Aza-peptide epoxides

A method of alleviation or stabilization of nerve degeneration in a mammal comprising:

• administering to a mammal in need thereof a therapeutically effective amount of a compound of the formula:
• or a pharmaceutically acceptable salt, or prodrug, thereof wherein,
• R1 is selected from the group consisting of M1, M2-AA1, M2-AA2-AA1, and M2-AA3-AA2-AA1;
• M1 is selected from the group consisting of NH2—CO—, NH2—CS—, NH2—SO2—, X—NH—CO—, X2N—CO—, X—NH—CS—, X2N—CS—, X—NH—SO2—, X2N—SO2—, X—CO—, X—CS—, Y—SO2—, Y—O—CO—, Y—O—CS—, phenyl substituted with K, phenyl disubstituted with K, and morpholine-CO—;
• M2 is selected from the group consisting of H, NH2—CO—, NH2—CS—, NH2—SO2—, X—NH—CO—, X2N—CO—, X—NH—CS—, X2N—CS—, X—NH—SO2—, X2N—SO2—, X—CO—, X—CS—, Y—SO2—, Y—O—CO—, Y—O—CS—, phenyl, phenyl substituted with K, phenyl disubstituted with K, and morpholine-CO—;
• X is selected from the group consisting of H, C1-10 alkyl, C3-15 cyclized alkyl, C1-10 fluoroalkyl, C1-10 alkyl substituted with J, C1-10 fluoroalkyl substituted with J, 1-admantyl, 9-fluorenyl, phenyl, phenyl substituted with K, phenyl disubstituted with K, phenyl trisubstituted with K, naphthyl, naphthyl substituted with K, naphthyl disubstituted with K, naphthyl trisubstituted with K, C1-10 fluoroalkyl with an attached phenyl group, C1-10 alkyl with an attached phenyl group, C1-10 alkyl with two attached phenyl groups, C1-10 alkyl with an attached phenyl group substituted with K, C1-10 alkyl with two attached phenyl groups substituted with K, C1-10 alkyl with an attached naphthyl group, C1-10 alkyl with an attached naphthyl group substituted with K, C1-10 alkyl with an attached phenoxy group, biotinyl, and C1-10 alkyl with an attached phenoxy group substituted with K on the phenoxy group;
• Y is selected from the group consisting of C1-10 alkyl, C3-15 cyclized alkyl, C1-10 fluoroalkyl, C1-10 alkyl substituted with J, C1-10 fluoroalkyl substituted with J, 1-admantyl, 9-fluorenyl, phenyl, phenyl substituted with K, phenyl disubstituted with K, phenyl trisubstituted with K, naphthyl, naphthyl substituted with K, naphthyl disubstituted with K, naphthyl trisubstituted with K, C1-10 fluoroalkyl with an attached phenyl group, C1-10 alkyl with an attached phenyl group, C1-10 alkyl with two attached phenyl groups, C1-10 alkyl with an attached phenyl group substituted with K, C1-10 alkyl with two attached phenyl groups substituted with K, C1-10 alkyl with an attached naphthyl group, C1-10 alkyl with an attached naphthyl group substituted with K, C1-10 alkyl with an attached phenoxy group, biotinyl, and C1-10 alkyl with an attached phenoxy group substituted with K on the phenoxy group;
• J is selected from the group consisting of halogen, CO2H, OH, CN, NO2, NH2, C1-10 alkoxy, C1-10 alkylamino, C2-12 dialkylamino, C1-10 alkyl-O—CO—, C1-10 alkyl-O—CO—NH—, and C1-10 alkyl-S—;
• K is selected from the group consisting of halogen, C1-10 alkyl, C1-10 perfluoroalkyl, C1-10 alkoxy, phenoxy, NO2, CN, OH, CO2H, amino, C1-10 alkylamino, C2-12 dialkylamino, C1-10 acyl, and C1-10 alkoxy-CO—, and C1-10 alkyl-S—;
• AA1, AA2, and AA3 are side chain blocked or unblocked amino acids with the L configuration, D configuration, or no chirality at the α-carbon selected from the group consisting of alanine, valine, leucine, isoleucine, proline, methionine, methionine sulfoxide, phenylalanine, tryptophan, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, phenylglycine, beta-alanine, norleucine, norvaline, alpha-aminobutanoic acid, epsilon-aminocaproic acid, citrulline, hydroxyproline, ornithine, homoarginine, sarcosine, indoline 2-carboxylic acid, 2-azetidinecarboxylic acid, pipecolinic acid (2-piperidine carboxylic acid), O-methylserine, O-ethylserine, S-methylcysteine, S-ethylcysteine, S-benzylcysteine, NH2—CH(CH2CHEt2)—CO2H, alpha-aminoheptanoic acid, NH2—CH(CH2-1-naphthyl)-CO2H, NH2—CH(CH2-2-naphthyl)-CO2H, NH2—CH(CH2-cyclohexyl)-CO2H, NH2—CH(CH2-cyclopentyl)-CO2H, NH2—CH(CH2-cyclobutyl)-CO2H, NH2—CH(CH2-cyclopropyl)-CO2H, trifluoroleucine, 4-fluorophenylalanine, lysine substituted on the epsilon nitrogen with a biotinyl group, and hexafluoroleucine;
• R2 is selected from the group consisting of C1-10 alkyl, C1-10 alkyl substituted with Q, C1-10 alkyl substituted with phenyl, C1-10 alkyl with an attached phenyl substituted with K, C1-10 alkyl substituted with naphthyl, C1-10 alkyl with an attached naphthyl substituted with K, phenyl, phenyl substituted with K, naphthyl, naphthyl substituted with K, C1-10 alkyl substituted with CONH2, C1-10 alkyl substituted with CONHR4, C1-10 alkyl substituted with CO2H, C1-10 alkyl substituted with CO2R4, CH2CH2SCH3, CH2-3-indolyl, CH2-2-thienyl, CH2-2-furyl, CH2-3-furyl, CH2-2-imidazyl, C1-10 alkyl substituted with G, C1-10 alkyl with an attached phenyl substituted with G, C1-10 alkyl with an attached naphthyl substituted with G, phenyl substituted with G, and naphthyl substituted with G;
• R4 is selected from the group consisting of C1-10 alkyl and C1-10 alkyl substituted with phenyl;
• Q is selected independently from the group consisting of C1-10 alkoxy, C1-10 alkyl-S—, C1-10 alkoxy substituted with phenyl, and C1-10 alkyl-S— substituted with phenyl;
• G is selected independently from the group consisting of amidino (—C(═NH)NH2), guanidino (—NHC(═NH)NH2), isothiureido (—S—C(═NH)NH2), amino, C1-6 alkylamino, C2-12 dialkylamino, and imidazyl;
• R3 is selected independently from the group consisting of R5, CO2H, CO2R5, CONHR6, CONR6R7, CO-AA4-T,
• R5 is selected independently from the group consisting of C1-10 alkyl, C3-15 cyclized alkyl, C1-10 alkyl with a phenyl group attached to the C1-10 alkyl, C3-15 cyclized alkyl with an attached phenyl group, C1-10 alkyl with an attached phenyl group substituted with K, C1-10 alkyl with an attached phenyl group disubstituted with K, C1-10 alkyl with an attached phenyl group trisubstituted with K, C3-15 cyclized alkyl with an attached phenyl group substituted with K, C1-10 alkyl with a naphthyl group attached to the C1-10 alkyl, C3-15 cyclized alkyl with an attached naphthyl group, C1-10 alkyl with an attached naphthyl group substituted with K, C1-10 alkyl with an attached naphthyl group disubstituted with K, C1-10 alkyl with an attached naphthyl group trisubstituted with K, and C3-15 cyclized alkyl with an attached naphthyl group substituted with K;
• T is selected independently from the group consisting of OH, OR8, NHR9, and NR8R9;
• AA4 is a side chain blocked or unblocked amino acid with the L configuration, D configuration, or no chirality at the α-carbon selected from the group consisting of alanine, valine, leucine, isoleucine, proline, methionine, methionine sulfoxide, phenylalanine, tryptophan, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, phenylglycine, beta-alanine, norleucine, norvaline, alpha-aminobutanoic acid, epsilon-aminocaproic acid, citrulline, hydroxyproline, ornithine, homoarginine, sarcosine, indoline 2-carboxylic acid, 2-azetidinecarboxylic acid, pipecolinic acid (2-piperidine carboxylic acid), O-methylserine, O-ethylserine, S-methylcysteine, S-ethylcysteine, S-benzylcysteine, NH2—CH(CH2CHEt2)-CO2H, alpha-aminoheptanoic acid, NH2—CH(CH2-1-naphthyl)-CO2H, NH2—CH(CH2-2-naphthyl)-CO2H, NH2—CH(CH2-cyclohexyl)-CO2H, NH2—CH(CH2-cyclopentyl)-CO2H, NH2—CH(CH2-cyclobutyl)-CO2H, NH2—CH(CH2-cyclopropyl)-CO2H, trifluoroleucine, 4-fluorophenylalanine, lysine substituted on the epsilon nitrogen with a biotinyl group, and hexafluoroleucine;
• R6 and R7 are selected independently from the group consisting of H, C1-10 alkyl, C3-20 cyclized alkyl, C1-10 alkyl with a phenyl group attached to the C1-10 alkyl, C1-10 alkyl with two phenyl groups attached to the C1-10 alkyl, C3-20 cyclized alkyl with an attached phenyl group, phenyl, phenyl substituted with K, C1-10 alkyl with an attached phenyl group substituted with K, C1-10 alkyl with an attached phenyl group disubstituted with K, C1-10 alkyl with an attached phenyl group trisubstituted with K, C1-10 alkyl with two phenyl groups attached to the C1-10 alkyl and substituted with K on the phenyl group, C1-10 alkyl with two phenyl groups attached to the C1-10 alkyl and disubstituted with K on the phenyl groups, C3-20 cyclized alkyl with an attached phenyl group substituted with K, C1-10 alkyl with a morpholine [—N(CH2CH2)O]ring attached through nitrogen to the alkyl, C1-10 alkyl with a piperidine ring attached through nitrogen to the alkyl, C1-10 alkyl with a pyrrolidine ring attached through nitrogen to the alkyl, C1-20 alkyl with an OH group attached to the alkyl, —CH2CH2CH2OCH3, C1-10 alkyl with an attached 4-pyridyl group, C1-10 alkyl with an attached 3-pyridyl group, C1-10 alkyl with an attached 2-pyridyl group, C1-10 alkyl with an attached cyclohexyl group, —NH—CH2CH2-(4-hydroxyphenyl), —NH—CH2CH2-(3-indolyl), C1-10 alkyl with an attached 2-furyl group, C1-10 alkyl with an attached 3-furyl group, and C1-5 alkyl with an attached phenyl and a hydroxyl attached to the C1-5 alkyl;
• and
• R8 and R9 are selected independently from the group consisting of H, C1-10 alkyl, phenyl, nitrophenyl, and C1-10 alkyl substituted with phenyl.