Aspartic protease inhibitors

An aspartic protease/inhibitor complex, comprising an aspartic protease and an aspartic protease inhibitor, said aspartic protease/inhibitor complex having said aspartic protease inhibitor chemically, physically and/or physicochemically interacting with said aspartic protease and said aspartic protease inhibitor having the following general formula (II):

• wherein,
• a) Het is a saturated, partially unsaturated or unsaturated and substituted or unsubstituted 3 to 7-membered heterocyclic ring having
• i) at least two heteroatoms, wherein the first heteroatom can interact with a first aspartate group in the active site of an aspartic protease and the second heteroatom can interact with a second aspartate group in the same active site, wherein at least one of the heteroatoms does interact with at least one of the first and second aspartate groups, and
• ii) a pKa value in the range from about 2.5 to about 12, and
• b) X is a hydrogen bond-accepting group;
• c) Y is a moiety having a backbone chain of at least 2 atoms selected from the group consisting of carbon, nitrogen, phosphorus, sulfur, oxygen, silicon and combinations thereof;
• d) each R1, R1′, R2 and R2′ group is covalently bonded to the Y moiety, and at least one of R1, R1′, R2 and R2′ has a chemical structure for occupying at least one of the S1, S1′, S2 and S2′ sub-sites;
• and
• e) n=0, 1, 2 or 3.

An aspartic protease/inhibitor complex, comprising an aspartic protease and an aspartic protease inhibitor, said aspartic protease/inhibitor complex having said aspartic protease inhibitor chemically physically and/or physicochemically interacting with said aspartic protease and said aspartic protease inhibitor having the following general formula (III):

• wherein,
• a) Het is a saturated, partially unsaturated or unsaturated and substituted or unsubstituted 3 to 7-membered heterocyclic ring having
• i) at least two heteroatoms, wherein the first heteroatom can interact with a first aspartate group in the active site of an aspartic protease and the second heteroatom can interact with a second aspartate group in the same active site, wherein at least one of the heteroatoms does interact with at least one of the first and second aspartate groups, and
• ii) a pKa value in the range from about 2.5 to about 12, and
• b) X is a hydrogen bond-accepting group;
• c) Y is a moiety having a backbone chain of at least 2 atoms selected from the group consisting of carbon, nitrogen, phosphorus, sulfur, oxygen, silicon and combinations thereof;
• and
• d) each R1, R1′, R2 and R2′ group is covalently bonded to the Y moiety, and at least one of R1, R1′, R2 and R2′ has a chemical structure for occupying at least one of the S1, S1′, S2 and S2′ sub-sites.

A method for inhibiting an aspartic protease comprising administering to a patient in need thereof a therapeutically effective amount of an aspartic protease inhibitor;

• said aspartic protease inhibitor having the following general formula (I):
• Z—Het— (I)
• wherein,
• a) Het is a saturated, partially unsaturated or unsaturated and substituted or unsubstituted 3 to 7-membered heterocyclic ring having
• (i) at least two heteroatoms, wherein the first heteroatom can interact with a first aspartate group in the active site of an aspartic protease and the second heteroatom can interact with a second aspartate group in the same active site, wherein at least one of the heteroatoms does interact with at least one of the first and second aspartate groups, and
• (ii) a pKa value in the range from about 2.5 to about 12, and
• c) wherein each Z can be the same or different, and has
• (i) a shape complementarity with at least a portion of the substrate binding site of the aspartic protease;
• (ii) a chemical structure for contacting multiple atoms of the substrate binding site;
• and
• (iii) at least one R group, which can be the same or different, at least one R group having a chemical structure for occupying at least one sub-site, proximate to the active site of the aspartic protease.

A compound selected from the group consisting of:

• 4,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-imidazole,
• 4,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-pyrazole,
• 4,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-triazole,
• 4,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-imidazoline,
• 4,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-oxazole,
• 4,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-thiazole,
• 4,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-pyridazine,
• 4,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-pyrimidine,
• 4,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-pyrazine,
• 4,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-piperazine,
• 4,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-triazine,
• 4,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-oxazine,
• 3,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-imidazole,
• 3,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-pyrazole,
• 3,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-triazole,
• 3,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-imidazoline,
• 3,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-oxazole,
• 3,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-thiazole,
• 3,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-pyridazine,
• 3,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-pyrimidine,
• 3,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-pyrazine,
• 3,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-piperazine,
• 3,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-triazine,
• 3,5-bis{[(1,1-dimethylethoxy)-(S)-phenylalanyl]carbonyl}-1H-oxazine,
• 4,5-bis{{[(1,1-dimethylethoxy)-(S)-valyl]-(S)-phenylalanyl}carbonyl}-1H-imidazole,
• 4,5-bis{{[(1,1-dimethylethoxy)-(S)-valyl]-(S)-phenylalanyl}carbonyl}-1 H-pyrazole, 4,5-bis{{[(1, 1-dimethylethoxy)-(S)-valyl]-(S)-phenylalanyl}carbonyl}-1H-triazole, 4,5-bis{{[(1,1-dimethylethoxy)-(S)-valyl]-(S)-phenylalanyl}carbonyl}-1H-imidazoline, 4,5-bis{{[(1,1-dimethylethoxy)-(S)-valyl]-(S)-phenylalanyl}carbonyl}-1H-oxazole, 4,5-bis{{[(1,1-dimethylethoxy>(S)-valyl]-(S) phenylalanyl}carbonyl}1H-thiazole, 4,5-bis{{[(l1,1 -dimethylethoxy)-(S)-valyl]-(S)-phenylalanyl}carbonyl}-1H-pyridazine, 4,5-bis{{[(1,1-dimethylethoxy)-(S)-valyl]-(S)-phenylalanyl}carbonyl}-1H-pyrimidine, 4,5-bis{{[(l ,1 -dimethylethoxy)-(S)-valyl]-(S)-phenylalanyl}carbonyl}-1 H-pyrazine, 4,5-bis{{([(1,1-dimethylethoxy)-(S)-valyl]-(S)-phenylalanyl}carbonyl}-1H-piperazine, 4,5-bis{{[(1,1-dimethylethoxy)-(S)-valyl]-(S)-phenylalanyl}carbonyl}-1H-triazine, 4,5-bis{{[(1,1-dimethylethoxy)-(S)-valyl]-(S)-phenylalanyl}carbonyl}-1H-oxazine, 3,5-bis{{[(1,1-dimethylethoxy)-(S)-valyl] -(S)-phenylalanyl}carbonyl}-1H-imidazole, 3,5-bis{{[(1,1-dimethylethoxy)-(S)-valyl]-(S)-phenylalanyl}carbonyl 1H-pyrazole, 3,5-bis{{[(1,1-dimethylethoxy)-(S)-valyl]-(S)-phenylalanyl}carbonyl}-1H-triazole, 3,5-bis{{[(1,1-dimethylethoxy)-(S)-valyl]-(S)-phenylalanyl}carbonyl}-1H-imidazoline, 3,5-bis{{[(1,1-dimethylethoxy)-(S)-valyl]-(S)-phenylalanyl}carbonyl}-1H-oxazole, 3,5-bis{{[(1,1-dimethylethoxy)-(S)-valyl]-(S)-phenylalanyl}carbonyl}-1H-thiazole, 3,5-bis{{[(1,1-dimethylethoxy)-(S)-valyl]-(S)-phenylalanyl}carbonyl}-1H-pyridazine, 3,5-bis{{[(1,1-dimethylethoxy)-(S)-valyl]-(S)-phenylalanyl}carbonyl}-1H-pyrimidine, 3,5-bis{{[(1,1-dimethylethoxy(S)-valyl]-(S)-phenylalanyl}carbonyl}-1H-pyrazine, 3,5-bis{{[(1,1-dimethylethoxy)-(S)valyl]-(S)-phenylalanyl}carbonyl}-1H-piperazine, 3,5-bis{[(1,1-dimethylethoxy)-(S)-valyl]-(S)-phenylalanyl}carbonyl}-1H-triazine, and 3,5-bis{{[(1,1-dimethylethoxy)-(S)-valyl]-(S)-phenylalanyl}carbonyl}-1H-oxazine.