Oxadiazolyl dihydropyrano[2,3-b]pyridine inhibitors of HIPK2 for treating kidney fibrosis
Compounds that are selective inhibitors of Smad3 activation are disclosed. The compounds are (3-aryl-1,2,4-oxadiazol-5-yl)-3,4-dihydro-2H-pyrano[2,3-b]pyridines of the following structure: in which Ar is aryl or heteroaryl. The compounds disclosed are useful in treatment of fibrotic disease, particularly renal fibrosis, and similar diseases associated with the dysregulation of the HIPK2/Smad3 signaling pathway.
1 . A compound of formula I
wherein
Ar is
(a) phenyl substituted at the meta and/or para positions with one or more substituents chosen independently from hydrogen, —(C 1 -C 8 )hydrocarbyl, OH, —O(C 1 -C 8 )hydrocarbyl, halogen, nitro, amino, (C 1 -C 3 )alkylamino, (C 1 -C 3 )dialkylamino, (C 1 -C 3 )acylamino, (C 1 -C 3 )alkylsulfonyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, 5- or 6-membered heterocyclyl, and —B(OH) 2 ; or
(b) 5-membered heteroaryl chosen from thiophene, pyrazole oxazole, and thiazole, said thiophene, pyrazole, oxazole, or thiazole substituted with one substituent chosen from hydrogen, —(C 1 -C 3 )alkyl, OH, —O(C 1 -C 3 )alkyl, halogen, amino, (C 1 -C 3 )alkylamino, (C 1 -C 3 )dialkylamino, (C 1 -C 3 )haloalkyl, and (C 1 -C 3 )haloalkoxy;
R 4 is chosen from hydrogen, hydroxy, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, amino, (C 1 -C 3 )alkylamino, and (C 1 -C 3 )dialkylamino;
R 5 is chosen from hydrogen, hydroxy, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, amino, (C 1 -C 3 )alkylamino, and (C 1 -C 3 )dialkylamino;
R 6 is chosen from hydrogen and (C 1 -C 6 )hydrocarbyl; and
R 7 is chosen from hydrogen and (C 1 -C 3 )alkyl;
with the proviso that not all of R 4 , R 5 , R 6 , and R 7 are hydrogen.
2 . A compound according to claim 1 wherein Ar is phenyl.
3 . A compound according to claim 2 wherein phenyl is para-substituted with a substituent chosen from bromo, chloro, fluoro, fluoromethyl, difluoromethyl, trifluoromethyl, and methyl.
4 . A compound according to claim 1 wherein Ar is chosen from thiophene, pyrazole, oxazole, and thiazole.
5 . A compound according to claim 4 wherein Ar is unsubstituted or substituted with a substituent chosen from —(C 1 -C 3 )hydrocarbyl, bromo, chloro, fluoro, fluoromethyl, difluoromethyl, and trifluoromethyl.
6 . A compound according to claim 1 wherein R 4 is chosen from hydrogen, hydroxy and amino.
7 . A compound according to claim 1 wherein R 5 is chosen from hydrogen, hydroxy, methoxy, and amino.
8 . A compound according to claim 1 wherein R 6 and R 7 are independently chosen from hydrogen and methyl.
9 . A compound according to claim 8 wherein R 6 and R 7 are methyl and one of R 4 and R 5 is hydroxyl.
10 . A compound according to claim 1 chosen from:
11 . A compound according to claim 8 wherein Ar is thiazol-2-yl substituted at 3- or 4-with chloro or methyl.
12 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1 .
13 . A method for inhibiting the interaction of homeodomain interacting protein kinase 2 (HIPK2) with Smad3, said method comprising bringing HIPK2 into contact with a compound according to claim 1 .
14 . A method for inhibiting Smad3 activation, said method comprising bringing Smad3 into contact with a compound according to claim 1 .
15 . An in vitro method according to claim 13 .
16 . An in vivo method according to claim 13 .
17 . An in vitro or in vivo method according to claim 14 .
18 . A method for treating a fibrotic disease comprising administering a compound according to claim 1 to a subject suffering from renal fibrosis, cardiac fibrosis, hepatic fibrosis, or pulmonary fibrosis.