2-arylbenzimidazoles as Ppargc1a activators for treating neurodegenerative diseases
A genus of compounds encompassed by formula (III) and their use is disclosed: The compounds activate Ppargc1a and, as a consequence, are useful for treating a variety of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal degeneration, dementia with Lewy bodies, motor neuron diseases, and a demyelinating disease.
1. A compound of formula (I):
wherein:
W 2 is C—R 2 ;
W 3 is N or C—R 3 ;
W 4 is N or C—R 4 ;
W 5 is N or C—R 5 ;
W 6 is CH;
W 7 is N or C—R 7 ;
W 8 is C—R 8 ;
wherein:
R 1 is —CH 2 OC(═O)R 30 ;
wherein:
R 30 is chosen from
(a) (C 1 -C 6 )alkyl,
(b) phenyl substituted with (Ci-C4)alkylamino,
(c) the descarboxy residue of a natural amino acid,
(d) (Ci-C3)hydrocarbyl substituted with carboxyl,
(e) (Ci-C5)oxaalkyl, and
(f) pyridyl;
R 2 , R 3 , R 4 and R 5 are chosen independently from hydrogen, halogen, and perfluoro(C 1 -C 4 )alkyl;
R 10 is hydrogen;
R 7 is H or (C3-C4)alkyl; R 9 is hydrogen; and
R 8 is chosen from (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, and NH 2 .
2. A compound according to claim 1 wherein from one to four of W 2 , W 3 , W 4 and W 5 are C—F.
3. A compound according to claim 1 wherein one of W 3 or W 4 is N and the other, along with W 2 and W 5 , is C—H.
4. A compound according to claim 1 wherein R 8 is t-butyl.
5. A compound of formula (II):
wherein
Ar is
W 1 is N—R 1 ;
W 2 is N or C—R 2 ;
W 3 is N or C—R 3 ;
W 4 is N or C—R 4 ;
W 5 is N or C—R 5 ;
W 9 is C;
wherein:
R 1 is chosen from H, —CH2OC(═O)R 30 , —CH2OP(═O)OR 40 OR 41 , —C(═O)OR 42 , and —C(═O)R 43 ;
wherein:
R 30 is chosen from (C 1 -C 10 )hydrocarbyl, (C 1 -C 10 )hydrocarbyl substituted with amino, (C 1 -C 10 )hydrocarbyl substituted with (C 1 -C 4 )alkoxycarbonyl, (C 1 -C 10 )hydrocarbyl substituted with carboxyl, carboxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxycarbonylamino, methylthio, heterocyclyl, (C 1 -C 10 )oxaalkyl, CHR 44 NHR 45 , and guanidino;
wherein:
R 44 is chosen from any naturally occurring amino acid sidechain; and
R 45 is chosen from H, methyl, and (C 1 -C 4 )alkoxycarbonyl; and
R 40 and R 41 are chosen independently from hydrogen and (C 1 -C 6 )hydrocarbyl;
R 42 is (C 1 -C 5 )alkyl; and
R 43 is (C 1 -C 3 )alkyl; and
R 2 , R 3 , R 4 and R 5 are chosen independently from hydrogen, deuterium, halogen, perfluoro(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, perfluoro(C 1 -C 4 )alkoxy, (C 1 -C 4 )acyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, hydroxy, carboxy, (C 1 -C 4 )alkoxycarbonylamino [—HNC(═O)O-alkyl], carboxamido [—C(═O)NH2], (C 1 -C 4 )alkylaminocarbonyl [—C(═O)NH-alkyl], cyano, acetoxy, nitro, amino, (C 1 -C 4 )alkylamino, di(C 1 -C 4 )alkylamino, mercapto, (C 1 -C 4 )alkylthio, aminosulfonyl, (C 1 -C 4 )alkylsulfonyl, and (C 1 -C 4 )acylamino;
with the provision that Ar includes
only when:
R 1 is not H.
6. A compound according to claim 5 wherein:
W 2 and W 5 are C—R 2 and C—R 5 , respectively; and
R 2 , R 3 , R 4 , and R 5 are independently selected from H, deuterium, halo, (C 1 -C 3 )alkoxy, perfluoro(C 1 -C 3 )alkoxy, nitrile, amino, hydroxyl, aminocarbonyl, (C 1 -C 3 )alkyl, and perfluoro(C 1 -C 3 )alkyl.
7. A compound according to claim 5 wherein:
R 2 , R 3 , R 4 , and R 5 are independently selected from H, halo, and perfluoro(C 1 -C 3 )alkyl.
8. A compound according to claim 5 wherein:
W 1 is N—H;
W 2 and W 5 are independently chosen from C—H, C—F, C-D, C—CF 3 , C—CH 3 , C—Cl, C—Br, C—OH, C—OCH 3 , C—NH 2 , C—CF 2 H, C—OCF 3 , C—OCF 2 H, C—CD 3 , and C—CONH 2 ;
W 3 is chosen from N, C—H, C—NH 2 , C—F, C—CF 3 , C-D, C—OCH 3 , C—CN, C—OH, C—Cl, C—CH 3 , C—CF 2 H, C—OCF 3 , C—OCF 2 H, C—CD 3 , and C—Br; and
W 4 is chosen from N, C—H, C—NH 2 , C—F, C—CF 3 , C-D, C—OCH 3 , C—CN, C—OH, C—Cl, C—CH 3 , C—CF 2 H, C—OCF 3 , C—OCF 2 H, C—CD 3 , and C—Br.
9. A compound according to claim 8 wherein:
W 2 and W 5 are independently chosen from C—H, C—F, C-D, C—CF 2 H, C—CD 3 , and C—CF 3 ;
W 3 is chosen from N, C—H, C—NH 2 , C—F, C—CF 3 , C—CF 2 H, C—CD 3 , and C-D;
W 4 is chosen from N, C—H, C—NH 2 , C—F, C—CF 3 , C—CF 2 H, C—CD 3 , and C-D.
10. A compound according to claim 5 wherein W 2 , W 3 , W 4 , and W 5 are C—H.
11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 5 .
12. The compound of formula: