Mitochondrial aldehyde dehyrogenase-2 modulators and methods of use thereof
The present disclosure provides compounds of formula (I) that function as modulators of mitochondrial aldehyde dehydrogenase-2 (ALDH2) activity, and methods of preparing these compounds.
1. A compound of formula:
or a pharmaceutically acceptable salt or solvate thereof, wherein
A is C;
X 2 is CR 2 ;
X 3 is CR 3 ;
X 4 is selected from N and NO;
X d is CR d ;
R a , R b , R d , and R e are independently selected from hydrogen, halogen, OH, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;
R c is selected from OH, C 1 -C 6 alkoxy, OCF 3 , OCF 2 H, and OCFH 2 ;
R f , R g , and R h are independently selected from hydrogen and C 1 -C 6 alkyl;
R 1 is halogen;
R 2 and R 3 are independently selected from hydrogen, halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OR 7 , NH 2 , NO 2 , NHR 7 , NR 7 R 7 , S(O) q R 7 , C(O)R 7 , C(O)OR 7 , CF 3 , CF 2 H, CFH 2 , OCF 3 , OCF 2 H, and OCFH 2 ;
R 5 is selected from halo en C 1 -C 6 alkyl, OR 7 , and NHR 7 ;
R 6 is selected from hydrogen and C 1 -C 6 alkyl;
R 7 is selected from (a) hydrogen, (b) C 1 -C 6 alkyl, (c) C 2 -C 6 alkenyl, (d) C 2 -C 6 alkynyl, (e) 3-14 membered saturated, partially saturated, or unsaturated carbocycle, and (f) 3-14 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from N, O, and S;
wherein (b)-(f) optionally is substituted with one or more R 8 ;
R 8 is selected from (a) halogen, (b) OH, (c) NO 2 , (c) NH 2 , (d) C(O)OH, (e) NH(C 1 -C 6 alkyl), (f) N(C 1 -C 6 alkyl) 2 , (g) C(O)O—(C 1 -C 6 alkyl), (h) C 1 -C 6 alkyl, (i) C 1 -C 6 alkoxy, (j) 3-14 membered saturated, partially saturated, or unsaturated carbocycle, (k) 3-14 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from N, O, and S; and (l) ═O
wherein (e)-(k) optionally is substituted with one or more R 9 ;
R 9 is selected from halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C(O)OH, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , NO 2 , and S(O) q —(C 1 -C 6 alkyl);
n is 1;
p is 1 or 2; and
q is 0, 1, or 2.
2. The compound of claim 1 , wherein R b is halogen, OH, or C 1 -C 6 alkoxy.
3. The compound of claim 1 , wherein R b is halogen.
4. The compound of claim 1 , wherein R c is OH, or C 1 -C 6 alkoxy.
5. The compound of claim 1 , wherein R c is C 1 -C 6 alkoxy.
6. The compound of claim 1 , wherein R c is methoxy or ethoxy.
7. The compound of formula (I) according to claim 1 , wherein the compound is formula IIa:
or a pharmaceutically acceptable salt or, solvate thereof.
8. The compound of formula (I) according to claim 1 , wherein the compound is formula IVa:
or a pharmaceutically acceptable salt or solvate thereof.
9. The compound of formula (I) according to claim 1 , wherein the compound is formula IIb:
or a pharmaceutically acceptable salt or solvate thereof.
10. The compound of formula (I) according to claim 1 , wherein the compound is formula IVb:
or a pharmaceutically acceptable salt or solvate thereof.
11. The compound of claim 1 , wherein R 1 is F, Cl, or Br.
12. The compound of claim 1 , wherein R 7 is C 1 -C 6 alkyl or 3-14 membered saturated, partially saturated, or unsaturated carbocycle; wherein the alkyl and carbocycle are optionally substituted with R 8 .
13. The compound of claim 12 , wherein R 7 is C 1 -C 6 alkyl optionally substituted with R 8 .
14. The compound of claim 1 , wherein R 8 is selected from (a) 3-14 membered saturated, partially saturated, or unsaturated carbocycle, and (b) 3-14 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from N, O, and S;
wherein the carbocycle and heterocycle are optionally substituted with R 9 .
15. The compound of claim 14 , wherein R 9 is selected from halogen, OH, and C 1 -C 6 alkoxy.
16. The compound of formula (I) according to claim 1 , wherein the compound is formula IIc:
wherein
R 5 is selected from halogen, C 1 -C 6 alkyl, OR 7 , and NHR 7 ,
R 7 is selected from C 1 -C 6 alkyl optionally substituted with R 8 ,
R 8 is 3-14 membered saturated, partially saturated, or unsaturated carbocycle optionally substituted with R 9 , and
R 9 is C 1 -C 6 alkyl,
or a pharmaceutically acceptable salt or solvate thereof.
17. The compound of formula (I) according to claim 1 , wherein the compound is IVc:
R 5 is selected from halogen, C 1 -C 6 alkyl, OR 7 , and NHR 7 ,
R 7 is selected from C 1 -C 6 alkyl optionally substituted with R 8 ,
R 8 is 3-14 membered saturated, partially saturated, or unsaturated carbocycle optionally substituted with R 9 , and
R 9 is C 1 -C 6 alkyl,
or a pharmaceutically acceptable salt or solvate thereof.
18. A compound or a pharmaceutically acceptable salt or solvate thereof selected from:
Compound no.
Structure
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19. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutical acceptable excipient.