Mitochondrial Aldehyde Dehyrogenase-2 Modulators and Methods of Use Thereof

A compound of formula:

• or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
• A is selected from C and S;
• X2 is selected from CR2, N, and NO;
• X3 is selected from CR3, N, and NO;
• X4 is selected from CR4, N, and NO;
• Xd is selected from CRd, N, and NO;
• Ra, Rb, Rc, Rd, and Re are independently selected from hydrogen, halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, NH2, NO2, NHR6, NR6R6, S(O)pR6, C(O)R6, C(O)OR6, CF3, CF2H, CFH2, OCF3, OCF2H, and OCFH2;
• alternatively, Rb and Rc together form a 3-14 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from N, O, and S;
• wherein the heterocycle is optionally substituted with one or more R8;
• Rf, Rg, and Rh are independently selected from hydrogen and C1-C6 alkyl;
• R1, R2, R3, R4, and R5 are independently selected from hydrogen, halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, OR7, NH2, NO2, NHR7, NR7R7, S(O)qR7, C(O)R7, C(O)OR7, CF3, CF2H, CFH2, OCF3, OCF2H, and OCFH2;
• R6 is selected from hydrogen and C1-C6 alkyl;
• R7 is selected from (a) hydrogen, (b) C1-C6 alkyl, (c) C2-C6 alkenyl, (d) C2-C6 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 R8;
• R8 is selected from (a) halogen, (b) OH, (c) NO2, (c) NH2, (d) C(O)OH, (e) NH(C1-C6 alkyl), (f) N(C1-C6 alkyl)2, (g) C(O)O—(C1-C6 alkyl), (h) C1-C6 alkyl, (i) C1-C6 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 R9;
• R9 is selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, C(O)OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NO2, and S(O)q—(C1-C6 alkyl);
• n is 1 or 2;
• p is 1 or 2;
• q is 0, 1, or 2;
• provided that
• is not
• and
• provided that the compound is not selected from:
• or a compound of formula (V):
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
• W is selected from C and S;
• Y2 is selected from CR2y, N, and NO;
• Y3 is selected from CR3y, N, and NO;
• Y4 is selected from CR4yR4y and NR4y;
• Y5 is selected from CR5yR5y and NR5y;
• R1y, R2y, R3y, R4y, and R5y are independently selected from (a) hydrogen, (b) halogen, (c) OH, (d) C1-C6 alkyl, (e) C1-C6 alkoxy, (f) OR9y, (g) NH2, (h) NO2, (i) NHR9y, (j) NR9yR9y, (k) S(O)tR9y, (l) C(O)R9y, (m) C(O)OR9y, (n) CF3, (o) CF2H, (p) CFH2, (q) OCF3, (r) OCF2H, (s) OCFH2, (t) (CH2)u-3-14 membered saturated, partially saturated, or unsaturated carbocycle, and (u) (CH2)v-3-14 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from N, O, and S;
• wherein (t)-(u) optionally is substituted with R10y;
• alternatively, two R4y or two R5y together form a ═O;
• R6y is selected from hydrogen and C1-C6 alkyl;
• R7y and R8y are independently selected from halogen, OH, NO2, NH2, C(O)OH, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C(O)O-(C1-C6 alkyl), C1-C6 alkyl, C1-C6 alkoxy, CF3, CF2H, CFH2, OCF3, OCF2H, and OCFH2;
• R9y is selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, C(O)OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NO2, and S(O)t—(C1-C6 alkyl);
• R10y is selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, C(O)OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NO2, CF3, CF2H, CFH2, OCF3, OCF2H, and OCFH2
• m is 1 or 2;
• t is 0, 1, or 2;
• u is 0, 1, 2, 3, 4, 5, or 6;
• and
• v is 0, 1, 2, 3, 4, 5, or 6;
• or a compound chosen from: