Potent HIV Protease Inhibitor Containing a Tricyclic P2 Ligand

Abstract

Compounds of formula (I), pharmaceutical compositions comprising compounds of formula (I), and methods of treating HIV infection comprising administering an effective amount of one or more compounds of formula (I) or pharmaceutical compositions comprising them.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of priority of U.S. Provisional Patent Application No. 62 / 991,391, filed on March 18, 2020, which is hereby incorporated by reference in its entirety.

[0002] Description of Government Support This invention was made with government support under Grant No. AI150466 awarded by the National Institutes of Health. The government has certain rights in the invention.

Background Art

[0003] Background The AIDS pandemic is one of the most difficult problems in 21st - century medicine. Among the many strategies to combat this disease, highly active antiretroviral therapy (HAART) with HIV protease inhibitors (PIs) in combination with reverse transcriptase inhibitors (RTIs) has remained the primary treatment for the control of HIV infection. Such combination therapies have improved the quality of life, enhanced HIV management, and halted the progression of the disease, but many challenges remain in the treatment of this serious disease, including reducing both the toxicity and complexity of these treatment regimens. In addition, the number of patients expressing multi - drug - resistant strains of HIV is increasing. There is also sufficient evidence that these strains can be further transmitted.

[0004] HAART has had a major impact on the AIDS epidemic in industrialized countries, but has not led to the eradication of human immunodeficiency virus type 1 (HIV-1), in part due to viral reservoirs remaining in blood and infected tissues. The limitations of antiretroviral therapy for AIDS are also exacerbated by the complexity of regimens, the emergence of drug-resistant HIV-1 variants, and many specific adverse effects. Furthermore, attempts to achieve the maximum effect of HAART have faced numerous challenges, including (i) drug-related toxicity; (ii) partial restoration of immune function when an individual develops AIDS; (iii) the development of various cancers as a result of extended survival; (iv) an increase in inflammation (flame-up), i.e., immune reconstitution syndrome (IRS), in individuals receiving HAART; and (v) an increase in the cost of antiretroviral therapy. Such limitations of HAART are exacerbated by the emergence of drug-resistant HIV-1 variants.

[0005] There is currently a shortage of antiretroviral drugs or agents that are not only substantially specific for HIV-1 but also have no toxicity or side effects in the treatment of AIDS.

Summary of the Invention

[0006] Summary The present disclosure is directed to a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, prodrug, solvate, or inclusion complex thereof: TIFF0007702424000001.tif39128wherein, n is an integer from 0 to 3; G 1 and G 2 are each independently (-CHR 5 -) p and p is 0 or 1; X is (-CHR 5 -) m O-; m is 0, 1, or 2; X 3 is (-CHR 5 -) d O-; d is 1 or 2; X 1 and X 2 are each independently (-CHR 5 -) m ; each R 1 is independently alkyl, alkoxy, aryl, heterocyclyl, halo, hydroxy, or amino; R 2 is alkyl; R 3 is aryl, benzothiazole, benzoxazole, benzofuranyl, or indolyl; R 4 and R 4' are each independently H or alkyl; and each R 5 is independently H or alkyl.

[0007] The disclosure also relates to a pharmaceutical composition comprising a compound of formula (I).

[0008] The disclosure relates to a method of treating HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds of formula (I).

[0009] The disclosure also relates to a compound of formula (II) or a pharmaceutically acceptable salt, polymorph, prodrug, solvate, or inclusion complex thereof, which can function, inter alia, as a component for the various compounds described herein: TIFF0007702424000002.tif28128wherein the groups X, X 1 , X 2 , X 3 , G 1 , G 2 , R 4 , and R 4' are as defined herein; and wherein X 5 is hydroxy, alkoxy, amino, C(O)R, C(O)OR, OC(O)OR, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2) 0~2O(R)C(O)R, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 O(R)C(O)OR, (CH2) 0~2 O(R)C(O)OR, or (CH2) 0~2 selected from the group consisting of N(R)N(R)2, wherein each R is independently hydrogen, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, where any alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, or two R groups attached to one nitrogen atom or adjacent nitrogen atoms may together with the one or more nitrogen atoms form a heterocyclyl.

Mode for Carrying Out the Invention

[0010] Description The concepts of the present disclosure are shown and described in detail in the drawings and description herein, but the results in the drawings and their description should be considered illustrative rather than limiting the features; it is understood that only exemplary embodiments are shown and described and that protection is desired for all changes and modifications that fall within the spirit of the disclosure.

[0011] Compound The disclosure is directed to a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, prodrug, solvate, or inclusion complex thereof: TIFF0007702424000003.tif39128 wherein n is an integer from 0 to 3; G 1 and G 2 are each independently (-CHR 5 -), p wherein p is 0 or 1, and each R 5 is independently H or alkyl; X is (-CHR 5 -), m O-, where m is 0, 1, or 2, and each R 5 is independently H or alkyl; X3 is (-CHR 5 -), d where d is 1 or 2, and each R 5 is independently H or alkyl; X 1 and X 2 are each independently (-CHR 5 -), m where m is 0, 1, or 2, and each R 5 is independently H or alkyl; each R 1 is independently alkyl, alkoxy, aryl, heterocyclyl, halo, hydroxy, or amino; R 2 is alkyl; R 3 is aryl, benzothiazole, benzoxazole, benzofuranyl, or indolyl; and R 4 and R 4' are each independently H or alkyl. In some instances, n is 0. Additionally, (i) X 1 can be (-CHR 5 -) when m is 2, X m can be (-CHR 2 -) when m is 1, and each R 5 is as defined herein, either the same or different; (ii) X m and X 5 can be (-CHR 1 -) where each m is 1 and each R 2 is as defined herein, either the same or different; (iii) X 5 can be (-CHR 5 -) when m is 0, X m can be (-CHR 1 -) when m is 1, and each R 5 is as defined herein, either the same or different; or (iv) X m and X 2 can be (-CHR 5 -) when m is 0, provided that G m is as defined herein, either the same or different; or (iv) X 5 and X 1 can be (-CHR 2 -) when m is 0, provided that G 5 is (-CHR m -), provided that G1 and G 2 at least one of which is (-CHR 5 -) p wherein at least one p is 1 and each R 5 is independently H or alkyl.

[0012] In any of (i), (ii), (iii), or (iv), X can be O, X 3 can be O, or X and X 3 can be O. Additionally, in any of (i), (ii), (iii), or (iv), at least one p is 0 such that at least one of G 1 and G 2 is a bond. In any of the foregoing examples, R 4 and R 4' can each independently be H or alkyl. For example, R 4 can be H. In another example, R 4' can be H. In yet another example, R 4 and R 4' are each H. In another example, each p is 0; X and X 3 are each O, X 1 and X 2 are each independently (-CHR 5 -) m and R 4 and R 4' are each H. In yet another example, each p is 1; X and X 3 are each O, X 1 and X 2 are each independently (-CHR 5 -) m and R 4 and R 4' are each H. In another example, when the compound of formula (I) is the compound of formula: TIFF0007702424000004.tif32128, each p is 0; X and X 3 are each O; X 1 and X 2each independently has m = 1 (-CH2-) m and R 4 and R 4' are each H. In yet another example, when the compound of formula (I) is the compound of formula: TIFF0007702424000005.tif32128, G 1 and G 2 each independently has p = 1 (-CH2-) p and X is (-CH2-) m O-, where m = 1; X 3 is O; X 1 and X 2 are each a bond; and R 4 and R 4' are each H.

[0013] All diastereomers of the compounds of formula (I) or their pharmaceutically acceptable salts, polymorphs, prodrugs, solvates, or inclusion complexes are contemplated herein, including: TIFF0007702424000006.tif149128 wherein n is an integer from 0 to 3; G 1 and G 2 are each independently (-CHR 5 -) p where p is 0 or 1 and each R 5 is independently H or alkyl; X is (-CHR 5 -) m O- where m is 0, 1, or 2 and each R 5 is independently H or alkyl; X 3 is (-CHR 5 -) d O- where d is 1 or 2 and each R 5 is independently H or alkyl; X 1 and X 2 are each independently (-CHR 5 -) m where m is 0, 1, or 2 and each R 5 is independently H or alkyl; each R1 is independently alkyl, alkoxy, aryl, heterocyclyl, halo, hydroxy, or amino; R 2 is alkyl; R 3 is aryl, benzothiazole, benzoxazole, benzofuranyl, or indolyl; and R 4 is H, alkyl, or alkoxy. In some instances, n is 0. Additionally, (i) X 1 can be, where m is 2 (-CHR 5 -), m X 2 can be, where m is 1 (-CHR 5 -), m and each R 5 is the same or different as defined herein; (ii) X 1 and X 2 can each be, where each m is 1 and each R 5 is the same or different as defined herein (-CHR 5 -); m (iii) X 1 can be, where m is 0 (-CHR 5 -), m X 2 can be, where m is 1 (-CHR 5 -), m and each R 5 is the same or different as defined herein; or (iv) X 1 and X 2 can be, where m is 0 (-CHR 5 -), m provided that at least one of G 1 and G 2 is (-CHR 5 -), p where at least one p is 1 and each R 5 is independently H or alkyl.

[0014] In any of cases (i), (ii), (iii), or (iv), X can be O, or X 3 can be O, or X and X3 may be O. In addition, in any of (i), (ii), (iii), or (iv), at least one p is 0 such that at least one of G 1 and G 2 is a bond. In any of the foregoing examples, R 4 and R 4' may each independently be H or alkyl. For example, R 4 may be H. In another example, R 4' may be H. In yet another example, R 4 and R 4' are each H. In another example, each p is 0; X and X 3 are each O; X 1 and X 2 are each independently (-CHR 5 -) m ; and R 4 and R 4' are each H. In yet another example, each p is 1; X and X 3 are each O; X 1 and X 2 are each independently (-CHR 5 -) m ; and R 4 and R 4' are each H. In another example, the compound of formula (I) is of the formula: TIFF0007702424000007.tif71128 such that each p is 0; X and X 3 are each O; X 1 and X 2 are each independently (-CH2-) m ; m is 1; and R 4 and R 4' are each H. In yet another example, the compound of formula (I) is of the formula: TIFF0007702424000008.tif68128 such that G 1 and G 2 are each (-CH2-) p ; p is 1; X is (-CH2-) mis O, where m is 1; X 3 is O; X 1 and X 2 are each a bond; and R 4 and R 4' are each H.

[0015] In any of the examples disclosed herein, R 3 can be unsubstituted or substituted aryl. R 3 can be, for example, phenyl. However, R 3 can be substituted aryl. The substituted aryl group represented by R 3 in this specification can be selected from the group consisting of, for example: TIFF0007702424000009.tif86128.

[0016] In any of the examples disclosed herein, R 3 is benzothiazole or benzoxazole: TIFF0007702424000010.tif13128, and wherein R 6 is alkyl (e.g., C1-C6 alkyl), alkylamino (e.g., C1-C6 alkylamino), cycloalkylamino (e.g., C3-C6 cycloalkylamino), cycloalkylheterocycloamino (e.g., C3-C6 cycloalkyl-C3-C6 heterocycloamino), heterocyclocycloalkylamino (e.g., C3-C6 heterocyclo-C3-C6 cycloalkylamino), or heterocycloamino (e.g., C3-C6 heterocycloamino); and X 4 is S, O, or NR 7 where R 7 is H, alkyl, cycloalkyl, or alkylaryl. X 4 can be S or O.

[0017] Examples of the compound of formula (I) are of the formula: TIFF0007702424000011.tif133143TIFF0007702424000012.tif192141TIFF0007702424000013.tif31144 includes, without limitation, the compound or its pharmaceutically acceptable salts, polymorphs, prodrugs, solvates, or inclusion compounds.

[0018] The present disclosure also relates to compounds of formula (II) or pharmaceutically acceptable salts, polymorphs, prodrugs, solvates, or inclusion compounds thereof that can function as components for the various compounds described herein, inter alia: TIFF0007702424000014.tif28128 wherein the groups X, X 1 , X 2 , X 3 , G 1 , G 2 , and R 4 are as defined herein; and wherein X 5 is selected from the group consisting of hydroxy, alkoxy, amino, C(O)R, C(O)OR, OC(O)OR, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2) 0~2 O(R)C(O)R, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 O(R)C(O)OR, (CH2) 0~2 O(R)C(O)OR, or (CH2) 0~2 N(R)N(R)2, wherein each R is independently hydrogen, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, wherein any alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, or two R groups bonded to one nitrogen atom or adjacent nitrogen atoms may together with the one or more nitrogen atoms form a heterocyclyl.

[0019] The compound of formula (II) is X 1 is, when m is 2, (-CHR5 -) m where X 2 is (-CHR 5 -) when m is 1; m ; X 1 and X 2 are each (-CHR 5 -) when each m is 1; m ; X 1 is (-CHR 5 -) when m is 0, and X m is (-CHR 2 -) when m is 1; or 5 -) m X and X 1 are each (-CHR 2 -) when m is 0, provided that at least one of G 5 -) m and G 1 is (-CHR 2 -) where at least one p is 1, 5 -) p and the compound of formula (II) may be such a compound. The compound of formula (II) may be a compound of formula (II) where

[0020] X is O; X is O; or 3 X and X are O, 3 and the compound of formula (II) may be such a compound. The compound of formula (II) may be a compound of formula (II) where at least one p is 0 such that at least one of G

[0021] and G 1 is a bond. 2 The compound of formula (II) may be a compound of formula (II) where R

[0022] and R 4 are each independently H or alkyl. 4' The compound of formula (II) may be such a compound.

[0023] The compound of formula (II) is each p is 0; X and X 3 are each O, X 1 and X 2 are each independently (-CHR 5 -) m ; and R 4 and R 4' are each H, which may be a compound of formula (II).

[0024] The compound of formula (II) may be a compound of the formula: TIFF0007702424000015.tif38128 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate, or inclusion complex thereof.

[0025] All diastereomers of the compound of formula (II) or their pharmaceutically acceptable salts, polymorphs, prodrugs, solvates, or inclusion complexes, including the following, are contemplated herein: TIFF0007702424000016.tif69128 wherein X, X 1 ~X 3 X 5 R 4 and R 4' are as defined herein.

[0026] Pharmaceutical composition Also provided are pharmaceutical compositions comprising one or more compounds described herein (e.g., compounds of formula (I)) and one or more pharmaceutically acceptable carriers, diluents, excipients, or combinations thereof. A "pharmaceutical composition" refers to a chemical or biological composition suitable for administration to a subject (e.g., a mammal such as a human). Such compositions may be formulated for administration via one or more of a number of routes including, but not limited to, buccal, dermal, topical, epidural, infusion, inhalation, intraarterial, intracardiac, intraventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, pulmonary, rectal via enema or suppository, subcutaneous, subdermal, sublingual, transdermal, and transmucosal. Additionally, administration can be effected by means of capsules, drops, foams, gels, gums, injections, liquids, patches, pills, porous pouches, powders, tablets, or other suitable means of administration.

[0027] A "pharmaceutical excipient" or "pharmaceutically acceptable excipient" includes a carrier, which may in some cases be a liquid, in which the active therapeutic agent is formulated. Generally, excipients impart chemical and / or biological stability and release characteristics to the formulation, but do not impart any pharmacological activity. Examples of suitable formulations can be found, for example, in Remington, The Science And Practice of Pharmacy, 20th Edition, (Gennaro, A. R., Chief Editor), Philadelphia College of Pharmacy and Science, 2000, which is incorporated herein by reference in its entirety.

[0028] As used herein, "pharmaceutically acceptable carrier" or "excipient" includes any physiologically compatible solvent, dispersion medium, coating, antibacterial and antifungal agents, as well as isotonic and absorption delaying agents. In one aspect, the carrier is suitable for parenteral administration. Alternatively, the carrier may be suitable for intravenous, intraperitoneal, intramuscular, sublingual, or oral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions, and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. The use of such media and agents for pharmaceutically active substances is well known in the art. Their use in the pharmaceutical compositions of the invention is contemplated, except where any conventional media or agent is incompatible with the active compound. Auxiliary active compounds can also be incorporated into the compositions.

[0029] The pharmaceutical compositions may be sterile and may be stable under the conditions of manufacture and storage. The compositions can be formulated as solutions, microemulsions, liposomes, or other ordered structures suitable for high drug concentrations. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0030] In some cases, tonicity agents can be included in the pharmaceutical composition. For example, sugars, polyhydric alcohols such as mannitol, sorbitol, or sodium chloride can be included in the composition. Prolonged absorption of an injectable composition can be brought about by including agents that retard absorption, such as monostearates and gelatin, in the composition. Further, the compounds described herein can be formulated into sustained release formulations, for example, compositions containing sustained release polymers. The active compounds can be prepared using carriers that protect the compound from rapid release, such as controlled release formulations including implants and microencapsulation delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and polylactic acid - polyglycolic acid copolymer (PLG) may be used. Many methods for the preparation of such formulations are known to those skilled in the art.

[0031] Oral dosage forms are also contemplated herein. The pharmaceutical composition can be orally administered as capsules (hard or soft), tablets (film - coated, enteric - coated, or uncoated), powders or granules (coated or uncoated), or solutions (solutions or suspensions). The formulations can be readily prepared by any of the methods well - known in the art. The pharmaceutical composition can include one or more suitable manufacturing aids or excipients, including fillers, binders, disintegrants, lubricants, diluents, glidants, buffers, wetting agents, preservatives, coloring agents, sweeteners, flavoring agents, and pharmaceutically compatible carriers.

[0032] For each of the described embodiments, the compounds can be administered in various dosage forms known in the art. Biologically acceptable dosage forms known to those skilled in the art and combinations thereof are contemplated. Examples of such dosage forms include chewable tablets, fast-dissolving tablets, effervescent tablets, reconstitutable powders, elixirs, solutions, suspensions, emulsions, tablets, multilayer tablets, bilayer tablets, capsules, soft gelatin capsules, hard gelatin capsules, caplets, lozenges, chewable lozenges, beads, powders, gums, granules, pellets, microparticles, dispersible granules, cachets, infusions, suppositories, creams, topical agents, inhalants, aerosol inhalants, patches, particle inhalants, implants, depot implants, oral agents, injections (including subcutaneous, intramuscular, intravenous, and intradermal), infusions, and combinations thereof, including but not limited to these.

[0033] Other compounds that can be included by mixing are, for example, medicinally inactive components (e.g., solid and liquid diluents) such as lactose, dextrose saccharose, cellulose, starch or calcium phosphate for tablets or capsules, olive oil or ethyl oleate for soft capsules, water or vegetable oil for suspensions or emulsions; lubricants such as silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycol; gelling agents such as colloidal clay; thickening agents such as tragacanth gum or sodium alginate, binders such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrants such as starch, alginic acid, alginate or sodium starch glycolate; foaming agents; dyes; sweeteners; wetting agents such as lecithin, polysorbate or lauryl sulfate; and other therapeutically acceptable auxiliary components that are known additives for such formulations, such as humectants, preservatives, buffers and antioxidants.

[0034] The dispersion for oral administration can be a syrup, an emulsion, a solution, or a suspension. The syrup can contain, as a carrier, for example, sucrose or a combination of sucrose with glycerol and / or mannitol and / or sorbitol. The suspension and the emulsion can contain a carrier such as natural gums, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

[0035] The amount of the active compound in the therapeutic composition according to various aspects may vary depending on factors such as the individual's medical condition, age, gender, weight, medical history, risk factors, predisposition to the disease, route of administration, existing treatment regimen (e.g., the possibility of interaction with other drugs), and weight. The dosing regimen can be adjusted to provide an optimal therapeutic response. For example, a single bolus dose can be administered, several divided doses can be administered over time, or the dose can be increased or decreased in proportion to the urgency of the treatment situation.

[0036] As used herein, the term "dosage unit form" refers to physically discrete units suitable as a single dose for a mammalian subject to be treated; each unit contains a predetermined quantity of the active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification of the dosage unit forms of the invention is determined by and directly dependent on the unique properties of the active compound and the particular therapeutic effect to be achieved, as well as the limitations inherent in the art of compounding such active compounds for the treatment of sensitivity in individuals. In the therapeutic use for the treatment of conditions in mammals (e.g., humans) in which the compounds or their suitable pharmaceutical compositions described in various aspects herein are effective, the compounds described in various aspects herein can be administered in an effective amount. A suitable dosage for the present invention can be the composition, the pharmaceutical composition, or other compositions described herein.

[0037] The dosage can be administered once, twice, or three times a day, although more frequent dosing intervals are possible. The dosage can be administered daily, every two days, every three days, every four days, every five days, every six days, and / or every seven days (once a week). In one embodiment, the dosage can be administered daily for up to 30 days, preferably for 7 to 10 days. In another embodiment, the dosage can be administered twice a day for 10 days. If the patient requires treatment for a chronic disease or condition, the dosage can be administered as long as the signs and / or symptoms persist. The patient may also require "maintenance therapy" in which the patient is given the dosage daily for months, years, or a lifetime. In addition, the composition can be administered to prevent recurrence of symptoms. For example, the dosage can be administered once or twice a day, particularly for asymptomatic patients, to prevent the occurrence of symptoms in at-risk patients.

[0038] The compositions described herein may be administered by any of the following routes: buccal, on the skin, epidural, injection, inhalation, intra-arterial, intracardiac, intraventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, pulmonary, rectal via enema or suppository, subcutaneous, subdermal, sublingual, transdermal, and transmucosal. Preferred routes of administration are buccal and oral. Administration may be local, where the composition is administered directly, in the vicinity, locally, near, at, around, or in the neighborhood of the site of the disease, e.g., inflammation, or systemic, where the composition is given to the patient and spreads throughout the body, thereby reaching the site of the disease. Local administration may be to cells, tissues, organs, and / or organ systems that contain and / or are affected by the disease and / or in which the signs and / or symptoms of the disease are active or likely to occur. Administration may be local with a local effect, i.e., the composition is applied directly to the place where its action is desired. Administration may be enteral, in which case the desired effect is systemic (non-local), e.g., the composition may be delivered via the digestive tract. Administration may be parenteral, in which case the desired effect is systemic, e.g., the composition is delivered by a route other than the digestive tract.

[0039] Method of treatment Compositions comprising a therapeutically effective amount of one or more compounds of the various aspects described herein (e.g., a compound of formula (I)) are also contemplated. The compositions are useful in a method for treating HIV (e.g., HIV-1) infection or AIDS, the method comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds described herein. The use of one or more compounds described herein as a medicament for treating a patient in need of alleviation of HIV infection or AIDS is also contemplated herein.

[0040] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to an amount of one or more of the compounds described herein (e.g., a compound of formula (I)) that produces a biological or medical response, including alleviation of the symptoms of a disease or disorder being treated, as determined by a researcher, veterinarian, physician, or other clinician in a tissue system, animal, or human. In some embodiments, a therapeutically effective amount is an amount that can treat or alleviate a disease or the symptoms of a disease at a reasonable benefit / risk ratio applicable to any medical treatment. However, it should be understood that the total daily dosage of the compounds and compositions described herein can be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dosage level for any particular patient will vary depending on a variety of factors, including the condition being treated and the severity of the condition; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender, and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; and other drugs used in combination with or concurrently with the specific compound employed, factors well known to researchers, veterinarians, physicians, or other clinicians. It is also recognized that a therapeutically effective amount can be selected in view of any toxicity or other adverse side effects that may occur upon administration of one or more of the compounds described herein.

[0041] The compounds described herein can have an HIV-1 protease inhibition constant (K i ) of from about 1 fM to about 200 nM (e.g., from about 100 fM to about 200 nM, from about 100 fM to about 100 pM, from about 250 fM to about 100 pM, from about 500 fM to about 5 pM, from about 5 pM to about 100 pM, from about 50 pM to about 250 pM, from about 500 pM to about 100 nM, or from about 300 pM to about 75 nM).

[0042] Alternatively, or in addition, the compounds described herein can have a 50% inhibitory concentration (IC LAI ) against wild-type laboratory strain HIV-1 in vitro 50) has antiviral activity with an IC of about 1 fM to about 200 nM (for example, about 100 fM to about 200 nM, about 100 fM to about 100 pM, about 250 fM to about 100 pM, about 500 fM to about 5 pM, about 10 pM to about 50 nM, about 10 pM to about 500 pM, about 100 pM to about 750 pM, about 500 pM to about 1 nM or about 500 pM to about 50 nM).

[0043] Alternatively, or in addition, the compounds described herein have an antiviral IC of about 200 fM to about 100 nM (for example, about 200 fM to about 600 fM, about 200 fM to about 50 pM, about 500 fM to about 500 pM, about 300 fM to about 1 pM) against darunavir-resistant HIV-1 variants (for example, NL4-3R, DRV R P20, DRV R P30, and DRV R P51). 50

[0044] Alternatively, or in addition, the compounds described herein have an IC of about 50 pM to about 50 nM (for example, about 100 pM to about 50 nM or about 500 pM to about 10 nM) against darunavir-resistant HIV-1 variants (for example, NL4-3R, DRV R P20, DRV R P30, and DRV R P51). In yet another aspect, the compounds of the various aspects described herein have an antiviral IC of about 1 nM to about 100 nM (for example, about 10 nM to about 75 nM or about 10 nM to about 75 nM) against darunavir-resistant HIV-1 protease (for example, NL4-3R, DRV 50 P20, DRV R P30, and DRV R P51). R 50

[0045] Values expressed in a range format should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also all individual numerical values or sub-ranges included within that range, as if each numerical value and sub-range were explicitly recited. For example, a range of "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not only about 0.1% to about 5%, but also the individual values within the indicated range (e.g., 1%, 2%, 3%, and 4%) and sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%). The expression "about X to Y" has the same meaning as "about X to about Y" unless otherwise specified. Similarly, the expression "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z" unless otherwise specified.

[0046] Additional Definitions In this book, the terms "a", "an", or "the" are used to include one or more, unless the context clearly indicates otherwise. The term "or" is used to mean non-exclusive "or", unless otherwise specified. The inventions exemplified in this specification may be suitably practiced in the absence of any element or limitation not specifically disclosed herein. Thus, for example, any of the terms "comprising", "consisting essentially of", and "consisting of" may be replaced by either of the other two terms. In addition, it should be understood that the expressions or terms employed herein and not otherwise defined are for illustrative purposes only and not for purposes of limitation. Any use of section headings is intended to aid in the reading of the document and is not to be construed as limiting. Further, information related to a section heading may be found within and outside that particular section. Still further, all publications, patents, and patent documents referred to in this book are hereby incorporated by reference in their entirety as if individually incorporated by reference. Where there is a conflict in usage between this book and the documents so incorporated by reference, the usage in the incorporated reference is to be considered as supplementing the usage in this book, and for irreconcilable conflicts, the usage in this book prevails.

[0047] In the methods described herein, steps may be performed in any order, unless the temporal or operational sequence is explicitly stated, provided that no departure from the principles of the invention occurs. Further, specified steps may be performed simultaneously, unless the claim language explicitly states that they are to be performed separately. For example, the step of performing X and the step of performing Y in a claim may be performed simultaneously within a single operation, and the resulting process will be encompassed within the scope of the claim language for the process.

[0048] The term "about" may tolerate a degree of variation in a value or range, for example, within 10%, 5%, or 1% of the recited value or the limits of the recited range.

[0049] The term "substantially" refers to a majority or almost all of, for example, at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more.

[0050] The term "substituted" or "substituent" refers to a group that can be or is substituted on a molecule or another group (e.g., an aryl or alkyl group). Examples of substituents are halogen (e.g., F, Cl, Br, and I), OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azide, CF3, OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, -(CH2) 0~2 P(O)(OR)2, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)C(O)OR, (CH2) 0~2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, or C(=NOR)R, including without limitation, where each R is independently hydrogen, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, and where any alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, or two R groups bonded to one nitrogen atom or adjacent nitrogen atoms may together with the one or more nitrogen atoms form a heterocyclyl, which may be mono-substituted or independently multi-substituted.

[0051] The term "alkyl" refers to substituted or unsubstituted straight-chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms (C1-C 40 ), from 1 to about 20 carbon atoms (C1-C 20 ), from 1 to 12 carbon atoms (C1-C 12 ), from 1 to 8 carbon atoms (C1-C8), or in some embodiments, from 1 to 6 carbon atoms (C1-C6). Examples of straight-chain alkyl groups include those having from 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, without limitation, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. The term "alkyl" encompasses n-alkyl, isoalkyl, and anteisoalkyl groups and other branched forms of alkyl. Representative substituted alkyl groups may be substituted one or more times with any of the groups enumerated herein, such as amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0052] The term "cycloalkyl" refers to substituted or unsubstituted cyclic alkyl groups such as, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have from 3 to about 8 to 12 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. In some embodiments, the cycloalkyl group can have from 3 to 6 carbon atoms (C3-C6). The cycloalkyl group further includes, for example, without limitation, polycyclic cycloalkyl groups such as norbornyl, adamantyl, bornyl, camphyl, isocampphyl, and carenyl groups, and fused rings such as, without limitation, decalinyl.

[0053] The term "cycloalkylalkyl" refers to a substituted or unsubstituted alkyl group as defined herein, wherein a hydrogen or carbon bond of the alkyl group as defined herein is replaced by a bond to a cycloalkyl group as defined herein. Representative cycloalkylalkyl groups include, without limitation, cyclopentylalkyl.

[0054] The term "acyl" refers to a group containing a carbonyl moiety and attached via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom which may be part of, for example, a substituted or unsubstituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group. In the special case where the carbonyl carbon atom is bonded to hydrogen, this group is the "formyl" group which is an acyl group as defined herein. The acyl group may contain from 0 to about 12 - 40, 6 - 10, 1 - 5 or 2 - 5 additional carbon atoms bonded to the carbonyl group. The acryloyl group is an example of an acyl group. The acyl group may also contain heteroatoms within the meaning herein. The nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups. When the group containing a carbon atom bonded to the carbonyl carbon atom contains a halogen, the group is called a "haloacyl" group. An example is the trifluoroacetyl group.

[0055] The term "aryl" refers to a substituted or unsubstituted cyclic aromatic hydrocarbon that does not contain a heteroatom within the ring. Thus, aryl groups include, without limitation, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylene, anthracenyl, and naphthyl groups. In some embodiments, the aryl group contains from about 6 to about 14 carbons (C6 - C 14 ) or 6 to 10 carbon atoms (C6 - C 10 ) in the ring portion of the group. The aryl group may be unsubstituted or substituted as defined herein. Representative substituted aryl groups may be mono-substituted or substituted more than once, and include, without limitation, 2, 3, 4, 5, or 6-substituted phenyl or 2 - 8-substituted naphthyl groups, which may be substituted with carbon or non-carbon groups such as those listed herein.

[0056] The terms "aralkyl" and "arylalkyl" refer to an alkyl group as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups, and fused (cycloalkylaryl) alkyl groups such as 4-ethyl-indanyl. An aralkenyl group is an alkenyl group as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined herein.

[0057] The terms "heterocyclyl" or "heterocyclo" refer to substituted or unsubstituted aromatic and non-aromatic ring compounds containing three or more ring members, one or more (e.g., 1, 2, or 3) of which are heteroatoms, such as, without limitation, N, O, and S. Thus, heterocyclyl can be cycloheteroalkyl or heteroaryl, or in the case of polycyclic, any combination thereof. In some embodiments, the heterocyclyl group contains from 3 to about 20 ring members, while another heterocyclyl group contains from 3 to about 15 ring members. In some embodiments, the heterocyclyl group includes a heterocyclyl group containing from 3 to 8 carbon atoms (C3-C8), from 3 to 6 carbon atoms (C3-C6), from 3 to 5 carbon atoms (C3-C5), or from 6 to 8 carbon atoms (C6-C8). A heterocyclyl group designated as C2-heterocyclyl can be, for example, a 5-membered ring with 2 carbon atoms and 3 heteroatoms, a 6-membered ring with 2 carbon atoms and 4 heteroatoms, and the like. Similarly, C4-heterocyclyl can be, for example, a 5-membered ring with 1 heteroatom, a 6-membered ring with 2 heteroatoms, and the like. The sum of the number of carbon atoms and the number of heteroatoms is equal to the total number of ring atoms. The heterocyclyl ring can also contain one or more double bonds. Heteroaryl ring is one embodiment of the heterocyclyl group. The expression "heterocyclyl group" includes fused ring species, including those containing fused aromatic and non-aromatic groups. Representative heterocyclyl groups include, without limitation, pyrrolidinyl, azetidinyl, piperidynyl, piperazinyl, morpholinyl, chromanyl, indolinonyl, isoindolinonyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, triazyolyl, tetrazolyl, benzoxazolinyl, benzthiazolinyl, and benzimidazolinyl groups. Examples of indolinonyl groups include groups having the general formula: TIFF0007702424000017.tif20128, wherein R is as defined herein. Examples of isoindolinonyl groups include the general formula: It contains a group having TIFF0007702424000018.tif18128, where R is as defined herein. Examples of benzoxazolinyl groups are of the general formula: It contains a group having TIFF0007702424000019.tif13128, where R is as defined herein. Examples of benzothiazolinyl groups are of the general formula: It contains a group having TIFF0007702424000020.tif13128, where R is as defined herein. In some embodiments, the group R in benzoxazolinyl and benzothiazolinyl groups is an N(R)2 group. In some embodiments, each R is hydrogen or alkyl, where the alkyl group is substituted or unsubstituted. In some embodiments, the alkyl group is substituted with a heterocyclyl group (e.g., a pyrrolidinyl group).

[0058] The term "heterocyclylalkyl" refers to an alkyl group as defined herein, wherein a hydrogen or carbon bond of the alkyl group is replaced by a bond to a heterocyclyl group as defined herein. Representative heterocyclylalkyl groups include, without limitation, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylmethyl, and indol-2-ylpropyl.

[0059] The term "heterocyclylalkoxy" refers to an alkyl group where a hydrogen or carbon bond of the alkyl group is replaced by a bond to a heterocyclyl group and the alkyl group is bonded to oxygen. Representative heterocyclylalkoxy groups are -O-(CH2) q Containing heterocyclyl without limitation, where q is an integer from 1 to 5. In some embodiments, the heterocyclylalkoxy group is -O-(CH2) such as -O-CH2CH2-morpholine q Containing morpholinyl.

[0060] The term "heteroarylalkyl" refers to an alkyl group in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to a heteroaryl group as defined herein.

[0061] The term "alkoxy" refers to an oxygen atom connected to an alkyl group that includes a cycloalkyl group as defined herein. Examples of straight-chain alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc. Examples of branched alkoxy include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, etc. Examples of cyclic alkoxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. An alkoxy group can contain from 1 to about 12-20 or about 12-40 carbon atoms bonded to the oxygen atom, can further contain double or triple bonds, and can also contain heteroatoms. For example, an allyloxy group is an alkoxy group. A methoxyethoxy group is also an alkoxy group, and a methylenedioxy group is also the same in the context where two adjacent atoms in a certain structure are substituted thereby.

[0062] The term "amine" refers to primary, secondary, and tertiary amines having, for example, the formula N(group)3, where each group can independently be H or other than H, for example, alkyl, aryl, etc. Amines include R-NH2, for example, alkylamine, arylamine, alkylarylamine; R2NH as defined herein, for example, dialkylamine, diarylamine, aralkylamine, heterocyclylamine, etc.; and R3N where each R is independently selected, for example, trialkylamine, dialkylarylamine, alkyldiarylamine, triarylamine, etc. The term "amine" also includes ammonium ions as used herein.

[0063] The term "amino group" means -NH2, -NHR, -NR2, -NR3 where each R is as defined herein +Substituents of the form, and non-protonatable -NR3 + Each protonated form except is meant. Thus, any compound substituted with an amino group can be regarded as an amine. "Amino group" can be a primary, secondary, tertiary, or quaternary amino group. "Alkylamino" groups include monoalkylamino, dialkylamino, and trialkylamino groups.

[0064] Examples of "alkylamino" are -NH-alkyl and -N(alkyl)2.

[0065] Examples of "cycloalkylamino" groups are -NH-cycloalkyl and -N(cycloalkyl)2.

[0066] Examples of "cycloalkylheterocycloamino" groups are -NH-(heterocyclocycloalkyl), where the heterocyclic group is bonded to nitrogen and the cycloalkyl group is bonded to the heterocyclic group.

[0067] Examples of "heterocyclocycloamino" groups are -NH-(cycloalkylheterocycle), where the cycloalkyl group is bonded to nitrogen and the heterocyclic group is bonded to the cycloalkyl group.

[0068] The terms "halo", "halogen", and "halide" groups mean fluorine, chlorine, bromine, or iodine atoms, either by themselves or as part of another substituent, unless otherwise specified.

[0069] The term "haloalkyl" group includes monohaloalkyl groups, polyhaloalkyl groups where the halo atoms may be the same or different, and perhaloalkyl groups where all hydrogen atoms are replaced by halogen atoms such as fluorine. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, -CF(CH3)2, etc.

[0070] The terms "salt" and "pharmaceutically acceptable salt" refer to derivatives of the disclosed compounds in which the parent compound is modified by formation of its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines, and alkali or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts are derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acid; and organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, and isethionic acid, etc.

[0071] Pharmaceutically acceptable salts can be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods. In some cases, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, the disclosure of which is hereby incorporated by reference.

[0072] The term "solvate" means a compound or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0073] The term "clathrate" means a chemical substance consisting of a lattice that captures or encloses a molecule. A clathrate can be a polymer, or it can be a host-guest complex and an inclusion compound. A clathrate can be an inclusion compound in which a guest molecule is present within a cage formed by a host molecule or by the lattice of the host molecule.

[0074] The term "polymorph" refers to a specific form of a compound. For example, a polymorph may represent a crystalline form in which, under different crystallization conditions, environmental conditions, hygroscopic activity of the compound, etc., pharmaceutically relevant physical properties may differ between one form and another.

[0075] The term "prodrug" means a derivative of a compound that can undergo hydrolysis, oxidation, or react in some way under biological conditions (in vitro or in vivo) to provide an active compound. Examples of prodrugs include derivatives and metabolites of compounds containing biodegradable moieties such as biodegradable amides, biodegradable esters, biodegradable carbamates, biodegradable carbonates, biodegradable ureas, and biodegradable phosphate analogs. Specific prodrugs of compounds having a carboxyl functional group are lower alkyl esters of carboxylic acids. Carboxylic acid esters are readily formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well-known methods such as those described in Burger's Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers GmbH).

[0076] The term "patient" or "subject" refers to a mammal suffering from a disease, disorder, or condition. The patient or subject can be a primate, dog, cat, or horse. The patient or subject can be a bird. The bird can be a domesticated bird such as a chicken. The bird can be a poultry. The patient or subject can be a human.

[0077] All patents, patent application publications, journal articles, textbooks, and other publications mentioned in the specification indicate the level of skill of those skilled in the art in the relevant field of disclosure. All such publications are incorporated herein by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

Examples

[0078] The present invention can be better understood by referring to the following examples presented as illustrations. The present invention is not limited to the examples provided herein.

[0079] Introduction The synthetic methods for the optically active synthesis of various ligands described herein are shown in Scheme 1. The enantiomeric ligand 6 can be obtained from the functionalized cyclohexane-1,2-diol derivative 7. Structure 7 can be obtained from the cyclohexene derivative 9 by an asymmetric dihydroxylation reaction. The optically active aldehyde derivative can be readily derived from the meso-diol derivative 8 by enzymatic asymmetricization as an important reaction. The meso-diol 9 can be derived from the commercially available and inexpensive 1,2,3,6-tetrahydrophthalic anhydride 10. TIFF0007702424000021.tif84128

[0080] The synthesis of the optically active ligand 6 is shown in Scheme 2. Meso-1,2,3,6-tetrahydrophthalic anhydride 10 was reduced with LiAlH4 in THF at 0 °C for 3 hours to obtain the meso-diol derivative 9 on a several-gram scale. The diol 9 was subjected to an enzymatic asymmetric reaction using porcine pancreatic lipase (PPL) in ethyl acetate at 23 °C for 12 hours, and the monoacetate derivative 11 was obtained on a gram scale in a yield of 82% and 95% ee as determined by HPLC analysis. 37 An aldehyde was obtained by the Swern oxidation of the alcohol 11, which was reacted with trimethyl orthoformate in the presence of a catalytic amount of tetrabutylammonium bromide (TBAB) at 23 °C for 8 hours to obtain the dimethyl acetal derivative 12 in a yield of 76% in two steps. For the diastereoselective dihydroxylation, Sharpless asymmetric dihydroxylation was carried out using AD-mix-β. Thus, a 1:1 mixture of diastereomeric diols was obtained by the reaction of 12 and AD-mix-β in a mixture of t-butanol and water (1:1) at 0 °C to 23 °C for 24 hours. The obtained diol was subjected to saponification with 1N aqueous NaOH solution in MeOH at 0 °C to 23 °C for 3 hours to obtain the triol derivatives 13 and 14 in a yield of 90% in two steps. These triol derivatives were separated by silica gel chromatography using 5% MeOH in CH2Cl2 as the eluent. The triol derivative 13 was reacted with a catalytic amount of camphorsulfonic acid (CSA) in CH2Cl2 at 0 °C for 1 hour to obtain the optically active tricyclic ligand alcohol 6 in a yield of 82%. TIFF0007702424000022.tif88128 Scheme 2. Synthesis of Substituted Tricyclic P2 Ligand 6. Reagents and Conditions. (a) LiAlH4, THF, 0 °C, 3 h (85%); (b) porcine pancreatic lipase, EtOAc, 23 °C, 12 h (82%); (c) (COCl)2, DMSO, TEA, CH2Cl2, -78 °C to 0 °C, 1.5 h; (d) CH(OMe)3, TBABr3, MeOH, 23 °C, 8 h (72% over two steps); (e) AD-mix-β, CH3SO2NH2, t-BuOH / H2O (1:1), 0 °C to 23 °C; (f) 1 N NaOH, MeOH, 0 °C to 23 °C, 3 h (90% over two steps); (g) CSA, CH2Cl2, 0 °C, 1 h (82%).

[0081] The synthesis of enantiomeric ligand ent-6 from meso-diol 10 is shown in Scheme 3. Diol 10 was converted to diacetate derivative 15 by reaction with acetic anhydride and pyridine at 23 °C for 16 h in the presence of a catalytic amount of DMAP. The diacetate was exposed to PPL in 0.1 M phosphate buffer at pH 7 in the presence of aqueous NaHCO3 at 23 °C for 16 h to afford optically active alcohol 16 in 84% yield. Alcohol 16 was converted to dimethyl acetal 17 in 80% yield as described above. Dimethyl acetal 17 was exposed to the Sharpless asymmetric dihydroxylation reaction with AD-mix-β to give a 1:1 mixture of diastereomeric diols. 34 Deprotection of the acetate derivatives gave triol derivatives 18 and 19, which were separated by silica gel chromatography. The major triol derivative 18 was treated with a catalytic amount of CSA in CH2Cl2 to afford ligand alcohol ent-6 in 79% yield. TIFF0007702424000023.tif105128 Scheme 3. Synthesis of Optically Active Ligand Alcohols. Reagents and Conditions. (a) Ac2O, Py, DMAP, CH2Cl2, 0 °C to 23 °C (98%); (b) Porcine Pancreatic Lipase, 0.1 M Phosphate Buffer pH -7, 1N NaHCO3, 23 °C, 16 h (84%); (c) (COCl)2, DMSO, TEA, CH2Cl2, -78 °C to 0 °C, 1.5 h; (d) CH(OMe)3, TBABr3, MeOH, 23 °C, 12 h (80% over two steps); (e) AD-mix-β, CH3SO2NH2, t-BuOH / H2O (1:1), 0 °C to 23 °C; (f) 1N NaOH, MeOH, 0 °C to 23 °C, 1 h; (g) CSA, CH2Cl2, 0 °C, 1 h (79%).

[0082] The synthesis of the designed protease inhibitors was carried out in a two-step sequence involving the synthesis of activated carbonates followed by the reaction of these carbonates with the appropriate hydroxyethylamine sulfonamide ligands. The synthesis of various activated carbonates is shown in Scheme 4. The optically active ligand alcohols 6 and ent-6 synthesized above were converted to the respective activated carbonates 19 and 20. As shown, the reaction of ligand alcohols 6 and ent-6 with 4-nitrophenyl chloroformate in CH2Cl2 at 0 °C to 23 °C for 12 h in the presence of pyridine gave the activated carbonates 19 and 20 in 87% and 88% yields, respectively. These carbonates were then converted to urethane derivatives using amines 21 - 26. The synthesis of various inhibitors containing Chf-THF as the P2 ligand on the hydroxyethylamine sulfonamide ligand is shown in Scheme 5. The reaction of the activated carbonate 6 with the known amine derivatives 21 - 26 in CH3CN at 23 °C for 72 h in the presence of diisopropylethylamine (DIPEA) gave the inhibitors 4a - f in good yields (65 - 86%). Similarly, the reaction of the carbonate ent-6 with amines 21 - 26 under the same conditions gave the inhibitors 5a - 5f in very good yields (59 - 87%). TIFF0007702424000024.tif159128Scheme 4. Synthesis of activated carbonates 19 and 20. Reagents and conditions. (a) 4-NO2PhOCOCl, Py, CH2Cl2, 0 °C to 23 °C, 8 h (87% for 19 and 88% for 20). TIFF0007702424000025.tif139128Scheme 5. Synthesis of PIs 4a - 4f and 5a - f. Reagents and conditions. (a) DIPEA, CH3CN, 23 °C, (59 - 87%).

[0083] Experiment Unless otherwise specified, all chemicals and reagents were purchased from commercial sources and used without further purification. The following reaction solvents were distilled before use: dichloromethane from calcium hydride, diethyl ether and tetrahydrofuran from Na / benzophenone, and methanol and ethanol from activated magnesium under argon. All reactions were carried out under an argon atmosphere in glass vessels dried either by flame or in an oven (120 °C). TLC analysis was performed using glass - reinforced thin - layer silica gel chromatography plates (60 Å, thickness 250 μm, F - 254 indicator). Column chromatography was carried out using silica gel with a pore size of 60 Å and a mesh size of 230 - 400. 1 H and 1313C NMR spectra were recorded at room temperature on a Bruker AV800, DRX-500, and ARX-400. Chemical shifts (δ values) were reported in ppm units, referenced to the deuterated residual solvent peak. NMR data were reported as follows: δ value (chemical shift), J value (Hz), integration, where s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet. Optical rotations were recorded on a PerkinElmer 341 polarimeter. HRMS and LRMS spectra were recorded at the Purdue University Department of Chemistry Mass Spectrometry Center. HPLC analysis and purification were performed on an Agilent 1100 series instrument using a YMC Pack ODS-A column with an inner diameter of 4.6 mm for analysis and either 10 mm or 20 mm inner diameter for purification. The purity of all test compounds was confirmed by HPLC analysis to be ≥95%.

[0084] cis-Cyclohex-4-ene-1,2-diyldimethanol (9): TIFF0007702424000026.tif23128A slurry of lithium aluminum hydride in THF (300 mL) was added dropwise to a solution of cis-4-cyclohexene-1,2-dicarboxylic anhydride 10 (7 g, 46.00 mmol) in THF (300 mL) at 0 °C over 20 minutes. The reaction mixture was stirred at 0 °C for 3 hours, quenched by dropwise addition of methanol at 0 °C over 30 minutes. The reaction mixture was warmed to room temperature, aqueous sodium sulfate was added, and the mixture was stirred at 23 °C overnight. The resulting slurry was filtered, and the solid was washed with ethyl acetate. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give cis-diol 9 (g, 85%) as a liquid. TIFF0007702424000027.tif22128The spectral data were consistent with the reported data 1 。

[0085] ((1S,6R)-6-(Hydroxymethyl)cyclohex-3-en-1-yl)methyl acetate (11): A mixture of diol 9 (500 mg, 3.52 mmol) and PPL (porcine pancreatic lipase Sigma type 2, 2.27 g) in ethyl acetate (50 mL) was stirred at 23 °C for 12 h. After completion of the diol by TLC, the reaction mixture was filtered and the solvent was removed in vacuo to give a crude residue, which was purified by column chromatography on silica gel (30% EtOAc / hexane) to afford monoacetate 11 (530 mg, 82%) along with diacetate (40 mg, 5%) as a by-product. R f = 0.5 (50% EtOAc / hexane). [α] D 20 + 17.5 (c 2.2, CHCl3), {literature data 2 : [α] D 20 + 19.0 (c 5.85, CHCl3)}; TIFF0007702424000029.tif29128The spectral data was consistent with the reported data 1 .

[0086] References: (1) J. Am. Chem. Soc. 2012, 134, 4037 - 4040. (2) J. Org. Chem. 1995, 60, 2506 - 2513.

[0087] Acetic acid ((1S,6R)-6-(dimethoxymethyl)cyclohex-3-en-1-yl)methyl (12): TIFF0007702424000030.tif In 27128 dry CH2Cl2 (60 mL), oxalyl chloride (1.34 mL, 15.21 mmol) was cooled to -78 °C under a nitrogen atmosphere. Dimethyl sulfoxide (2.2 mL, 30.43 mmol) was added dropwise. After 15 minutes, alcohol 11 (1.4 g, 7.60 mmol) in dry CH2Cl2 (20 mL) was added to the reaction mixture via a cannula, and the mixture was stirred at -78 °C for 30 minutes. Then, Et3N (5.3 mL, 38.04 mmol) was added, and the mixture was stirred for 15 minutes. Further reaction was carried out at 0 °C. The solvent was concentrated, extracted with EtOAc (2 × 100 mL), washed with H2O and brine, the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (15% EtOAc / hexane) to obtain aldehyde (1.25 g, 90%) as a colorless oil. R f = 0.5 (30% EtOAc / hexane). [α] D 20 -47.9 (c 0.73, CHCl3); TIFF0007702424000031.tif 29128

[0088] To a stirred solution of the above aldehyde (1.25 g, 6.86 mmol) in methanol (20 mL), trimethyl orthoformate (7.5 mL, 68.60 mmol) was followed by tetrabutylammonium bromide (66 mg, 0.137 mmol) was added at 23 °C. The reaction mixture was stirred at 23 °C for 8 hours. After this period, the reaction mixture was quenched by the addition of saturated aqueous NH4Cl. Methanol was removed under reduced pressure, and the reaction mixture was diluted with ethyl acetate. The layers were separated, the aqueous layer was extracted with EtOAc, the combined organic extracts were dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (10% EtOAc / hexane) to give 12 (1.32 g, 84%). R f = 0.5 (10% EtOAc / hexane, 3 times). [α] D 20 +5.9 (c 1.2, CHCl3). TIFF0007702424000032.tif 41128

[0089] (1R,2S,4R,5S)-4-(Dimethoxymethyl)-5-(hydroxymethyl)cyclohexane-1,2-diol (13) and (1S,2R,4R,5S)-4-(Dimethoxymethyl)-5-(hydroxymethyl)cyclohexane-1,2-diol (14): TIFF0007702424000033.tif22136 AD - Mix-β (3.0 g) was dissolved in 1:1 tert-butyl alcohol / water (22 mL), and the mixture was stirred for 10 minutes. Then MeSO2NH2 (208 mg, 2.19 mmol) was added, and stirring was continued for an additional 10 minutes. After cooling the mixture to 0 °C, 12 (500 mg, 2.19 mmol) in t-BuOH (2 mL) was added. The reaction was slowly warmed to ambient temperature and stirred for 24 hours. At this time, solid Na2SO3 was added, and the reaction was stirred for an additional 30 minutes. The reaction was then partitioned between EtOAc / water, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a mixture of inseparable diols, which was further purified and used in the next step.

[0090] Methanol (6 mL) was dissolved in the stirred solution of the above diol, and 1N NaOH (0.6 mL) was added at 0 °C. The reaction mixture was slowly warmed to ambient temperature and stirred for 3 hours. After completion of the starting material, methanol was evaporated, and the residue was extracted with dichloromethane (3 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (5% MeOH / CH2Cl2) to obtain triols 13 (207 mg, 43%) and 14 (227 mg, 47%) as oily liquids.

[0091] Compound 13: R f = 0.4 (10% MeOH / CH2Cl2). [α] D 20 -3.2 (c 0.58, CHCl3). TIFF0007702424000034.tif35128

[0092] Compound 14: R f = 0.2 (10% MeOH / CH2Cl2). [α] D 20 -0.77 (c 3.49, CHCl3). TIFF0007702424000035.tif41128

[0093] (1R,3aS,5S,7aR)-Octahydro-1,6-epoxyisobenzofuran-5-ol (6): TIFF0007702424000036.tif22128 A stirred solution of triol 13 (340 mg, 1.54 mmol) in dichloromethane (16 mL) was treated with 10-camphorsulfonyl chloride (36 mg, 0.15 mmol) at 0 °C for 1 h. The crude residue was purified by silica gel column chromatography (40% EtOAc / hexane) to afford alcohol 6 (198 mg, 82%) as a white amorphous solid. R f = 0.3 (70% EtOAc / hexane). [α] D 20 +45.5 (c 0.77, CHCl3). TIFF0007702424000037.tif35128

[0094] Cis-cyclohex-4-ene-1,2-diylbis(methylene) diacetate (15): TIFF0007702424000038.tif23128 A stirred solution of diol 9 (11.5 g, 80.98 mmol) was treated with pyridine (26.1 mL, 323.94 mmol), acetic anhydride (15.3 mL, 161.97 mmol) followed by DMAP (495 mg, 4.05 mmol) at 0 °C. The resulting mixture was stirred at 23 °C overnight. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over NaSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (20% EtOAc / hexane) to afford alcohol 15 (18.1 g, 98%). R f= 0.8 (50% EtOAc / hexane). TIFF0007702424000039.tif23128

[0095] ((1R,6S)-6-(Hydroxymethyl)cyclohex-3-en-1-yl)methyl acetate (16): TIFF0007702424000040.tif211280.1 M phosphate buffer (242 mL, pH 7) was added to a stirred solution of diacetate 15 (18.6 g, 82.30 mmol) at 23 °C. PPL (1.86 g, Sigma type II, crude) was added at 23 °C. 1 N NaHCO3 solution (93 mL) was added dropwise and the heterogeneous mixture was stirred for 16 h. The mixture was then filtered through a pad of Celite. The filtrate was extracted with dichloromethane (×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (30% EtOAc / hexane) to give 16 (12.75 g, 84%) as a colorless oil. R f = 0.6 (50% EtOAc / hexane). [α] = -17.5 (c = 1.43, CHCl3); {Literature data 3 : [α] D 23 = -17.0 (c = 0.42, CHCl3)}.

[0096] References: (3) Tetrahedron: Asymmetry 1997, 28, 677 - 681.

[0097] ((1R,6S)-6-(Dimethoxymethyl)cyclohex-3-en-1-yl)methyl acetate (17): TIFF0007702424000041.tif28128The title compound 17 (9 g, 80% over 2 steps) was obtained from 16 (9 g, 48.91 mmol) according to the procedure outlined for compound 12. R f = 0.5 (10% EtOAc / hexane, 3 times). [α] D 20 -5.5 (c 1.0, CHCl3). 1 H and 13The 13C NMR spectral data was consistent with 12.

[0098] (1S,2R,4S,5R)-4-(Dimethoxymethyl)-5-(hydroxymethyl)cyclohexane-1,2-diol (18) and (1R,2S,4S,5R)-4-(Dimethoxymethyl)-5-(hydroxymethyl)cyclohexane-1,2-diol (19): TIFF0007702424000042.tif75150Triol 18 (405 mg, 42%) and 19 (445 mg, 46%) were synthesized from 17 (1 g, 4.38 mmol) according to the procedure outlined for compounds 13 and 14.

[0099] (1S,3aR,7aS)-Octahydro-1,6-epoxyisobenzofuran-5-ol (ent-6): TIFF0007702424000043.tif22128The title compound ent-6 (62 mg, 79%) was obtained from 18 (110 mg, 0.5 mmol) according to the procedure outlined for compound 6. R f = 0.3 (70% EtOAc / hexane); [α] D 20 = -47.3 (c 0.76, CHCl3). 1 H and 13 The 1H and 13C NMR data was consistent with 6.

[0100] 4-Nitrophenyl ((1R,3aS,7aR)-octahydro-1,6-epoxyisobenzofuran-5-yl) carbonate (19): TIFF0007702424000044.tif24128A stirred solution of 6 (22 mg, 0.14 mmol) in dichloromethane (1.0 mL) was treated with pyridine (30 μL, 0.32 mmol) and 4-nitrophenyl chloroformate (63 mg, 0.31 mmol) at 0 °C under an argon atmosphere. The reaction mixture was warmed to 23 °C and stirred for 12 h. Upon completion, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (35% EtOAc in hexane) to afford 19 (39.5 mg, 87%) as an amorphous solid. R f=0.5 (70% EtOAc / hexane). [α] D 20 +77.4 (c 0.7, CHCl3). TIFF0007702424000045.tif41128

[0101] 4-Nitrophenyl carbonate ((1S,3aR,7aS)-octahydro-1,6-epoxyisobenzofuran-5-yl) (20): TIFF0007702424000046.tif24128 The title compound 20 (100 mg, 88%) was obtained from ent-6 (55 mg, 0.352 mmol) according to the procedure outlined for compound 19. R f =0.5 (70% EtOAc / hexane). [α] D 20 -79.1 (c 0.8, CHCl3). 1 H and 13 1H and 13C NMR data were consistent with 19.

[0102] ((2S,3R)-3-Hydroxy-4-((N-isobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl) carbamic acid (1R,3aS,7aR)-octahydro-1,6-epoxyisobenzofuran-5-yl (4a): TIFF0007702424000047.tif30128 To a stirred solution of activated alcohol 19 (15 mg, 0.046 mmol) and isostar 21 (21 mg, 0.051 mmol) in acetonitrile (2 mL) was added DIPEA (40 μL, 0.233 mmol) at 23 °C under an argon atmosphere. The reaction mixture was stirred at 23 °C until complete. Upon completion, the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (50% EtOAc in hexane) to afford 4a (22 mg, 81%) as an amorphous solid. R f =0.3 (70% EtOAc / hexane). TIFF0007702424000048.tif72128

[0103] ((2S,3R)-4-((2-(Cyclopropylamino)-N-isobutylbenzothiazole)-6-sulfonamide)-3-hydroxy-1-phenylbutan-2-yl)carbamic acid (1R,3aS,7aR)-octahydro-1,6-epoxyisobenzofuran-5-yl (4b): TIFF0007702424000049.tif29128 Activated alcohol 19 (8 mg, 0.024 mmol) was treated with isostearamine 22 (14 mg, 0.027 mmol) according to the procedure outlined for inhibitor 4a to afford inhibitor 4b (12.5 mg, 75%) as an amorphous solid. R f = 0.15 (80% EtOAc / hexane). TIFF0007702424000050.tif71128

[0104] ((2S,3R)-3-Hydroxy-4-((N-isobutyl-2-(isopropylamino)benzoxazole)-6-sulfonamide)-1-phenylbutan-2-yl)carbamic acid (1R,3aS,7aR)-octahydro-1,6-epoxyisobenzofuran-5-yl (4c): TIFF0007702424000051.tif27128 Activated alcohol 19 (10 mg, 0.031 mmol) was treated with isostearamine 26 (16 mg, 0.034 mmol) according to the procedure outlined for inhibitor 4a to afford inhibitor 4c (17.5 mg, 86%) as an amorphous solid. R f = 0.4 (5% MeOH / CH2Cl2). TIFF0007702424000052.tif78128

[0105] ((2S,3R)-4-((2-(Cyclopropylamino)-N-isobutylbenzothiazole)-6-sulfonamide)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)carbamic acid (1R,3aS,7aR)-octahydro-1,6-epoxyisobenzofuran-5-yl (4d): Activated alcohol 19 (7 mg, 0.021 mmol) was treated with isostearamine 23 (13 mg, 0.023 mmol) according to the procedure outlined for inhibitor 4a to afford inhibitor 4d (10 mg, 65%) as an amorphous solid. R f = 0.1 (70% EtOAc / hexane). TIFF0007702424000054.tif77128

[0106] ((2S,3R)-4-((2-(Cyclopropylamino)-N-isobutylbenzo[d]thiazole)-6-sulfonamido)-1-(3-fluorophenyl)-3-hydroxybutan-2-yl)carbamic acid (1R,3aS,7aR)-octahydro-1,6-epoxyisobenzofuran-5-yl (4e): Activated alcohol 19 (12 mg, 0.037 mmol) was treated with isostearamine 24 (21 mg, 0.041 mmol) according to the procedure outlined for inhibitor 4a to afford inhibitor 4e (18 mg, 70%) as an amorphous solid. R f = 0.2 (80% EtOAc / hexane). TIFF0007702424000056.tif83128

[0107] ((2S,3R)-4-((2-(Cyclopropylamino)-N-isobutylbenzo[d]thiazole)-6-sulfonamido)-1-(4-fluorophenyl)-3-hydroxybutan-2-yl)carbamic acid (1R,3aS,7aR)-octahydro-1,6-epoxyisobenzofuran-5-yl (4f): Activated alcohol 19 (12 mg, 0.037 mmol) was treated with isostearamine 25 (21 mg, 0.041 mmol) according to the procedure outlined for inhibitor 4a to afford inhibitor 4f (17.5 mg, 68%) as an amorphous solid. R f = 0.2 (80% EtOAc / hexane). TIFF0007702424000058.tif84128

[0108] ((2S,3R)-3-Hydroxy-4-((N-isobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl)carbamic acid (1S,3aR,5S,7aS)-octahydro-1,6-epoxyisobenzofuran-5-yl(5a): TIFF0007702424000059.tif30128 According to the procedure outlined for inhibitor 4a, activated alcohol 20 (15 mg, 0.046 mmol) was treated with isostearamine 21 (21 mg, 0.051 mmol) to afford inhibitor 5a (22 mg, 80%) as an amorphous solid. R f = 0.3 (70% EtOAc / hexane). TIFF0007702424000060.tif59128

[0109] ((2S,3R)-4-((2-(Cyclopropylamino)-N-isobutylbenzo[d]thiazole)-6-sulfonamido)-3-hydroxy-1-phenylbutan-2-yl)carbamic acid (1S,3aR,5S,7aS)-octahydro-1,6-epoxyisobenzofuran-5-yl(5b): TIFF0007702424000061.tif30128 According to the procedure outlined for inhibitor 4a, activated alcohol 20 (15 mg, 0.046 mmol) was treated with isostearamine 22 (25 mg, 0.051 mmol) to afford inhibitor 5b (22 mg, 70%) as an amorphous solid. R f = 0.2 (80% EtOAc / hexane). TIFF0007702424000062.tif71128

[0110] ((2S,3R)-3-Hydroxy-4-((N-isobutyl-2-(isopropylamino)benzo[d]oxazole))-6-sulfonamido)-1-phenylbutan-2-yl)carbamic acid (1S,3aR,5S,7aS)-octahydro-1,6-epoxyisobenzofuran-5-yl(5c): Activated alcohol 20 (8 mg, 0.024 mmol) was treated with isostearamine 26 (13 mg, 0.027 mmol) according to the procedure outlined for inhibitor 4a to afford inhibitor 5c (14 mg, 86%) as an amorphous solid. R f = 0.4 (5% MeOH / CH2Cl2). TIFF0007702424000064.tif71128

[0111] ((2S,3R)-4-((2-(Cyclopropylamino)-N-isobutylbenzo[d]thiazole)-6-sulfonamido)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)carbamic acid (1S,3aR,5S,7aS)-octahydro-1,6-epoxyisobenzofuran-5-yl (5d): Activated alcohol 20 (12 mg, 0.037 mmol) was treated with isostearamine 23 (21 mg, 0.041 mmol) according to the procedure outlined for inhibitor 4a to afford inhibitor 5d (15.5 mg, 59%) as an amorphous solid. R f = 0.3 (5% MeOH / CH2Cl2). TIFF0007702424000066.tif78128

[0112] ((2S,3R)-4-((2-(Cyclopropylamino)-N-isobutylbenzo[d]thiazole)-6-sulfonamido)-1-(3-fluorophenyl)-3-hydroxybutan-2-yl)carbamic acid (1S,3aR,5S,7aS)-octahydro-1,6-epoxyisobenzofuran-5-yl (5e): Activated alcohol 20 (4 mg, 0.012 mmol) was treated with isostearamine 24 (7 mg, 0.013 mmol) according to the procedure outlined for inhibitor 4a to afford inhibitor 5e (7.5 mg, 87%) as an amorphous solid. R f = 0.2 (80% EtOAc / hexane). TIFF0007702424000068.tif83128

[0113] ((2S,3R)-4-((2-(Cyclopropylamino)-N-isobutylbenzo[d]thiazole)-6-sulfonamide)-1-(4-fluorophenyl)-3-hydroxybutan-2-yl)carbamic acid (1S,3aR,5S,7aS)-octahydro-1,6-epoxyisobenzofuran-5-yl (5f): TIFF0007702424000069.tif36128 According to the procedure outlined for inhibitor 4a, activated alcohol 20 (4 mg, 0.012 mmol) was treated with isostearamine 25 (7 mg, 0.013 mmol) to afford inhibitor 5f (6.6 mg, 77%) as an amorphous solid. R f = 0.2 (80% EtOAc / hexane). TIFF0007702424000070.tif83128

[0114] The present invention provides the following exemplary embodiments, the numbering of which should not be construed as defining importance:

[0115] Embodiment 1 relates to a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, prodrug, solvate, or inclusion complex thereof: TIFF0007702424000071.tif39128 wherein, n is an integer from 0 to 3; G 1 and G 2 are each independently (-CHR 5 -) p wherein p is 0 or 1, and each R 5 is independently H or alkyl; X is (-CHR 5 -) m O- wherein m is 0, 1, or 2, and each R 5 is independently H or alkyl; X 3 is (-CHR 5 -) dis O—, where d is 1 or 2, and each R 5 is independently H or alkyl; X 1 and X 2 are each independently (—CHR 5 —) m where m is 0, 1, or 2, and each R 5 is independently H or alkyl; each R 1 is independently alkyl, alkoxy, aryl, heterocyclyl, halo, hydroxy, or amino; R 2 is alkyl; R 3 is aryl, benzothiazole, benzoxazole, benzofuranyl, or indolyl; and R 4 and R 4' are each independently H or alkyl.

[0116] Aspect 2 is X 1 is (—CHR 5 —) m where m is 2, and X 2 is (—CHR 5 —) m where m is 1; X 1 and X 2 are each (—CHR 5 —) m where each m is 1; X 1 is (—CHR 5 —) m where m is 0, and X 2 is (—CHR 5 —) m where m is 1; or X 1 and X 2 are each (—CHR 5 —) m where m is 0, provided that at least one of G 1 and G 2 is (—CHR 5 —) pand wherein at least one p is 1, relates to the compound of Embodiment 1.

[0117] Embodiment 3 is X is O; X 3 is O; or X and X 3 are O, relates to the compound of Embodiment 1 or 2.

[0118] Embodiment 4 is that at least one p is 0 such that at least one of G 1 and G 2 is a bond, relates to the compounds of Embodiments 1 to 3.

[0119] Embodiment 5 is that R 4 and R 4' are each independently H or alkyl, relates to the compounds of Embodiments 1 to 4.

[0120] Embodiment 6 is each p is 0; X and X 3 are each O, X 1 and X 2 are each independently (-CHR 5 -) m ; and R 4 and R 4' are each H, relates to the compounds of Embodiments 1 to 3.

[0121] Embodiment 7 is that the compound of formula (I) is of the formula: TIFF0007702424000072.tif32128, relates to the compound of Embodiment 1.

[0122] Embodiment 8 is that the compound of formula (I) is of the formula: TIFF0007702424000073.tif32128, relates to the compound of Embodiment 1.

[0123] Aspect 9 relates to the compounds of Aspects 1-8, wherein R 3 is unsubstituted or substituted aryl.

[0124] Aspect 10 relates to the compounds of Aspects 1-9, wherein R 3 is selected from the group consisting of TIFF0007702424000074.tif86128.

[0125] Aspect 11 relates to the compounds of Aspects 1-8, wherein R 3 is benzothiazole or benzoxazole TIFF0007702424000075.tif13128, and in the formula, R is alkyl, alkylamino, cycloalkylamino, cycloalkylheterocycloamino, heterocyclocycloalkylamino, or heterocycloamino; and X 6 is S, O, or NR 4 wherein R 7 is H, alkyl, cycloalkyl, or alkylaryl, and X 7 is S or O. 4 X may be S or O.

[0126] Aspect 12 relates to the compounds of Aspects 1-8, wherein the compound is a compound of the formula: TIFF0007702424000076.tif196143TIFF0007702424000077.tif162141 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate, or inclusion complex thereof.

[0127] Aspect 13 relates to a pharmaceutical composition comprising a compound of Aspects 1-12 and one or more pharmaceutically acceptable excipients.

[0128] Aspect 14 relates to a method for treating HIV infection, comprising administering a therapeutically effective amount of one or more compounds of Aspects 1-12 to a patient in need thereof.

[0129] Aspect 15 relates to the compounds of Aspects 1 to 12 for use as a medicament for treating patients in need of palliation from HIV infection.

[0130] Aspect 16 relates to a compound of formula (II) or a pharmaceutically acceptable salt, polymorph, prodrug, solvate, or inclusion complex thereof: TIFF0007702424000078.tif28128wherein, n is an integer from 0 to 3; G 1 and G 2 are each independently (-CHR 5 -) p wherein p is 0 or 1, and each R 5 is independently H or alkyl; X is (-CHR 5 -) m O- wherein m is 0, 1, or 2, and each R 5 is independently H or alkyl; X 3 is (-CHR 5 -) d O- wherein d is 1 or 2, and each R 5 is independently H or alkyl; X 1 and X 2 are each independently (-CHR 5 -) m wherein m is 0, 1, or 2, and each R 5 is independently H or alkyl; each R 1 is independently alkyl, alkoxy, aryl, heterocyclyl, halo, hydroxy, or amino; R 4 and R 4' are each independently H or alkyl; and X 5 is hydroxy, alkoxy, amino, C(O)R, C(O)OR, OC(O)OR, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2) 0~2 O(R)C(O)R, (CH2) 0~2 N(R)C(O)R, (CH2)0~2 O(R)C(O)OR, (CH2) 0~2 O(R)C(O)OR, or (CH2) 0~2 Selected from the group consisting of N(R)N(R)2, where each R is independently hydrogen, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, where any alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, or two R groups bonded to one nitrogen atom or adjacent nitrogen atoms may together with said one or more nitrogen atoms form a heterocyclyl.

[0131] Aspect 17 is X 1 is (-CHR 5 -) where m = 2 m and X 2 is (-CHR 5 -) where m = 1 m ; X 1 and X 2 are each (-CHR 5 -) where each m = 1 m ; X 1 is (-CHR 5 -) where m = 0 m and X 2 is (-CHR 5 -) where m = 1 m ; or X 1 and X 2 are each (-CHR 5 -) where m = 0, provided that at least one of G m and G 1 is (-CHR 2 -) where at least one p = 1 5 ; p relates to the compound of aspect 16. Relates to the compound of aspect 16.

[0132] Aspect 18 is X is O; X 3 is O; or X and X 3 are O, relates to the compounds of embodiment 16 or 17.

[0133] Embodiment 19 relates to the compounds of embodiments 16 - 18, wherein at least one p is 0 such that at least one of G 1 and G 2 is a bond.

[0134] Embodiment 20 relates to the compounds of embodiments 16 - 19, wherein R 4 and R 4' are each independently H or alkyl.

[0135] Embodiment 21 is such that each p is 0; X and X 3 are each O, X 1 and X 2 are each independently (-CHR 5 -) m ; and R 4 and R 4' are each H, relates to the compounds of embodiments 16 - 18.

[0136] Embodiment 22 relates to the compounds of embodiment 16, wherein the compound of formula (II) is a compound of formula: TIFF0007702424000079.tif38128 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate, or inclusion complex thereof.

Claims

**Claim 1**: A compound of the following formula, or a pharmaceutically acceptable salt or solvate thereof: or wherein n is an integer from 0 to 3; Each R 1 is independently alkyl, alkoxy, aryl, heterocyclyl, halo, hydroxy, or amino; R 2 is alkyl; R 3 is unsubstituted or substituted aryl, benzothiazole, benzoxazole, benzofuranyl, or indolyl; here, when R3 is a substituted aryl, R3 is selected from the group consisting of and when R3 is benzothiazole or benzoxazole, R3 is wherein R6 is alkyl, alkylamino, cycloalkylamino, cycloalkylheterocycloamino, heterocyclocycloalkylamino, or heterocycloamino; and X4 is S or O. **Claim 2**: The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is a compound of the formula: ​ ​ ​

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