The HIV-protease enzyme is absolutely essential for the replication and dissemination of HIV throughout the body (Navia M A and McKeever B M, Ann. New York Acad. Sci., 1990; 616:73-85) and has become an extremely important target for the design and development of anti-HIV therapeutic agents (von der Helm K, Biol. Chem. 1996; 377:756-774). Several peptidomimetic HIV protease inhibitors have been successfully developed (such as indinavir, saquinavir, ritonavir, and nelfinavir), which demonstrate significant clinical success in lowering plasma viral load, reducing the onset to AIDS, and decreasing the frequency of opportunistic infections (Deeks S G, Smith M, Holodniy M, Kahn J O, JAMA, 1997; 277:145-153).
Yet the current HIV protease inhibitors by their peptidomimetic nature have relatively poor solubility, high biliary excretion, limited bioavailabilities and significant liver metabolism. These drawbacks in turn increase the need for high doses of a drug, which increases the frequency of various side effects and multiple drug interactions (Barry M, Gibbons S, Back D, Mulcahy F, Clin. Pharmacokinet., 1997;32:194-209). More importantly, resistance to the current HIV protease inhibitors has emerged (Shock H B, Garsky V M, Kuo L, J. Biol. Chem., 1996;271:31957-31963) resulting in treatment failures (Fatkenheuer G, Theisen A, Rockstroh J. Grabow T, et al., AIDS, 1997; 11:F, 113-F 116). From this discussion, it is apparent that while HIV protease is an excellent antiviral target for the treatment of HIV infection and AIDS, there is a need to identify non-peptide inhibitors with improved pharmacological properties and which are not cross resistant with the current drugs (Wallace R W, DDT, 1997;2:83-84).
U.S. Pat. No. 5,789,440 recites nonpeptidic HIV protease inhibitors of formula A. 
The patent is hereby incorporated by reference. Excellent HIV protease inhibition was achieved, but the antiviral activity at the cellular level was in some cases less than desired for an ideal therapeutic agent due to poor overall pharmacological properties (Tummino P J, Vara Prasad J V N, Ferguson D, Nauhan C, et al., BioOrganic and Med Chem., 1996;4:1401-1410). These efforts, however, led to a core structure B where R1 and R2 were alkyl groups filling the S1′ and S2′ pockets, respectively, and the phenyl of the phenethyl group at C6 filled the S2 pocket very efficiently. This core structure was recognized as a valuable platform for additional study (Tait B D, Hagen S, Domagala J M, Ellsworth E L, et al., J. Med. Chem., 1997;40:3781-3792).
Additional dihydropyrones C were reported when it was unexpectedly discovered that certain groups which reduced lipophilicity judiciously placed at R1-R5 led to greatly improved antiviral cellular activity (see U.S. Pat. No. 5,834,506). The patent is hereby incorporated by reference. Among the preferred compounds were those where R1 and R5 were OH, NH2, or CH2OH. In such cases, the preferred R4 included a small alkyl chain or ring, and R6 was methyl. In addition to improved cellular antiviral activity, the compounds also showed good pharmacokinetics in animals relative to the less polar-substituted compounds. These compounds were also not cross resistant with current HIV Protease inhibitors (Hagen S E, Vara Prasad J V N, Boyer F E, Domagala J M, et al., J. Med., 1997;40:3707-3711; Vander Roest S, Wold S, Saunders J, 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Sep. 28-Oct. 1, 1997, Toronto, Canada. Abstract I-84; Domagala J. M, Boyer F, Ellsworth E, Gajda C, et al., 5th Conference on Retroviruses and Opportunistic Infections, Feb. 1-5, 1998, Chicago, Ill., Abstract 638).
While the compounds C were notable for their improved pharmacological properties relative to the nonpolar-substituted core molecules B, these highly favorable properties were conferred directly by the use of OH, NH2 and NR2 groups placed on the lipophilic rings. The rings themselves were important for binding to the enzyme “pockets” and for holding the t-butyl group and the groups R1-R3 and R5 in their proper places within the enzyme's active site.
This hereby incorporates by reference 5888L1-01-TMC filed on even date herewith entitled “A Method of Making Dihydropyrone HIV Protease Inhibitors” by Victor Fedij, et al.