenyl-C 1-2 alkyl-, pyridyl-methyl-, phenyl-, indanyl-, pyridyl-, thienyl-, thiazolyl-, or benzothiazolyl-, in which groups the alkyl-, cycloalkyl- and heterocycloalkyl-fragments are optionally substituted by one or more substituents selected from —F, —CH 3 , —CH 2 F, —CHF 2 , or —CF 3 , and the aryl and heteroaryl fragments are optionally substituted by —F, —Cl, —Br, —CN, —CH 3 , —CH 2 F, —CHF 2 , or —CF 3 ;
or a pharmaceutically acceptable salt thereof.
7. A compound according to claim 1 , wherein
M represents
—C 1-4 alkyl, or —C 3-5 cycloalkyl, both of which groups are optionally substituted by one or more groups selected from —F, —OH, —CN, —NH 2 , —OCH 3 , —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , or cyclopropyl;
or
oxetanyl-, tetrahydrofuranyl-, azetidinyl- or pyrrolidinyl-, all of which groups are optionally substituted by one or more substituents selected from —F, —CH 3 , —CH 2 F, —CHF 2 , or —CF 3 ;
or
phenyl-, indanyl-, thienyl-, pyrrolyl-, pyrazolyl-, thiazolyl-, or isoxazolyl-, all of which groups are optionally substituted by one or more substituents selected from —F, —CH 3 , —CH 2 F, —CHF 2 , or —CF 3 ;
or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 1 , which is a compound of formula Ia
in which
M represents
methyl, ethyl, propyl, i-propyl, n-butyl, s-butyl, t-butyl, cyclopropyl, —CH 2 -cyclopropyl, cyclobutyl, or cyclopentyl, all of which groups are optionally substituted by one or more groups selected from —F, —OH, —CN, —NH 2 , —OCH 3 , —CH 3 , or —CF 3 ;
or is selected from the following groups
which latter nine groups are optionally substituted by one or more substituents selected from —F, —CH 3 , or —CF 3 ;
or is selected from the following groups
which latter eleven groups are optionally substituted by one or more substituents selected from —F, —Cl, —CH 3 , or —CF 3 ;
and
A, R 1 , R 2 , R 6 , R 7 have the same meaning as defined in claim 1 ;
or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 8 , wherein
A represents methyl, ethyl, propyl, i-propyl, n-butyl, s-butyl, or t-butyl, which latter seven groups are optionally substituted by one or more fluorine atoms,
or cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, which latter four groups are optionally substituted by one or more substituents selected from —F, —CH 3 , —CHF 2 , or —CF 3 ;
or is selected from the following groups:
which latter seven groups are optionally substituted by one or more substituents selected from —F, —CH 3 , —CHF 2 , or —CF 3 ;
or is selected from the following groups:
in which latter eleven groups the aryl and heteroaryl fragments are optionally substituted by one or more substituents selected from —F, —Cl, —Br, —CN, —CH 3 , or —CF 3 ;
or a pharmaceutically acceptable salt thereof.
10. A compound according to claim 1 , which is a compound of formula Ia or Ib
in which
R 1 and R 2 independently represent -chloro or fluoro;
R 6 represents —H, —CH 3 , or cyclopropyl;
R 7 represents fluoro, —OCHF 2 , —OCF 3 , —OCH 2 CH 2 F, —OCH 2 CHF 2 , —OCH 2 CF 3 , tetrahydrofuran-3-yl-O—, or —O—CH 2 -cyclopropyl;
A represents methyl, ethyl, propyl, i-propyl, n-butyl, s-butyl, or t-butyl, which latter seven groups are optionally substituted by one or more fluorine atoms,
or cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, which latter four groups are optionally substituted by one or more substituents selected from —F, —CH 3 , —CHF 2 , or —CF 3 ;
or is selected from the following groups:
which latter seven groups are optionally substituted by one or more substituents selected from —F, —CH 3 , —CHF 2 , or —CF 3 ;
or is selected from the following groups:
in which latter eleven groups the aryl and heteroaryl fragments are optionally substituted by one or more substituents selected from —F, —Cl, —Br, —CN, —CH 3 , or —CF 3 ;
M represents
methyl, ethyl, propyl, i-propyl, n-butyl, s-butyl, t-butyl, cyclopropyl, —CH 2 -cyclopropyl, cyclobutyl, or cyclopentyl, all of which groups are optionally substituted by one or more groups selected from —F, —OH, —CN, —NH 2 , —OCH 3 , —CH 3 , or —CF 3 ;
or is selected from the following groups
which latter nine groups are optionally substituted by one or more substituents selected from —F, —CH 3 , or —CF 3 ;
or is selected from the following groups
which latter eleven groups are optionally substituted by one or more substituents selected from —F, —Cl, —CH 3 , or —CF 3 ;
or a salt thereof.
11. A compound according to claim 1 selected from the compounds in the following table, or the pharmaceutically acceptable salts thereof:
Structure
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and
182
.
12. A pharmaceutical composition comprising at least one compound according to claim 1 , or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
13. Compound 1 according to claim 11 :
or a pharmaceutically acceptable salt thereof.
14. Compound 3 according to claim 11 :
or a pharmaceutically acceptable salt thereof.
15. Compound 5 according to claim 11 :
or a pharmaceutically acceptable salt thereof.
16. Compound 6 according to claim 11 :
or a pharmaceutically acceptable salt thereof.
17. Compound 7 according to claim 11 :
or a pharmaceutically acceptable salt thereof.
18. Compound 29 according to claim 11 :
or a pharmaceutically acceptable salt thereof.
19. Compound 33 according to claim 11 :
or a pharmaceutically acceptable salt thereof.
20. Compound 39 according to claim 11 :
or a pharmaceutically acceptable salt thereof.
21. Compound 40 according to claim 11 :
or a pharmaceutically acceptable salt thereof.
22. Compound 45 according to claim 11 :
or a pharmaceutically acceptable salt thereof.
23. Compound 58 according to claim 11 :
or a pharmaceutically acceptable salt thereof.
24. Compound 66 according to claim 11 :
or a pharmaceutically acceptable salt thereof.
25. Compound 67 according to claim 11 :
or a pharmaceutically acceptable salt thereof.
26. Compound 73 according to claim 11 :
or a pharmaceutically acceptable salt thereof.
27. Compound 75 according to claim 11 :
or a pharmaceutically acceptable salt thereof.