Imidazo-pyridine derivatives as activin-like receptor kinase (ALK4 or ALK5) inhibitors
Compounds of formula (I): in free or salt or solvate form, where X, R 1 , R 2 , R 3 and R 4 have the meanings as indicated in the specification, are useful for treating diseases mediated by the ALK-5 and/or ALK-4 receptor. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.
1. A compound of Formula I,
or hydrates or pharmaceutically acceptable salts thereof, wherein
X is CR x or N;
R 1 is NR 7 R 8 ;
R 2 is selected from aryl, heterocyclyl, C 1 -C 7 alkyl, C 3 -C 10 -cycloalkyl, C 5 -C 10 cycloalkenyl, C(O)NR 5 R 6 , halo, C 1 -C 7 alkoxy, alkylthio, hydroxyl, C 1 -C 7 alkylcarbonyl, carboxy, carbonyl, cyano and sulfonamide, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted by one or more substituents selected from halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy;
R 3 is selected from H, halo, NR 19 R 20 and OR 21 ;
R 4 is hydrogen;
R x is selected from H, OH and C 1 -C 3 alkoxy;
R 5 , R 6 and R 7 are each independently selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl and C 1 -C 3 alkyl-C 3 -C 8 cycloalkyl;
R 8 is selected from C 3 -C 10 cycloalkyl and a 5- or 6-membered heterocyclic group, each optionally substituted by one or more groups selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OH and C 1 -C 6 alkyl substituted by OH or NH 2 ; and
R 19 , R 20 and R 21 are each independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl; or R 19 and R 20 , together with the nitrogen atom to which they are attached form a 4-, 5- or 6-membered N-containing heterocyclic group.
2. A compound according to claim 1 , wherein R 2 is selected from C(O)NR 5 R 6 , C 1 -C 6 alkoxy, C 5 -C 6 cycloalkenyl, halogen, 5- or 6-membered heteroaryl and aryl, wherein the cycloalkenyl, heteroaryl and aryl groups are optionally substituted by one or more groups independently selected from halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy.
3. A compound according to claim 2 , wherein R 2 is 5- or 6-membered heteroaryl or aryl, each optionally substituted by one or more groups independently selected from halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy.
4. A compound according to any preceding claim, wherein R 3 is H.
5. A pharmaceutical composition including a compound according to claim 1 and one or more pharmaceutically acceptable excipients, diluents or carriers.
6. The compound of claim 1 , which compound is selected from compounds of Formula Ia:
wherein
R 1
R 2
7. A pharmaceutical composition including a compound according to claim 6 and one or more pharmaceutically acceptable excipients.