Compounds and methods to treat cardiac failure and other disorders

A method to treat a condition characterized by a proinflammation response which method comprises administering to a subject in need of such treatment a compound of the formula

• 26
• or a pharmaceutically acceptable salt thereof
• wherein Ar1 is indole, benzimidazole, or benzotriazole, optionally substituted with lower alkyl (1-4C), halo, or lower alkoxy (1-4C);
• X1 is CO or an isostere thereof;
• Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
• n is 0 or 1;
• Z is CH or N;
• X2 is CH, CH2 or an isostere thereof;
• and
• Ar2 consists of one or two phenyl moieties directly coupled to X2 and optionally substituted by halo, nitro, alkyl (1-6C), CN or CF3, or by RCO, COOR, CONR2, NR2, OR or SR, wherein R is H or alkyl (1-6C) or by phenyl, itself optionally substituted by the foregoing substituents;
• with the proviso that if Z is N, X1 is CO, and Ar1 is indole, Ar1 must be coupled to X1 through the 2-, 5-, 6- or 7-position.

A method to treat a heart condition associated with cardiac failure which method comprises administering to a subject in need of such treatment a compound of the formula

• 27
• or a pharmaceutically acceptable salt thereof
• wherein Ar1 is indole, benzimidazole, or benzotriazole, optionally substituted with lower alkyl (1-4C), halo, or lower alkoxy (1-4C);
• X1 is CO or an isostere thereof;
• Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
• n is 0 or 1;
• Z is CH or N;
• X2 is CH, CH2 or an isostere thereof;
• and
• Ar2 consists of one or two phenyl moieties directly coupled to X2and optionally substituted by halo, nitro, alkyl (1-6C), CN or CF3, or by RCO, COOR, CONR2, NR2, OR or SR, wherein R is H or alkyl (1-6C) or by phenyl, itself optionally substituted by the foregoing substituents.

A method to prepare a compound of the formula

• 28
• or a pharmaceutically acceptable salt thereof
• wherein Ar1 is indole, benzimidazole, or benzotriazole, optionally substituted with lower alkyl (1-4C), halo, or lower alkoxy (1-4C);
• X1 is CO or an isostere thereof;
• Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
• n is 0 or 1;
• Z is CH or N;
• X2 is CH, CH2 or an isostere thereof;
• and
• Ar2 consists of one or two phenyl moieties directly coupled to X2 and optionally substituted by halo, nitro, alkyl (1-6C), CN or CF3, or by RCO, COOR, CONR2, NR2, OR or SR, wherein R is H or alkyl (1-6C) or by phenyl, itself optionally substituted by the foregoing substituents;
• which method comprises
• (a) reacting a compound of the formula
• Ar1—COOH (2)
• with a compound of the formula
• 29
• under conditions wherein the carboxamide is formed;
• or
• (b) reacting an optionally substituted indole, benzimidazole or benzotriazole with a compound of the formula
• 30
• wherein L is leaving group;
• or
• (c) reacting a compound of the formula
• 31
• with a compound of the formula
• Ar2—X2—M (6)
• wherein M is a halide,
• under conditions of mild base.