Proteasome inhibitors

A method of treating Alzheimer's disease in a subject, comprising:

• administering to the subject an effective amount of a pharmaceutical composition containing a compound, a pharmaceutically acceptable salt, or a solvate thereof, of the formula:
• wherein
• (a) X and Y are independently selected from the group consisting of —CH2—, —CH2CH2—, —O—, —CH2O—, —NH—, —CH2NH—, —N(CH3)—, —CH2N(CH3)—, —C(═O)—, —CH2C(═O)—, —C6H4—, —CH2—(C6H4)—, —(C6H4)-F1-4-, —CH2—C6H4-(F)1-4-, -pyrazole-, -imidazole-, -thiazole-, -oxazole-, -morpholine-, -pyridine-, -piperazine-, and -pyrrole-;
• (b) W is —CH2—, —CH2OCH2—, —CH2CH2O—, or —CH2CH2OCH2CH2—;
• (c) n is 1, 2, 3, 4, 5, 6, 7, or 8;
• (d) R0 is H, OH, F, CH3, or OCH3;
• (e) R1 is selected from the group consisting of:
• (i)
• wherein R is H, CH3, isopropyl, t-butyl, methoxymethyl (MOM), menthoxyethoxy methyl (MEM), or (CH2)nCH3 wherein n is 1, 2, or 3;
• (ii)
• wherein X, Y, and Z are independently selected from the group consisting of H, CH, N, CH3, and CH2CH3;
• (iii)
• wherein X and Y are independently selected from the group consisting of H, CH3, and (CH2)nCH3 wherein n is 1, 2, or 3;
• (iv)
• wherein X is CH2 or C═O;
• and R is H, CH3, N(CH3)2, or Fn, wherein n is 0, 1, 2, 3, 4, or 5;
• (v)
• (vi)
• (v)
• wherein X is CH or N;
• Y is CH2, O, or N-R, wherein R is H, CH3 or COCH3;
• and n is 0, 1, or 2;
• (vi)
• wherein X, Y, and Z are independently selected from the group consisting of CH, CH2, N, NH, and O;
• and W is CH2 or CH2CH2;
• (vii)
• (viii)
• wherein R is CH3, CH2CH2Ph-Fn, or CH2PhFn, wherein n is 0, 1, 2, 3, 4, or 5;
• (ix)
• wherein X, Y, and Z are independently selected from N and CH, and n is 0, 1, 2, or 3;
• (f) R2, R3 and R4 are independently selected from the group consisting of:
• (i) Gly, Ala, Pro, Leu, Ile, Phe, Tyr, Val, Ser, methyloxySerine, homoPhe, norVal, or norLeu;
• (ii)
• wherein X and Y are independently selected from the group consisting of H, CH3, and CH2CH3;
• R and Z are independently selected from the group consisting of H, OH, OCH3, OCH2CH3, Ph, and OPh;
• and n is 1, 2, or 3;
• (iii)
• wherein X is cyclopropyl, cyclopentyl, or cyclohexyl, and n is 1, 2, or 3;
• (iv)
• wherein X and Y are independently selected from the group consisting of H, CH3, CO(CH3), and CO2Bzl, and n is 1, 2, or 3;
• (v)
• wherein R is H, CH3, or (F)1-3, and n is 1, 2, or 3;
• (vi)
• wherein X and Y are independently selected from the group consisting of H, Fn, Cl, CH3, OCH3, OHCOCH3, NH2, NH(CH3) and NHFmoc, and n is 1, 2, or 3;
• (vii)
• wherein X, Y, and Z are independently selected from CH and N, and n is 1, 2, or 3;
• (viii)
• wherein X and Y are independently selected from the group consisting of H, CH3, and COCH3, and n is 1, 2, 3, or 4;
• (ix)
• wherein X is H, Fn, CH3, or OCH3;
• Y is H or OH, and n is 1, 2, 3, 4, or 5;
• (x)
• wherein X and Y are independently selected from the group consisting of H, Fn, CH3 OCH3, OH, COCH3;
• and n is 1, 2, 3, 4, or 5;
• (xi)
• (xii)
• wherein n is 0, 1, 2, 3, 4, or 5;
• (xii)
• wherein X, Y, and Z are independently selected from the group consisting of CH, CH2, N, NH, N(CH3), and O, and n is 1, 2, or 3;
• (xiv)
• wherein R is H, CH3, or Fn, wherein n is 0, 1, 2, or 3;
• (xv)
• and
• (xvi)
• wherein R is H, Fn, or (CH3)n;
• wherein n is 0, 1, 2, 3, or 4 and
• (g) A is selected from:
• (i)
• wherein
• R5 is selected from the group consisting of:
• H, CH3, (CH2)1-3CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH(CH3)2, CH2OH, CH2OCH3, CH2(C6H5), CH2CH2(C6H5), and CH2(C6H4)—OH, and
• X is selected from the group consisting of CH2, NH, and N(CH3);
• (ii)
• wherein X, Y, and Z are independently selected from the group consisting of CH, CH2, C═O, N, NH, O, S, and N-R, R is H, OH, (F)1-4, CH3, OCH3, CH2OCH3, NH2, NH(CH3), N(CH3)2, N(C═O)CH3, phenyl, phenyl(F)1=4, pyrazole, imidazole, thiazole, oxazole, morpholine, pyridine, piperazine, or pyrrole, and n is 2, 3, 4, or 5.