RENIN INHIBITORS

BACKGROUND OF THE INVENTION

Aspartic proteases, including renin, β-secretase (BACE), Candida albicans secreted aspartyl proteases, HIV protease, HTLV protease and plasmepsins I and II, are implicated in a number of disease states. In hypertension elevated levels of angiotensin I, the product of renin catalyzed cleavage of angiotensinogen are present. Elevated levels of β-amyloid, the product of BACE activity on amyloid precursor protein, are widely believed to be responsible for the amyloid plaques present in the brains of Alzheimer's disease patients. Secreted aspartyl proteases play a role in the virulence of the pathogen Candida albicans. The viruses HIV and HTLV depend on their respective aspartic proteases for viral maturation. Plasmodium falciparum uses plasmepsins I and II to degrade hemoglobin.

In the renin-angiotensin-aldosterone system (RAAS) the biologically active peptide angiotensin II (Ang II) is generated by a two-step mechanism. The highly specific aspartic protease renin cleaves angiotensinogen to angiotensin I (Ang I), which is then further processed to Ang II by the less specific angiotensin-converting enzyme (ACE). Ang II is known to work on at least two receptor subtypes called AT₁and AT₂. Whereas AT₁seems to transmit most of the known functions of Ang II, the role of AT₂is still unknown.

Modulation of the RAAS represents a major advance in the treatment of cardiovascular diseases (Zaman, M. A. et al Nature Reviews Drug Discovery 2002, 1, 621-636). ACE inhibitors and AT₁blockers have been accepted as treatments of hypertension (Waeber B. et al., “The renin-angiotensin system: role in experimental and human hypertension”, in Berkenhager W. H., Reid J. L. (eds): Hypertension, and human hypertension”, in Berkenhager W. H., Reid J. L. (eds): Hypertension, Amsterdam, Elsevier Science Publishing Co, 1996, 489-519; Weber M. A., Am. J. Hypertens., 1992, 5, 247S). In addition, ACE inhibitors are used for renal protection (Rosenberg M. E. et al., Kidney International, 1994, 45, 403; Breyer J. A. et al., Kidney International, 1994, 45, S156), in the prevention of congestive heart failure (Vaughan D. E. et al., Cardiovasc. Res., 1994, 28, 159; Fouad-Tarazi F. et al., Am. J. Med., 1988, 84 (Suppl. 3A), 83) and myocardial infarction (Pfeffer M. A. et al., N Engl. J. Med, 1992, 327, 669).

Interest in the development of renin inhibitors stems from the specificity of renin (Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645). The only substrate known for renin is angiotensinogen, which can only be processed (under physiological conditions) by renin. In contrast, ACE can also cleave bradykinin besides Ang I and can be bypassed by chymase, a serine protease (Husain A., J. Hypertens., 1993, 11, 1155). In patients, inhibition of ACE thus leads to bradykinin accumulation causing cough (5-20%) and potentially life-threatening angioneurotic edema (0.1-0.2%) (Israili Z. H. et al., Annals of Internal Medicine, 1992, 117, 234). Chymase is not inhibited by ACE inhibitors. Therefore, the formation of Ang II is still possible in patients treated with ACE inhibitors. Blockade of the ATI receptor (e.g., by losartan) on the other hand overexposes other AT-receptor subtypes to Ang II, whose concentration is dramatically increased by the blockade of AT1 receptors.

In summary, renin inhibitors are not only expected to be superior to ACE inhibitors and AT₁blockers with regard to safety, but more importantly also with regard to their efficacy in blocking the RAAS.

Only limited clinical experience (Azizi M. et al., J. Hypertens., 1994, 12, 419; Neutel J. M. et al., Am. Heart, 1991, 122, 1094) has been generated with renin inhibitors because their peptidomimetic character imparts insufficient oral activity (Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645). The clinical development of several compounds has been stopped because of this problem together with the high cost of goods. It appears as though only one compound has entered clinical trials (Rahuel J. et al., Chem. Biol., 2000, 7, 493; Mealy N. E., Drugs of the Future, 2001, 26, 1139). Thus, metabolically stable, orally bioavailable and sufficiently soluble renin inhibitors that can be prepared on a large scale are not available. Recently, the first non-peptide renin inhibitors were described which show high in vitro activity (Oefner C. et al., Chem. Biol., 1999, 6, 127; Patent Application WO 97/09311; Maerki H. P. et al., II Farmaco, 2001, 56, 21). The present invention relates to the unexpected identification of renin inhibitors of a non-peptidic nature and of low molecular weight. Orally active renin inhibitors which are active in indications beyond blood pressure regulation where the tissular renin-chymase system may be activated leading to pathophysiologically altered local functions such as renal, cardiac and vascular remodeling, atherosclerosis, and restenosis, are described.

All documents cited herein are incorporated by reference.

SUMMARY OF THE INVENTION

Compounds have now been found that bind to aspartic proteases to inhibit their activity. Such compounds are useful in the treatment or amelioration of diseases associated with aspartic protease activity.

One embodiment of the invention is a compound represented by Structural Formula (I):

wherein:

R¹is (C₃-C₇)cycloalkyl, phenyl, heteroaryl, or bicyclic heteroaryl each optionally substituted with 1 to 3 groups independently selected from: fluorine, chlorine, bromine, cyano, nitro, hydroxyl, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, (C₅-C₇)cycloalkylalkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, halo(C₂-C₆)alkenyl, halo(C₃-C₆)alkynyl, halo(C₅-C₇)-cycloalkylalkynyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy and (C₁-C₆)alkanesulfonyl; and phenyl, heteroaryl, phenoxy, heteroaryloxy, phenylthio, heteroarylthio, benzyl, heteroarylmethyl, benzyloxy and heteroarylmethoxy, each optionally substituted with 1 to 3 groups independently selected from: fluorine, chlorine, bromine, cyano, nitro, hydroxyl, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)-alkoxy, and halo(C₁-C₃)alkoxy, and aminocarbonyl;

R²is (C₁-C₁₂)alkyl, (C₂-C₁₂)alkenyl, (C₂-C₁₂)alkynyl, (C₃-C₇)cycloalkyl, R^2a—O—, R^2d—O—, R^2a—S—, R^2a—O—Y₁—, R^2a—S—Y₁—, R^2a—O—Y₁—O—, R^2a—O—Y₁—S—, R^2a—S—Y₁—O—, R^2a—S—Y₁—S—, R^2a—O—Y₁—O—Y₁—, NH₂—C(O)—NH—Y₁—, NH₂—C(O)—NH—Y₁—O—, NH₂—C(O)—NH—Y₁—S—, R^2a—C(O)—NH—Y₁—, R^2a—C(O)—NH—Y₁—O—, R^2a—C(O)—NH—Y₁—S—, NH₂—S(O)₂—NH—Y₁—, NH₂—S(O)₂—NH—Y₁—O—, NH₂—S(O)₂—NH—Y₁—S—, R^2a—S(O)₂—NH—Y₁—, R^2a—S(O)₂—NH—Y₁—O—, R^2a—S(O)₂—NH—Y₁—S—, H—C(O)—NH—, H—C(O)—NH—Y₁—, H—C(O)—NH—Y₁—O—, H—C(O)—NH—Y₁—S—, R^2a—O—C(O)—NH—, R^2a—O—C(S)—NH—, R^2a—O—C(O)—NH—Y₁—, R^2a—O—C(O)—NH—Y₁—O—, R^2a—O(O)—NH—Y₁—S—, R^2a—NH—C(O)—NH—Y₁—, (R^2a)₂—N—C(O)—NH—Y₁—, R^2a—NH—C(O)—NH—Y₁—O—, (R^2a)₂—N—C(O)—NH—Y₁—O—, R^2a—NH—C(O)—NH—Y₁—S—, (R^2a)₂—N—C(O)—NH—Y₁—S—, NH₂—C(O)—, NH₂—C(S)—, NH₂—C(O)—Y₁—, NH₂—C(O)—Y₁—O—, NH₂—C(O)—Y₁—S—, R^2a—NH—C(O)—, R^2a—NH—C(S)—, R^2a—NH—C(O)—Y₁—, R^2a—NH—C(O)—Y₁—O—, R^2a—NH—C(O)—Y₁—S—, NH₂—C(O)—O—, NH₂—C(S)—O—, NH₂—C(O)—O—Y₁, NH₂—C(O)—O—Y₁—O—, NH₂—C(O)—O—Y₁—S—, R^2a—NH—C(O)—O—, R^2a—NH—C(S)—O—, R^2a—NH—C(O)—O—Y₁—, R^2a—NH—C(O)—O—Y₁—O—, R^2a—NH—C(O)—O—Y₁—S—, R^2a—NH—C(O)—NH—, R^2a—C(O)—NH—, NH₂—C(S)—S—, NH₂—C(O)—S—, R^2a—NH—C(S)—S—, R^2a—NH—C(O)—S—, R^2a—S—C(S)—NH—, R^2a—S—C(O)—NH—, R^2a—C(O)—, R^2a—C(S)—, NHC(═NR^2e)(NH₂), —NHC(═NR^2e)(NHR^2a)

R^2ais straight or branched (C₁-C₁₂)alkyl, straight or branched (C₁-C₁₂)haloalkyl, (C₃-C₇)cycloalkyl, or straight or branched C₁-C₁₂alkoxyalkyl, R^2d═(C₂-C₁₂)alkenyl, and R^2eis H, (C₁-C₆)alkyl, phenyl, heteroaryl, cyano, nitro, —S(O)R^2a, —S(O)₂R^2a, —S(O)₂NHR^2a, —S(O)₂NR^2aR^2a, —C(O)R^2a, —C(S)R^2a, —C(O)OR^2a, —C(S)OR^2a, —C(O)(NH₂), —C(O)(NHR^2a);

Y₁is a straight or branched C₁-C₁₂alkylene optionally substituted with one or more halogens and optionally interrupted at an internal carbon atom with oxygen;

R²can be substituted by at least one of:

- a) 1 to 6 halogen atoms; or
- b) one substituent selected from the group consisting of cyano, hydroxyl, (C₁-C₃)alkoxy, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkoxy, halo(C₁-C₃)alkoxy, halo(C₃-C₆)cycloalkyl and halo(C₃-C₆)cycloalkoxy; and

wherein the thio-moiety of said unsubstituted or substituted R^2a—S—, R^2a—S—Y₁, R^2a—O—Y₁—S—, R^2a—S—Y₁—O—, R^2a—S—Y₁—S—, NH₂—C(O)—NH—Y₁—S—, R^2a—C(O)—NH—Y₁—S—, NH₂—S(O)₂—NH—Y₁—S—, R^2a—S(O)₂—NH—Y₁—S—, H—C(O)—NH—Y₁—S—, R^2a—O—C(O)—NH—Y₁—S—, R^2a—NH—C(O)—NH—Y₁—S—, (R^2a)₂—N—C(O)—NH—Y₁—S—, NH₂—C(O)—Y₁—S—, R^2a—NH—C(O)—Y₁—S—, NH₂—C(O)—O—Y₁—S—, R^2a—NH—C(O)—O—Y₁—S—, NH₂—C(S)—S—, NH₂—C(O)—S—, R^2a—NH—C(S)S—, R^2a—NH—C(O)—S—, R^2a—S—C(S)—NH—, R^2a—S—C(O)—NH—, and

is optionally replaced by —S(O)— or —S(O)₂—; and

wherein the carbonyl moiety of said unsubstituted or substituted NH₂—C(O)—NH—Y₁—, NH₂—C(O)—NH—Y₁—O—, NH₂—C(O)—NH—Y₁—S—, R^2a—C(O)—NH—Y₁—, R^2a—C(O)—NH—Y₁—O—, R^2a—C(O)—NH—Y₁—S—, H—C(O)—NH—, H—C(O)—NH—Y₁—, H—C(O)—NH—Y₁—O—, H—C(O)—NH—Y₁—S—, R^2a—O—C(O)—NH—, R^2a—O—C(O)—NH—Y₁—, R^2a—O—C(O)—NH—Y₁—O—, R^2a—O—C(O)—NH—Y₁—S—, R^2a—NH—C(O)—NH—Y₁—, (R^2a)₂—N—C(O)—NH—Y₁—, R^2a—NH—C(O)—NH—Y₁—O—, (R^2a)₂—N—C(O)—NH—Y₁—, R^2a—NH—C(O)—NH—Y₁—S—, (R^2a)₂—N—C(O)—NH—Y₁—S—, NH₂—C(O)—, NH₂—C(O)—Y₁—, NH₂—C(O)—Y₁—O—, NH₂—C(O)—Y₁—S—, R^2a—NH—C(O)—, R^2a—NH—C(O)—Y₁—, R^2a—NH—C(O)—Y₁—O—, R^2a—NH—C(O)—Y₁—S—, NH₂—C(O)—O—, NH₂—C(O)—O—Y₁—, NH₂—C(O)—O—Y₁—O—, NH₂—C(O)—O—Y₁—S—, R^2a—NH—C(O)—O—, R^2a—NH—C(O)—O—Y₁—, R^2a—NH—C(O)—O—Y₁—O—, R^2a—NH—C(O)—O—Y₁—S—, R^2a—NH—C(O)—NH—, R^2a—C(O)—NH—, NH₂—C(O)—S—, R^2a—NH—C(O)—S—, R^2a—S—C(O)—NH—, and R^2a—C(O)—

is optionally replaced by a thiocarbonyl moiety;

provided that when R₂is attached to

through a heteroatom, Y can not be a covalent bond;

A is a saturated or unsaturated 4-, 5-, 6-, or 7-membered ring which is optionally bridged by (CH₂)_pvia bonds to two members of said ring, wherein said ring is composed of carbon atoms and 0-2 hetero atoms selected from the group consisting of 0, 1, or 2 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms, said ring being optionally and independently substituted with zero to four halogen atoms, (C₁-C₆)alkyl groups, halo(C₁-C₆)alkyl groups or oxo groups such that when there is substitution with one oxo group on a carbon atom it forms a carbonyl group, and when there is substitution of one or two oxo groups on sulfur it forms sulfoxide or sulfone groups, respectively;

p is 1 to 3;

Y is a covalent bond or C₁-C₁₀alkylene, C₁-C₁₀alkenylene or C₁-C₁₀alkynylene, each optionally substituted at one or more substitutable carbon atoms with halogen, cyano, hydroxyl, (C₁-C₃)alkyl, (C₁-C₃)alkoxy or halo(C₁-C₃)alkoxy,

Q is Q1, Q2, Q3, Q4, Q5, or Q6:

R⁴is H, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl; (C₁-C₃)alkoxy(C₁-C₃)alkyl, or cyano(C₁-C₆)alkyl;

G is OH, OR^e, NH₂, NHR^e, NR^eR^f, C(═NH)NH₂, C(═NH)NHR^e, NHC(═NH)NH₂, or NHC(═NH)NHR^e;

L is 1) a linear (C₂-C₄)alkyl chain when G is OH, OR^e, NH₂, NHR^e, NR^eR^f, NHC(═NH)NH₂, or NHC(═NH)NHR^e, or 2) a linear (C₁-C₃)alkyl chain when G is C(═NH)NH₂or C(═NH)NHR^e;

L is optionally substituted by 1-4 groups independently selected from R⁵, R^5a, R⁶, and R^6a; one or more of the carbon atoms of L may be part of a 3-, 4-, 5-, 6-, or 7-membered saturated ring composed of carbon atoms, and 0-2 hetero atoms selected from 0 or 1 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms; said saturated ring being optionally substituted with up to four groups selected from halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, halo(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, halo(C₄-C₇)cycloalkylalkyl, and oxo, such that when there is substitution with one oxo group on a carbon atom it forms a carbonyl group and when there is substitution of one or two oxo groups on sulfur it forms sulfoxide or sulfone groups, respectively);

R⁵, R^5a, R⁶, and R^6ais each independently selected from 1) H, (C₁-C₁₂)alkyl, halo(C₁-C₁₂)alkyl, hydroxy(C₁-C₁₂)alkyl, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkylalkyl, halo(C₃-C₁₀)cycloalkylalkyl, hydroxy(C₃-C₁₀)cycloalkylalkyl, (C₁-C₂)alkyl(C₃-C₁₀)cycloalkylalkyl, halo(C₁-C₂)alkyl(C₃-C₁₀)cycloalkylalkyl, di(C₁-C₂)alkyl(C₃-C₁₀)cycloalkylalkyl, hydroxy(C₁-C₂)alkyl (C₃-C₁₀)cycloalkylalkyl, hydroxy di(C₁-C₂)alkyl(C₃-C₁₀)cycloalkylalkyl, (C₂-C₁₂)alkenyl, (C₅-C₈)cycloalkyl(C₁-C₃)alkenyl, (C₂-C₁₂)alkynyl, (C₃-C₈)cycloalkyl(C₁-C₃)alkynyl, (C₄-C₁₂)bicycloalkyl(C₁-C₃)alkyl, (C₈-C₁₄)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₃)alkyl, (C₁-C₆)alkylthio(C₁-C₆)alkyl, halo(C₁-C₆)alkylthio(C₁-C₆)alkyl, (C₃-C₈)cycloalkylthio(C₁-C₃)alkyl, saturated heterocyclyl, and saturated heterocyclyl(C₁-C₃)alkyl wherein (a) hydrogen atoms in these groups are optionally substituted by 1 to 6 groups independently selected from halogen, cyano, nitro, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, (C₃-C₇)cycloalkylalkyl, halo(C₃-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, (C₃-C₇)cycloalkylalkenyl, (C₂-C₆)alkynyl, halo(C₂-C₆)alkynyl, (C₃-C₇)cycloalkylalkoxy, halo(C₃-C₇)cycloalkylalkoxy, (C₃-C₇)cycloalkoxy, halo(C₁-C₆)alkyl, (C₃-C₇)cycloalkylalkynyl, halo(C₃-C₇)cycloalkylalkynyl, halo(C₁-C₆)alkoxy, halo(C₃-C₇)cycloalkyl, halo(C₃-C₇)cycloalkoxy, (C₁-C₆)alkylsulfonyl, aminocarbonyl and wherein (b) divalent sulfur atoms are optionally oxidized to sulfoxide or sulfone;

or 2) phenyl, naphthyl, heteroaryl, phenyl(C₁-C₃)alkyl, phenoxymethyl, naphthyl(C₁-C₃)alkyl, and heteroaryl(C₁-C₃)alkyl, each optionally substituted with 1 to 3 groups independently selected from: halogen (e.g., fluorine, chlorine, bromine, iodine), cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, (C₃-C₆)cycloalkylalkenyl, (C₂-C₆)alkynyl, halo(C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl-(C₂-C₄)alkynyl, halo(C₃-C₇)cycloalkylalkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio, (C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl, halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)-cycloalkylalkanesulfonyl, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, aminocarbonyl, (C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl, cyano(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₆)alkyl, (C₄-C₈)cycloalkylalkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkoxy(C₁-C₆)alkyl, halo(C₄-C₈)-cycloalkylalkoxy(C₁-C₆)alkyl, (C₁-C₈)alkylthio(C₁-C₆)alkyl, (C₃-C₈)cycloalkylthio(C₁-C₆)alkyl, (C₄-C₈)cycloalkylalkylthio(C₁-C₆)alkyl, halo(C₁-C₈)alkylthio(C₁-C₆)alkyl, halo(C₃-C₈)cycloalkylhio(C₁-C₆)alkyl, halo(C₄-C₈)-cycloalkylalkylthio(C₁-C₆)alkyl, (C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl, (C₃-C₈)-cycloalkanesulfinyl(C₁-C₆)alkyl, (C₄-C₈)cycloalkyl-alkanesulfinyl(C₁-C₆)alkyl, halo(C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl, halo(C₃-C₈)cycloalkanesulfinyl(C₁-C₆)alkyl, halo(C₄-C₈)cycloalkylalkanesulfinyl(C₁-C₆)alkyl, (C₁-C₈)alkane-sulfonyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl, (C₄-C₈)cycloalkylalkanesulfonyl(C₁-C₆)alkyl, halo(C₁-C₈)alkanesulfonyl(C₁-C₆)alkyl, halo(C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl, halo(C₄-C₈)cycloalkylalkanesulfonyl(C₁-C₆)alkyl, (C₁-C₈)alkylamino(C₁-C₆)alkyl, di(C₁-C₈)alkylamino(C₁-C₆)alkyl, (C₁-C₈)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₈)acyloxy(C₁-C₆)alkyl, aminocarbonyl(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carbonyl(C₁-C₆)alkyl, di(C₁-C₈)alkylaminocarbonyl(C₁-C₆)alkyl and (C₁-C₈)acylamino(C₁-C₆)alkyl, (C₁-C₈)alkoxycarbonylamino, (C₁-C₈)alkoxycarbonylamino(C₁-C₆)alkyl, aminocarboxy(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carboxy(C₁-C₆)alkyl and di(C₁-C₈)alkylaminocarboxy(C₁-C₆)alkyl, phenyl, naphthyl, heteroaryl, bicyclic heteroaryl, phenoxy, naphthyloxy, heteroaryloxy, bicyclic heteroaryloxy, phenylthio, naphthylthio, heteroarylthio, bicyclic heteroarylthio, phenylsulfinyl, naphthylsulfinyl, heteroarylsulfinyl, bicyclic heteroarylsulfinyl, phenylsulfonyl, naphthylsulfonyl, heteroarylsulfonyl, bicyclic heteroarylsulfonyl, phenyl(C₁-C₃)alkyl, naphthyl(C₁-C₃)alkyl, heteroaryl(C₁-C₃)alkyl, and bicyclic heteroaryl(C₁-C₃)alkyl, wherein the aromatic and heteroaromatic groups are optionally substituted with 1 to 3 groups independently selected from fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, halo(C₁-C₃)-alkoxy, (C₁-C₃)alkanesulfonyl, and (C₁-C₃)alkoxycarbonyl;

R^eis a) (C₁-C₁₂)alkyl, (C₄-C₁₂)cycloalkylalkyl, halo(C₁-C₁₂)alkyl, halo(C₄-C₂)cycloalkylalkyl, (C₂-C₁₂)alkenyl, (C₈-C₁₂)cycloalkylalkenyl, halo(C₂-C₁₂)alkenyl, halo(C₈-C₁₂)cycloalkylalkenyl, (C₂-C₁₂)alkynyl, (C₅-C₁₂)cycloalkylalkynyl, halo(C₂-C₁₂)alkynyl, halo(C₈-C₁₂)cycloalkylalkynyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkylthio(C₁-C₆)alkyl, halo(C₁-C₆)alkylthio(C₁-C₆)alkyl, (C₁-C₆)alkanesulfinyl(C₁-C₆)alkyl, halo(C₁-C₆)alkane-sulfinyl(C₁-C₆)alkyl, (C₁-C₆)alkanesulfonyl(C₁-C₆)alkyl, halo(C₁-C₆)alkanesulfonyl(C₁-C₆)alkyl, aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl, di(C₁-C₆)alkylamino-carbonyl(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, saturated heterocyclyl, or saturated heterocyclyl(C₁-C₆)alkyl or b) phenyl, naphthyl, heteroaryl, phenyl(C₁-C₃)alkyl, naphthyl(C₁-C₃)alkyl, or heteroaryl(C₁-C₃)alkyl, each of a) and b) is optionally substituted by 1 to 3 groups independently selected from:

1) fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl-(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio, (C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl, halo(C₃-C₆)cycloalkane-sulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)-cycloalkylalkanesulfonyl, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy-(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, aminocarbonyl, (C₁-C₆)alkylaminocarbonyl and di(C₁-C₆)alkylaminocarbonyl, cyano(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₆)alkyl, (C₄-C₈)cycloalkylalkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkoxy(C₁-C₆)alkyl, halo(C₄-C₈)-cycloalkylalkoxy(C₁-C₆)alkyl, (C₁-C₈)alkylthio(C₁-C₆)alkyl, (C₃-C₈)cycloalkylhio(C₁-C₆)alkyl, (C₄-C₈)cycloalkylalkylthio(C₁-C₆)alkyl, halo(C₁-C₈)alkylthio(C₁-C₆)alkyl, halo(C₃-C₈)cycloalkylhio(C₁-C₆)alkyl, halo(C₄-C₈)-cycloalkylalkylthio(C₁-C₆)alkyl, (C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl, (C₃-C₈)-cycloalkanesulfinyl(C₁-C₆)alkyl, (C₄-C₈)cycloalkyl-alkanesulfinyl(C₁-C₆)alkyl, halo(C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl, halo(C₃-C₈)cycloalkanesulfinyl(C₁-C₆)alkyl, halo(C₄-C₈)cycloalkylalkanesulfinyl(C₁-C₆)alkyl, (C₁-C₈)alkane-sulfonyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl, (C₄-C₈)cycloalkylalkanesulfonyl(C₁-C₆)alkyl, halo(C₁-C₈)alkanesulfonyl(C₁-C₆)alkyl, halo(C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl, halo(C₄-C₈)cycloalkylalkanesulfonyl(C₁-C₆)alkyl, (C₁-C₈)alkylamino(C₁-C₆)alkyl, di(C₁-C₈)alkylamino(C₁-C₆)alkyl, (C₁-C₈)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₈)acyloxy(C₁-C₆)alkyl, aminocarbonyl(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carbonyl(C₁-C₆)alkyl, di(C₁-C₈)alkylaminocarbonyl(C₁-C₆)alkyl(C₁-C₈)acylamino(C₁-C₆)alkyl, (C₁-C₈)alkoxycarbonylamino, (C₁-C₈)alkoxycarbonylamino(C₁-C₆)alkyl, aminocarboxy(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carboxy(C₁-C₆)alkyl and di(C₁-C₈)alkylaminocarboxy(C₁-C₆)alkyl; or 2) phenyl, naphthyl, heteroaryl, bicyclic heteroaryl, phenoxy, naphthyloxy, heteroaryloxy, bicyclic heteroaryloxy, phenylthio, naphthylthio, heteroarylthio, bicyclic heteroarylthio, phenylsulfinyl, naphthylsulfinyl, heteroarylsulfinyl, bicyclic heteroarylsulfinyl, phenylsulfonyl, naphthylsulfonyl, heteroarylsulfonyl, bicyclic heteroarylsulfonyl, phenyl(C₁-C₃)alkyl, naphthyl(C₁-C₃)alkyl, heteroaryl(C₁-C₃)alkyl, and bicyclic heteroaryl(C₁-C₃)alkyl, each optionally substituted with 1 to 3 groups independently selected from fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, (C₁-C₃)alkanesulfonyl, and (C₁-C₃)-alkoxycarbonyl; or

b) R^eis a saturated divalent radical composed of carbon atoms, and 0, 1 or 2 hetero atoms selected from 0 or 1 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms that is attached to any core carbon atom on L to form a saturated 3-, 4-, 5-, 6-, or 7-membered L-G ring; said L-G ring being optionally substituted with 1 to 4 groups selected from halogen, fluorine, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, halo(C₃-C₈)cycloalkyl, hydroxy(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₃)alkyl, halo(C₃-C₈)cycloalkyl(C₁-C₃)alkyl, hydroxy(C₃-C₈)cycloalkyl(C₁-C₃)alkyl, (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy, (C₃-C₈)cycloalkoxy, halo(C₃-C₈)cycloalkoxy, hydroxy(C₃-C₈)cycloalkoxy, (C₁-C₈)alkoxy(C₁-C₃)alkyl, halo(C₁-C₈)alkoxy(C₁-C₃)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₃)alkyl, halo(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl, hydroxy(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl, (C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl, halo(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl, hydroxy(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl, (C₁-C₈)alkylthio, halo(C₁-C₈)alkylthio, (C₃-C₈)cycloalkylthio, halo(C₃-C₈)cycloalkylthio, hydroxy(C₃-C₈)cycloalkylthio, (C₃-C₈)cycloalkyl(C₁-C₃)alkylthio, halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio, hydroxy(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio, (C₁-C₈)alkylthio(C₁-C₃)alkyl, halo(C₁-C₈)alkylthio(C₁-C₃)alkyl, (C₃-C₈)cycloalkylthio(C₁-C₃)alkyl, halo(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl, hydroxy(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl, (C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl, halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl, hydroxy(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl, heterocyclyl, and oxo;

R^fis (C₁-C₆)alkyl or halo(C₁-C₆)alkyl; or

an enantiomer, diastereomer or pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to pharmaceutical compositions comprising a compound described herein or enantiomers, diastereomers, or salts thereof and a pharmaceutically acceptable carrier or excipient.

In another embodiment, the present invention is directed to a method of antagonizing aspartic protease inhibitors in a subject in need thereof comprising administering to the subject an effective amount of a compound described herein or an enantiomer, diastereomer, or salt thereof.

In another embodiment the present invention is directed to method for treating or ameliorating an aspartic protease mediated disorder in a subject in need thereof comprising administering to said subject an effective amount of a compound described herein or an enantiomer, diastereomer, or salt thereof.

In another embodiment, the present invention is directed to a method for treating or ameliorating a renin mediated disorder in a subject in need thereof comprising administering to the subject an effective amount of a compound described herein or an enantiomer, diastereomer, or salt thereof.

In another embodiment, the present invention is directed to a method for the treatment of hypertension in a subject in need thereof comprising administering to the subject a compound described herein in combination therapy with one or more additional agents said additional agent selected from the group consisting of α-blockers, β-blockers, calcium channel blockers, diuretics, angiotensin converting enzyme (ACE) inhibitors, dual ACE and neutral endopeptidase (NEP) inhibitors, angiotensin-receptor blockers (ARBs), aldosterone synthase inhibitors, aldosterone-receptor antagonists, and endothelin receptor antagonists.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to an aspartic protease inhibitor compounds represented by Structural Formula I or enantiomers, diastereomers or pharmaceutically acceptable salts thereof (i.e., pharmaceutically acceptable salts of the compounds, enantiomers and diastereomers). Values and particular values for the variables in Structural Formula I are provided in the following paragraphs. It is understood that the invention encompasses all combinations of the substituent variables (i.e., R¹, R², R³, etc.) defined herein. For Structural Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

In one embodiment, R¹is (C₃-C₇)cycloalkyl, phenyl, heteroaryl, or bicyclic heteroaryl each optionally substituted with 1 to 3 groups independently selected from: fluorine, chlorine, bromine, cyano, nitro, hydroxyl, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, (C₅-C₇)cycloalkylalkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, halo(C₂-C₆)alkenyl, halo(C₃-C₆)alkynyl, halo(C₅-C₇)-cycloalkylalkynyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy and (C₁-C₆)alkanesulfonyl; and phenyl, heteroaryl, phenoxy, heteroaryloxy, phenylthio, heteroarylthio, benzyl, heteroarylmethyl, benzyloxy and heteroarylmethoxy, each optionally substituted with 1 to 3 groups independently selected from: fluorine, chlorine, bromine, cyano, nitro, hydroxyl, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)-alkoxy, and halo(C₁-C₃)alkoxy, and aminocarbonyl.

In another embodiment, R¹is a phenyl optionally substituted with (R₁₁)_n, wherein n-0-3 and R¹¹is independently selected from: fluorine, chlorine, bromine, cyano, nitro, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, (C₅-C₇)cycloalkylalkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, halo(C₂-C₆)alkenyl, halo(C₃-C₆)alkynyl, halo(C₅-C₇)-cycloalkylalkynyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy and (C₁-C₆)alkanesulfonyl; or 2) phenyl, heteroaryl, phenoxy, heteroaryloxy, phenylthio, heteroarylthio, benzyl, heteroarylmethyl, benzyloxy and heteroarylmethoxy, each optionally substituted with 1 to 3 groups independently selected from: fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)-alkoxy, and halo(C₁-C₃)alkoxy, and aminocarbonyl

In another particular embodiment, R¹is phenyl optionally substituted with 1-3 groups independently selected from chloro, fluoro or methyl. In another particular embodiment, R¹is phenyl substituted with chloro. In a most particular embodiment, R¹is phenyl substituted with chloro at the carbon atom that is meta to the carbon atom that links phenyl to the rest of the molecule.

In one embodiment, R²is (C₁-C₁₂)alkyl, (C₂-C₁₂)alkenyl, (C₂-C₁₂)alkynyl, (C₃-C₇)cycloalkyl, R^2a—O—, R^2d—O—, R^2a—S—, R^2a—Y₁—, R^2a—S—Y₁—, R^2a—O—Y₁—O—, R^2a—O—Y₁—S—, R^2a—S—Y₁—O—, R^2a—S—Y₁—S—, R^2a—O—Y₁—O—Y₁—, NH₂—C(O)—NH—Y₁—, NH₂—C(O)—NH—Y₁—O—, NH₂—C(O)—NH—Y₁—S—, R^2a—C(O)—NH—Y₁—, R^2a—C(O)—NH—Y₁—O—, R^2a—C(O)—NH—Y₁—S—, NH₂—S(O)₂—NH—Y₁—, NH₂—S(O)₂—NH—Y₁—O—, NH₂—S(O)₂—NH—Y₁—S—, R^2a—S(O)₂—NH—Y₁—, R^2a—S(O)₂—NH—Y₁—O—, R^2a—S(O)₂—NH—Y₁—S—, H—C(O)—NH—, H—C(O)—NH—Y₁—, H—C(O)—NH—Y₁—O—, H—C(O)—NH—Y₁—S—, R^2a—O—C(O)—NH—, R^2a—O—C(S)—NH—, R^2a—O—C(O)—NH—Y₁—, R^2a—O—C(O)—NH—Y—O—, R^2a—O—C(O)—NH—Y —S—, R^2a—NH—C(O)—NH—Y₁—, (R^2a)₂—N—C(O)—NH—Y₁—, R^2a—NH—C(O)—NH—Y₁—O—, (R^2a)₂—N—C(O)—NH—Y₁—O—, R^2a—NH—C(O)—NH—Y₁—S—, (R^2a)₂—N—C(O)—NH—Y₁—S—, NH₂—C(O)—, NH₂—C(S)—, NH₂—C(O)—Y₁—, NH₂—C(O)—Y₁—O—, NH₂—C(O)—Y₁—S—, R^2a—NH—C(O)—, R^2a—NH—C(S)—, R^2a—NH—C(O)—Y₁—, R^2a—NH—C(O)—Y₁—O—, R^2a—NH—C(O)—Y₁—S—, NH₂—C(O)—O—, NH₂—C(S)—O—, NH₂—C(O)—O—Y₁—, NH₂—C(O)—O—Y₁—O—, NH₂—C(O)—O—Y₁—S—, R^2a—NH—C(O)—O—, R^2a—NH—C(S)—O—, R^2a—NH—C(O)—O—Y₁—, R^2a—NH—C(O)—O—Y₁—O—, R^2a—NH—C(O)—O—Y₁—S—, R^2a—NH—C(O)—NH—, R^2a—C(O)—NH—, NH₂—C(S)—S—, NH₂—C(O)—S—, R^2a—NH—C(S)—S—, R^2a—NH—C(O)—S—, —R^2a—S—C(S)—NH—, R^2aS—C(O)—NH—, R^2a—C(O)—, R^2a—C(S)—, NHC(═NR^2e)(NH₂), —NHC(═NR^2e)(NHR^2a),

R²can be substituted by at least one of:

- a) 1 to 6 halogen atoms; or
- b) one substituent selected from the group consisting of cyano, hydroxyl, (C₁-C₃)alkoxy, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkoxy, halo(C₁-C₃)alkoxy, halo(C₃-C₆)cycloalkyl and halo(C₃-C₆)cycloalkoxy; and

wherein the thio-moiety of said unsubstituted or substituted R^2a—S—, R^2a—S—Y₁, R^2a—O—Y₁—S—, R^2a—S—Y₁—O—, R^2a—S—Y₁—S—, NH₂—C(O)—NH—Y₁—S—, R^2a—C(O)—NH—Y₁—S—, NH₂—S(O)₂—NH—Y₁—S—, R^2a—S(O)₂—NH—Y₁—S—, H—C(O)—NH—Y₁—S—, R^2a—O—C(O)—NH—Y₁—S—, R^2a—NH—C(O)—NH—Y₁—S—, (R^2a)₂—N—C(O)—NH—Y₁—S—, NH₂—C(O)—Y₁—S—, R^2a—NH—C(O)—Y₁—S—, NH₂—C(O)—O—Y₁—S—, R^2a—NH—C(O)—O—Y —S—, NH₂—C(S)—S—, NH₂—C(O)—S—, R^2a—NH—C(S)—S—, R^2a—NH—C(O)—S—, R^2a—S—C(S)—NH—, R^2a—S—C(O)—NH—, and

is optionally replaced by —S(O)— or —S(O)₂—; and

wherein the carbonyl moiety of said unsubstituted or substituted NH₂—C(O)—NH—Y₁—, NH₂—C(O)—NH—Y₁—O—, NH₂—C(O)—NH—Y₁—S—, R^2a—C(O)—NH—Y₁—, R^2a—C(O)—NH—Y₁—O—, R^2a—C(O)—NH—Y₁—S—, H—C(O)—NH—, H—C(O)—NH—Y₁—, H—C(O)—NH—Y₁—O—, H—C(O)—NH—Y₁—S—, R^2a—O—C(O)—NH—, R^2a—O—C(O)—NH—Y₁—, R^2a—O—C(O)—NH—Y₁—O—, R^2a—O—C(O)—NH—, R^2a—NH—Y₁—, (R^2a)₂—N—(O)—NH—Y₁—, R^2a—NH—C(O)—NH—Y₁—O—, (R^2a)₂—N—C(O)—NH—Y₁—O—, R^2a—NH—C(O)—NH—Y₁—S—, (R^2a)₂—N—C(O)—NH—Y₁—S—, NH₂—C(O)—, NH₂—C(O)—Y₁—, NH₂—C(O)—Y₁—O—, NH₂—C(O)—Y₁—S—, R^2a—NH—C(O)—, R^2a—NH—C(O)—Y₁—, R^2a—NH—C(O)—Y—O—, R^2a—NH—C(O)—Y₁—S—, NH₂—C(O)—O—O—, NH₂—C(O)—O—Y₁—, NH₂—C(O)—O—Y₁—O—, NH₂—C(O)—O—Y₁—S—, R^2a—NH—C(O)—O—, R^2a—NH—C(O)—O—Y₁—, R^2a—NH—C(O)—O—Y₁—O—, R^2a—NH—C(O)—O—Y₁—S—, R^2a—NH—C(O)—NH—, R^2a—C(O)—NH—, NH₂—C(O)—S—, R^2a—NH—C(O)—S—, R^2a—S—C(O)—NH—, and R^2a—C(O)—

is optionally replaced by a thiocarbonyl moiety; provided that when R₂is attached to

through a heteroatom, Y can not be a covalent bond.

In another particular embodiment of this invention, R²is —OC(O)(NHR^2a), —NHC(O)OR^2a, —C(O)R^2a, —C(O)(NHR^2a), or —NHC(O)H. In a more particular embodiment, R²is —OC(O)(NHR^2a), —NHC(O)OR^2a, —C(O)R^2a, —C(O)(NHR^2a) and R^2ais methyl or ethyl.

In another particular embodiment of this invention, R²is —NHC(O)OR^2a. In a more particular embodiment, R²is —NHC(O)OR^2aand R^2ais methyl or ethyl. In a most particular embodiment, R²is —NHC(O)OCH₃

In one embodiment of this invention, R^2ais straight or branched (C₁-C₁₂)alkyl, straight or branched (C₁-C₁₂)haloalkyl, (C₃-C₇)cycloalkyl, or straight or branched C₁-C₁₂alkoxyalkyl, R^2dis (C₂-C₁₂)alkenyl, and R^2eis H, (C₁-C₆)alkyl, phenyl, heteroaryl, cyano, nitro, —S(O)R^2a, —S(O)₂R^2a, —S(O)₂NHR^2a, —S(O)₂NR^2aR^2a, —C(O)R^2a, —C(S)R^2a, —C(O)OR^2a, —C(S)OR^2a, —C(O)(NH₂), —C(O)(NHR^2a). In a particular embodiment, R^2ais methyl or ethyl.

Y₁is a straight or branched C₁-C₁₂alkylene optionally substituted with one or more halogens and optionally interrupted at an internal carbon atom with oxygen.

In one embodiment, A is a saturated or unsaturated 4-, 5-, 6-, or 7-membered ring which is optionally bridged by (CH₂)_pvia bonds to two members of said ring, wherein said ring is composed of carbon atoms and 0-2 hetero atoms selected from the group consisting of 0, 1, or 2 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms, said ring being optionally and independently substituted with zero to four halogen atoms, (C₁-C₆)alkyl groups, halo(C₁-C₆)alkyl groups or oxo groups such that when there is substitution with one oxo group on a carbon atom it forms a carbonyl group, and when there is substitution of one or two oxo groups on sulfur it forms sulfoxide or sulfone groups, respectively and p is 1 to 3.

In a particular embodiment, A is selected from phenyl, cyclohexyl, 1,3-dimethylpiperidine, and 2,4-dimethylmorpholine. In a more particular embodiment of, A is phenyl or 1,3-dimethylpiperidine.

In one embodiment of this invention, Y is a covalent bond or C₁-C₁₀alkylene, C₁-C₁₀alkenylene or C₁-C₁₀alkynylene, each optionally substituted at one or more substitutable carbon atoms with halogen, cyano, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)alkoxy or halo(C₁-C₃)alkoxy. In a particular embodiment of this invention, Y is a covalent bond. In another particular embodiment, Y is C₁-C₅alkylene optionally substituted as described above. In another more particular embodiment, Y is a C₂-C₃alkylene optionally substituted as described above.

In one embodiment of the invention, Q1, Q2, Q3, Q4, Q5, Q6:

In a particular embodiment of the invention, Q is Q1: —C(O)—.

In one embodiment, R⁴is H, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₃)alkoxy(C₁-C₃)alkyl, or cyano(C₁-C₆)alkyl. In a particular embodiment of the invention, R⁴is H.

In one embodiment, G is OH, OR^e, NH₂, NHR^e, NR^eR^f, C(═NH)NH₂, C(═NH)NHR^e, NHC(═NH)NH₂, or NHC(═NH)NHR^eand R^eand R^fare as described below.

In another particular embodiment of this invention, G is OH, NH₂or NHR^e.

An a more particular embodiment, G is OH, NH₂or NHR^eand R^eis a) (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₄-C₁₀)cycloalkylalkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, or aminocarbonyl(C₁-C₆)alkyl or b) phenyl(C₁-C₂)alkyl optionally substituted with 1 to 3 groups independently selected from: fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; or c) R⁵and R^etogether are —CH₂—, —(CH₂)₂—, —(CH₂)₃—, or —(CH₂)₄—, optionally substituted with 1 or 2 groups independently selected from fluorine, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₃-C₆)cycloalkyl, halo(C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₂)alkyl, halo(C₃-C₆)cycloalkyl(C₁-C₂)alkyl, hydroxy(C₃-C₆)cycloalkyl(C₁-C₂)alkyl, (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy, (C₃-C₆)cycloalkoxy, halo(C₃-C₆)cycloalkoxy, and heterocyclyl.

In another particular embodiment, G is NH₂or NHR^e.

In another particular embodiment, G is NHR^eand R^e. In a more particular embodiment, G is NHR^eand R^eis methyl or R^sand R^etogether are —(CH₂)₃-optionally substituted with C₁-C₄alkyl or cyclohexyl. In a more particular embodiment, G is NHR^eand R^eis methyl.

In one embodiment of this invention, L is 1) a linear (C₂-C₄)alkyl chain when G is OH, OR^e, NH₂, NHR^e, NR^eR^f, NHC(═NH)NH₂, or NHC(═NH)NHR^e, or 2) a linear (C₁-C₃)alkyl chain when G is C(═NH)NH₂or C(═NH)NHR^eand L is optionally substituted by 1-4 groups independently selected from R⁵, R^5a, R⁶, and R^6a; one or more of the carbon atoms of L may be part of a 3-, 4-, 5-, 6-, or 7-membered saturated ring composed of carbon atoms, and 0-2 hetero atoms selected from 0 or 1 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms; said saturated ring being optionally substituted with up to four groups selected from halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, halo(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, halo(C₄-C₇)cycloalkylalkyl, and oxo, such that when there is substitution with one oxo group on a carbon atom it forms a carbonyl group and when there is substitution of one or two oxo groups on sulfur it forms sulfoxide or sulfone groups, respectively.

In another embodiment of this invention L is a C₂alkyl chain, optionally substituted with R⁵and R⁶.

In one embodiment, each of R⁵, R^5a, R⁶, and R^6ais independently 1) H, (C₁-C₁₂)alkyl, halo(C₁-C₁₂)alkyl, hydroxy(C₁-C₁₂)alkyl, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkylalkyl, halo(C₃-C₁₀)cycloalkylalkyl, hydroxy(C₃-C₁₀)cycloalkylalkyl, (C₁-C₂)alkyl(C₃-C₁₀)cycloalkylalkyl, halo(C₁-C₂)alkyl(C₃-C₁₀)cycloalkylalkyl, di(C₁-C₂)alkyl(C₃-C₁₀)cycloalkylalkyl, hydroxy(C₁-C₂)alkyl (C₃-C₁₀)cycloalkylalkyl, hydroxy di(C₁-C₂)alkyl(C₃-C₁₀)cycloalkylalkyl, (C₂-C₁₂)alkenyl, (C₅-C₈)cycloalkyl(C₁-C₃)alkenyl, (C₂-C₁₂)alkynyl, (C₃-C₈)cycloalkyl(C₁-C₃)alkynyl, (C₄-C₁₂)bicycloalkyl(C₁-C₃)alkyl, (C₈-C₁₄)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₃)alkyl, (C₁-C₆)alkylthio(C₁-C₆)alkyl, halo(C₁-C₆)alkylthio(C₁-C₆)alkyl, (C₃-C₈)cycloalkylthio(C₁-C₃)alkyl, saturated heterocyclyl, and saturated heterocyclyl(C₁-C₃)alkyl wherein (a) hydrogen atoms in these groups are optionally substituted by 1 to 6 groups independently selected from halogen, cyano, nitro, hydroxyl, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, (C₃-C₇)cycloalkylalkyl, halo(C₃-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, (C₃-C₇)cycloalkylalkenyl, (C₂-C₆)alkynyl, halo(C₂-C₆)alkynyl, (C₃-C₇)cycloalkylalkoxy, halo(C₃-C₇)cycloalkylalkoxy, (C₃-C₇)cycloalkoxy, halo(C₁-C₆)alkyl, (C₃-C₇)cycloalkylalkynyl, halo(C₃-C₇)cycloalkylalkynyl, halo(C₁-C₆)alkoxy, halo(C₃-C₇)cycloalkyl, halo(C₃-C₇)cycloalkoxy, (C₁-C₆)alkylsulfonyl, aminocarbonyl and wherein (b) divalent sulfur atoms are optionally oxidized to sulfoxide or sulfone; or 2) phenyl, naphthyl, heteroaryl, phenyl(C₁-C₃)alkyl, phenoxymethyl, naphthyl(C₁-C₃)alkyl, and heteroaryl(C₁-C₃)alkyl, each optionally substituted with 1 to 3 groups independently selected from: fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, (C₃-C₆)cycloalkylalkenyl, (C₂-C₆)alkynyl, halo(C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl-(C₂-C₄)alkynyl, halo(C₃-C₇)cycloalkylalkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio, (C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl, halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)-cycloalkylalkanesulfonyl, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, aminocarbonyl, (C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl, cyano(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₆)alkyl, (C₄-C₈)cycloalkylalkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkoxy(C₁-C₆)alkyl, halo(C₄-C₈)-cycloalkylalkoxy(C₁-C₆)alkyl, (C₁-C₈)alkylthio(C₁-C₆)alkyl, (C₃-C₈)cycloalkylhio(C₁-C₆)alkyl, (C₄-C₈)cycloalkylalkylthio(C₁-C₆)alkyl, halo(C₁-C₈)alkylthio(C₁-C₆)alkyl, halo(C₃-C₈)cycloalkylhio(C₁-C₆)alkyl, halo(C₄-C₈)-cycloalkylalkylthio(C₁-C₆)alkyl, (C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl, (C₃-C₈)-cycloalkanesulfinyl(C₁-C₆)alkyl, (C₄-C₈)cycloalkyl-alkanesulfinyl(C₁-C₆)alkyl, halo(C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl, halo(C₃-C₈)cycloalkanesulfinyl(C₁-C₆)alkyl, halo(C₄-C₈)cycloalkylalkanesulfinyl(C₁-C₆)alkyl, (C₁-C₈)alkane-sulfonyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl, (C₄-C₈)cycloalkylalkanesulfonyl(C₁-C₆)alkyl, halo(C₁-C₆)alkanesulfonyl(C₁-C₆)alkyl, halo(C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl, halo(C₄-C₈)cycloalkylalkane-sulfonyl(C₁-C₆)alkyl, (C₁-C₈)alkylamino(C₁-C₆)alkyl, di(C₁-C₈)alkylamino(C₁-C₆)alkyl, (C₁-C₈)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₈)acyloxy(C₁-C₆)alkyl, aminocarbonyl(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carbonyl(C₁-C₆)alkyl, di(C₁-C₈)alkylaminocarbonyl(C₁-C₆)alkyl and (C₁-C₈)acylamino(C₁-C₆)alkyl, (C₁-C₈)alkoxycarbonylamino, (C₁-C₈)alkoxycarbonylamino(C₁-C₆)alkyl, aminocarboxy(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carboxy(C₁-C₆)alkyl and di(C₁-C₈)alkylaminocarboxy(C₁-C₆)alkyl, phenyl, naphthyl, heteroaryl, bicyclic heteroaryl, phenoxy, naphthyloxy, heteroaryloxy, bicyclic heteroaryloxy, phenylthio, naphthylthio, heteroarylthio, bicyclic heteroarylthio, phenylsulfinyl, naphthylsulfinyl, heteroarylsulfinyl, bicyclic heteroarylsulfinyl, phenylsulfonyl, naphthylsulfonyl, heteroarylsulfonyl, bicyclic heteroarylsulfonyl, phenyl(C₁-C₃)alkyl, naphthyl(C₁-C₃)alkyl, heteroaryl(C₁-C₃)alkyl, and bicyclic heteroaryl(C₁-C₃)alkyl, wherein the aromatic and heteroaromatic groups are optionally substituted with 1 to 3 groups independently selected from fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, halo(C₁-C₃)-alkoxy, (C₁-C₃)alkanesulfonyl, and (C₁-C₃)alkoxycarbonyl.

In another particular embodiment, one of R⁵and R⁶is —H or methyl and the other is selected from a) H, (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₄-C₁₀)cycloalkylalkyl, (C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, (C₄-C₁₀)bicycloalkyl(C₁-C₃)alkyl, (C₈-C₁₂)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl; or b) phenyl(C₁-C₂)alkyl, phenoxymethyl or heteroaryl(C₁-C₂)alkyl each optionally substituted with 1 to 3 groups independently selected from fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy.

In a more particular embodiment, R⁶is —H or methyl and R⁵is selected from a) H, (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₄-C₁₀)cycloalkylalkyl, (C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, (C₄-C₁₀)bicycloalkyl(C₁-C₃)alkyl, (C₈-C₁₂)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl; or b) phenyl(C₁-C₂)alkyl, phenoxymethyl or heteroaryl(C₁-C₂)alkyl each optionally substituted with 1 to 3 groups independently selected from fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy.

In another more particular embodiment, R⁵is —H or methyl and R⁶is selected from a) H, (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₄-C₁₀)cycloalkylalkyl, (C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, (C₄-C₁₀)bicycloalkyl(C₁-C₃)alkyl, (C₈-C₁₂)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl; or b) phenyl(C₁-C₂)alkyl, phenoxymethyl or heteroaryl(C₁-C₂)alkyl each optionally substituted with 1 to 3 groups independently selected from fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy.

In another particular embodiment, R⁶is —H or methyl and R⁵is selected from a) H, (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₄-C₁₀)cycloalkylalkyl, (C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, (C₄-C₁₀)bicycloalkyl(C₁-C₃)alkyl, (C₈-C₁₂)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl; or b) phenyl(C₁-C₂)alkyl, phenoxymethyl or heteroaryl(C₁-C₂)alkyl each optionally substituted with 1 to 3 groups independently selected from fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy.

In another particular embodiment, R⁵is —H or methyl and R⁶is selected from a) H, (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₄-C₁₀)cycloalkylalkyl, (C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, (C₄-C₁₀)bicycloalkyl(C₁-C₃)alkyl, (C₈-C₁₂)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl; or b) phenyl(C₁-C₂)alkyl, phenoxymethyl or heteroaryl(C₁-C₂)alkyl each optionally substituted with 1 to 3 groups independently selected from fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy.

In another particular embodiment, R⁵is (C₁-C₇)alkyl, halo(C₁-C₇)alkyl, hydroxy(C₁-C₇)alkyl, cyclohexylmethyl, halocyclohexylmethyl, hydroxy cyclohexylmethyl, 2-(cyclohexyl)ethyl, (C₁-C₂)alkyl cyclohexylmethyl, di(C₁-C₂)alkyl cyclohexylmethyl, hydroxy(C₁-C₂)alkyl cyclohexylmethyl, hydroxy di(C₁-C₂)alkylcyclohexylmethyl, (3-noradamantyl)methyl, (tetrahydropyranyl)methyl, or oxepanyl methyl and R⁶is —H or methyl.

In another particular embodiment, R⁶is (C₁-C₇)alkyl, halo(C₁-C₇)alkyl, hydroxy(C₁-C₇)alkyl, cyclohexylmethyl, halocyclohexylmethyl, hydroxy cyclohexylmethyl, 2-(cyclohexyl)ethyl, (C₁-C₂)alkyl cyclohexylmethyl, di(C₁-C₂)alkyl cyclohexylmethyl, hydroxy(C₁-C₂)alkyl cyclohexylmethyl, hydroxy di(C₁-C₂)alkylcyclohexylmethyl, (3-noradamantyl)methyl, (tetrahydropyranyl)methyl, or oxepanyl methyl and R⁵is —H or methyl.

In a more particular embodiment of this invention, R⁵is cyclohexylmethyl, (tetrahydropyranyl)methyl, or oxepanyl methyl and R⁶is —H. In another more particular embodiment of this invention, R⁶is cyclohexylmethyl, (tetrahydropyranyl)methyl, or oxepanyl methyl and R⁵is —H.

In one embodiment of this invention, R^eis a) (C₁-C₁₂)alkyl, (C₄-C₁₂)cycloalkylalkyl, halo(C₁-C₁₂)alkyl, halo(C₄-C₁₂)cycloalkylalkyl, (C₂-C₁₂)alkenyl, (C₅-C₁₂)cycloalkylalkenyl, halo(C₂-C₁₂)alkenyl, halo(C₅-C₁₂)cycloalkylalkenyl, (C₂-C₁₂)alkynyl, (C₅-C₁₂)cycloalkylalkynyl, halo(C₂-C₁₂)alkynyl, halo(C₅-C₁₂)cycloalkylalkynyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkylthio(C₁-C₆)alkyl, halo(C₁-C₆)alkylthio(C₁-C₆)alkyl, (C₁-C₆)alkanesulfinyl(C₁-C₆)alkyl, halo(C₁-C₆)alkane-sulfinyl(C₁-C₆)alkyl, (C₁-C₆)alkanesulfonyl(C₁-C₆)alkyl, halo(C₁-C₆)alkanesulfonyl(C₁-C₆)alkyl, aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl, di(C₁-C₆)alkylamino-carbonyl(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, saturated heterocyclyl, or saturated heterocyclyl(C₁-C₆)alkyl or b) phenyl, naphthyl, heteroaryl, phenyl(C₁-C₃)alkyl, naphthyl(C₁-C₃)alkyl, or heteroaryl(C₁-C₃)alkyl, each optionally substituted by 1 to 3 groups independently selected from: 1) fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl-(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio, (C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl, halo(C₃-C₆)cycloalkane-sulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)-cycloalkylalkanesulfonyl, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy-(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, aminocarbonyl, (C₁-C₆)alkylaminocarbonyl and di(C₁-C₆)alkylaminocarbonyl, cyano(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₆)alkyl, (C₄-C₈)cycloalkylalkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkoxy(C₁-C₆)alkyl, halo(C₄-C₈)-cycloalkylalkoxy(C₁-C₆)alkyl, (C₁-C₈)alkylthio(C₁-C₆)alkyl, (C₃-C₈)cycloalkylhio(C₁-C₆)alkyl, (C₄-C₈)cycloalkylalkylthio(C₁-C₆)alkyl, halo(C₁-C₈)alkylthio(C₁-C₆)alkyl, halo(C₃-C₈)cycloalkylhio(C₁-C₆)alkyl, halo(C₄-C₈)-cycloalkylalkylthio(C₁-C₆)alkyl, (C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl, (C₃-C₈)-cycloalkanesulfinyl(C₁-C₆)alkyl, (C₄-C₈)cycloalkyl-alkanesulfinyl(C₁-C₆)alkyl, halo(C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl, halo(C₃-C₈)cycloalkanesulfinyl(C₁-C₆)alkyl, halo(C₄-C₈)cycloalkylalkanesulfinyl(C₁-C₆)alkyl, (C₁-C₈)alkane-sulfonyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl, (C₄-C₈) cycloalkylalkanesulfonyl(C₁-C₆)alkyl, halo(C₁-C₈)alkanesulfonyl(C₁-C₆)alkyl, halo(C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl, halo(C₄-C₈)cycloalkylalkane-sulfonyl(C₁-C₆)alkyl, (C₁-C₈)alkylamino(C₁-C₆)alkyl, di(C₁-C₈)alkylamino(C₁-C₆)alkyl, (C₁-C₈)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₈)acyloxy(C₁-C₆)alkyl, aminocarbonyl(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carbonyl(C₁-C₆)alkyl, di(C₁-C₈)alkylaminocarbonyl(C₁-C₆)alkyl(C₁-C₈)acylamino(C₁-C₆)alkyl, (C₁-C₈)alkoxycarbonylamino, (C₁-C₈)alkoxycarbonylamino(C₁-C₆)alkyl, aminocarboxy(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carboxy(C₁-C₆)alkyl and di(C₁-C₈)alkylaminocarboxy(C₁-C₆)alkyl; or 2) phenyl, naphthyl, heteroaryl, bicyclic heteroaryl, phenoxy, naphthyloxy, heteroaryloxy, bicyclic heteroaryloxy, phenylthio, naphthylthio, heteroarylthio, bicyclic heteroarylthio, phenylsulfinyl, naphthylsulfinyl, heteroarylsulfinyl, bicyclic heteroarylsulfinyl, phenylsulfonyl, naphthylsulfonyl, heteroarylsulfonyl, bicyclic heteroarylsulfonyl, phenyl(C₁-C₃)alkyl, naphthyl(C₁-C₃)alkyl, heteroaryl(C₁-C₃)alkyl, and bicyclic heteroaryl(C₁-C₃)alkyl, each optionally substituted with 1 to 3 groups independently selected from fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, (C₁-C₃)alkanesulfonyl, and (C₁-C₃)-alkoxycarbonyl; or b) R^eis a saturated divalent radical composed of carbon atoms, and 0, 1 or 2 hetero atoms selected from 0 or 1 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms that is attached to any core carbon atom on L to form a saturated 3-, 4-, 5-, 6-, or 7-membered L-G ring; said L-G ring being optionally substituted with 1 to 4 groups selected from halogen, fluorine, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, halo(C₃-C₈)cycloalkyl, hydroxy(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₃)alkyl, halo(C₃-C₈)cycloalkyl(C₁-C₃)alkyl, hydroxy(C₃-C₈)cycloalkyl(C₁-C₃)alkyl, (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy, (C₃-C₈)cycloalkoxy, halo(C₃-C₈)cycloalkoxy, hydroxy(C₃-C₈)cycloalkoxy, (C₁-C₈)alkoxy(C₁-C₃)alkyl, halo(C₁-C₈)alkoxy(C₁-C₃)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₃)alkyl, halo(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl, hydroxy(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl, (C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl, halo(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl, hydroxy(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl, (C₁-C₈)alkylthio, halo(C₁-C₈)alkylthio, (C₃-C₈)cycloalkylthio, halo(C₃-C₈)cycloalkylthio, hydroxy(C₃-C₈)cycloalkylthio, (C₃-C₈)cycloalkyl(C₁-C₃)alkylthio, halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio, hydroxy(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio, (C₁-C₈)alkylthio(C₁-C₃)alkyl, halo(C₁-C₈)alkylthio(C₁-C₃)alkyl, (C₃-C₈)cycloalkylthio(C₁-C₃)alkyl, halo(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl, hydroxy(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl, (C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl, halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl, hydroxy(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl, heterocyclyl, and oxo.

In another particular embodiment of this invention, R^eis a) (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₄-C₁₀)cycloalkylalkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, or aminocarbonyl(C₁-C₆)alkyl or b) phenyl(C₁-C₂)alkyl optionally substituted with 1 to 3 groups independently selected from: fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; or c) R⁵and R^etogether are —CH₂—, —(CH₂)₂—, —(CH₂)₃—, or —(CH₂)₄—, optionally substituted with 1 or 2 groups independently selected from fluorine, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₃-C₆)cycloalkyl, halo(C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₂)alkyl, halo(C₃-C₆)cycloalkyl(C₁-C₂)alkyl, hydroxy(C₃-C₆)cycloalkyl(C₁-C₂)alkyl, (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy, (C₃-C₆)cycloalkoxy, halo(C₃-C₆)cycloalkoxy, and heterocyclyl.

In another particular embodiment, R^eis methyl or R⁵and R^etogether are —(CH₂)₃— optionally substituted with C₁-C₄alkyl or cyclohexyl. In a more particular embodiment, R^eis methyl or R⁶and R^etogether are —(CH₂)₃— optionally substituted with C₁-C₄alkyl or cyclohexyl. In a most particular embodiment, R^eis methyl.

In one embodiment, R^fis (C₁-C₆)alkyl or halo(C₁-C₆)alkyl.

In a first specific embodiment, the aspartic protease inhibitor of the invention is represented by Structural Formulas (Ia), (Ib) and (Ic) or an enantiomer, diastereomer or a pharmaceutically acceptable salt of the aspartic protease inhibitor represented by Structural Formula (Ia):

Values and particular values for the variables in Structural Formulas (Ia), (Ib) and (Ic) are as provided for Structural Formula (I) above.

A first set of values for Structural Formulas (Ia), (Ib) and (Ic) is provided in the following paragraphs:

R²is (C₁-C₁₂)alkyl, (C₂-C₁₂)alkenyl, (C₂-C₁₂)alkynyl, (C₃-C₇)cycloalkyl, R^2a—O—, R^2d—O—, R^2a—S—, R^2a—O—Y₁, R^2a—S—Y₁—, R^2a—O—Y₁—O—, R^2a—O—Y₁—S—, R^2a—S—Y₁—O—, R^2a—S—Y₁—S—, R^2a—O—Y₁—O—Y —, NH₂—C(O)—NH—Y₁—, NH₂—C(O)—NH—Y₁—O—, NH₂—C(O)—NH—Y₁—S—, R^2a—C(O)—NH—Y₁—, R^2a—C(O)—NH—Y₁—, R^2a—C(O)—NH—Y₁—S—, NH₂—S(O)₂—NH—Y₁—, NH₂—S(O)₂—NH—Y—O—, NH₂—S(O)₂—NH—Y —S—, R^2a—S(O)₂—NH—Y₁—, R^2a—S(O)₂—NH—Y—O—, R^2a—S(O)₂—NH—Y₁—S—, H—C(O)—NH—, H—C(O)—NH—Y₁—, H—C(O)—NH—Y₁—O—, H—C(O)—NH—Y₁—S—, R^2a—O—C(O)—NH—, R^2a—O—C(S)—NH—, R^2a—O—C(O)—NH—Y₁—, R^2a—C(O)—NH—Y₁—O—, R^2a—O—C(O)—NH—Y₁—S—, R^2a—NH—C(O)—NH—Y₁—, (R^2a)₂—N—C(O)—NH—Y₁—, R^2a—NH—C(O)—NH—Y₁—O—, (R^2a)₂—N—C(O)—NH—Y₁—O—, R^2a—NH—C(O)—NH—Y₁—S—, (R^2a)₂—N—C(O)—NH—Y₁—S—, NH₂—C(O)—, NH₂—C(S)—, NH₂—C(O)—Y₁—, NH₂—C(O)—Y₁—O—, NH₂—C(O)—Y₁—S—, R^2a—NH—C(O)—, R^2a—NH—C(S)—, R^2a—NH—C(O)—Y₁—, R^2a—NH—C(O)—Y₁—O—, R^2a—NH—C(O)—Y₁—S—, NH₂—C(O)—O—, NH₂—C(S)—O—, NH₂—C(O)—O—Y₁—, NH₂—C(O)—O—Y₁—O—, NH₂—C(O)—O—Y₁—S—, R^2a—NH—C(O)—O—, R^2a—NH—C(S)—O—, R^2a—NH—C(O)—O—Y₁—, R^2a—NH—C(O)—O—Y₁—, R^2a—NH—C(O)—O—Y₁—S—, R^2a—NH—C(O)—NH—, R^2a—C(O)—NH—, NH₂—C(S)—S—, NH₂—C(O)—S—, R^2a—NH—C(S)—S—, R^2a—NH—C(O)—S—, R^2a—S—C(S)—NH—, R^2a—S—C(O)—NH—, R^2a—C(O)—, R^2a—C(S)—, NHC(═NR^2e)(NH₂), —NHC(═NR^2e)(NHR^2a)

and

R²can be substituted by at least one of:

- a) 1 to 6 halogen atoms; or
- b) one substituent selected from the group consisting of cyano, hydroxyl, (C₁-C₃)alkoxy, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkoxy, halo(C₁-C₃)alkoxy, halo(C₃-C₆)cycloalkyl and halo(C₃-C₆)cycloalkoxy; and

wherein the thio-moiety of said unsubstituted or substituted R^2a—S—, R^2a—S—Y₁—, R^2a—O—Y₁—S—, R^2a—S—Y₁—O—, R^2a—S—Y₁—S—, NH₂—C(O)—NH—Y₁—S—, R^2a—C(O)—NH—Y₁—S—, NH₂—S(O)₂—NH—Y₁—S—, R^2a—S(O)₂—NH—Y₁—S—, H—C(O)—NH—Y₁—S—, R^2a—O—C(O)—NH—Y₁—S—, R^2a—NH—C(O)—NH—Y₁—S—, (R^2a)₂—N—C(O)—NH—Y₁—S—, NH₂—C(O)—Y₁—S—, R^2a—NH—C(O)—Y₁—S—, NH₂—C(O)—O—Y₁—S—, R^2a—NH—C(O)—O—Y₁—S—, NH₂—C(S)—S—, NH₂—C(O)—S—, R^2a—NH—C(S)—S—, R^2a—NH—C(O)—S—, R^2a—S—C(S)—NH—, R^2a—S—C(O)—NH—, and

is optionally replaced by —S(O)— or —S(O)₂—; and

wherein the carbonyl moiety of said unsubstituted or substituted NH₂—C(O)—NH—Y₁—, NH₂—C(O)—NH—Y₁—O—, NH₂—C(O)—NH—Y₁—S—, R^2a—C(O)—NH—Y₁, R^2a—C(O)—NH—Y₁—O—, R^2a—C(O)—NH—Y₁—S—, H—C(O)—NH—, H—C(O)—NH—Y₁—, H—C(O)—NH—Y₁—O—, H—C(O)—NH—Y₁—S—, R^2a—O—C(O)—NH—, R^2a—O—C(O)—NH—Y₁—, R^2a—O—C(O)—NH—Y₁—, R^2a—O—C(O)—NH—Y₁—S—, R^2a—NH—C(O)—NH—Y₁—, (R^2a)₂—N—C(O)—NH—Y₁—, R^2a—NH—C(O)—NH—Y₁—O—, (R^2a)₂—N—C(O)—NH—Y₁—O—, R^2a—NH—C(O)—NH—Y₁—S—, (R^2a)₂—N—C(O)—NH—Y₁—S—, NH₂—C(O)—, NH₂—C(O)—Y₁—, NH₂—C(O)—Y₁—O—, NH₂—C(O)—Y₁—S—, R^2a—NH—C(O)—, R^2a—NH—C(O)—Y₁—, R^2a—NH—C(O)—Y₁—O—, R^2a—NH—C(O)—Y₁—S—, NH₂—C(O)—O—, NH₂—C(O)—O—Y₁—, NH₂—C(O)—O—Y₁—, NH₂—C(O)—O—Y₁—S—, R^2a—NH—C(O)—O—, R^2a—NH—C(O)—O—Y₁—, —R^2a—NH—C(O)—O—Y₁—O—, R^2a—NH—C(O)—O—Y₁—S—, R^2a—NH—C(O)—NH—, R^2a—C(O)—NH—, NH₂—C(O)—S—, R^2a—NH—C(O)S—, R^2a—S—C(O)—NH—, and R^2a—C(O)—

is optionally replaced by a thiocarbonyl moiety;

provided that when R₂is attached to

through a heteroatom, Y can not be a covalent bond; and

the remainder of the values and particular values for Structural Formulas (Ia), (Ib) and (Ic) are as described for Structural Formula I.

A second set of values for Structural Formulas (Ia), (Ib) and (Ic) is provided in the following paragraphs:

R²is —OC(O)(NHR^2a), —NHC(O)OR^2a, —C(O)R^2a, —C(O)(NHR^2a) or —NHC(O)H; and

the remainder of the values and particular values for Structural Formulas (Ia), (Ib) and (Ic) are as described for Structural Formula I.

A third set of values for Structural Formulas (Ia), (Ib) and (Ic) is provided in the following paragraphs:

R²is —OC(O)(NHR^2a), —NHC(O)OR^2a, —C(O)R^2a, —C(O)(NHR^2a), or —NHC(O)HR^2a

R^2ais methyl or ethyl; and

the values and particular values for Structural Formulas (Ia), (Ib) and (Ic) are as described for Structural Formula (I).

A fourth set of values for Structural Formulas (Ia), (Ib) and (Ic) is provided in the following paragraphs:

R²is —NHC(O)OR^2a;

R^2ais methyl or ethyl; and

the remainder of the values and particular values for Structural Formulas (Ia), (Ib) and (Ic) are as described for Structural Formula (I).

A fifth set of values for Structural Formulas (Ia), (Ib) and (Ic) is provided in the following paragraphs:

R²is —NHC(O)OCH₃; and

the remainder of the values and particular values for Structural Formulas (Ia), (Ib) and (Ic) are as described for Structural Formula (I).

A sixth set of values for Structural Formulas (Ia), (Ib) and (Ic) is provided in the following paragraphs:

G is OH, NH₂or NHR^e;

R^eis a) (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₄-C₁₀)cycloalkylalkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, or aminocarbonyl(C₁-C₆)alkyl or b) phenyl(C₁-C₂)alkyl optionally substituted with 1 to 3 groups independently selected from: fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; or c) R⁵and R^etogether are —CH₂—, —(CH₂)₂—, —(CH₂)₃—, or —(CH₂)₄—, optionally substituted with 1 or 2 groups independently selected from fluorine, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₃-C₆)cycloalkyl, halo(C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₂)alkyl, halo(C₃-C₆)cycloalkyl(C₁-C₂)alkyl, hydroxy(C₃-C₆)cycloalkyl(C₁-C₂)alkyl, (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy, (C₃-C₆)cycloalkoxy, halo(C₃-C₆)cycloalkoxy, and heterocyclyl;

and the remainder of the values and particular values for Structural Formulas (Ia), (Ib) and (Ic) are as described for Structural Formula (I).

In a second specific embodiment, the aspartic protease inhibitor of the invention is represented by Structural Formula (II) or Structural Formula (IIa), or an enantiomer, diastereomer or a pharmaceutically acceptable salt of the aspartic protease inhibitor represented by Structural Formula (II) or (IIa):

Values and particular values for the variables in Structural Formula (II) and Structural Formula (IIa) are as provided for Structural Formula (I) above.

A first set of values for Structural Formula (II) and Structural Formula (IIa) is provided in the following paragraphs:

one of R⁵and R⁶is —H or methyl and the other is as described for Structural Formula (I); and

the remainder of the values and particular values for Structural Formula (II) and (IIa) are as described for Structural Formula (I).

A second set of values for Structural Formula (II) and Structural Formula (IIa) is provided in the following paragraphs:

R⁶is —H or methyl; and

the remainder of the values and particular values for Structural Formulas (II) and (IIa) are as described for Structural Formula (I).

A third set of values for Structural Formula (II) and Structural Formula (IIa) is provided in the following paragraphs:

R⁵is —H or methyl; and

the remainder of the values and particular values for Structural Formulas (II) and (IIa) are as described for Structural Formula (I).

A fourth set of values for Structural Formula (II) and Structural Formula (IIa) is provided in the following paragraphs:

one of R⁵and R⁶is H or methyl and the other is selected from a) H, (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₄-C₁₀)cycloalkylalkyl, (C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, (C₄-C₁₀)bicycloalkyl(C₁-C₃)alkyl, (C₈-C₁₂)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl; or b) phenyl(C₁-C₂)alkyl, phenoxymethyl or heteroaryl(C₁-C₂)alkyl each optionally substituted with 1 to 3 groups independently selected from fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; and

the remainder of the values and particular values for Structural Formulas (II) and (IIa) are as described for Structural Formula (I).

A fifth set of values for Structural Formula (II) and Structural Formula (IIa) is provided in the following paragraphs:

R⁶is H or methyl and R⁵is selected from a) H, (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₄-C₁₀)cycloalkylalkyl, (C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₂)alkyl(C₄-C₁)cycloalkylalkyl, di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, (C₄-C₁₀)bicycloalkyl(C₁-C₃)alkyl, (C₈-C₁₂)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl; or b) phenyl(C₁-C₂)alkyl, phenoxymethyl or heteroaryl(C₁-C₂)alkyl each optionally substituted with 1 to 3 groups independently selected from fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; and

the remainder of the values and particular values for Structural Formulas (II) and (IIa) are as described for Structural Formula (I).

A sixth set of values for Structural Formula (II) and Structural Formula (IIa) is provided in the following paragraphs:

R⁵is H or methyl and R⁶is selected from a) H, (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₄-C₁₀)cycloalkylalkyl, (C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, (C₄-C₁₀)bicycloalkyl(C₁-C₃)alkyl, (C₈-C₁₂)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl; or b) phenyl(C₁-C₂)alkyl, phenoxymethyl or heteroaryl(C₁-C₂)alkyl each optionally substituted with 1 to 3 groups independently selected from fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; and

the remainder of the values and particular values for Structural Formulas (II) and (IIa) are as described for Structural Formula (I).

A seventh set of values for Structural Formula (II) and Structural Formula (IIa) is provided in the following paragraphs:

G is OH, NH₂or NHR^e;

A eighth set of values for Structural Formula (II) and Structural Formula (IIa) is provided in the following paragraphs:

G is OH, NH₂or NHR^e;

and the remainder of the values and particular values for Structural Formulas (II) and (IIa) are as described for the fourth set of values for Structural Formulas (II) and (IIa).

A ninth set of values for Structural Formula (II) and Structural Formula (IIa) is provided in the following paragraphs:

G is OH, NH₂or NHR^e;

and the remainder of the values and particular values for Structural Formulas (II) and (IIa) are as described for the fifth set of values for Structural Formulas (II) and (IIa).

A tenth set of values for Structural Formula (II) and Structural Formula (IIa) is provided in the following paragraphs:

G is OH, NH₂or NHR^e;

R^eis a) (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₄-C₁₀)cycloalkylalkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, or aminocarbonyl(C₁-C₆)alkyl or b) phenyl(C₁-C₂)alkyl optionally substituted with 1 to 3 groups independently selected from: fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; or c) R^sand R^etogether are —CH₂—, —(CH₂)₂—, —(CH₂)₃—, or —(CH₂)₄—, optionally substituted with 1 or 2 groups independently selected from fluorine, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₃-C₆)cycloalkyl, halo(C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₂)alkyl, halo(C₃-C₆)cycloalkyl(C₁-C₂)alkyl, hydroxy(C₃-C₆)cycloalkyl(C₁-C₂)alkyl, (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy, (C₃-C₆)cycloalkoxy, halo(C₃-C₆)cycloalkoxy, and heterocyclyl;

and the remainder of the values and particular values for Structural Formulas (II) and (IIa) are as described for the sixth set of values for Structural Formulas (II) and (IIa).

In a third specific embodiment, the aspartic protease inhibitor of the invention is represented by Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa), or enantiomers, diastereomers or a pharmaceutically acceptable salt thereof:

Values and particular values for the variables in Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa) are as provided for Structural Formula (I) above. A first set of values of Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa) is described in the following paragraphs:

one of R⁵and R⁶is —H or methyl and the other is as described for Structural Formula (I); and the remainder of the values and particular values for Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa) are as described for Structural Formula (I).

A second set of values and particular values for Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa) is described in the following paragraphs:

R⁶is —H or methyl; and

- the remainder of the values and particular values for Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa) are as described for Structural Formula (I).

A third set of values for Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa) is described in the following paragraphs:

R⁵is —H or methyl; and

the remainder of the values and particular values for Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa) are as described for Structural Formula (I).

A fourth set of values for Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa) is described in the following paragraphs:

one of R⁵and R⁶is H or methyl and the other is a) H, (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₄-C₁₀)cycloalkylalkyl, (C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, (C₄-C₁₀)bicycloalkyl(C₁-C₃)alkyl, (C₈-C₁₂)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl; or b) phenyl(C₁-C₂)alkyl, phenoxymethyl or heteroaryl(C₁-C₂)alkyl each optionally substituted with 1 to 3 groups independently selected from fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; and

the remainder of the values and particular values for Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa) are as described for Structural Formula (I).

A fifth set of values for Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa) is described in the following paragraphs:

R⁶is H or methyl and R⁵is a) H, (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₄-C₁₀)cycloalkylalkyl, (C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, (C₄-C₁₀)bicycloalkyl(C₁-C₃)alkyl, (C₈-C₁₂)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl; or b) phenyl(C₁-C₂)alkyl, phenoxymethyl or heteroaryl(C₁-C₂)alkyl each optionally substituted with 1 to 3 groups independently selected from fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; and

the remainder of the values and particular values for Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa) are as described for Structural Formula (I).

A sixth set of values for Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa) is described in the following paragraphs:

R⁵is H or methyl and R⁶is a) H, (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₄-C₁₀)cycloalkylalkyl, (C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, (C₄-C₁₀)bicycloalkyl(C₁-C₃)alkyl, (C₈-C₁₂)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl; or b) phenyl(C₁-C₂)alkyl, phenoxymethyl or heteroaryl(C₁-C₂)alkyl each optionally substituted with 1 to 3 groups independently selected from fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; and

the remainder of the values and particular values for Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa) are as described for Structural Formula (I).

A seventh set of values for (III)-(VII) and Structural Formulas (IIIa)-(VIIa) is provided in the following paragraphs:

G is OH, NH₂or NHR^e;

and the remainder of the values and particular values for (III)-(VII) and Structural Formulas (IIIa)-(VIIa) are as described for Structural Formula (I).

A eighth set of values for (III)-(VII) and Structural Formulas (IIIa)-(VIIa) is provided in the following paragraphs:

G is OH, NH₂or NHR^e;

and the remainder of the values and particular values for Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa) are as described for the fourth set of values for Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa).

A ninth set of values for Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa) is provided in the following paragraphs:

G is OH, NH₂or NHR^e;

R^eis a) (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₄-C₁₀)cycloalkylalkyl, (C₁-C₈)alkoxy(C₁-C₅)alkyl, or aminocarbonyl(C₁-C₆)alkyl or b) phenyl(C₁-C₂)alkyl optionally substituted with 1 to 3 groups independently selected from: fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; or c) R⁵and R^etogether are —CH₂—, —(CH₂)₂—, —(CH₂)₃—, or —(CH₂)₄—, optionally substituted with 1 or 2 groups independently selected from fluorine, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₃-C₆)cycloalkyl, halo(C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₂)alkyl, halo(C₃-C₆)cycloalkyl(C₁-C₂)alkyl, hydroxy(C₃-C₆)cycloalkyl(C₁-C₂)alkyl, (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy, (C₃-C₆)cycloalkoxy, halo(C₃-C₆)cycloalkoxy, and heterocyclyl;

and the remainder of the values and particular values for Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa) are as described for the fifth set of values for Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa).

A tenth set of values for Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa) is provided in the following paragraphs:

G is OH, NH₂or NHR^e;

and the remainder of the values and particular values for Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa) are as described for the sixth set of values for Structural Formulas (III)-(VII) and Structural Formulas (IIIa)-(VIIa).

In a fourth specific embodiment, the aspartic protease inhibitor of the invention is represented by a structural formula selected from Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa), or an enantiomer, diastereomer or a pharmaceutically acceptable salt thereof:

Values and particular values for the variables in Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) are as provided for in Structural Formula (I) above.

A first set of values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) is described in the following paragraphs:

n is 0, 1, 2, or 3;

R¹¹is fluorine, chlorine, bromine, cyano, nitro, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, (C₅-C₇)cycloalkylalkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, halo(C₂-C₆)alkenyl, halo(C₃-C₆)alkynyl, halo(C₅-C₇)-cycloalkylalkynyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy and (C₁-C₆)alkanesulfonyl; or 2) phenyl, heteroaryl, phenoxy, heteroaryloxy, phenylthio, heteroarylthio, benzyl, heteroarylmethyl, benzyloxy and heteroarylmethoxy, each optionally substituted with 1 to 3 groups independently selected from: fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)-alkoxy, and halo(C₁-C₃)alkoxy, and aminocarbonyl; and the values and particular values for the remainder of the variables in Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) are as provided for Structural Formula (I) above.

A second set of values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) is provided in the following paragraphs:

G is OH, NH₂or NHR^e;

and the remainder of the values and particular values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) are as described for the first set of values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa).

A third set of values for the compounds represented by Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) is provide in the following paragraphs:

R⁵is (C₁-C₇)alkyl, halo(C₁-C₇)alkyl, hydroxy(C₁-C₇)alkyl, cyclohexylmethyl, halocyclohexylmethyl, hydroxylated cyclohexylmethyl, 2-(cyclohexyl)ethyl, (C₁-C₂)alkyl cyclohexylmethyl, di(C₁-C₂)alkyl cyclohexylmethyl, hydroxylated (C₁-C₂)alkyl cyclohexylmethyl, hydroxylated di(C₁-C₂)alkylcyclohexylmethyl, (3-noradamantyl)methyl, (tetrahydropyranyl)methyl, or oxepanyl methyl;

R⁶is —H or methyl;

G is NH₂or NHR^e;

R^eis methyl or R⁵and R^etogether are —(CH₂)₃— optionally substituted with C₁-C₄alkyl or cyclohexyl; and

the remainder of the values and particular values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) are as described for the first set of values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa).

A fourth set of values for the compounds of Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) is described in the following paragraphs:

R⁶is (C₁-C₇)alkyl, halo(C₁-C₇)alkyl, hydroxy(C₁-C₇)alkyl, cyclohexylmethyl, halocyclohexylmethyl, hydroxylated cyclohexylmethyl, 2-(cyclohexyl)ethyl, (C₁-C₂)alkyl cyclohexylmethyl, di(C₁-C₂)alkyl cyclohexylmethyl, hydroxylated (C₁-C₂)alkyl cyclohexylmethyl, hydroxylated di(C₁-C₂)alkylcyclohexylmethyl, (3-noradamantyl)methyl, (tetrahydropyranyl)methyl, or oxepanyl methyl;

R⁵is —H or methyl;

G is NH₂or NHR^e;

R^eis methyl or R⁵and R^etogether are —(CH₂)₃— optionally substituted with C₁-C₄alkyl or cyclohexyl; and

A fifth set of values for the compounds represented Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) is provided in the following paragraphs

R^2ais methyl or ethyl;

R¹¹is chloro, fluoro or methyl; and the remainder of the values and particular values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) are as described in the third set of values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa)

A sixth set of values for the compounds represented Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) is provided in the following paragraphs

R^2ais methyl or ethyl;

R¹¹is chloro, fluoro or methyl; and

the remainder of the values and particular values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) are as described in the fourth set of values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa).

A seventh set of values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) is described in the following paragraphs: one of R⁵and R⁶is H or methyl and the other is a) H, (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₄-C₁₀)cycloalkylalkyl, (C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, (C₄-C₁₀)bicycloalkyl(C₁-C₃)alkyl, (C₈-C₁₂)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl; or b) phenyl(C₁-C₂)alkyl, phenoxymethyl or heteroaryl(C₁-C₂)alkyl each optionally substituted with 1 to 3 groups independently selected from fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; and

the remainder of the values and particular values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) are as described in the first set of values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa).

A eighth set of values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) is described in the following paragraphs:

R⁶is H or methyl and R⁵is selected from a) H, (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₄-C₁₀)cycloalkylalkyl, (C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, (C₄-C₁₀)bicycloalkyl(C₁-C₃)alkyl, (C₈-C₁₂)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl; or b) phenyl(C₁-C₂)alkyl, phenoxymethyl or heteroaryl(C₁-C₂)alkyl each optionally substituted with 1 to 3 groups independently selected from fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; and

A ninth set of values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) is described in the following paragraphs:

R⁵is H or methyl and R⁶is selected from a) H, (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₄-C₁₀)cycloalkylalkyl, (C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₂)alkyl(C₄-C₁)cycloalkylalkyl, di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxy di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, (C₄-C₁₀)bicycloalkyl(C₁-C₃)alkyl, (C₈-C₁₂)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl; or b) phenyl(C₁-C₂)alkyl, phenoxymethyl or heteroaryl(C₁-C₂)alkyl each optionally substituted with 1 to 3 groups independently selected from fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; and

the remainder of the values and particular values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) are as described for the first set of values in Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa).

A tenth set of values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) is provided in the following paragraphs:

G is OH, NH₂or NHR^e;

and the remainder of the values and particular values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) are as described for the seventh set of values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa).

A eleventh set of values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) is provided in the following paragraphs:

G is OH, NH₂or NHR^e;

and the remainder of the values and particular values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) are as described for the eighth set of values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa).

A twelfth set of values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) is provided in the following paragraphs:

G is OH, NH₂or NHR^e;

and the remainder of the values and particular values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa) are as described for the ninth set of values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa).

In a fifth specific embodiment, the aspartic protease inhibitor of the invention is represented by a structural formula selected from Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa), or enantiomers, diastereomers or pharmaceutically acceptable salts thereof:

A first set of values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) is described in the following paragraphs:

m is 2 or 3; and

the remainder of the values and particular values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) are as described for the first set of values for Structural Formulas (VIII)-(XII) and Structural formulas (VIIIa)-(XIIa).

A second set of values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) is described in the following paragraphs:

m is 2 or 3; and

the remainder of the values and particular values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) are as described for the second set of values for Structural Formulas (VIII)-(XII) and Structural formulas (VIIIa)-(XIIa).

A third set of values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) is described in the following paragraphs:

m is 2 or 3; and

the remainder of the values and particular values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) are as described for the third set of values for Structural Formulas (VIII)-(XII) and Structural formulas (VIIIa)-(XIIa).

A fourth set of values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) is described in the following paragraphs:

m is 2 or 3; and

the remainder of the values and particular values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) are as described for the fourth set of values for Structural Formulas (VIII)-(XII) and Structural formulas (VIIIa)-(XIIa).

A fifth set of values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) is described in the following paragraphs:

m is 2 or 3; and

the remainder of the values and particular values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) are as described for the fifth set of values for Structural Formulas (VIII)-(XII) and Structural formulas (VIIIa)-(XIIa).

A sixth set of values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) is described in the following paragraphs:

m is 2 or 3; and

the remainder of the values and particular values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) are as described for the sixth set of values for Structural Formulas (VIII)-(XII) and Structural formulas (VIIIa)-(XIIa).

A seventh set of values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) is described in the following paragraphs:

m is 2 or 3; and the remainder of the values and particular values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) are as described for the seventh set of values for Structural Formulas (VIII)-(XII) and Structural formulas (VIIIa)-(XIIa).

An eighth set of values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) is described in the following paragraphs:

m is 2 or 3; and

the remainder of the values and particular values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) are as described for the eighth set of values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa).

A ninth set of values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) is described in the following paragraphs:

m is 2 or 3; and

the remainder of the values and particular values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) are as described for the ninth set of values for Structural Formulas (VIII)-(XII) and Structural Formulas (VIIIa)-(XIIa).

A tenth set of values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) is described in the following paragraphs:

m is 2 or 3; and

the remainder of the values and particular values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) are as described for the tenth set of values for Structural Formulas (VIII)-(XII) and Structural formulas (VIIIa)-(XIIa).

A eleventh set of values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) is described in the following paragraphs:

m is 2 or 3; and

the remainder of the values and particular values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) are as described for the eleventh set of values for Structural Formulas (VIII)-(XII) and Structural formulas (VIIIa)-(XIIa).

A twelfth set of values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) is described in the following paragraphs:

m is 2 or 3; and

the remainder of the values and particular values for Structural Formulas (XIII)-(XVII) and Structural Formulas (XIIIa)-(XVIIa) are as described for the twelfth set of values for Structural Formulas (VIII)-(XII) and Structural formulas (VIIIa)-(XIIa).

In a sixth embodiment, the aspartic protease inhibitor is represented by Structural Formula (XVIII) and enantiomers, diastereomer and pharmaceutically acceptable salts thereof:

A first set of values for Structural Formula (XVIII) is provided in the following paragraphs:

W═CH₂or O and Z═CH or N

one of R⁵and R⁶is —H or methyl and the other is as described for Structural Formula (I); and