Use of prodrugs of fumarates in treating heart failure diseases

A method of treating heart failure with preserved ejection fraction in a subject having heart failure with preserved ejection fraction, the method comprising administering to the subject a therapeutically effective amount of one or more prodrugs of monomethyl fumarate comprising a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, or co-crystal thereof:

• wherein:
• R1 is unsubstituted C1-C6 alkyl;
• La is substituted or unsubstituted C1-C6 alkyl linker, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S;
• and
• R2 and R3 either:
• (a) are each, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S;
• or
• (b) together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S.

A method of treating heart failure with preserved ejection fraction in a subject having heart failure with preserved ejection fraction, the method comprising administering to the subject a therapeutically effective amount of one or more prodrugs of monomethyl fumarate comprising a compound of Formula (III), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, or co-crystal thereof:

• wherein:
• R1 is unsubstituted C1-C6 alkyl;
• is selected from the group consisting of:
• X is N, O, S, or SO2;
• Z is C or N;
• m is 0, 1, 2, or 3;
• n is 1 or 2;
• w is 0, 1, 2, or 3;
• t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
• R6, R7, R8 and R9 are each, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl or C(O)ORa;
• and
• Ra is H or substituted or unsubstituted C1-C6 alkyl;
• and either:
• (a) each R10 is, independently, H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S;
• or
• (b) two R10 attached to the same carbon atom, together with the carbon atom to which they are attached, form a carbonyl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S;
• or
• (c) two R10 attached to different atoms, together with the atoms to which they are attached, form a substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S.

A method of treating heart failure with preserved ejection fraction in a subject having heart failure with preserved ejection fraction, the method comprising administering to the subject a therapeutically effective amount of one or more prodrugs of monomethyl fumarate comprising a compound of Formula (Ib), or a pharmaceutically acceptable polymorph, hydrate, solvate, or co-crystal thereof:

• A− is a pharmaceutically acceptable anion;
• R1 is unsubstituted C1-C6 alkyl;
• La is substituted or unsubstituted C1-C6 alkyl linker, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S;
• R3′ is substituted or unsubstituted C1-C6 alkyl;
• and either:
• (a) R2 and R3 are each, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S;
• or
• (b) R2 and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S, or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.