Plasminogen activator inhibitor-1 inhibitors and methods of use thereof

A compound of formula VIII or a salt, ester, or prodrug thereof:

• wherein:
• W is C or N;
• X1, X2, X3, X4, and X5 are independently selected from the group consisting of —H, —OH, —OR, —F, —Cl, —Br, —I, —NO2, —NO, —N(R)2, —N(R)3+, —C(O)R, —C(O)OR, —CHO, —C(O)NH2, —C(O)SR, —CN, —S(O)2R, —SO3R, —SO3H, —SO2N(R)2, —S═O, C1 to C12 alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• R is selected from the group consisting of C1 to C6 alkyl, C3 to C6 cycloalkyl, CH2—C3-C6 cycloalkyl, phenyl, tolyl, and benzyl;
• Ra is selected from the group consisting of C1 to C12 alkyl, C3 to C6 cycloalkyl, (CH2)m—C3-C6 cycloalkyl, C2 to C6 heterocycloalkyl, (CH2)m—C2-C6 heterocycloalkyl, C2 to C6 heterocycloalkyl, (CH2)m—C2-C6 heterocycloalkyl, benzyl, aryl, (CH2)m-aryl, heteroaryl, (CH2)m-heteroaryl, and substituted derivatives thereof;
• and
• m is 1, 2, 3, 4, 5, or 6;
• with the proviso that at most two of X1, X2, X3, X4, and X5 are OH;
• and excluding a compound of formula

A compound of formula X or a salt, ester, or prodrug thereof:

• wherein
• Ra is C1 to C12 alkyl,
• Rb is selected from the group consisting of C1 to C12 alkyl, aryl, heteroaryl, (CH2)m—R, and
• or
• Ra and Rb taken together with the N atom to which they are bonded form an optionally substituted 3-, 4-, 5-, 7-, or 8-membered heterocyclic ring;
• m is 1, 2, 3, 4, 5, or 6;
• n is 0, 1, 2, 3, 4, 5, or 6;
• Y is selected from the group consisting of NH2 and OH;
• and
• R selected from the group consisting of
• substituted phenyl and heteroaryl.

A compound of formula XI or a salt, ester, or prodrug thereof:

• wherein
• Rb is selected from the group consisting of aryl, heteroaryl, (CH2)m—R, and
• m is 1, 2, 3, 4, 5, or 6;
• n is 0, 1, 2, 3, 4, 5, or 6;
• Y is selected from the group consisting of NH2 and OH;
• and
• R selected from the group consisting of
• CO2H, phenyl, substituted phenyl and heteroaryl.

A compound of formula XII or a salt, ester, or prodrug thereof:

• wherein
• Rb is selected from the group consisting of aryl, heteroaryl, (CH2)m—R, and
• m is 1, 2, 3, 4, 5, or 6;
• n is 0, 1, 2, 3, 4, 5, or 6;
• Y is selected from the group consisting of NH2 and OH;
• and
• R selected from the group consisting of
• CO2H, phenyl, substituted phenyl and heteroaryl.

A compound of formula XIII or a salt, ester, or prodrug thereof:

• wherein
• n is 0 or 1;
• Ra and Rb are independently selected from the group consisting of C1 to C12 alkyl, C3 to C6 cycloalkyl, (CH2)m—C3-C6 cycloalkyl, C2 to C6 heterocycloalkyl, (CH2)m—C2-C6 heterocycloalkyl, C2 to C6 heterocycloalkyl, (CH2)m—C2-C6 heterocycloalkyl, benzyl, aryl, (CH2)m-aryl, heteroaryl, (CH2)m-heteroaryl, and substituted derivatives thereof;
• and
• m is 1, 2, 3, 4, 5, or 6.

A compound of formula XV or a salt, ester, or prodrug thereof:

• wherein:
• V is selected from the group consisting of (CH2)n, C3 to C8 cycloalkyl, (CH2)n—C3-C8 cycloalkyl-(CH2)p, aryl, (CH2)n-aryl-(CH2)p, heteroaryl, (CH2)n-heteroaryl-(CH2)p,
• and substituted derivatives thereof;
• n and p are independently 0, 1, 2, 3, 4, 5, or 6;
• X1, X2, X3, X4, X5 and X6 are independently selected from the group consisting of H, —OH, —OR, —F, —Cl, —Br, —I, —NO2, —NO, —N(R)2, —N(R)3+, —C(O)R, —C(O)OR, —CHO, —C(O)NH2, —C(O)SR, —CN, —S(O)2R, —SO3R, —SO3H, —SO2N(R)2, —S═O, C1 to C12 alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• R is selected from the group consisting of C1 to C6 alkyl, C3 to C6 cycloalkyl, CH2—C3-C6 cycloalkyl, phenyl, tolyl, and benzyl;
• Y1 is selected from the group consisting of O, NH, NRa, S, and CH2;
• Y2 is selected from the group consisting of O, NH, NRb, S, and CH2;
• Ra and Rb are independently selected from the group consisting of C1 to C12 alkyl, C3 to C6 cycloalkyl, (CH2)m—C3-C6 cycloalkyl, C2 to C6 heterocycloalkyl, (CH2)m—C2-C6 heterocycloalkyl, benzyl, aryl, (CH2)m-aryl, heteroaryl, (CH2)m-heteroaryl, and substituted derivatives thereof;
• m is 1, 2, 3, 4, 5, or 6;
• and
• Z1, Z2, Z3, and Z4 are independently selected from the group consisting of C, P—OH, S, and S═O.

A compound of formula XVII or a salt, ester, or prodrug thereof:

• wherein:
• X1, X2, X3, X4, X5 and X6 are independently selected from the group consisting of H, —OH, —OR, —F, —Cl, —Br, —I, —NO2, —NO, —N(R)2, —N(R)3+, —C(O)R,—C(O)OR, —CHO, —C(O)NH2, —C(O)SR, —CN, —S(O)2R, —SO3R, —SO3H, —SO2N(R)2, —S═O, C1 to C12 alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• R is selected from the group consisting of C1 to C6 alkyl, C3 to C6 cycloalkyl, CH2—C3-C6 cycloalkyl, phenyl, tolyl, and benzyl;
• Rb is selected from the group consisting of H, C1 to C12 alkyl, C3 to C6 cycloalkyl, (CH2)m—C3-C6 cycloalkyl, C2 to C6 heterocycloalkyl, (CH2)m—C2-C6heterocycloalkyl, benzyl, aryl, (CH2)m-aryl, heteroaryl, (CH2)m-heteroaryl, and substituted derivatives thereof;
• m is 1, 2, 3, 4, 5, or 6;
• and
• Z4 is selected from the group consisting of C, P—OH, S, and S═O.

A compound of formula XIX or a salt, ester, or prodrug thereof:

• wherein:
• X3, X4, and X6 are independently selected from the group consisting of —H, —OH, —OR, —F, —Cl, —Br, —I, —NO2, —NO, —N(R)2, —N(R)3+, —C(O)R, —C(O)OR, —CHO, —C(O)NH2, —C(O)SR, —CN, —S(O)2R, —SO3R, —SO3H, —SO2N(R)2, —S═O, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• R is selected from the group consisting of C1 to C6 alkyl, C3 to C6 cycloalkyl, CH2—C3-C6 cycloalkyl, phenyl, tolyl, and benzyl;
• Y1 is selected from the group consisting of CHRaRb, ORa, NHRa, NRaRb, and SRa;
• Ra and Rb are independently selected from the group consisting of C1 to C12 alkyl, C3 to C6 cycloalkyl, (CH2)m—C3-C6 cycloalkyl, C2 to C6 heterocycloalkyl, (CH2)m—C2-C6 heterocycloalkyl, benzyl, aryl, (CH2)m-aryl, heteroaryl, (CH2)m-heteroaryl, —U, (CH2)m—U, and substituted derivatives thereof, or Ra and Rb taken together with the N atom to which they are bonded form a 3- to 8-membered heterocyclic ring;
• U is selected from the group consisting of —NRcRd, —NRcC(O)Re, —NRcC(O)ORe, —NRcC(O)NRfRe, —NRcC(O)SRe, —NRcP(O)(OH)Re, —NRcP(O)(OH)ORe, —NRcP(O)(OH)NRfRc, —NRcP(O)(OH)SRc, —NRcS(O)Rc, —NRcS(O)ORc, —NRcS(O)NRfRe, —NRcS(O)SRe, —NRcS(O)2Re, —NRcS(O)2ORe, —NRcS(O)2NRfRe, —NRcS(O)2SRe, —ORf, —OC(O)Re, —OC(O)ORe, —OC(O)NRfRe, —OC(O)SRe, —OP(O)(OH)Rc, —OP(O)(OH)ORc, —OP(O)(OH)NRdRc, —OP(O)(OH)SRc, —OS(O)Rc, —OS(O)ORe, —OS(O)NRdRe, —OS(O)SRe, —OS(O)2Re, —OS(O) 2ORe, —OS(O)2NRdRe, —OS(O)2SR, —C(O)ORc, —C(O)NRcRd, —C(O)SRc, and —C(O)Rc;
• Rc and Rd are independently selected from the group consisting of H, C1 to C12 alkyl, C1 to C12 haloalkyl, C3 to C6 cycloalkyl, (CH2)m—C3-C6 cycloalkyl, C2 to C6 heterocycloalkyl, (CH2)m—C2-C6heterocycloalkyl, benzyl, aryl, (CH2)m-aryl, heteroaryl, (CH2)m-heteroaryl, and substituted derivatives thereof, or Rc and Rd taken together with the N atom to which they are bonded form a 3- to 8-membered heterocyclic ring;
• Re, Rf, and Rg are independently selected from the group consisting of H, C1 to C12 alkyl, C1 to C12 haloalkyl, C3 to C6 cycloalkyl, (CH2)m—C3-C6 cycloalkyl, C2 to C6 heterocycloalkyl, (CH2)m—C2-C6heterocycloalkyl, benzyl, aryl, (CH2)m-aryl, heteroaryl, (CH2)m-heteroaryl, and substituted derivatives thereof;
• m is 1, 2, 3, 4, 5, or 6;
• and
• Z1 and Z4 are independently selected from the group consisting of C, P—OH, S, and S═O.