WO2012092168A1

WO2012092168A1 - Fused 6,5 bicyclic ring system p2 ligands, and methods for treating hiv

Info

Publication number: WO2012092168A1
Application number: PCT/US2011/067112
Authority: WO
Inventors: Arun K. Ghosh
Original assignee: Purdue Research Foundation
Priority date: 2010-12-27
Filing date: 2011-12-23
Publication date: 2012-07-05

Abstract

Inhibitors of HIV-1 protease and compositions containing them are described. Use of the inhibitors and compositions containing them to treat HIV, AIDS, and AIDS-related diseases is described.

Description

FUSED 6,5 BICYCLIC RING SYSTEM P2 LIGANDS, AND

METHODS FOR TREATING HIV

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority under 35 U.S.C. § 119 of U.S.

Provisional Application Serial No. 61/427,341 filed on December 27, 2010, the entirety of which is incorporated by reference herein.

TECHNICAL FIELD

The invention described herein pertains to compounds, to compositions and formulations comprising the compounds, and to methods of use of the compounds and their compositions and formulations for the treatment of diseases, including diseases such as HIV, AIDS, and AIDS-related diseases.

BACKGROUND AND SUMMARY OF THE INVENTION

The AIDS epidemic is one of the most challenging problems in medicine in the 21 st century (United Nations. 2004 Report on the global HIV/AIDS Epidemic: 4th global report. New York, U.S.A., 2004). The disclosure of the foregoing is incorporated herein in its entirety by reference. In addition, the entirety of the disclosures of each of the publications cited herein are also incorporated herein by reference. Among many strategies to combat this disease, highly active antiretroviral therapy (HAART) with HIV protease inhibitors (Pis) in combination with reverse transcriptase inhibitors (RTIs) continues to be the first line treatment for control of HIV infection (Sepkowitz, K.A. AIDS - the first 20 years. N. Engl. J. Med. 2001, 344, 1764-1772). This treatment regimen has definitely improved quality of life, enhanced HIV management, and halted the progression of the disease. However, despite these impressive successes, there remain many challenges to treating this devastating disease, including decreasing both the toxicity and complexity of these treatment regimens. In addition, there is a growing population of patients that is developing multi-drug resistant strains of HIV, and there is ample evidence that these strains can be further transmitted (Staszewski et al., Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV- 1 infection in adults. N. Engl. J. Med. 1999, 341, 1865- 1873; Wainberg et al., Public health implications of antiretroviral therapy and HIV drug resistance. J. Am. Med. Assoc. 1998, 279, 1977-1983).

HAART has had a major impact on the AIDS epidemic in industrially advanced nations; however, eradication of human immunodeficiency virus type 1 (HIV 1) appears to be currently unachieved, in part due to the viral reservoirs remaining in blood and infected tissues. The limitation of antiviral therapy of AIDS is also exacerbated by complicated regimens, the development of drug-resistant HIV-1 variants, and a number of inherent adverse effects.

A number of challenges have nonetheless been encountered in bringing about the optimal benefits of the currently available therapeutics of AIDS and HIV-1 infection to individuals receiving HAART (De Clercq 2002. Strategies in the design of antiviral drugs. Nat Rev Drug Discov 1 : 13-25; Siliciano et al. 2004. A long-term latent reservoir for HIV-1 :

discovery and clinical implications. J Antimicrob Chemother 54:6-9; Simon, et al. 2003. HIV-1 dynamics in vivo : implications for therapy. Nat Rev Microbio 1 1 : 181-90). They include (i) drug-related toxicities; (ii) partial restoration of immunologic functions once individuals developed AIDS; (iii) development of various cancers as a consequence of survival

prolongation; (iv) flame-up of inflammation in individuals receiving HAART or immune reconstruction syndrome (IRS); and (v) increased cost of antiviral therapy. Such limitations of HAART are exacerbated by the development of drug-resistant HIV-1 variants (Carr 2003. Toxicity of antiretro viral therapy and implications for drug development. Nat Rev Drug Discov 2:624-34; Fumero et al. 2003. New patterns of HIV-1 resistance during HAART. Clin

Microbiol Infect 9: 1077-84; Grabar et al. 2006. HIV infection in older patients in the HAART era. J Antimicrob Chemother 57:4-7; Hirsch et al. 2004. Immune reconstitution in HIV-infected patients. Clin Infect Dis 38: 1159-66; Little et al. 2002. Antiretroviral-drug resistance among patients recently infected with HIV. N Engl J Med 347:385-94).

Successful antiviral drugs, in theory, exert their virus-specific effects by interacting with viral receptors, virally encoded enzymes, viral structural components, viral genes, or their transcripts without disturbing cellular metabolism or function. However, at present, no antiretroviral drugs or agents are likely to be completely specific for HIV-1 or to be devoid of toxicity or side effects in the therapy of AIDS, which has been an issue because patients with AIDS and its related diseases will have to receive antiretroviral therapy for a long period of time, perhaps for the rest of their lives.

In one embodiment, described herein are novel non-peptidyl compounds and compositions for treating patients in need of relief from HIV, AIDS, and AIDS-related diseases. Also described herein are methods for treating such diseases. In one embodiment, it has been discovered that the non-peptidyl compounds described herein are potent inhibitors of HIV-1 protease. It has also been discovered that these compounds may offer therapeutic benefits to patients suffering from or in need of relief from HIV-1/AIDS.

In another embodiment, described herein is structure-based design of novel HIV- 1 protease inhibitors (PI) incorporating a stereochemical^ defined 4-hexahydrofuropyranol- derived urethanes as the P2-ligand. In one aspect, the inhibitors herein are designed to make extensive interactions including hydrogen bonding with the protein backbone of the HIV-1 protease active site. In another embodiment, the inhibitors described herein appear to show excellent enzyme inhibitory activity and antiviral potency. In one aspect, this antiviral potency may be comparable to that of approved protease inhibitors. In another embodiment, the inhibitors described herein appear to show excellent activity against multi-PI-resistant variants.

In one illustrative embodiment, the HIV-1 protease inhibitors described herein are compounds of the following structure:

and pharmaceutically acceptable salts thereof, wherein

A is the following group, wherein (*) denotes the point of attachment:

one of γΐ and Y² is methylene, and the other of γΐ and Y² is defined as follows:

Y¹ is C(R^aPv^b) or oxygen; Y² is C(R^aR^b), CHNR^a, oxygen, or S0₂, where R^a and R^b are independently selected in each instance from hydrogen, alkyl, and alkoxy; m is an integer selected from 0, 1, 2, or 3; and R^c and R^d each represent one or more optional substituents, each of which is independently selected in each instance from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkylalkoxy, aryl, arylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heteroaryloxy, and heteroarylalkoxy, each of which is itself optionally substituted;

Q is oxygen, sulfur, nitrogen, or C(R^aR^b); where each of R^a and R^b is independently selected in each instance from the group consisting of hydrogen, alkyl, and alkoxy;

W is oxygen or sulfur;

R1 is hydrogen, a nitrogen protecting group, or a pro-drug substituent;

X is C(R^aR^b)_n, where each of R^a and R^b is independently selected in each instance from the group consisting of hydrogen, alkyl, and alkoxy;

R² is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; R3 is hydrogen, an oxygen protecting group, or a pro-drug substituent;

R4 is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;

Z is C(O), S(0)₂, NH, NHC(O), or NHS(0)₂; and

is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;

providing that the compound is not of the formula

or a pharmaceutically acceptable salt thereof.

In another embodiment, compositions containing one or more of the compounds are also described herein. In one aspect, the compositions include a therapeutically effective amount of the one or more compounds for treating a patient with HIV-1/AIDS. In another embodiment, methods for using the compounds and compositions for treating patients with HIV-1/AIDS are also described herein. In one aspect, the methods include the step of administering one or more of the compounds and/or compositions containing them to a patient with HIV-1/AIDS. In another aspect, the methods include administering a therapeutically effective amount of the one or more compounds and/or compositions described herein for treating patients with HIV-1/AIDS. Another embodiment is the use of the one or more compounds and/or compositions described herein for treating patients with HIV-1/AIDS. In another embodiment, uses of the compounds and compositions in the manufacture of a medicament for treating patients with HIV-1/AIDS are also described herein. In one aspect, the medicaments include a therapeutically effective amount of the one or more compounds and/or compositions for treating a patient with HIV-1/AIDS.

It is appreciated herein that the compounds described herein may be used alone or in combination with other compounds useful for treating HIV/ AIDS, including those compounds that may operate by the same or different modes of action. In addition, it is appreciated herein that the compounds described herein may be used in combination with other compounds that are administered to treat other symptoms of HIV/ AIDS.

DETAILED DESCRIPTION

Described herein are compounds that exhibit protease inhibition. In one aspect, the compounds described herein exhibit HIV-1 protease inhibition. In one illustrative embodiment, the compounds described herein have the following formula (I):

harmaceutically acceptable salts thereof, wherein

A is the following group, wherein (*) denotes point of attachment:

Y¹ is C(R^aR^b) or oxygen; Y² is C(R^aR^b), CHNR^a, oxygen, or S0₂, where R^a and R^b are independently selected in each instance from hydrogen, alkyl, and alkoxy; m is an integer selected from 0, 1 , 2, or 3; and R^c and R^d each represent one or more optional substituents, each of which is independently selected in each instance from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkylalkoxy, aryl, arylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heteroaryloxy, and heteroarylalkoxy, each of which is itself optionally substituted;

W is oxygen or sulfur;

R1 is hydrogen, a nitrogen protecting group, or a pro-drug substituent;

R² is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;

R^ is hydrogen, an oxygen protecting group, or a pro-drug substituent;

Z is C(O), S(0)₂, NH, NHC(O), or NHS(0)₂; and

R^ is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;

providing that the compound is not of the formula

or a pharmaceutically acceptable salts thereof.

In one illustrative embodiment, the compounds described herein have the following formulae (I):

and pharmaceutically acceptable salts thereof, wherein

Y¹ is C(R^aR^b) or oxygen; Y² is C(R^aR^b), CHNR^a, oxygen, or S0₂, where R^a and R^b are independently selected in each instance from hydrogen, alkyl, and alkoxy; m is an integer selected from 0, 1, 2, or 3; and R^c and R^d each represent one or more optional substituents, each of which is independently selected in each instance from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkylalkoxy, aryl, arylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heteroaryloxy, and heteroarylalkoxy, each of which is itself optionally substituted;

W is oxygen or sulfur;

R1 is hydrogen, a nitrogen protecting group, or a pro-drug substituent;

R^ is hydrogen, an oxygen protecting group, or a pro-drug substituent;

Z is C(O), S(0)₂, NH, NHC(O), or NHS(0)₂; and R5 is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;

providing that the compound is not of the formula

or a pharmaceutically acceptable salts thereof.

In other embodiments, described herein are compounds of formulae (I) above, wherein R^A and R^B are both hydrogen.

In another embodiment, compounds of the following formula are described herein:

wherein Q and R² are as described above; Ar is aryl or heteroaryl, each of which is optionally substituted; or Q, R² and Ar are as described in the various embodiments and aspects disclosed herein; and wherein A is selected from the following group, wherein (*) denotes point of attachment:

Illustrative non-limiting examples of A include the following:

In another embodiment, compounds having the following relative and/or absolute stereochemistry are described herein:

wherein A, Q, W, X, R¹, R², R⁴, and Ar are as described in the various embodiments and aspects disclosed herein.

In another embodiment compounds of the following formula are described herein:

wherein A, Q, W, R¹ , R , and Ar are as described in the various embodiments and aspects disclosed herein, and where Ar² is substituted aryl or substituted heteroaryl having one or more of the following illustrative substituents; halo, amino, hydroxy, alkyl, alkenyl, alkoxy, arylalkyl, arylalkyloxy, hydroxyalkyl, hydroxyalkenyl, alkylene dioxy, aminoalkyl, where the amino group may also be substituted with one or two alkyl groups, arylalkylgroups, and/or acylgroups, nitro, acyl and derivatives thereof such as oximes, hydrazones, and the like, cyano,

alkylsulfonyl, alkylsulfonylamino, and the like and Q, R¹, R³ and Ar have the meanings disclosed above. In another embodiment compounds of the following formula are described herein:

wherein A, R¹, and R⁴ are as described in the various embodiments and aspects disclosed herein, and where X^a and X^b are each independently selected from halo, amino, hydroxy, alkyl, alkenyl, alkoxy, arylalkyl, arylalkyloxy, hydroxyalkyl, hydroxyalkenyl, alkylene dioxy, aminoalkyl, where the amino group may also be substituted with one or two alkyl groups, arylalkylgroups, and/or acylgroups, nitro, acyl and derivatives thereof such as oximes, hydrazones, and the like, cyano, alkylsulfonyl, alkylsulfonylamino, and the like and R¹, R³ and Ar have the meanings disclosed above.

In another illustrative embodiment, compounds of the formula:

and pharmaceutically acceptable salts thereof are described herein, wherein

Z is C(R^cR^d) where each of R^c and R^d is independently selected in each instance from the group consisting of hydrogen, alkyl, and arylalkyl; R^4A, R^4B and R^4C are independently selected in each instance from the group consisting of hydrogen, alkyl, and arylalkyl, each of which may be optionally substituted, or R^4A, R^4B and the atoms to which they are attached form a ring, and R^4C is selected from the group consisting of hydrogen, alkyl, and arylalkyl, each of which may be optionally substituted; and A, R¹ and Ar^ have the meanings disclosed above.

In another embodiment, compounds of the formula:

and pharmaceutically acceptable salts thereof are described herein wherein

X^a and X^b are independently selected from H, OH or OR⁶, where R⁶ is alkyl, alkylaryl, an oxygen protecting group or a pro-drug substituent; and A, Q, W, R¹, Ar² and R⁴ have the meanings disclosed above.

In another embodiment, compounds of the formula:

and pharmaceutically acceptable salts thereof are described herein wherein

In another embodiment, compounds of the formula:

and pharmaceutically acceptable salts thereof are described herein wherein

A, R¹, R⁴ and Ar have the meanings disclosed above.

In any of the foregoing formulae and embodiments, the following compounds are described where:

γΐ is oxygen; or γΐ is C(R^aR^), where R^a is hydrogen, and R^ is hydrogen or alkoxy, such as methoxy; or is oxygen; or Y^ is C(R^aR^), where R^a is hydrogen, and R^ is hydrogen or alkoxy, such as methoxy; and/or

m is 1; and/or

R^c is hydrogen; and/or Rd is hydrogen; and/or

Q is oxygen; and/or

W is oxygen; and/or

R1 is hydrogen; and/or

R^ is hydrogen; and/or

R4 is a group CH2-K-R4A where K is a bond or NHCH2, and R^A i_s alkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, each of which is optionally substituted; or R^A is isopropyl, furanyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolidinonyl, oxazolidinonyl, thiazolidinonyl, isoxazolidionyl, or isothiazolidinonyl, each of which is optionally substituted; or R4 is branched alkyl; or R4 is isobutyl; or R4 is

lactamylalkyl; or R^ is pyrrolidin-4-on-2-ylalkyl; or R^ is pyrrolidin-4-on-2-ylmethyl; and/or

Z is SC"2; or Z is CO; or Z is NH; and/or

R^ is aryl or heteroaryl, each of which is optionally substituted; or R^ is substituted phenyl; or R^ is substituted phenyl, where the substituent is hydroxy or a derivative thereof, amino or a derivative thereof, thio or a derivative thereof, or any of the foregoing where the substituent is covalently attached to the aryl through a group C(R^xR^y); where each of R^x and R^y is independently selected in each instance from the group consisting of hydrogen and alkyl; or R^x and R^y are each hydrogen; and/or

R⁵ is phenyl substituted with NH₂, OH, OMe, CH₂OH, and/or OCH₂0; or R⁵ is optionally substituted benzofuran; or R^ is optionally substituted dihydrobenzofuran; or R^ is optionally substituted benzothiopene; or R^ is optionally substituted benzoxazole; or R^ is optionally substituted benzothiazole; or R^ is optionally substituted benzisoxazole; or R^ is optionally substituted benzoisothiazole; and/or

R^a and R^b are each hydrogen; and/or

m is 1; and/or

R^ is optionally substituted phenyl.

It is appreciated that when the integer m is 1 , the ring fusion is syn, whereas when the integer m is 0, 2, or 3, the ring fusion may be syn or anti. It is further appreciated that in each of these relative stereochemical configurations, there are potentially two absolute stereochemical configurations. Unless otherwise indicated by specific reference to a relative or absolute stereochemical configuration, the structures described herein refer both individually to each enantiomer, as well as collectively to all possible mixtures of such enantiomers. It is appreciated that the foregoing cyclic ethers may be optionally substituted with one or more groups R^a and/or R^b, each of which is independently selected, and is as described in the various embodiments and aspects disclosed herein. In another embodiment of the compounds described herein, the group A is a cyclic ether or another structurally related group, such as is illustratively represented by the following structures

and stereoisomers thereof and mixtures thereof, where (*) indicates the point of attachment of A. It is therefore appreciated that such groups are attached to the group Q, which is oxygen, sulfur, nitrogen, or C(R^aR^b); where each of R^a and R^b is independently selected in each instance, as defined in the various embodiments and aspects disclosed herein.

In another embodiment of the compounds described herein, R³ is alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy, cycloalkoxy, heterocyclyloxy, heterocyclylalkoxy, amino, mono or dialkylamino, cycloalkylamino, heterocyclylamino, or heterocyclylalkylamino, each of which is optionally substituted. In one aspect, R³ is amino substituted alkyl or heterocyclyl, or heterocyclylalkyl. In one variation of this aspect, the nitrogen atom of the amino group is mono or disubstituted with alkyl, cycloalkyl, or acyl, or is included in another heterocyclic group such as a pyrrolidinyl, piperidinyl, or piperazinyl group. In another variation of this aspect, the nitrogen atom of the hetetocylclyl group is substituted with alkyl, cycloalkyl, or acyl. In another aspect, R³ is optionally substituted alkyl or cycloalkyl, including both linear and branched variations thereof, such as methyl, ethyl, butyl, isobutyl, and the like, and cyclobutyl, cyclopentyl, 3-methylcyclopentyl, and the like. In another aspect, R³ is optionally substituted heterocyclyl or heterocyclylalkyl, where the heterocyclic portions includes, but is not limited to, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and the like.

In another embodiment of the compounds described herein, the group A is a cyclic ether, such as the following structures

where (*) indicates the point of attachment; m is an integer selected from 0, 1, 2, or 3; γΐ is C(R^aR^b) or oxygen; Y² is C(R^aR^b), CHNR^a, oxygen, or S0₂, where R^a and R^b are

independently selected in each instance as described herein for the various embodiments and aspects; and R^c and R^d each represent one or more optional substituents, each of which is independently selected in each instance from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkylalkoxy, aryl, arylalkoxy,

heterocyclyloxy, heterocyclylalkoxy, heteroaryloxy, and heteroarylalkoxy, each of which is itself optionally substituted. In one aspect, R^a and R^b are both hydrogen. In another aspect, R^c and R^d are both hydrogen. In another aspect, R^a, R^b, R^c, and R^d are each hydrogen. In another aspect, one or more of R^c and R^d is alkoxy.

In another embodiment, R² is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is substituted, where at least one substituent is a hydrogen bond forming group.

In another embodiment of the compounds of formula (I), R^a and R^b are both hydrogen. In another aspect, R^c and R^d are both hydrogen. In another aspect, R^a, R^b, R^c, and R^d are each hydrogen. In another aspect, one or more of R^c and R^d is alkoxy.

The compounds described herein may contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. It is to be understood that in one embodiment, the invention described herein is not limited to any particular sterochemical requirement, and that the compounds, and compositions, methods, uses, and medicaments that include them may be optically pure, or may be any of a variety of stereoisomeric mixtures, including racemic and other mixtures of enantiomers, other mixtures of diastereomers, and the like. It is also to be understood that such mixtures of stereoisomers may include a single stereochemical configuration at one or more chiral centers, while including mixtures of stereochemical configuration at one or more other chiral centers.

Similarly, the compounds described herein may include geometric centers, such as cis, trans, E, and Z double bonds. It is to be understood that in another embodiment, the invention described herein is not limited to any particular geometric isomer requirement, and that the compounds, and compositions, methods, uses, and medicaments that include them may be pure, or may be any of a variety of geometric isomer mixtures. It is also to be understood that such mixtures of geometric isomers may include a single configuration at one or more double bonds, while including mixtures of geometry at one or more other double bonds.

As used herein, the term "alkyl" includes a chain of carbon atoms, which is optionally branched. As used herein, the term "alkenyl" and "alkynyl" includes a chain of carbon atoms, which is optionally branched, and includes at least one double bond or triple bond, respectively. It is to be understood that alkynyl may also include one or more double bonds. It is to be further understood that in certain embodiments, alkyl is advantageously of limited length, including C1-C24, C1-C12, Ci-Cs, Ci-C₆, and C1-C4. It is to be further understood that in certain embodiments alkenyl and/or alkynyl may each be advantageously of limited length, including C2-C24, C₂-C₁₂, C2-C8, C2-C6, and C2-C4. It is appreciated herein that shorter alkyl, alkenyl, and/or alkynyl groups may add less lipophilicity to the compound and accordingly will have different pharmacokinetic behavior. Illustrative alkyl groups are, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2- pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl and the like.

As used herein, the term "cycloalkyl" includes a chain of carbon atoms, which is optionally branched, where at least a portion of the chain is cyclic. It is to be understood that cycloalkylalkyl is a subset of cycloalkyl. It is also to be understood that cycloalkyl may be polycyclic. Illustrative cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, eye lo hexyl, 2-methylcyclopropyl, cyclopentyleth-2-yl, adamantyl, and the like. As used herein, the term "cycloalkenyl" includes a chain of carbon atoms, which is optionally branched, and includes at least one double bond, where at least a portion of the chain in cyclic. It is to be understood that the one or more double bonds may be in the cyclic portion of cycloalkenyl and/or the non-cyclic portion of cycloalkenyl. It is to be understood that cycloalkenylalkyl and cycloalkylalkenyl are each subsets of cycloalkenyl. It is to be understood that cycloalkyl may be polycyclic. Illustrative cycloalkenyl include, but are not limited to, cyclopentenyl, cyclohexylethen-2-yl, cycloheptenylpropenyl, and the like. It is to be further understood that chain forming cycloalkyl and/or cycloalkenyl is advantageously of limited length, including C3- C24, C3-C12, C3-C8, C3-C6, and C5-C6. It is appreciated herein that shorter alkyl and/or alkenyl chains forming cycloalkyl and/or cycloalkenyl, respectively, may add less lipophilicity to the compound and accordingly will have different pharmacokinetic behavior.

As used herein, the term "heteroalkyl" includes a chain of atoms that includes both carbon and at least one heteroatom, and is optionally branched. Illustrative heteroatoms include nitrogen, oxygen, and sulfur. In certain variations, illustrative heteroatoms also include phosphorus, and selenium. As used herein, the term "cycloheteroalkyl" including heterocyclyl and heterocycle, includes a chain of atoms that includes both carbon and at least one

heteroatom, such as heteroalkyl, and is optionally branched, where at least a portion of the chain is cyclic. Illustrative heteroatoms include nitrogen, oxygen, and sulfur. In certain variations, illustrative heteroatoms also include phosphorus, and selenium. Illustrative cycloheteroalkyl include, but are not limited to, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, quinuclidinyl, and the like.

As used herein, the term "aryl" includes monocyclic and polycyclic aromatic carbocyclic groups, each of which may be optionally substituted. Illustrative aromatic carbocyclic groups described herein include, but are not limited to, phenyl, naphthyl, and the like. As used herein, the term "heteroaryl" includes aromatic heterocyclic groups, each of which may be optionally substituted. Illustrative aromatic heterocyclic groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl,

benzisoxazolyl, benzisothiazolyl, and the like.

As used herein, the term "amino" includes the group NH₂, alkylamino, and dialkylamino, where the two alkyl groups in dialkylamino may be the same or different, i.e. alkylalkylamino. Illustratively, amino includes methylamino, ethylamino, dimethylamino, methylethylamino, and the like. In addition, it is to be understood that when amino modifies or is modified by another term, such as aminoalkyl, or acylamino, the above variations of the term amino are included therein. Illustratively, aminoalkyl includes H₂N-alkyl, methylaminoalkyl, ethylaminoalkyl, dimethylaminoalkyl, methylethylaminoalkyl, and the like. Illustratively, acylamino includes acylmethylamino, acylethylamino, and the like.

As used herein, the term "amino and derivatives thereof includes amino as described herein, and alkylamino, alkenylamino, alkynylamino, heteroalkylamino,

heteroalkenylamino, heteroalkynylamino, cycloalkylamino, cycloalkenylamino,

cycloheteroalkylamino, cycloheteroalkenylamino, arylamino, arylalkylamino,

arylalkenylamino, arylalkynylamino, heteroarylamino, heteroarylalkylamino,

heteroarylalkenylamino, heteroarylalkynylamino, acylamino, and the like, each of which is optionally substituted. The term "amino derivative" also includes urea, carbamate, and the like.

As used herein, the term "hydroxy and derivatives thereof includes OH, and alkyloxy, alkenyloxy, alkynyloxy, heteroalkyloxy, heteroalkenyloxy, heteroalkynyloxy, cycloalkyloxy, cycloalkenyloxy, cycloheteroalkyloxy, cycloheteroalkenyloxy, aryloxy, arylalkyloxy, arylalkenyloxy, arylalkynyloxy, heteroaryloxy, heteroarylalkyloxy,

heteroarylalkenyloxy, heteroarylalkynyloxy, acyloxy, and the like, each of which is optionally substituted. The term "hydroxy derivative" also includes carbamate, and the like.

As used herein, the term "thio and derivatives thereof includes SH, and alkylthio, alkenylthio, alkynylthio, heteroalkylthio, heteroalkenylthio, heteroalkynylthio, cycloalkylthio, cycloalkenylthio, cycloheteroalkylthio, cycloheteroalkenylthio, arylthio, arylalkylthio, arylalkenylthio, arylalkynylthio, heteroarylthio, heteroarylalkylthio, heteroarylalkenylthio, heteroarylalkynylthio, acylthio, and the like, each of which is optionally substituted. The term "thio derivative" also includes thiocarbamate, and the like.

As used herein, the term "acyl" includes formyl, and alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, heteroalkylcarbonyl, heteroalkenylcarbonyl,

heteroalkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, cycloheteroalkylcarbonyl, cycloheteroalkenylcarbonyl, arylcarbonyl, arylalkylcarbonyl, arylalkenylcarbonyl,

arylalkynylcarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl, heteroarylalkenylcarbonyl, heteroarylalkynylcarbonyl, acylcarbonyl, and the like, each of which is optionally substituted.

As used herein, the term "carbonyl and derivatives thereof includes the group

C(O), C(S), C(NH) and substituted amino derivatives thereof.

As used herein, the term "carboxylate and derivatives thereof includes the group C0₂H and salts thereof, and esters and amides thereof, and CN.

As used herein, the term "sulfonyl or a derivative thereof includes SO₃H and salts thereof, and esters and amides thereof.

The term "optionally substituted" as used herein includes the replacement of hydrogen atoms with other functional groups on the radical that is optionally substituted. Such other functional groups illustratively include, but are not limited to, amino, hydroxyl, halo, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof, and the like. Illustratively, any of amino, hydroxyl, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and/or sulfonic acid is optionally substituted.

As used herein, the terms "optionally substituted aryl" and "optionally substituted heteroaryl" include the replacement of hydrogen atoms with other functional groups on the aryl or heteroaryl that is optionally substituted. Such other functional groups illustratively include, but are not limited to, amino, hydroxy, halo, thio, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof, and the like. Illustratively, any of amino, hydroxy, thio, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and/or sulfonic acid is optionally substituted.

Illustrative substituents include, but are not limited to, a radical -(CH₂)_XZ^X, where x is an integer from 0-6 and Z^x is selected from halogen, hydroxy, alkanoyloxy, including Ci-C₆ alkanoyloxy, optionally substituted aroyloxy, alkyl, including Ci-C₆ alkyl, alkoxy, including Ci-C₆ alkoxy, cycloalkyl, including C₃-C₈ cycloalkyl, cycloalkoxy, including C₃-C₈ cycloalkoxy, alkenyl, including C₂-C₆ alkenyl, alkynyl, including C₂-C₆ alkynyl, haloalkyl, including Ci-C₆ haloalkyl, haloalkoxy, including Ci-C₆ haloalkoxy, halocycloalkyl, including C₃-C₈ halocycloalkyl, halocycloalkoxy, including C₃-C₈ halocycloalkoxy, amino, Ci- C₆ alkylamino, (Ci-C₆ alkyl)(Ci-C6 alkyl)amino, alkylcarbonylamino, N-(Ci-C₆

alkyl)alkylcarbonylamino, aminoalkyl, Ci-C₆ alkylaminoalkyl, (Ci-C₆ alkyl)(Ci-C₆

alkyl)aminoalkyl, alkylcarbonylamino alky 1, N-(Ci-C₆ alkyl)alkylcarbonylaminoalkyl, cyano, and nitro; or Z^x is selected from -C0₂R⁴ and -CONR⁵R⁶, where R⁴, R⁵, and R⁶ are each independently selected in each occurrence from hydrogen, Ci-C₆ alkyl, aryl-Ci-C₆ alkyl, and heteroaryl-Ci-C6 alkyl.

The term "prodrug" as used herein generally refers to any compound that when administered to a biological system generates a biologically active compound as a result of one or more spontaneous chemical reaction(s), enzyme-catalyzed chemical reaction(s), and/or metabolic chemical reaction(s), or a combination thereof. In vivo, the prodrug is typically acted upon by an enzyme (such as esterases, amidases, phosphatases, and the like), simple biological chemistry, or other process in vivo to liberate or regenerate the more pharmacologically active drug. This activation may occur through the action of an endogenous host enzyme or a non- endogenous enzyme that is administered to the host preceding, following, or during

administration of the prodrug. Additional details of prodrug use are described in U.S. Pat. No. 5,627,165; and Pathalk et al, Enzymic protecting group techniques in organic synthesis, Stereosel. Biocatal. 775-797 (2000). It is appreciated that the prodrug is advantageously converted to the original drug as soon as the goal, such as targeted delivery, safety, stability, and the like is achieved, followed by the subsequent rapid elimination of the released remains of the group forming the prodrug.

Prodrugs may be prepared from the compounds described herein by attaching groups that ultimately cleave in vivo to one or more functional groups present on the compound, such as -OH-, -SH, -C0₂H, -NR₂. Illustrative prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyloxyalkyl, alkoxy carbonyloxy alkyl as well as esters of hydroxyl, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate.

Illustrative esters, also referred to as active esters, include but are not limited to 1-indanyl, N- oxysuccinimide; acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl,

β-acetoxyethyl, β-pivaloyloxyethyl, l-(cyclohexylcarbonyloxy)prop-l-yl, (1

-aminoethyl)carbonyloxymethyl, and the like; alkoxy carbonyloxy alkyl groups, such as ethoxycarbonyloxymethyl, a-ethoxycarbonyloxyethyl, β-ethoxycarbonyloxyethyl, and the like; dialkylaminoalkyl groups, including di-lower alkylamino alkyl groups, such as dimethylamino methyl, dimethylaminoethyl, diethylamino methyl, diethylamino ethyl, and the like; 2-(alkoxycarbonyl)-2-alkenyl groups such as 2-(isobutoxycarbonyl) pent-2-enyl,

2-(ethoxycarbonyl)but-2-enyl, and the like; and lactone groups such as phthalidyl,

dimethoxyphthalidyl, and the like.

Further illustrative prodrugs contain a chemical moiety, such as an amide or phosphorus group functioning to increase solubility and/or stability of the compounds described herein. Further illustrative prodrugs for amino groups include, but are not limited to, (C₃- C₂o)alkanoyl; halo-(C₃-C₂o)alkanoyl; (C₃-C₂o)alkenoyl; (C4-Cy)cycloalkanoyl; (C₃-C₆)- cycloalkyl(C₂-Ci6)alkanoyl; optionally substituted aroyl, such as unsubstituted aroyl or aroyl substituted by 1 to 3 substituents selected from the group consisting of halogen, cyano, trifluoromethanesulphonyloxy, (Ci-C₃)alkyl and (Ci-C₃)alkoxy, each of which is optionally further substituted with one or more of 1 to 3 halogen atoms; optionally substituted aryl(C₂- Ci6)alkanoyl and optionally substituted heteroaryl(C₂-Ci6)alkanoyl, such as the aryl or heteroaryl radical being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, (Ci-C₃)alkyl and (Ci-C₃)alkoxy, each of which is optionally further substituted with 1 to 3 halogen atoms; and optionally substituted heteroarylalkanoyl having one to three heteroatoms selected from O, S and N in the heteroaryl moiety and 2 to 10 carbon atoms in the alkanoyl moiety, such as the heteroaryl radical being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, cyano, trifluoromethanesulphonyloxy, (Ci-C₃)alkyl, and (Ci-C₃)alkoxy, each of which is optionally further substituted with 1 to 3 halogen atoms. The groups illustrated are exemplary, not exhaustive, and may be prepared by conventional processes.

It is understood that the prodrugs themselves may not possess significant biological activity, but instead undergo one or more spontaneous chemical reaction(s), enzyme- catalyzed chemical reaction(s), and/or metabolic chemical reaction(s), or a combination thereof after administration in vivo to produce the compound described herein that is biologically active or is a precursor of the biologically active compound. However, it is appreciated that in some cases, the prodrug is biologically active. It is also appreciated that prodrugs may often serves to improve drug efficacy or safety through improved oral bioavailability, pharmacodynamic half- life, and the like. Prodrugs also refer to derivatives of the compounds described herein that include groups that simply mask undesirable drug properties or improve drug delivery. For example, one or more compounds described herein may exhibit an undesirable property that is advantageously blocked or minimized may become pharmacological, pharmaceutical, or pharmacokinetic barriers in clinical drug application, such as low oral drug absorption, lack of site specificity, chemical instability, toxicity, and poor patient acceptance (bad taste, odor, pain at injection site, and the like), and others. It is appreciated herein that a prodrug, or other strategy using reversible derivatives, can be useful in the optimization of the clinical application of a drug.

The term "therapeutically effective amount" as used herein, refers to that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. In one aspect, the therapeutically effective amount is that which may treat or alleviate the disease or symptoms of the disease at a reasonable benefit/risk ratio applicable to any medical treatment. However, it is to be understood that the total daily usage of the compounds and compositions described herein may be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; 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; drugs used in combination or coincidentally with the specific compound employed; and like factors well known to the researcher, veterinarian, medical doctor or other clinician of ordinary skill.

It is also appreciated that the therapeutically effective amount, whether referring to monotherapy or combination therapy, is advantageously selected with reference to any toxicity, or other undesirable side effect, that might occur during administration of one or more of the compounds described herein. Further, it is appreciated that the co-therapies described herein may allow for the administration of lower doses of compounds that show such toxicity, or other undesirable side effect, where those lower doses are below thresholds of toxicity or lower in the therapeutic window than would otherwise be administered in the absence of a cotherapy.

As used herein, the term "composition" generally refers to any product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. It is to be understood that the compositions described herein may be prepared from isolated compounds described herein or from salts, solutions, hydrates, solvates, and other forms of the compounds described herein. It is also to be understood that the compositions may be prepared from various amorphous, non-amorphous, partially crystalline, crystalline, and/or other morphological forms of the compounds described herein. It is also to be understood that the compositions may be prepared from various hydrates and/or solvates of the compounds described herein. Accordingly, such pharmaceutical compositions that recite compounds described herein are to be understood to include each of, or any combination of, the various morphological forms and/or solvate or hydrate forms of the compounds described herein.

Illustratively, compositions may include one or more carriers, diluents, and/or excipients. The compounds described herein, or compositions containing them, may be formulated in a therapeutically effective amount in any conventional dosage forms appropriate for the methods described herein. The compounds described herein, or compositions containing them, including such formulations, may be administered by a wide variety of conventional routes for the methods described herein, and in a wide variety of dosage formats, utilizing known procedures (see generally, Remington: The Science and Practice of Pharmacy, (21^st ed., 2005)). Thus, one embodiment is a pharmaceutical composition comprising one or more compounds of any of the descriptions herein together with a diluent, excipient or carrier.

The term "administering" as used herein includes all means of introducing the compounds and compositions described herein to the patient, including, but are not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, and the like. The compounds and compositions described herein may be administered in unit dosage forms and/or formulations containing conventional nontoxic pharmaceutically-acceptable carriers, adjuvants, and vehicles.

It is appreciated that compounds described herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. It is to be understood that the solvated forms and the unsolvated forms are described herein, either individually or collectively with reference to the compounds and compositions. It is also to be understood that the compounds described herein may exist in multiple amorphous, non-amorphous, partially crystalline, crystalline, and/or other morphological forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be included in the methods, uses,

compositions, and medicaments described herein. It is also to be understood that the compounds described herein may be present in the form of a salt.

Embodiments of the invention include those described by the following emumerated clauses:

1. A compound of the following formula

harmaceutically acceptable salts thereof, wherein

A is the following group, wherein (*) denotes point of attachment:

W is oxygen or sulfur;

R1 is hydrogen, a nitrogen protecting group, or a pro-drug substituent;

R^ is hydrogen, an oxygen protecting group, or a pro-drug substituent;

Z is C(O), S(0)₂, NH, NHC(O), or NHS(0)₂; and

providing that the compound is not of the formula

or a pharmaceutically acceptable salts thereof.

2. The compound of the preceding clause, wherein R^a and R^b are both hydrogen.

3. The compound of any of the preceding clauses, where the compound has the formula:

wherein Q and R are as described in any of the preceding clauses; Ar is aryl or heteroaryl, each of which is optionally substituted; and wherein A is selected from the following group, wherein (*) denotes point of attachment:

4. The compound of any of the preceding clauses, wherein A is selected from the following group, wherein (*) denotes point of attachment:

5. The compound of any of the preceding clauses, wherein the compound has the following relative and/or absolute stereochemistry:

wherein A, Q, W, X, R¹, R², R⁴, and Ar are as described in any of the preceding clauses.

6. The compound of any of the preceding clauses, wherein the compound has the following formula:

wherein A, Q, W, R¹, R⁴, and Ar are as described in any of the preceding clauses, and where Ar² is substituted aryl or substituted heteroaryl having one or more of the following illustrative substituents; halo, amino, hydroxy, alkyl, alkenyl, alkoxy, arylalkyl, arylalkyloxy, hydroxyalkyl, hydroxyalkenyl, alkylene dioxy, aminoalkyl, where the amino group may also be substituted with one or two alkyl groups, arylalkylgroups, and/or acylgroups, nitro, acyl and derivatives thereof including oximes, hydrazones, and the like, cyano, alkylsulfonyl, alkylsulfonylamino, and the like.

7. The compound of any of the preceding clauses, wherein the compound has the following formula:

wherein A, R , and R are as described in any of the preceding clauses, and where X^a and X^b are each independently selected from halo, amino, hydroxy, alkyl, alkenyl, alkoxy, arylalkyl, arylalkyloxy, hydroxyalkyl, hydroxyalkenyl, alkylene dioxy, aminoalkyl, where the amino group may also be substituted with one or two alkyl groups, arylalkylgroups, and/or acylgroups, nitro, acyl and derivatives thereof including oximes, hydrazones, and the like, cyano, alkylsulfonyl, alkylsulfonylamino, and the like. 8. The compound of any of the preceding clauses, wherein the compound has the following formula:

and pharmaceutically acceptable salts thereof, wherein

Z is C(R^cR^d) where each of R^c and R^d is independently selected in each instance from the group consisting of hydrogen, alkyl, and arylalkyl; R^4A, R^4B and R^4C are independently selected in each instance from the group consisting of hydrogen, alkyl, and arylalkyl, each of which may be optionally substituted, or R^4A, R^4B and the atoms to which they are attached form a ring, and R^4C is selected from the group consisting of hydrogen, alkyl, and arylalkyl, each of which may be optionally substituted; and A, R¹, Ar and Ar^ have the meanings disclosed in any of the preceding clauses.

9. The compound of any of the preceding clauses, wherein the compound has the following formula:

and pharmaceutically acceptable salts thereof wherein

X^a and X^b are independently selected from H, OH or OR⁶, where R⁶ is alkyl, alkylaryl, an oxygen protecting group or a pro-drug substituent; and A, Q, W, R¹, Ar² and R⁴ have the meanings disclosed in any of the preceding clauses.

10. The compound of any of the preceding clauses, wherein the compound has the following formula:

and pharmaceutically acceptable salts thereof wherein

11. The compound of any of the preceding clauses, wherein the compound has the following formula:

and pharmaceutically acceptable salts thereof wherein

A, R¹, R⁴ and Ar have the meanings disclosed in any of the preceding clauses.

12. The compound of any of the preceding clauses, where: γΐ is oxygen; or γΐ is C(R^AR^), where R^A is hydrogen, and R^ is hydrogen or alkoxy, such as methoxy; or is oxygen; or Y^ is C(R^AR^), where R^A is hydrogen, and R^ is hydrogen or alkoxy, such as methoxy; and/or

m is 1; and/or

R^C is hydrogen; and/or

R^ is hydrogen; and/or

Q is oxygen; and/or

W is oxygen; and/or

R1 is hydrogen; and/or

R^ is hydrogen; and/or

R4 is a group CH2-K-R4A where K is a bond or NHCH2, and R^A _1S alkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, each of which is optionally substituted; or R^A is isopropyl, furanyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolidinonyl, oxazolidinonyl, thiazolidinonyl, isoxazolidionyl, or isothiazolidinonyl, each of which is optionally substituted; or R4 is branched alkyl; or R4 is isobutyl; or R4 is lactamylalkyl; or R^ is pyrrolidin-4-on-2-ylalkyl; or R^ is pyrrolidin-4-on-2-ylmethyl; and/or

Z is SC"2; or Z is CO; or Z is NH; and/or

R^a and R^b are each hydrogen; and/or

m is 1; and/or

R^ is optionally substituted phenyl.

13. The compound of any of the preceding clauses, wherein when the integer m is 1, the ring fusion is syn, or wherein when the integer m is 0, 2, or 3, the ring fusion may be syn or anti; and wherein each of the relative stereochemical configurations may include either or both of the two absolute stereochemical configurations.

14. The compound of any of the preceding clauses, wherein the structures refer both individually to each enantiomer, as well as collectively to all possible mixtures of such enantiomers.

15. The compound of any of the preceding clauses, wherein the cyclic ethers may be optionally substituted with one or more groups R^a and/or R^b, each of which is independently selected, and is as described in any of the preceding clauses.

16. The compound of any of the preceding clauses, wherein the group A is a cyclic ether or another structurally related group selected from the following structures:

and stereoisomers thereof and mixtures thereof, where (*) indicates the point of attachment of A to the group Q, which is oxygen, sulfur, nitrogen, or C(R^aR^b); where each of R^a and R^b is independently selected in each instance, as defined in any of the preceding clauses.

17. The compound of any of the preceding clauses, wherein R³ is alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy, cycloalkoxy, heterocyclyloxy, heterocyclylalkoxy, amino, mono or dialkylamino, cycloalkylamino, heterocyclylamino, or heterocyclylalkylamino, each of which is optionally substituted.

18. The compound of any of the preceding clauses, wherein R³ is amino substituted alkyl or heterocyclyl, or heterocyclylalkyl.

19. The compound of any of the preceding clauses, wherein R³ is amino substituted alkyl or heterocyclyl, or heterocyclylalkyl in which the nitrogen atom of the amino group is mono or disubstituted with alkyl, cycloalkyl, or acyl, or is included in another heterocyclic group including a pyrrolidinyl, piperidinyl, or piperazinyl group.

20. The compound of any of the preceding clauses, wherein R³ is amino substituted alkyl or heterocyclyl, or heterocyclylalkyl in which the nitrogen atom of the hetetocylclyl group is substituted with alkyl, cycloalkyl, or acyl.

21. The compound of any of the preceding clauses, wherein R³ is optionally substituted alkyl or cycloalkyl, including both linear and branched variations thereof, including methyl, ethyl, butyl, isobutyl, and the like, and cyclo butyl, cyclopentyl, 3-methylcyclopentyl, and the like.

22. The compound of any of the preceding clauses, wherein R³ is optionally substituted heterocyclyl or heterocyclylalkyl, where the heterocyclic portions includes, but is not limited to, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and the like.

23. The compound of any of the preceding clauses, wherein the group A is a cyclic ether, selected from the following structures

where (*) indicates the point of attachment; m is an integer selected from 0, 1, 2, or 3; Y is C(R^aR^b) or oxygen; Y² is C(R^aR^b), CHNR^a, oxygen, or S0₂, where R^a and R^b are

independently selected in each instance as described above; and R^c and R^d each represent one or more optional substituents, each of which is independently selected in each instance from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkylalkoxy, aryl, arylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heteroaryloxy, and heteroarylalkoxy, each of which is itself optionally substituted.

24. The compound of any of the preceding clauses, wherein R^a and R^b are both hydrogen.

25. The compound of any of the preceding clauses, wherein R^c and R^d are both hydrogen.

26. The compound of any of the preceding clauses, wherein R^a, R^b, R^c, and R^d are each hydrogen.

27. The compound of any of the preceding clauses, wherein one or more of R^c and R^d is alkoxy.

28. The compound of any of the preceding clauses, wherein R² is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is substituted, where at least one substituent is a hydrogen bond forming group.

29. A pharmaceutical composition comprising one or more compounds of any of the preceding clauses together with a diluent, excipient or carrier.

30. A method for treating patients with HIV-l/AIDS comprising administering a therapeutically effective amount of the one or more compounds and/or compositions of any of the preceding clauses.

31. Use of one or more compounds and/or compositions of any of the preceding clauses for treating patients with HIV-l/AIDS.

32. Use of one or more compounds and/or compositions of any of the preceding clauses in the manufacture of a medicament for treating patients with HIV-l/AIDS.

33. The compound of any of the preceding clauses, or the compositions, methods, uses, and medicaments of any of the preceding clauses that include the compound, wherein the compound is optically pure, or includes any of a variety of stereoisomeric mixtures, including racemic and other mixtures of enantiomers, other mixtures of diastereomers, and the like; and/or including a single stereochemical configuration at one or more chiral centers, while including mixtures of stereochemical configuration at one or more other chiral centers.

The following examples further illustrate additional features of the various embodiments of the invention described herein. However, it is to be understood that the examples are illustrative and are not to be construed as limiting other embodiments of the invention described herein. In addition, it is appreciated that other variations of the examples are included in the various embodiments of the invention described herein.

METHODS AND EXAMPLES GENERAL SYNTHESIS EXAMPLE. The synthesis of enantiomerically pure (3a5',45',7ai?)-hexahydro-2H-furo[2,3-b]pyran-4-ol is shown in Scheme 1. It was achieved starting from known enantiomerically pure lactone 4.²⁷ Lactone 4 was reduced into the corresponding diol using lithium aluminum hydride in 95% yield. Selective monoacetylation at the primary alcohol using AcCl and 2,4,6-collidine at -78 °C,²⁸ and subsequent silylation of the remaining free hydroxyl furnished intermediate 5 in 86% yield (2 steps). Removal of the acetate group, followed by ozonolysis of the olefin, furnished a bicyclic bis-acetal intermediate.

Reduction of the hemiacetal moiety using EtsSiH and BF3-Et₂0 afforded bicyclic intermediate 6 in 55% yield in three steps. Removal of the silyl group with TBAF in THF furnished the desired hexahydrofuropyran-4-ol ligand (-)-7.

MeOH

S BF₃-Et₂O

8 (+)-7

Scheme 1. Synthesis of ligand (-)-7 and its respective enantiomer (+)-7.

To demonstrate the importance of the absolute stereochemistry of the bicyclic structure of ligand (-)-7, its corresponding enantiomer (+)-7 was synthesized starting from intermediate 8 (Scheme 1). Intermediate 8 was synthesized by an enzyme-catalyzed

desymmetrization of cyclopentene meso-diacetate followed by a Claisen rearrangement step.^27b' ²⁹ The resulting diester was reduced by LAH to provide 8. It was used for the synthesis of (+)-7 and subjected to the same synthetic sequence applied from lactone (-)-4 in the synthesis of (-)-7 (Scheme 1). To examine the importance of each of the two cyclic ether oxygens in the furopyranol ligand (-)-7, the corresponding cyclohexane and cyclopentane derivatives were prepared (Schemes 2 and 3). C

(-)-12 (35%) 13

Scheme 2. Synthesis of furocyclohexanol P₂ ligand (-)-12

The synthesis of 4-hydroxy octahydrobenzofuran ligand (-)-12 is shown in Scheme 2. Reaction of diazocyclohexanedione 9³⁰ with ethylvinyl ether in presence of a catalytic amount of Rh₂(OAc)4 at 23 °C gave derivative 10.³¹ Hydrogenation of the ketofuran in the presence of Pd/C under H₂ (1 atm) furnished the corresponding crude ketone 11 as a 9: 1 mixture of diastereoisomers. A one-pot procedure involving L-selectride reduction of the ketone followed by EtsSiH/TMSOTf-promoted reduction of the acetal furnished the racemic alcohol (±)-12 (71% from 10). Enzymatic resolution of (±)-12 using lipase Amano PS-30 provided the desired enantiopure alcohol (-)-12 (98.8%> ee by chiral HPLC analysis of the 2,4- dinitrobenzoate derivative), after ca. 55% conversion to the acetate.

1 . DMSO,

77% (CF₃CO)₂O

(2 steps) 2. TFA, CH₂CI₂

(-)-18, X = O (37%) 20, X = O

(-)-19, X = CH₂ (45%) 21 , X = CH₂

Scheme 3. Syntheses of ligands (-)-18 and (-)-19.

The synthesis of cyclopentapyranol ligand is shown in Scheme 3. Pentanone 14 was treated with LDA then reacted with t-butyldimethylsilyloxypropionaldehyde³² to furnish intermediate 15 (dr 3 : 1) in 95% yield. A DMSO-TFAA promoted oxidation of the free hydroxy group followed by TFA-promoted cyclocondensation furnished the bicyclic α,β-unsaturated ketone 16. Hydrogenation in presence of 10%> Pd/C followed by L-selectride reduction of the ketone gave racemic alcohol (±)-18 as a single diastereomer in 68% yield over 2 steps. Lipase- catalyzed resolution of the alcohol provided enantiomerically pure alcohol (-)18. For the synthesis of a P2 ligand devoid of any cyclic oxygen, known tetrahydroindanone 17³³ was similarly hydrogenated in presence of 10%> Pd/C to give the corresponding bicyclic ketone. Accordingly, L-selectride-promoted reduction of the ketone provided the corresponding alcohol (dr = 10: 1, as observed by 1H and ¹³C NMR). Lipase-mediated resolution of the major cis- alcohol gave the respective chiral ligand (-)-19 (90% ee determined by chiral HPLC).

Scheme 4. Synthesis of hexahydrofuro[3,4-b]pyran-4-ol ligand 25. Without being bound by theory, it was hypothesized that the introduction of a six-membered ring in the P₂ ligand structure may introduce more structural flexibility. Thus, ligands in which the cyclic oxygens were moved to adjacent positions were explored. Such ligands may also demonstrate the importance of the oxygen positions in the bicyclic structure of ligand (-)-7. Thus, isomeric ligand 25 was synthesized with the furan oxygen moved to a vicinal position. The synthesis of 4-hydroxyhexahydro-2H-furo[3,4-b]pyran 25 is shown in Scheme 4. Iodoalkoxylation of the 2,5-dihydrofuran 22 using propanediol in the presence of N- iodosuccinimide and catalytic NH₄OAc provided iodoalcohol 23. Swern oxidation gave aldehyde 24 in 86% yield. An intramolecular Barbier-type reaction was then conducted using indium in the presence of copper (I) iodide and iodine, to furnish a mixture of diastereoisomeric alcohols.³⁴ Oxidation followed by stereoselective reduction using NaBH₄ furnished the racemic cis,cis-bicyclic alcohol (±)-25 as the sole product. Lipase-mediated resolution finally gave the enantiomerically pure alcohol 25. To ascertain the importance of the position of the urethane in (-)-7, hexahydrofuropyran-5-ol ligand 30 was synthesized, as shown in Scheme 5. The free hydroxyl on the pyran ring was moved to the C3 position. The synthesis was accomplished starting from enantiomerically pure bis-THF ligand 27 synthesized by us previously.³⁵ Dess-Martin oxidation of 27 provided the corresponding ketone. Homologation of the resulting ketone using trimethylsilyldiazomethane in the presence of AlMe3 followed by treatment of the crude mixture with TBAF and acetic acid provided the furanopyranone 29. Stereoselective reduction of ketone 29 using L-selectride furnished alcohol 30 as a mixture of inseparable

diastereoisomers (dr = 5: 1). Both isomers were separated after formation of the corresponding activated mixed carbonate 31g.

TMSCHN₂,

63% AIMe₃, then

TBAF, AcOH

c s rans :

Scheme 5. Synthesis of hexahydrofuro[2,3-b]pyran-5-ol ligand 30

The synthesis of the protease inhibitors was accomplished in a two-step sequence shown in Schemes 6 and 7. Each ligand alcohol synthesized above was reacted with 4-nitrophenyl chloro formate in presence of pyridine to form mixed activated carbonates 31a-g in 70-99% yield. The synthesis of the corresponding protease inhibitors was achieved by coupling the mixed activated carbonates with previously reported hydroxyethylsulfonamide isosteres 32-34 (Scheme 7).¹⁵ The syntheses of various HIV-PI containing the Tp-THF {-)-!, were achieved by respectively treating the Boc-protected isosteres 32-34 with TFA in CH₂CI₂ and subsequently, by coupling the resulting free amine isosteres with activated mixed carbonate 31a in THF/CH₃CN in presence of Et₃N. The corresponding inhibitors 35a, 36, and 37 were obtained in good yields (Scheme 7). Inhibitors 35b-g were made in a similar manner.

(yields 31b-31g: 70-99%)

Scheme 6. Synthesis of activated mixed carbonates 31a-g

Scheme 7. Syntheses of inhibitors 35a-g, 36 and 37. EXAMPLE 1. General Experimental Methods. All anhydrous solvents were obtained according to the following procedures: diethyl ether and tetrahydrofuran (THF) were distilled from sodium/benzophenone under argon; toluene, methanol, acetonitrile, and dichloromethane from calcium hydride and benzene from sodium. Other solvents were used without purification. All moisture-sensitive reactions were carried out in flame-dried flasks under argon atmosphere. Reactions were monitored by thin layer chromatography (TLC) using Silicycle 6OA-F254 silica gelpre-coated plates. Flash column chromatography was performed using Silicycle 230-400 mesh silica gel. Yields refer to chromatographically and

spectroscopically pure compounds. Optical rotations were recorded on a Perkin Elmer 341 polarimeter. 1H NMR and ¹³C NMR spectra were recorded on a Varian Inova-300 (300 and 75 MHz), Bruker Avance ARX- 400 (400 and 100 MHz) or DRX- 500 (500 and 125 MHz). High and low resolution mass spectra were carried out by the Mass Spectroscopy Center at Purdue University. The purity of all test compounds was determined by HRMS and HPLC analysis in the different solvent systems. All test compounds showed >95% purity.

EXAMPLE 2. (15;2i? -2-[l-(tert-Butyldimethylsilyloxy)-cyclopent-3-en-2- yl]ethyl acetate (5). To a stirred suspension of lithium aluminum hydride (93 mg, 2.45 mmol) in dry Et₂0 (6 mL) was added dropwise a solution of (-)-(15',5i?)-2-oxabicyclo[3.3.0]oct-6-en-3- one (4) (150 mg, 1.19 mmol) in Et₂0 (4 mL + 1 mL rinse) at 0 °C under argon. The reaction mixture was vigorously stirred at this temperature for 1.5 h. Water (0.1 mL) was then carefully added followed by addition of 3M NaOH (0.1 mL) then water (0.3 mL). The solution was stirred until formation of a white precipitate was complete. EtOAc (3 mL) then Na₂S0₄ were added and the resulting suspension was filtered out. The amorphous solid was washed several time with EtOAc (5 x 5 mL). The combined organic layers were dried over Na₂S0₄, filtered, and concentrated in vacuo. The crude oil was purified by flash chromatography on silica gel using hexanes/EtOAc (1 :1) as the eluent to give the resulting diol (145 mg, 95%) as a colorless oil. TLC: R/= 0.28 (hexanes/EtOAc = 1 :2); 1HNMR (CDC1₃, 300 MHz) δ 5.74 (m, 1H), 5.56 (m, 1H), 4.48 (dt, J= 2.4, 6.6 Hz, 1H), 3.84 (m, 1H), 3.71 (ddd, J= 3.6, 8.7, 10.0 Hz, 1H), 2.75 (m, 1H), 2.67 (m, 1H), 2.36 (d, J= 17.1 Hz, 1H), 1.98-1.75 (m, 1H).

To a stirred solution of the diol (76 mg, 0.59 mmol) in CH₂C1₂ (3 mL) was added 2,4,6-collidine (1.2 mmol, 155 μί) followed by acetyl chloride (50 μί, 0.71 mmol) at -78 °C under argon. The resulting solution was stirred at this temperature for 5 h at which point additional acetyl chloride (0.25 μί, 0.24 mmol) was added. The solution was stirred for 2 h then sat. aq. NaHC0₃ solution was added. The two layers were separated and the aqueous layer was washed with CH₂C1₂ (3 x 5 mL). The combined organic layer was dried over Na₂S0₄, filtered, and concentrated in vacuo. The crude oil was purified by flash chromatography on silica gel using hexanes/EtOAc (6: 1 then 4: 1) as the eluent to give the monoacetate (88 mg, 87%) as a colorless oil. TLC: R/ = 0.26 (hexanes/EtOAc = 2: 1); 1H NMR (CDC1₃, 300 MHz) δ 5.80-5.72 (m, 1H), 5.64-5.58 (m, 1H), 4.40 (dt, J= 2.4, 5.6 Hz, 1H), 4.20 (t, J= 7.2 Hz, 2H), 2.74-2.56 (m, 2H), 2.33 (d, J= 17.1 Hz, 1H), 2.06 (s, 3H), 2.04-1.88 (m, 1H), 1.87-1.73 (m, 1H); ¹³C NMR (CDC1₃, 75 MHz) δ 171.1, 132.4, 128.4, 72.7, 63.9, 47.2, 42.1, 26.8, 21.0.

HRMS-ESI (m/z): [M + H]⁺ calcd for C₉Hi₅0₃ 171.1021; found 171.1020.

To a stirred solution of the above acetate (54 mg, 0.32 mmol) and 2,6-lutidine (74 μΕ, 0.63 mmol) in CH₂CI₂ (1 mL) was added tert- butyldimethylsilyltrifluoromethanesulfonate (125 mg, 108 μί) at -78 °C under argon. The mixture was stirred for 10 min at which point reaction completion was observed. Sat. aq.

NaHC0₃ solution (1 mL) and additional CH₂CI₂ (2 mL) were added. The two layers were separated and the aqueous layer was further extracted with CH₂CI₂ (2 x 2 mL). The combined organic layer was washed with brine, dried (MgS0₄), filtered, and concentrated under reduced pressure. The crude oil was purified by column chromatography on silica gel using

hexanes/EtOAc (20: 1) as the eluent to afford silylated product 5 (90 mg, > 99%) as a colorless oil. TLC: R/= 0.68 (hexanes/EtOAc = 3: 1); 1H NMR (CDC1₃, 300 MHz) δ 5.68 (s, 2H), 4.45 (dt, J= 5.1, 6.3 Hz, 1H), 4.14 (t, J= 6.9 Hz, 2H), 2.67-2.55 (m, 1H), 2.47 (dd, J= 6.9, 15.4 Hz, 1H), 2.23 (dd, J= 4.8, 15.4 Hz, 1H), 2.04 (s, 3H), 2.01-1.85 (m, 1H), 1.72-1.56 (m, 1H), 0.88 (s, 9H), 0.06 (s, 6H); ¹³C NMR (CDC1₃, 75 MHz) δ 171.2, 132.7, 128.4, 73.6, 63.8, 45.9, 41.0, 27.4, 25.8, 21.0, 18.1, -4.6, -5.0.

EXAMPLE 3. (4_lS,4a_lS,7ai?)-4-(tert-Butyldimethylsilyloxy)-hexahydrofuro-[2,3- b]pyrane (6). To a stirred solution of 5 (76 mg, 0.27 mmol) in MeOH (2 mL) was added K₂C0₃ (37 mg, 0.27 mmol). The solution was stirred at 23 °C for 2 h then sat. aq. NH₄C1 solution (2 mL) was added to the mixture. EtOAc was added and the two layers were separated. The aqueous layer was extracted with EtOAc (4 x 3 mL). The combined organic layer was washed with brine, dried (Na₂S0₄), filtered, and concentrated under reduced pressure. The resulting oil was purified by flash chromatography on silica gel using hexanes/EtOAc (7: 1) as the eluent to give the corresponding alcohol (64 mg, 98%>) as a colorless oil. This intermediate was used immediately for the subsequent reaction. TLC : R_f = 0.29 (hexanes/EtO Ac = 5 : 1 ); ¹ H NMR

(CDC1₃, 300 MHz) δ 5.72.5.62 (m, 2H), 4.52 (dt, J= 6.0, 6.9 Hz, 1H), 3.74-3.60 (m, 2H), 2.80- 2.68 (m, 1H), 2.49 (ddt, J= 1.8, 7.2, 16.3 Hz, 1H), 2.34-2.29 (m, 1H), 2.06 (br. s, 1H), 1.90- 1.62 (m, 2H); ¹³C NMR (CDC1₃, 75 MHz) δ 132.9, 128.3, 74.0, 61.1, 46.5, 40.6, 31.2, 25.8, 18.2, -4.7, -5.0. A stream of ozonized oxygen was bubbled through a solution of the above alcohol (63.8 mg, 0.26 mmol) in CH₂CI₂ (15 mL) at -78 °C until the blue color persisted (5 min). After the solution was flushed with nitrogen, Me₂S (0.5 mL) was added. The solution was warmed to 0 °C and stirred over a 2 h period following which anhydrous Na₂S0₄ was added. The solution was left at room temperature overnight then filtered and concentrated in vacuo. The resulting solid was quickly passed through a short column of silica gel using

hexanes/EtOAc (3: 1) as the eluent to afford the hemiacetal (99 mg) as a white-solid mixture of isomers which was submitted directly to the next step. TLC: R/= 0.26 (hexanes/EtOAc = 3: 1). To an ice-cold solution of the crude diacetal (ca. 0.25 mmol) and Et₃SiH (0.16 mL, 1.0 mmol) in CH₂C1₂ (3 mL) under argon, was slowly added BF₃-Et₂0 (60 μί, 0.5 mmol). The mixture was stirred at 0 °C for 10 min. Sat. aq. NaHC0₃ solution (2 mL) and additional CH₂C1₂ were added. The two phases were separated and the aqueous layer was further extracted with CH₂C1₂ (3 x 2 mL). The combined organic layer was washed with brine, dried (MgS0₄), filtered, and concentrated in vacuo. The crude oil was purified by column chromatography on silica gel using hexanes/EtOAc (7: 1) as the eluent to give bicyclic acetal 6 (38 mg, 55% 3 steps) as a amorphous solid. TLC: R/= 0.50 (hexanes/EtOAc = 3: 1); 1H NMR (CDC1₃, 300 MHz) δ 4.95 (d, J= 3.4 Hz, 1H), 4.24-4.08 (m, 2H), 3.92 (dt, J= 8.1, 9.1 Hz, 1H), 3.85 (ddd, J= 2.0, 4.5, 12.2 Hz, 1H), 3.30 (dt, J= 2.0, 12.3 Hz, 1H), 2.39 (m, 1H), 2.07 (tt, J= 9.4, 12.0 Hz, 1H), 1.91- 1.66 (m, 2H), 1.58-1.48 (m, 1H), 0.89 (s, 9H), 0.07 (s, 3H), 0.067 (s, 3H); ¹³C NMR (CDC1₃, 75 MHz) δ 101.2, 68.4, 67.8, 61.1, 47.2, 30.3, 25.7, 22.4, 18.2, -4.6, -4.8.

EXAMPLE 4. (3a_lS,4_lS,7ai?)-Hexahydro-2H-furo[2,3-b]pyran-4ol (-)-7. Bicyclic compound 6 (36 mg, 0.139 mmol) was dissolved in THF (1 mL) and tetrabutylammonium fluoride (1M solution THF, 0.21 mL, 0.21 mmol) was added to the solution. The mixture was stirred for 2 h at 23 °C. Sat. aq. NH₄C1 solution was added (2 mL), followed by EtOAc (2 mL). The two phases were separated and the aqueous layer was further extracted with EtOAc (4 x 3 mL). The combined organic layer was washed with brine, dried (Na₂S0₄), filtered, and concentrated in vacuo. The resulting compound was purified by flash chromatography on silica gel using hexanes/EtOAc (1 :2 then 1 :3) as the eluent to afford pure alcohol (-)-7 (19 mg, 94%) as a amorphous solid. TLC: R/= 0.15 (hexanes/EtOAc = 1 :3); [a] -29.6 (c 1.06, CHC1₃); 1H NMR (CDC1₃, 300 MHz) δ 4.99 (d, J= 2.7 Hz, 1H), 4.25-4.16 (m, 2H), 3.96 (q, J= 7.5 Hz, 1H), 3.90 (ddd, J= 2.4, 4.8, 12.3 Hz, 1H), 3.34 (td, J= 3.0, 11.7 Hz, 1H), 2.58-2.45 (m, 1H), 2.14-1.98 (m, 1H), 1.96-1.82 (m, 1H), 1.80-1.62 (m, 2H); ¹³C NMR (CDC1₃, 75 MHz) δ 101.4, 68.4, 67.5, 61.0, 46.3, 29.4, 21.8. HRMS-CI (m/z): [M + H]⁺ calcd for C₉Hi₅0₃ 127.0759; found 127.0757. EXAMPLE 5. (3ai?,4i?,7a5)-Hexahydro-2H-furo[2,3-b]pyran-4-ol (+)-7.

Cyclopentenediol 8 was prepared as described previously.²⁷¹¹ The same synthetic sequence was the applied on diol as for the synthesis of (-)-7. Ligand (+)-7 was obtained in high enantiomeric purity (99% ee, [a] + 22.3, c 0.22, CHC1₃).

EXAMPLE 6. 2-Ethoxy-2,3,6,7-tetrahydrobenzofuran-4(5H)-one (10). To a stirred solution of 2-diazo-l,3-cyclohexanedione (300 mg, 2.17 mmol) in freshly distilled ethyl vinyl ether (5 mL) was added [Rh₂(OAc)4] (10 mg, 0.02 mmol). The mixture was stirred at room temperature for 5 h, after which the reaction was diluted with Et₂0 and few drops of pyridine were added. A red precipitate formed. The solution was filtered on a short pad of silica, flushing with Et₂0/THF (4: 1) as eluent. After evaporation, the residue was purified by column chromatography on silica gel using hexanes/CH₂Cl₂/THF (8: 1 : 1) as the eluent to furnish benzofuranone derivative 17 (347 mg, 88%). TLC: R/= 0.29 (hexanes/EtOAc = 1 : 1); 1H NMR (CDC1₃, 400 MHz) δ 5.72 (dd, J= 3.3, 7.4 Hz, 1H), 3.88 (m, 1H), 3.62 (m, 1H), 2.92 (ddt, J= 2.2, 7.4, 15.8 Hz, 1H), 2.70-2.62 (m, 1H), 2.52-2.37 (m, 2H), 2.33 (t, J= 6.5 Hz, 2H), 2.12-1.95 (m, 2H), 1.24 (t, J= 7.1 Hz, 3H); ¹³C NMR (CDC1₃, 100 Hz) δ 195.2, 175.7, 112.3, 108.5, 65.0, 36.3, 32.7, 23.8, 21.5, 14.9.

EXAMPLE 7. 2-Ethoxyhexahydrobenzofuran-4(2H)-one (11). To a solution of the ketone 10 (140 mg, 0.77 mmol) in EtOAc (9 mL) was added 5% Pd/C (128 mg, 60 μιηοΐ) and the mixture was stirred under H₂ (1 atm) for 1.5 h at room temperature. The mixture was then filtered on Celite and the pad washed with EtOAc. Evaporation of the solvent furnished the corresponding crude ketone 11 as an essentially pure mixture of diastereoisomers (130 mg, dr = 9: 1). The ketone was directly submitted to the next step without purification. TLC Major isomer: R_f = 0.35 (hexanes: EtOAc = 2: 1).

EXAMPLE 8. cz^'s-Octahydrobenzofuran-4-ol [(±)-12]. A solution of ketone 11 (130 mg, ca. 0.7 mmol) in CH₂C1₂ (10 mL) was cooled to -78 °C under Ar. L-Selectride (1M solution, 0.9 mL, 0.9 mmol) was slowly added to the solution over 5 min and the reaction mixture was stirred for 1.5 h at -78 °C. Upon complete conversion, Et₃SiH (0.6 mL, 437 mg, 3.7 mmol) was added followed by dropwise addition of TMSOTf (380 μί, 466 mg, 2.1 mmol). The solution was stirred for 2.5 h while slowly warming to 0 °C. The reaction was quenched by addition of saturated aq. NaHC0₃ solution (5 mL). The two phases were separated and the aqueous phase was extracted with Et₂0 (5x). The combined organic layer was washed with brine, dried (MgS0₄), and evaporated under vacuum. The residue was purified by column chromatography on silica gel using hexanes :EtO Ac (3: 1 to 2: 1) as the eluent to yield the desired alcohol (±)-12 (78 mg, 71 > over 2 steps) as a colorless oil. TLC: R = 0.25 (hexanes/EtOAc = 1 :2); 1H NMR (CDC1₃, 400 MHz) δ 4.01 (dt, J= 4.6, 8.8 Hz, 1H), 3.88-3.82 (m, 2H), 3.78 (dt, J = 7.1, 8.7 Hz, 1H), 2.31 (m, 1H), 2.12-1.90 (m, 2H), 1.74-1.50 (m, 5H), 1.32-1.22 (m, 1H); ¹³C NMR (CDCI3, 100 Hz) δ 77.6, 69.1, 66.7, 43.2, 30.2, 26.9, 25.9, 16.2.

EXAMPLE 9. (3aS,4S,7ai?)-Octahydrobenzofuran-4-ol [(-)-12]. Racemic alcohol 12 (70 mg, 0.5 mmol) was dissolved in THF (5 mL), vinyl acetate (120 μί, 1.25 mmol) was added. Amano lipase PS-30 (30 mg) was added and the resulting suspension was stirred at 15-17 °C. After 48 h, 30 mg additional enzyme was added and the mixture was left for additional 48 h until which ca. 54 % conv. was reached (NMR and GC). The resulting suspension was diluted with Et₂0 and filtered on celite, the filter cake rinsed with Et₂0. After evaporation of the remaining solvent, the residue was purified by column chromatography using hexanes/EtOAc (5: 1, 3: 1 then 2:1) as the eluent to yield acetyl furanol 13 (38 mg, 41%) and the desired enantio enriched (-)-hexahydrobenzofuranol (-)-12 (24 mg, 35%). The enantiomeric excess of the 2,4-dinitrobenzoate derivative of (-)-12 was determined to be 98.8% ee by chiral HPLC, Column ChiralPak IA, hexane/isopropanol (90/10 to 50/50, 40 min), 1 mL/min, 35 °C, λ = 254 nm, R_t Major = 16.54 min, R_t minor = 37.1 min.

EXAMPLE 10. 2-[3-(tert-Butyldimethylsilyl)oxy)-l- hydroxypropyl]cyclopentanone (15). A solution of lithium diisopropylamide (14 mmol), freshly prepared by adding nBuLi (1.6 M solution in hexanes, 8.75 mL, 14 mmol) to diisopropylamine (1.97 mL, 1.42 g, 14 mmol) in THF (30 mL) at 0 °C under argon followed by stirring for 30 min, was cooled to -78 °C and cyclopentanone 14 (1.12 mL, 1.07 g, 12.7 mmol) in THF (5 mL) was added dropwise over 10 min. After stirring at -78 °C for 1.5 h, 3-tert- butyldimethylsilyloxy-propionaldehyde (1.55 g, 8.2 mmol) in THF (20 mL) was added dropwise over 5 min. The mixture was stirred for an additional 2 h and the reaction was quenched by addition of saturated aqueous NH₄C1 solution (10 mL). Following dilution with Et₂0, the two phases were separated, and the aqueous phase was extracted with Et₂0 (2x). The combined organic phase was washed with brine, dried (MgS0₄), filtered, and evaporated. The residue was quickly purified by column chromatography on silica gel using hexanes/EtOAc (20:1 to 10: 1) as the eluent to give 15 as a 3:1 mixture of diastereoisomers (2.13 g, 95%>). Light yellow oil. TLC: R/ = 0.37 and 0.23 (hexanes/EtOAc = 5: 1); 1H NMR (CDC1₃, 400 MHz) δ 4.27 (dt, J= 3.1, 9.3 Hz, 0.3H), 4.10 (s, 1H), 3.91 (m, 1H), 3.87 (m, 0.3H), 3.85-3.75 (m, 2.6H), 2.38-2.30 (m, 6.5H), 1.80-1.56 (m, 5.2H), 0.88 (brs, 12H), 0.06 (s, 2H), 0.05 (s, 6H); ¹³C NMR (CDCI3, 100 MHz) δ 222.8, 220.4, 70.4, 70.2, 62.6, 60.5, 54.5, 53.9, 39.1, 38.7, 37.0, 36.6, 26.4, 25.9, 25.8, 23.5, 20.7, 20.5, 18.2, -5.5, -5.6; HRMS-CI (m/z): [M - OH]⁺ calcd for

Ci₄H₂₇0₂Si 255.1780; found 255.1785. EXAMPLE 11. 2,3,6,7-Tetrahydrocyclopenta[b]pyran-4(5H)-one (16). To a solution of DMSO (425 μΐ,, 468 mg, 6 mmol) in CH₂C1₂ (3 mL) was added (CF₃CO)₂0 (406 μί, 609 mg, 2.9 mmol) dropwise at -78 °C under argon. The resulting mixture was stirred at that temperature for 45 min then a pre-cooled solution of ketone 15 (272 mg, 1 mmol) in CH₂C1₂ (3 mL) was added. The reaction mixture was stirred at -78 °C for 30 min, then at -15 °C for 15 min and cooled back to -78 °C. Et₃N (1.25 mL, 911 mg, 9 mmol) was added and the mixture was stirred at -78 °C for 45 min. The reaction was quenched by addition of sat. aq. NH₄CI solution and the mixture warmed to room temperature. The two phases were separated and the aqueous phase was extracted with CH₂C1₂ (3x) then EtOAc (lx). The combined organic phase was washed with brine, dried (Na₂S0₄), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography using hexanes/EtOAc (20:1 then 15: 1 with a few drops of acetic acid) as the eluent to give the corresponding diketone (221 mg, 82%) as a light orange oil. TLC: R/= 0.37 (hexanes/EtOAc = 10: 1); 1H NMR (CDC1₃, 400 MHz) δ 12.7 (br.s., 1H), 3.90 (t, J= 6.2 Hz, 0.66H), 3.89 (t, J= 6.5 Hz, 2H), 3.46 (t, J = 7.8 Hz, 0.33H), 2.86 (dt, J= 3.0, 6.2 Hz, 0.66H), 2.58 (t, J= 7.2 Hz, 2H), 2.45 (t, J= 6.5 hz, 2H), 2.40 (t, J= 7.9 Hz, 2H), 2.31-2.19 (m, 0.66H), 2.10-1.97 (m, 0.66H), 1.95-1.82 (m, 2H), 0.86 (s, 9H), 0.86 (s, 3H), 0.04 (s, 1H), 0.03 (s, 1H), 0.03 (s, 6H); ¹³C NMR (CDC1₃, 100 MHz) δ 212.9, 206.1, 203.6, 175.4, 110.9, 62.4, 59.6, 58.5, 45.6, 38.7, 37.8, 37.0, 25.7, 25.6, 25.0, 20.6, 20.3, 18.1, -5.6; HRMS-CI (m/z): [M + H]⁺ calcd for Ci₄H₂₆0₃Si 271.1729; found 271.1733.

A solution of this diketone (54 mg, 0.2 mmol) was dissolved in CH₂C1₂ (2 mL) and cooled to 0 °C under argon. Trifluoroacetic acid (90 μί, 134 mg, 1.2 mmol) was then added dropwise. The mixture was stirred at 0 °C for 30 min then warmed to room temperature and stirred for 4 h. As completion was reached, solid NaHC0₃ (ca. 150 mg) was then added and the mixture diluted with EtOAc. After stirring for 10 min, the suspension was filtered on a small celite pad. The solvent was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using hexanes/EtOAc (4: 1) as the eluent to furnish α,β- unsaturated ketone 16 (26 mg, 94%) as a colorless oil. TLC: R = 0.23 (hexanes/EtOAc = 3: 1); 1H NMR (CDCI3, 400 MHz) δ 4.49 (t, J= 6.9 Hz, 2H), 2.59-2.45 (m, 6H), 1.89 (m, 2H); ¹³C NMR (CDCI3, 100 MHz) δ 189.6, 178.5, 114.5, 69.5, 35.4, 32.6, 25.6, 19.0.

EXAMPLE 12. Octahydrocyclopenta[b]pyran-4-ol [(±)-18]. A solution of α,β- unsaturated ketone 16 (109 mg, 0.79 mmol) in EtOAc (6 mL) was added with 10% Pd/C (50 mg, 0.047 mmol) and carefully placed under H₂ (1 atm). The mixture was stirred at room temperature for 12 h. The suspension was then filtered over a Celite pad, the pad washed with EtOAc, and the resulting solution evaporated under reduced pressure. The essentially pure ketone (81 mg) was directly carried out to the next step without further purification. TLC: R/ = 0.37 (hexanes/EtOAc = 3: 1); 1H NMR (CDC1₃, 400 MHz) δ 4.22-4.15 (m, 2H), 3.69 (td, J = 2.8, 12.0 Hz, 1H), 2.71 (ddd, J= 7.2, 12.3, 15.7 Hz, 1H), 2.48 (dt, J= 4.0, 9.0 Hz, 1H), 2.23 (ddt, J= 1.4, 2.8, 15.7 Hz, 1H), 2.00-1.80 (m, 5H), 1.71-1.63 (m, 1H); ¹³C NMR (CDC1₃, 100 MHz) δ 210.2, 82.8, 65.9, 55.1, 38.5, 33.3, 28.4, 22.8.

The ketone was diluted in CH₂CI₂ (5 mL) under argon and cooled to -78 °C. L- Selectride (1M solution in THF, 0.80 mL, 0.8 mmol) was added dropwise and the resulting mixture was stirred at this temperature for 2 h. Hydrogen peroxide (30% aqueous solution, 3 mL) and 3N NaOH aqueous solution were added and the mixture was warmed to 23 °C, and stirred for 5 h. The phases were separated and the aqueous phase extracted with CH₂CI₂ (4x). The combined organic phase was washed with brine, dried (Mg₂S0₄), filtered, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using hexanes/EtOAc (4: 1 then 1.5:1) as the eluent to yield cz^'s-bicyclic alcohol (±)-18 (77 mg, 68% 2 steps) as a colorless oil. TLC: R_f = 0.13 (hexanes/EtOAc = 2: 1); 1H NMR (CDC1₃, 400 MHz) δ 4.11 (dt, J= 5.6, 11.1 Hz, 1H), 3.91 (ddd, J = 2.0, 4.5, 11.7 Hz, 1H), 3.84-3.81 (m, 1H), 3.33 (dt, J= 2.3, 11.9 Hz, 1H), 2.17-2.08 (m, 1H), 1.92-1.81 (m, 1H), 1.79-1.55 (m, 7H); ¹³C NMR (CDC1₃, 125 MHz) δ 80.5, 68.3, 65.4, 47.0, 32.6, 29.7, 21.6, 21.3.

EXAMPLE 13. (4_lS,4a_lS,7a5)-Octahydrocyclopenta[b]pyran-4-ol ((-)-18).

Racemic alcohol (±)-18 (68 mg, 0.48 mmol) was dissolved in THF (5 mL) and vinyl acetate (225 μί, 2.4 mmol) was added. Amano lipase PS-30 (30 mg) was added and the resulting suspension was stirred at 15-20 °C. The mixture was left stirring for >48 h until around 50 % conversion was reached (as seen by NMR). The resulting suspension was diluted with Et₂0 and filtered on celite, the filter cake rinsed with Et₂0. After evaporation of the remaining solvent, the residue was purified by column chromatography using hexanes/EtOAc (5: 1, 3: 1 then 1.5 : 1) to yield the desired enantioenriched pyranol (-)-18 (25 mg, 37%>). [α]η -47.5 (c 1.32, CHC1₃). An enantiopurity of 94.1% ee for the alcohol was measured by chiral HPLC analysis of the corresponding activated carbonate 31d: Column ChiralPak IA, 0.7 mL/min, Hexanes/IPA (98:2 to 85: 15, from 0 to 45 min), λ = 210 nm, T = 30 °C, R_t minor = 22.4 min, R_t Major = 23.3 min.

EXAMPLE 14. (±)-ercdo-cz^'s-Bicyclo[4.3.0]nonan-2-ol [(±)-19]. Enone 17³³

(106 mg, 0.77 mol) was dissolved in THF (10 mL), the flask was purged with argon. Pd/C 10%> (60 mg, 0.06 mmol) was added to the solution and the resulting suspension was stirred under hydrogen (1 atm). TLC monitoring first shows isomerization of the enone, through migration of the olefin to the internal position, followed by slow formation of the reduced czs-product. After 12 h, the solution was filtered on a pad of celite and the solvent removed in vacuo. The residue was purifed by flash column chromatography on silica gel using hexanes/EtOAc (30: 1 to 10: 1) to give the reduced ketone (98 mg, 92%). TLC: R/= 0.65 (hexanes/EtOAc = 5: 1); 1H NMR (CDCls, 400 MHz) δ 2.62-2.54 (m, 1H), 2.48-2.38 (m, 1H), 2.38-2.23 (m, 2H), 2.08-1.98 (m, 1H), 1.94-1.30 (m, 9H); ¹³C NMR (CDC1₃, 100 MHz) δ 214.6, 53.1, 42.9, 39.6, 31.0, 27.2,

26.6, 23.8, 23.0. A solution of the ketone (135 mg, 0.98 mmol) in CH₂CI₂ (3 mL) was cooled to -78 °C under argon. L-Selectride (1M solution THF, 1.2 mL) was added dropwise to the solution and the reaction mixture was stirred at -78 °C for 1 h. Hydrogen peroxide solution (30%) solution, 1.5 mL) then NaOH (3M solution, 1.5 mL) were added and the reaction was warmed to 23 °C, and stirred for 1 h. After dilution with water (2 mL) then addition of Na₂S0₃ saturated aqueous solution (3 mL), the aqueous phase was successively extracted with CH₂C1₂ (4x). The combined organic phase was dried (Na₂S0₄), filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel using hexanes/EtOAc (6:1) to yield racemic alcohol (±)-19 (92 mg, 66%) as a colorless oil. TLC: R = 0.25 (hexanes/EtOAc = 5: 1); 1H NMR (CDC1₃, 500 MHz) δ 3.96 (m, 1H), 2.26-2.17 (m, 1H), 1.93 (m, 1H), 1.79-1.53 (m, 7H), 1.47-1.15 (5 H), 0.96 (dq, J= 3.3, 13.0 Hz, 1H); ¹³C NMR (CDC1₃, 125 MHz) δ 71.6, 46.4, 40.1, 31.5, 29.5, 27.0, 23.9, 21.4, 21.2; HRMS-EI (m/z): [M - OH]^" calcd for C₉Hi₅ 122.1096, found 122.1097.

EXAMPLE 15. (-)-(li?,2S,6i?)-Bicyclo[4.3.0]nonan-2-ol [(-)-19]. Racemic 19 (86 mg, 0.62 mmol) was dissolved in THF (5 mL), vinyl acetate (0.5 mL) was added. Amano lipase PS-30 (60 mg) was added and the resulting suspension was stirred at 23 °C until 50%> conv. was reached (NMR) in ca. 6 h. The resulting suspension was diluted with Et₂0 and filtered on celite, the filter cake rinsed with Et₂0. After evaporation of the remaining solvent, the residue was purified by column chromatography using hexanes/EtOAc (8: 1, 6: 1 then 4: 1) to yield acetate 21 and the desired enantioenriched (-)-indanol (-)-19 (38.5 mg, 45%> yield). [α] η - 28.3° (c 1.02, CHC1₃), ([a]" lit. -27.2° (c 1.0, CHC1₃).³⁸ The enantiomeric excess of the 2,4- dinitrobenzoate derivative was determined to be 89.9% ee by chiral HPLC, Column ChiralPak IA, hexane/isopropanol (100/0 to 90/10, 15min; 90/10 to 80/20, 15 min), 1 mL/min, R_t minor = 16.58 min, R_t Major = 19.5 min.

EXAMPLE 16. 3-((4-Iodotetrahydrofuran-3-yl)oxy)propan-l-ol (23). To a solution of freshly distilled 2,5-dihydrofuran (700 mg, 0.740 mL, 10 mmol), in a mixture of dry 1,3-propanediol/dimethoxyethane (1 : 1, 5 mL) at 0 °C under argon, were successively added NH₄OAc (77 mg, 1 mmol), followed by N-iodosuccinimide (11 mmol, 2.47 g). The mixture was warmed to 23 °C and stirred for 12 h protected from light. The reaction was quenched by addition of sat. aq. Na₂S0₃ then diluted with water. The mixture was extracted with Et₂0/EtOAc (1 : 1). The combined organic phase was dried (Na₂S0₄), filtered, and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using hexanes/EtOAc (4: 1, 3: 1 then 2.5: 1) to give iodoalcohol 23 (1.2g, 45%) as a pale yellow oil. TLC: R/ = 0.3 (hexanes/EtOAc = 1 :1); 1H NMR (CDC1₃, 400 MHz) δ 4.33 (m, 1H), 4.29- 4.19 (m, 3H), 4.04 (dd, J= 2.2, 9.8 Hz, 1H), 3.79 (dd, J = 1.5, 9.8 Hz, 1H), 3.76-3.69 (m, 3H), 3.60 (m, 1H), 1.81 (m, 2H); ¹³C NMR (CDC1₃, 100 MHz) δ 88.2, 76.1, 71.8, 67.9, 60.6, 32.3, 23.4.

EXAMPLE 17. 3-((4-Iodotetrahydrofuran-3-yl)oxy)propanal (24). Oxalyl chloride (580 mg, 392 μΕ, 4.6 mmol) was diluted in CH₂C1₂ (12 mL) under argon and the solution was cooled to -78 °C. Dry DMSO (715 mg, 650 μΕ, 9.15 mmol) in CH₂C1₂ (3 mL) was added to the cold solution dropwise and the mixture was stirred for 30 min. A solution of alcohol 23 (500 mg, 1.83 mmol) in CH₂C1₂ (4 mL) was then added slowly, and the mixture was kept stirring for an additional hour at -78 °C. Et₃N (1.3 g, 1.8 mL, 12.8 mmol) was then introduced, the white suspension was stirred at -78 °C for 20 min and slowly warmed to rt. A 0.5 M phosphate buffer solution pH 5.5 (20 mL) was added, the two phases were separated and the resulting aqueous phase was extracted with Et₂0 (4x). The combined organic phase was dried (MgS0₄), filtered, and evaporated. The residue was purified by flash column

chromatography using hexanes/EtOAc (6: 1 to 4: 1) to yield the desired aldehyde 24 (433 mg, 86%) as a light yellow oil. TLC: R/= 0.76 (hexanes/EtOAc = 1 : 1); 1H NMR (CDC1₃, 300 MHz) 5 9.77 (t, J= 1.3 Hz, 1H), 4.35 (m, 1H), 4.30-4.19 (m, 3H), 4.04 (dd, J= 2.3, 9.8 Hz, 1H), 3.92 (ddd, J= 5.3, 6.7, 9.5 Hz, 1H), 3.77 (dd, J= 1.7, 10.1 Hz, 1H), 3.75 (ddd, J= 5.2, 6.2, 9.5 Hz, 1H), 2.69 (m, 2H); ¹³C NMR (CDC1₃, 75 MHz) δ 200.1, 88.3, 76.1, 71.8, 63.1, 43.7, 23.3.

EXAMPLE 18. Hexahydro-2H-furo[3,4-b]pyran-4-ol ((±)-25). To a solution of aldehyde 24 (100 mg, 0.37 mmol) in DME (10 mL) was successively added indium (60 mg, 0.55 mmol), Cul (48 mg, 0.25 mmol), and a catalytic amount of iodine (10 mg, 0.037 mmol). After stirring the suspension for 5 min, water (4 mL) was added and the mixture was stirred at room temperature for 4 h. The suspension was filtered on a celite pad, washing the pad with THF. The solvent was reduced under vacuum and the resulting aqueous phase acidified with 1M HC1 and saturated with NaCl. The aqueous phase was extracted with EtOAc and the combined organic phase was dried over MgS0₄. After filtration, and evaporation, the crude was purified by flash column chromatography on silica gel using hexanes/EtOAc (1 : 1 to 1 :5) to provide the bicyclic alcohol (±)-25 (25 mg, 47%>) as a mixture of diastereoisomers. TLC: R = 0.28 (EtOAc 100%). Pyridinium chlorochromate (74 mg, 0.346 mmol) was added to a suspension of flame-dried 4A MS in CH₂CI₂ (2 mL) at room temperature under argon. A solution of the above alcohol (25 mg, 0.173 mmol) in CH₂CI₂ (1.5 mL) was transferred to the suspension at 0 °C and the solution was stirred for 1 h at 0 °C. The reaction was quenched by addition of isopropanol and the mixture was filtered on a silica pad flushing with Et₂0. After evaporation of the solvent, the corresponding ketone thus obtained was used directly to the next step. TLC: R/ = 0.45 (hexanes/EtOAc = 1 : 1); The ketone was re-dissolved in EtOH (1.5 mL), the solution was cooled to -20 °C and NaBH₄ (25 mg, 0.66 mmol) was added at once. After stirring at this temperature for 30 min, the reaction was quenched by addition of sat. aq. NH₄C1 solution (1.5 mL). The solution was extracted with EtOAc and the combined organic phase dried (Na₂S0₄), filtered, and evaporated. The corresponding racemic alcohol (±)-25 was purified by flash column chromatography using hexanes/EtOAc (1 : 1 to 1 :5) as the eluent. Colorless oil (12 mg, 50% 2 steps). TLC: R_f = 0.25 (100 % EtOAc). 1H NMR (CDC1₃, 300 MHz) δ 4.26 (m, 1H), 4.05 (t, J= 3.0 Hz, 1H), 4.04-3.95 (m, 3H), 3.94-3.85 (m, 2H), 3.40 (dt, J = 2.5, 11.8 Hz, lH), 2.60 (m, 1H), 1.94 (d, J= 4.0 Hz, 1H), 1.80 (ddt, J= 4.6, 11.5, 12.5 Hz, 1H), 1.74 (m, 1H); ¹³C NMR (CDC1₃, 75 MHz) δ 78.3, 74.5, 67.1, 66.4, 65.0, 45.5, 30.0.

To a solution of racemic (±)-25 (10 mg, 0.07 mmol) in dry THF (1 mL) under an argon atmosphere, was added vinyl acetate (60 mg, 65 μί, 0.7 mmol) followed by addition of Immobilized Amano Lipase PS-30 (10 mg) on Celite-545. The mixture was stirred at 15-20 °C for 2 days until >50% conversion could be observed by NMR of aliquots. The resulting suspension was diluted in Et₂0 and filtered on a small celite pad. The solvents were evaporated and the residue purified by flash chromatography using hexanes/EtOAc (1 : 1 to 1 :5) as the eluent to give enantiomeric alcohol 25 (4.6 mg, 46%) as a colorless oil. An enantiopurity of >99.5% ee for the alcohol was measured by analysis of the corresponding activated carbonate 31f on chiral HPLC (Column ChiralPak IC, hexane/isopropanol 52:48, 1 mL/min, λ = 215 nm, T = 24 °C, R_t minor = 14.4 min, R_t Major = 15.5 min).

EXAMPLE 19. (3ai?,6ai?)-Tetrahydrofuro[2,3-b]furan-3(2H)-one (28).

Enantiomerically pure (3i?,3a5',6ai?)-hexahydrofuro[2,3-b]furan-3-ol (bis-THF) 27 (85 mg, 0.65 mmol) was diluted in dry CH₂CI₂ (6 mL) under argon, the solution was cooled to 0 °C and anhydrous Na₂HP0₄ (52 mg, 0.36 mol) was added. Dess-Martin periodinane (360 mg, 0.85 mmol) was added at once at 0 °C and the resulting suspension warmed to 23 °C and stirred for 3 h. The reaction was then quenched by successive addition of sat. aq. NaHC0₃ and sat. aq. Na₂S0₃ solutions (1.5 + 1.5 mL). The phases were separated and the aqueous phase was extracted with CH₂CI₂ then EtOAc. The combined organic phases were dried (Na₂S0₄), filtered on a small pad of silica gel, and evaporated to dryness. The residue was purified by column chromatography on silica gel using hexanes/EtOAc (3: 1) to furnish ketone 28 (73 mg, 87%) as a white crystalline solid. TLC: R/ = 0.57 (hexanes/EtOAc = 1 : 1); Spectral data corresponded to those previously reported in the literature.³⁵

EXAMPLE 20. (3a_lS,7ai?)-Tetrahydro-2H-furo[2,3-b]pyran-5(3H)-one (29). AlMe3 (25% w/w hexanes, 250 μί, 0.6 mmol) was diluted in dry CH₂CI₂ (5 mL) under argon and the solution was cooled to -78 °C. A solution of ketone 28 (64 mg, 0.5 mmol) in dry CH₂CI₂ (5 mL) was slowly added dropwise. After 10 min, TMSCHN₂ (2 M solution in Et₂0, 275 μί, 0.55 mmol) was added. The reaction was stirred for 2 h while warmed to -30 °C.

Saturated Rochelle's salts solution (5 mL) was added and the mixture was stirred for 1 h. The phases were separated, the aqueous phase extracted with CH₂CI₂, and the combined organic phase was dried (MgS0₄). The solution was filtered on a small silica gel pad, flushing with Et₂0, and the collected organic phase evaporated. A crude mixture of the desired ketone along with a-silylated derivatives and isomers was then obtained. The mixture was re-dissolved in THF (5 mL). AcOH (6 drops) and TBAF (0.5 mL, 0.5 mmol) were successively added. The resulting mixture was stirred at 23 °C for 3 h and evaporated to dryness. The residue was purified by flash column chromatography on silica gel using hexanes/EtOAc (5: 1) as the eluent to give ketone 29 (45 mg, 63%). TLC: R_f = 0.35 (hexanes/EtOAc = 2: 1); 1H NMR (CDC1₃, 400 MHz) δ 5.49 (d, J= 6.8 Hz, 1H), 4.11 (d, J= 18.2 Hz, lH), 4.10 (m , 1H), 3.92 (d, J= 18.2 Hz, 1H), 3.74 (dt, J= 6.5, 8.9 Hz, 1H), 2.85 (m, 1H), 2.71 (d, J= 6.3, 15.6 Hz, 1H), 2.48 (d, J= 3.9, 15.6 Hz, 1H), 2.15 (m, 1H), 1.55 (ddt, J= 7.7, 8.9, 12.7 Hz, 1H); ¹³C NMR (CDC1₃, 100 MHz) δ 210.7, 100.9, 67.5, 67.1, 39.2, 36.2, 31.3.

EXAMPLE 21. (3a,S,5i?,7ai?)-Hexahydro-2H-furo[2,3-b]pyran-5-ol (30). A solution of the ketone 29 (25 mg, 0.173 mmol) dissolved in CH₂CI₂ (5 mL) was cooled to -78 °C under argon. L-Selectride (1M in THF, 200 μί, 0.2 mmol) was added dropwise. The solution was stirred at this temperature for 3 h and quenched by addition of sat. aq. NH₄CI solution. The aqueous phase was extracted with EtOAc, the combined organic extract was dried (Na₂S0₄), filtered, and evaporated. The crude was purified by column chromatography on silica gel using hexanes/EtOAc (2: 1, 1 : 1, then 1 :2) to yield alcohol 30 as a 5 : 1 mixture of

diastereoisomers (18 mg, cis major). The stereoisomers were separated in the subsequent synthesis of the mixed activated carbonate 31g. TLC: R = 0.25 (hexanes/EtOAc = 1 :2); 1H NMR (CDCI3, 300 MHz) δ 5.08 (d, J= 3.8 Hz, 0.2H), 5.05 (d, J= 3.3 Hz, 1H), 4.16-4.11 (m, 1.2H), 3.95-3.84 (m, 1.6H), 3.81-3.70 (m, 2H), 3.63 (m, 1H), 3.27 (dd, J= 7.9, 11.2 Hz, 0.2H), 2.35-1.70 (m, 6H). EXAMPLE 22. (3aS,4S,7ai?)-Hexahydro-2H-furo[2,3-b]pyran-4-yl (4- nitrophenyl) carbonate (31a). Furopyranol ligand (-)-7 (9 mg, 0.063 mmol) was diluted in CH₂CI₂ (0.5 mL) under argon. The solution was cooled to 0 °C and dry pyridine (17 μί, ca. 0.21 mmol) was added 4-nitrophenyl chloro formate (24 mg, 0.12 mmol) was added at once to the solution upon which a white precipitate formed. The reaction was stirred for 2 h while warming to rt. Upon completion, the mixture was concentrated reduced pressure and the residue was purified by column chromatography on silica gel using hexanes/EtOAc (6: 1 then 3: 1) as the eluent to give the corresponding activated carbonate 31a (18 mg, >99%). TLC: R/ = 0.25 (hexanes/EtOAc = 3: 1); 1H NMR (CDC1₃, 300 MHz) δ 8.29 (d, J= 8.7 Hz, 2H), 7.39 (d, J= 8.7 Hz, 2H), 5.30-5.19 (m, 1 H), 5.07 (d, J= 2.7 Hz, 1H), 4.28 (dt, J= 3 Hz, 1H), 4.04-3.95 (m, 2H), 3.47-3.37 (m, 1H), 2.80-2.68 (m, 1H), 2.30-2.10 (m, 1H), 2.05-1.90 (m, 3H); ¹³C NMR (CDCI3, 75 MHz) δ 155.3, 151.7, 145.4, 125.3, 121.7, 101.1, 75.4, 68.5, 60.5, 43.2, 25.8, 22.5.

EXAMPLE 23. (3ai?,4i?,7a5)-Hexahydro-2H-furo[2,3-b]pyran-4-yl (4- nitrophenyl) carbonate (31b). The title compound was obtained from (+)-7 as described for (-)- 7 in 86% yield after purification on column chromatography on silica gel using hexanes/EtOAc (6: 1 then 3: 1). Spectral data were consistent with those recorded for 31a.

EXAMPLE 24. (3ai?,45^*,7ai?)-Octahydrobenzofuran-4-yl (4-nitrophenyl) carbonate (31c). The title compound was obtained from (-)-12 as described for (-)-7 in 83%> yield after purification by column chromatography on silica gel using hexanes/EtOAc (8: 1 to 6: 1). TLC: R/= 0.7 (hexanes/EtOAc = 3: 1); 1H NMR (CDC1₃, 400 MHz) δ 8.28 (d, J= 9.2 Hz, 2H), 7.39 (d, J= 9.2 Hz, 2H), 5.07 (m, 1H), 4.13-4.05 (m, 2H), 3.90 (q, J= 8.2 Hz, 1H), 2.72 (m, 1H), 2.10-2.00 (m, 2H), 1.90-1.68 (m, 4H), 1.55-1.45 (m, 1H), 1.34-1.23 (m, 1H); ¹³C NMR (CDC1₃, 100 MHz) δ 155.4, 151.9, 145.2, 125.2, 121.7, 77.7, 77.1, 66.5, 41.2, 27.0, 26.2, 25.4, 18.0.

EXAMPLE 25. ((4_lS,4ai?,7a5)-Octahydrocyclopenta[b]pyran-4-yl) (4- nitrophenyl) carbonate (3 Id). The title compound was obtained from (-)-18 as described for (-)- 7 in 85% yield after purification by column chromatography on silica gel using

hexanes/CH₂Cl₂/THF (4: 1 :0 then 4: 1 :0.1) as the eluent. TLC: R/= 0.31 (hexanes/EtOAc = 1 : 1); 1H NMR (CDCI₃, 400 MHz) δ 8.28 (d, J= 9.1 Hz, 2H), 7.38 (d, J= 9.1 Hz, 2H), 5.21 (m, 1H), 4.00 (ddd, J= 1.8, 4.7, 12.0 Hz, 1H), 3.93 (dt, J= 2.5, 2.7 Hz, 1H), 3.43 (dt, J= 2.1, 12.0 Hz, 1H), 2.36 (m, 1H), 2.04-1.82 (m, 4H), 1.82-1.62 (m, 4H); ¹³C NMR (CDC1₃, 100 MHz) δ 155.5, 151.9, 145.3, 125.3, 121.8, 80.7, 77.3, 65.0, 43.7, 32.6, 26.3, 22.3, 21.7.

EXAMPLE 26. (3ai?,4S,7ai?)-Octahydro-lH-inden-4-yl (4-nitrophenyl) carbonate (31e). The title compound was obtained from (-)-19 as described for (-)-7 in 90%> yield after purification by column chromatography on silica gel using hexanes/EtOAc (20: 1 to 10: 1) as the eluent. 1H NMR (CDC1₃, 400 MHz) δ 8.27 (d, J= 9.1 Hz, 2H), 7.38 (d, J= 9.1 Hz, 2H), 5.05 (m, 1H), 2.41 (m, 1H), 2.05 (m, 1H), 1.98-1.24 (m, 11H), 1.05 (dq, J= 3.4, 12.7 Hz, 1H); ¹³C NMR (CDC1₃, 100 MHz) δ 155.7, 151.9, 145.2, 125.2, 121.8, 80.7, 42.8, 40.2, 31.3, 26.6, 25.7, 23.4, 22.4, 21.3.

EXAMPLE 27. (4_lS,4a_lS,7ai?)-Hexahydro-2H-furo[3,4-b]pyran-4-yl (4- nitrophenyl) carbonate (3 If). The title was obtained from (-)-25 as described for (-)-7 in >99% yield following column chromatography purification on silica gel using hexanes/EtOAc (3: 1 then 2: 1) as the eluent. 1H NMR (CDC1₃, 400 MHz) δ 8.29 (d, J= 9.1 Hz, 2H), 7.38 (d, J= 9.1 Hz, 2H), 5.32 (m, 1H), 4.20-3.88 (m, 6H), 3.50 (m, 1H), 2.81 (m, 1H), 2.10-1.90 (m, 2H).

EXAMPLE 28. [(3a,S,5i?,7ai?)-Hexahydro-2H-furo[2,3-b]pyran-5-yl]-(4- nitrophenyl) carbonate (31g). The title compound was obtained from 30 as described for (-)-7 in 70% yield. Purified and separated from the 5-epi diastereoisomer following flash column chromatography on silica gel using hexanes/EtOAc (3: 1, 2: 1, then 1 : 1) as the eluent.

Amorphous solid (70% from a 5:1 mixture of diastereoisomers). TLC: R = 0.16

(hexanes/EtOAc = 2: 1); 1H NMR (C₆D₆, 800 MHz) δ 7.64 (d, J= 9.0 Hz, 2H), 6.69 (d, J= 9.0 Hz, 2H), 4.76 d, J= 3.6 Hz, 1H), 4.35 (m, 1H), 4.02 (dt, J= 3.8, 8.6 Hz, 1H), 3.94 (dt, J= 2.8, 13.0 Hz, 1H), 3.60 (q, J= 8.0 Hz, 1H), 3.12 (dd, J= 2.0, 13.0 Hz), 2.04 (m, 1H), 1.67 (dq, J = 3.1, 15.1 Hz, 1H), 1.50 (m, 1H), 1.46-1.38 (m, 2H); ¹³C NMR (C₆D₆, 200 MHz) δ 154.9, 151.9, 145.2, 124.9, 121.2, 100.7, 72.0, 67.4, 63.8, 35.9, 27.9, 27.3.

EXAMPLE 29. (3a_lS,4_lS,7ai?)-Hexahydro-2H-furo[2,3-b]pyran-4-yl-(2_lS,3i?)-4- (N-isobutyl-4-methoxyphenyl sulfonamido)-3 -hydroxy- l-phenylbutan-2-yl carbamate (35a). Sulfonamide isostere 32 (42 mg, 0.08 mmol) was dissolved in a 30%> TFA solution in CH₂CI₂ (3 mL), the solution was stirred at 23 °C for 2 h after which the solvent was evaporated under reduced pressure. The corresponding Boc-deprotected intermediate (0.08 mmol) was then diluted in dry acetonitrile (0.8 mL) at 0 °C under argon and Et₃N (0.3 mL, 0.2 mmol) was added. A solution of activated carbonate 31a (18.6 mg, 0.06 mmol) in acetonitrile or THF (0.5 mL) was then added to the mixture. The reaction was stirred at 23 °C until completion was reached (2-3 days). The solution was then evaporated in vacuo and the resulting residue purified by flash chromatography on silica gel using hexanes/EtOAc (2: 1 then 1 : 1) as the eluent to afford the inhibitor 35a as a amorphous solid (19.8 mg, 55%). TLC R = 0.35 (hexanes/EtOAc = 1 : 1); 1H NMR (CDC1₃, 300 MHz) δ 7.71 (d, J= 8.9 Hz, 2H), 7.33-7.17 (m, 5H), 6.97 (d, J = 8.9 Hz, 2H), 5.05-4.90 (m, 1H), 4.93 (d, J= 3.6 Hz, 1H), 4.84 (d, J= 8.4 Hz, 1H), 4.15 (dt, J = 2.4, 9.0 Hz, 1H), 3.87 (s, 3H), 3.98-3.76 (m, 4H), 3.31 (t, J= 11.7 Hz, 1H), 3.22-2.90 (m, 4H), 2.90-2.78 (m, 2H), 2.48-2.32 (m, 1H), 1.96-1.25 (m, 5H), 0.92 (d, J= 6.6 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H); ¹³C NMR (CDC1₃, 75 MHz) δ 163.1, 155.5, 137.6, 129.8, 129.4, 128.4, 126.5, 114.3, 101.1, 72.9, 70.2, 68.5, 60.9, 58.9, 55.7, 54.9, 53.8, 43.5, 35.6, 27.3, 26.2, 22.3, 20.2, 19.9. HRMS-ESI (m/z): [M + Na]⁺ calcd for Cz^oNzOsNaS 599.2403, found 599.2406.

EXAMPLE 30. (3aS,4S,7ai?)-Hexahydro-2H-furo[2,3-b]pyran-4-yl (2,S,3i?)-4-

(4-amino-N-isobutylphenylsulfonamido)-3-hydroxy-l-phenylbutan-2-yl carbamate (36). The title compound was obtained from 31a and sulfonamide isostere 33 as described for inhibitor 35a, in 64% yield following purification by flash-chromatography using CHCl₃/2% MeOH as the eluent. TLC: R_f= 0.45 (hexanes/EtOAc = 1 :3); 1H NMR (CDC1₃, 300 MHz) δ 7.55 (d, J = 8.7 Hz, 2H), 7.32-7.16 (m, 5H), 6.67 (d, J= 8.7 Hz, 2H), 4.97 (m, 1H), 4.93 (d, J= 3.4 Hz, 1H), 4.85 (d, J= 8.7 Hz, 1H), 4.20-4.11 (m, 3H), 3.92-3.80 (m, 5H), 3.31 (dt, J= 2.2, 11.9 Hz, 1H), 3.15 (dd, J= 8.1, 15.2 Hz, 1H), 3.05 (dd, J= 4.2, 14.1 Hz, 1H), 3.01-2.80 (m, 3H), 2.75 (dd, J = 6.6, 13.4 Hz, 1H), 2.40 (m, 1H), 1.97-1.60 (m, 4H), 1.46 (m, 1H), 0.92 (d, J= 6.6 Hz, 3H), 0.87 (d, J= 6.6 Hz, 3H); ¹³C NMR (CDC1₃, 100 MHz) δ 155.5, 150.7, 137.7, 129.5, 129.5, 128.4, 126.5, 126.2, 114.1, 101.1, 72.8, 70.1, 68.5, 60.8, 58.9, 54.8, 53.8, 43.4, 35.5, 27.3, 26.2, 22.2, 20.2, 19.9; HRMS-ESI (m z): [M + Na]⁺ calcd for C₂8H₃₉N₃0₇NaS 584.2406; found 584.2402.

EXAMPLE 31. (3aS,4S,7ai?)-Hexahydro-2H-furo[2,3-b]pyran-4-yl (2^,3^)-3- hydroxy-4-(4-(hydroxymethyl)-N-isobutylphenylsulfonamido)- 1 -phenylbutan-2-yl carbamate (37). The title compound was obtained from 31a and sulfonamide isostere 34 as described for inhibitor 35a in 72% yield following purification by flash-chromatography on silica gel using CHCl₃/2%MeOH as the eluent. Amorphous solid. TLC: R/ = 0.23 (hexanes/EtOAc = 1 :2); 1H NMR (CDC1₃, 400 MHz) δ 7.76 (d, J= 8.1 Hz, 2H), 7.52 (d, J= 8.1 Hz, 2H), 7.32-7.17 (m, 5H), 4.96 (m, 1H), 4.93 (d, J= 3.2 Hz, 1H), 4.85 (d, J= 8.5 Hz, 1H), 4.80 (s, 2H), 4.15 (t, J = 8.5 Hz, 1H), 3.92-3.80 (m, 4H), 3.70 (s, 1H), 3.31 (t, J= 11.6 Hz, 1H), 3.16 (dd, J= 8.0, 15.0 Hz, 1H), 3.10-2.95 (m, 3H), 2.88-2.76 (m, 2H), 2.41 (m, 1H), 2.04 (m, 1H), 1.95-1.78 (m, 2H), 1.76-1.56 (m, 2H), 1.47 (m, 1H), 0.93 (d, J= 6.6 Hz, 3H), 0.88 (d, J= 6.6 Hz, 1H); ¹³C NMR (CDC1₃, 100 MHz) δ 155.6, 146.2, 137.6, 137.1, 129.4 128.5, 127.6, 127.1, 126.5, 101.1, 72.8, 70.2, 68.4, 64.2, 60.8, 58.8, 54.9, 53.7, 43.4, 35.5, 27.3, 26.2, 22.2, 20.1, 19.9; HRMS-ESI (m/z): [M + Na]⁺ calcd for Cz^oNzOsNaS 599.2403, found 599.2414.

EXAMPLE 32. (3ai?,4i?,7a5)-Hexahydro-2H-furo[2,3-b]pyran-4-yl ((2^,3i?)-3- hydroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)- 1 -phenylbutan-2-yl)carbamate (35b). The title compound was obtained from 31b and sulfonamide isostere 32 in 65 %> yield as described for inhibitor 35a, following purification by column chromatography on silica gel using hexanes/EtOAc (3:1 then 1.5: 1) as the eluent. White amorphous solid. TLC: R = 0.44 (hexanes/EtOAc = 1 : 1); 1H NMR (CDC1₃, 400 MHz) δ 7.70 (d, J= 8.9 Hz, 2H), 7.31-7.26 (m, 2H), 7.25-7.20 (m, 3H), 6.98 (d, J= 8.9 Hz, 2H), 5.00 (m, 1H), 4.97 (d, J= 2.7 Hz, 1H), 4.88 (d, J= 8.0 Hz, 1H), 4.17 (t, J= 7.7 Hz, 1H), 3.99-3.72 (m, 6H), 3.87 (s, 3H), 3.31 (dt, J= 1.9, 12.0 Hz, 1H), 3.13 (dd, J= 8.4, 15.0 Hz, 1H), 3.08-2.84 (m, 4H), 2.79 (dd, J= 6.7, 13.4 Hz, 1H), 2.53 (m, 1H), 2.00 (m, 1H), 1.83 (m, 1H), 1.73 (m, 1H), 1.68-1.54 (m, 2H); ¹³C NMR (CDCI₃, 100 MHz) δ 163.1, 155.7, 137.7, 129.8, 129.5, 128.5, 126.5, 114.3, 101.2, 72.6, 70.2, 68.4, 60.8, 58.7, 55.6, 55.1, 53.7, 43.6, 35.3, 27.3, 26.2, 22.5, 20.1, 19.9; HRMS-ESI (m/z): [M + Na]⁺ calcd for

599.2403, found 599.2407.

EXAMPLE 33. (3ai?,4S,7ai?)-Octahydrobenzofuran-4-yl (2S,3i?)-3-hydroxy-4- (/V-isobutyl-4-methoxyphenylsulfonamido)-l-phenylbutan-2-yl carbamate (35c). The title compound was obtained from 31c and sulfonamide isostere 32 in 75 % yield as described for inhibitor 35a, following purification by column chromatography on silica gel using

hexanes/EtOAc (3: 1 then 2.5: 1) as the eluent. TLC: R/= 0.39 (hexanes/EtOAc = 1 : 1); 1H NMR (CDCI3, 400 MHz) δ 7.72 (d, J= 8.9 Hz, 2H), 7.311-7.16 (m, 5H), 6.98 (d, J= 8.9 Hz, 2H), 4.83 (m, 2H), 3.95-3.75 (m, 5H), 3.87 (s, 3H), 3.68 (q, J= 8.1 Hz, 1H), 3.14 (dd, J= 8.4, 15.2 Hz, 1H), 3.08 (dd, J= 4.1, 14.1 Hz, 1H), 3.05-2.99 (m, 1H), 2.96 (dd, J= 8.4, 13.4 Hz, 1H), 2.87-2.75 (m, 2H), 2.35 (m, 1H), 1.83 (m, 1H), 1.70-1.40 (m, 7H), 1.20 (m, 1H), 0.92 (d, J = 6.6 Hz, 3H), 0.87 (d, J= 6.6 Hz, 3H); ¹³C NMR (CDC1₃, 100 MHz) δ 163.0, 156.1, 137.7,

129.7, 129.5, 129.4, 128.4, 126.4, 114.3, 73.0, 71.8, 66.6, 58.8, 55.6, 54.7, 53.7, 41.2, 35.6, 27.3, 27.2, 27.0, 25.7, 20.1, 19.9, 17.7; HRMS-ESI (m/z): [M + Na]⁺ calcd for C₃oH₄₂N₂0₇NaS 597.2610, found 597.2621.

EXAMPLE 34. (4S,4a^7aS)-Octahydrocyclopenta[b]pyran-4-yl ((2^,3i?)-3- hydroxy-4-(/V-isobutyl-4-methoxyphenylsulfonamido)- 1 -phenylbutan-2-yl)carbamate (35d). The title compound was obtained from 3 Id and sulfonamide isostere 32 in 81 % yield as described for inhibitor 35a, following purification by column chromatography on silica gel using hexanes/EtOAc (3: 1 then 2.5: 1) as the eluent. TLC: R/= 0.58 (hexanes/EtOAc = 1 : 1); 1H NMR (CDCI₃, 400 MHz) δ 7.70 (d, J= 8.9 Hz, 2H), 7.30-7.17 (m, 5H), 6.96 (d, J= 8.9 Hz, 2H), 4.94 (m, 1H), 4.81 (d, J= 8.1 Hz, 1H), 3.86 (s, 3H), 3.90-3.76 (m, 4H), 3.33 (t, J= 11.9 Hz, 1H), 3.13 (dd, AB, J= 8.3, 15.0 Hz, 1H), 3.08-2.91 (m, 3H), 2.85 (m, 1H), 2.79 (dd, J = 6.8, 13.5 Hz, 1H), 2.04 (m, 1H), 1.81 (m, 2H), 1.76-1.64 (m, 3H), 1.64-1.49 (m, 3H), 0.90 (d, J = 6.6 Hz, 3H), 0.86 (d, J= 6.6 Hz, 3H); ¹³C NMR (CDC1₃, 100 MHz) δ 163.0, 156.0, 137.7,

129.8, 129.4, 128.4, 126.4, 114.3, 80.5, 72.7, 71.7, 65.2, 58.7, 55.6, 54.8, 53.7, 44.1, 35.6, 32.5, 27.2, 26.6, 22.0, 21.6, 20.1, 19.8; HRMS-ESI (m/z): [M + Na] calcd for C₃oH₄₂N₂0₇S

597.2610, found 597.2612. EXAMPLE 35. (3ai?,4_lS,7ai?)-Octahydro-lH-inden-4-yl- (2,S,3i?)-3-hydroxy-4- (N-isobutyl-4-methoxyphenylsulfonamido)-l-phenylbutan-2-yl carbamate (35e). The title compound was obtained from 31e and sulfonamide isostere 32 as described for inhibitor 35a. Following preliminary purification by flash-chromatography using

(8 : 1 : 1 ) as the eluent, the inhibitor was obtained as a mixture of unseparable isomeric compounds. Compound 35e was derivatized into the corresponding N, O-isopropylidene compound by treatment of 35e (20 mg) with 2,2-dimethoxypropane (0.1 mL) and a catalytic amount of pTSA (1.5 mg) in dry CH₂CI₂ (1 mL) for 8 h at 23 °C. After neutralization with Et₃N, the organic phase was evaporated to dryness. Following a quick silica gel column (hexanes/EtOAc = 8:1), the resulting inhibitor was purified by HPLC: Preparative HPLC column Sunfire™ Prep CI 8 OBD, 30 x 100 mm, Eluent: MeOH/H₂0 85: 15 (30 min) then 90: 10 (15 min), flow 15 mL.min^"1, R_t = 42 min. The isopropylidene derivative was then obtained as a colorless oil (24 mg). The product was then taken into MeOH (2 mL), /^TSA.FLO (36 μιηοΐ, 1.5 mg) was added and the resulting solution was refluxed for 6 h. After

neutralization with a few drops of Et₃N, the solution was evaporated and the residue purified by column chromatography on silica gel using hexanes/CFLCVTHF (8: 1 : 1) to give inhibitor 35e (15 mg, 43% from 31e). TLC: R/= 0.35 (hexanes//EtOAc = 5: 1); 1H NMR (CDC1₃, 400 MHz) δ 7.71 (d, J= 8.9 Hz, 2H), 7.32-7.18 (m, 5H), 6.97 (d, J= 8.9 Hz, 2H), 4.79 (m, 1H), 4.70 (d. J = 8.1 Hz, 1H), 3.90 (m, 1H), 3.87 (s, 3H), 3.81 (m, 1H), 3.18-3.02 (m, 3H), 2.98-2.82 (m, 2H), 2.78 (dd, J= 6.6, 13.2 Hz, lH), 2.10 (m, 1H), 1.90 (m, 1H), 1.82 (m, 1H), 1.74-1.19 (m, 11H), 0.95 (m, 1H), 0.90 (d, J= 6.6 Hz, 3H), 0.86 (d, J= 6.6 Hz, 3H); ¹³C NMR (CDC1₃, 100 MHz) δ 163.0, 156.4, 137.7, 129.9, 129.5, 129.4, 128.5, 126.4, 114.3, 74.9, 72.8, 58.8, 55.6, 54.8, 53.8, 43.1, 39.9, 35.7, 31.3, 27.2, 26.9, 26.1, 23.5, 22.2, 21.3, 20.1, 19.9; HRMS-ESI (m/z): [M + Na]⁺ calcd for C₃iH₄4N20₆NaS 595.2818, found 595.2816.

EXAMPLE 36. (4_lS,4a_lS,7ai?)-Hexahydro-2H-furo[3,4-b]pyran-4-yl ((2^,3i?)-3- hydroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)- 1 -phenylbutan-2-yl)carbamate (35f). The title compound was obtained from 31f and sulfonamide isostere 32 in 75 % yield as described for inhibitor 35a, following purification by column chromatography using

hexanes/EtOAc (3 : 1 then 2.5: 1) as the eluent. TLC: R/= 0.24 (hexanes/EtOAc = 1 : 1); 1H NMR (CDC1₃, 800 MHz) δ 7.70 (d, J= 8.8 Hz, 2H), 7.30 (m, 2H), 7.24-7.20 (m, 3H), 6.97 (d, J= 8.8 Hz, 2H), 5.05 (m, 1H), 4.83 (d, J= 8.5 Hz, 1H), 4.03 (t, J= 3.2 Hz, 1H), 3.96 (m, 1H), 3.87 (s, 3H), 3.87 (s, 3H), 3.88-3.81 (m, 5H), 3.62 (t, J= 8.3 Hz, 1H), 3.39 (t, J= 11.5 Hz, 1H), 3.14 (dd, J= 8.4, 15.0 Hz, 1H), 3.02 (dd, J= 4.0, 14.1 Hz, 1H), 2.99-2.94 (m, 2H), 2.84 (dd, J= 8.7, 14.1 Hz, 1H), 2.77 (dd, J= 6.6, 13.4 Hz, 1H), 2.51 (m, 1H), 1.81 (m, 1H), 1.78 (dq, J= 4.5, 12.4 Hz, 1H), 1.71 (dd, J= 5.4, 12.4 Hz, 1H), 0.91 (d J= 6.6 Hz, 3H), 0.87 (d, J= 6.6 Hz, 3H); ¹³C NMR (CDCls, 200 MHz) δ 163.0, 155.5, 137.5, 129.6, 129.45, 129.38, 128.5, 126.6, 114.3, 78.4, 74.4, 72.6, 70.0, 66.1, 64.9, 58.8, 55.6, 54.9, 53.7, 42.7, 35.4, 27.2, 26.9, 20.1, 19.8;

HRMS-ESI (m/z): [M + Na]⁺ calcd for C₂₉H₄₀N₂O₈S 599.2403, found 599.2397.

EXAMPLE 37. (3a^,5i?,7ai?)-Hexahydro-2H-furo[2,3-b]pyran-5-yl ((2^,3i?)-3- hydroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)- 1 -phenylbutan-2-yl)carbamate (35g). The title compound was obtained from 31g and sulfonamide isostere 32 in 86 % yield as described for inhibitor 35a, following purification by column chromatography on silica gel using hexanes/EtOAc (gradient 3: 1 to 1.5: 1) as the eluent. TLC: R/= 0.33 (hexanes/EtOAc = 1 : 1); 1H NMR (CDC1₃, 400 MHz) δ 7.72 (d, J= 8.9 Hz, 2H), 7.32-7.26 (m, 2H), 7.25-7.17 (m, 3H), 6.98 (d, J= 8.9 Hz, 2H), 4.98 (d, J= 3.5 Hz, 1H), 4.89 (d, J= 8.7 Hz, 1H), 4.54 (m, 1H), 4.11 (dt, J= 3.5, 8.3 Hz, 1H), 3.87 (s, 3H), 3.90-3.77 (m, 4H), 3.74 (m, 1H), 3.56 (d, J= 12.7 Hz, 1H), 3.12 (dd, J= 8.5, 15.1 Hz, 1H), 3.09-2.91 (m, 3H), 2.84 (dd, J= 8.5, 14.1 Hz, 1H), 2.79 (dd, J= 6.8, 13.4 Hz, 1H), 2.08 (m, 1H), 2.04-1.93 (m, 2H), 1.90-1.76 (m, 3H), 0.91 (d, J = 6.6 Hz, 3H), 0.87 (d, J= 6.6 Hz, 3H); ¹³C NMR (CDC1₃, 100 MHz) δ 163.4, 155.7, 137.6, 129.7, 129.5, 128.5, 126.5, 114.4, 101.0, 72.5, 68.0, 67.1, 65.4, 58.8, 55.6, 54.9, 53.8, 36.2, 35.8, 28.3, 27.8, 27.2, 20.1, 19.9; HRMS-ESI (m/z): [M + Na]⁺ calcd for Cz^oNzOsNaS 599.2403, found 599.2397.

EXAMPLE. As mentioned above, and without being bound by theory, preliminary modeling suggested that a hexahydrofuropyranol (-)-7 ligand may interact with backbone atoms and residues in the protease S2-site. All inhibitors in Table 1 were evaluated in enzyme inhibitory assays following a protocol described by Toth and Marshall.³⁶ Inhibitors that showed potent IQ values, were further evaluated through in vitro antiviral assays. As can be seen, inhibitor 35a, with Tp-THF (-)-7 exhibited an enzyme ¾ value of 2.7 pM. Antiviral activity of 35a and other inhibitors were determined in MT-2 human-T-lymphoid cells exposed to HIV- I_LAI- ¹⁹ AS shown, 35a seems to show antiviral potency (IC50 = 0.5 nM), comparable to Pis la and lb. The bicyclic ring stereochemistry of the P₂ ligand appears to be important, as inhibitor 35b, with enantiomeric ligand (+)-7, seems to display a significant reduction in enzyme inhibitory potency ( >20-fold increase in K) as well as antiviral activity (ID₅₀ = 19 nM). TABLE 1. Enzymatic Inhibitory and Antiviral Activity of Compounds 35a-g, 36, and 37.

Entry Inhibitor Ki (nM) IC₅₀ (μΜ)¹

"Values are means of at least two experiments. 1Human T-lymphoid (MT-2) cells (2X 10³) were exposed to 100 TCID₅₀s of HIV- I_LAI and cultured in the presence of each PI, and IC50 values were determined using the MTT assay. The IC₅₀ values of amprenavir (APV), saquinavir (SQV), and indinavir (IDV) were 0.03 μΜ, 0.015 μΜ, and 0.03 μΜ, respectively.

To probe the importance of the cyclic ether oxygens in the bicyclic structure of

(-)-7, inhibitors 35c-e were synthesized and evaluated. As shown, inhibitor 35c, with a cyclohexane ring in place of the tetrahydropyran ring, only displayed a 2-fold reduction in Revalues but a 16-fold decrease in antiviral activity compared to inhibitor 35a. A more dramatic loss of enzymatic potency was observed with compound 35d with a cyclopentane ring in place of a THF ring in the P2 ligand. The IQ value dropped to 1.43 nM. Inhibitor 35e, which lacks both cyclic ether oxygens, displayed even lower K[ and no appreciable antiviral activity.

Without being bound by theory, those results may indicate an important role of both cyclic ether oxygens in ligand (-)-7. Furthermore, the difference of activity observed between 35a and 35c, may suggest that the 07 oxygen on the THF-ring of (-)-7 exerts a stronger interaction with the enzyme compared to the pyran oxygen. Inhibitor 35f, in which the THF-oxygen of the P₂ ligand is located at a vicinal position, also exhibited a substantial loss of potency (i.e. K[ = 5.3 nM) and no antiviral activity. These results seem to corroborate previous observations with the bis-THF ligand in Pis 1-2. The THF-oxygen in (-)-7 likely has a stronger hydrogen bonding interaction with the Asp29 backbone NH, and may form a weak hydrogen bond with Asp30, in the S₂ subsite of the HIV protease. The position of the urethane oxygen on the bicyclic ligand in inhibitor 35g has been investigated. This has resulted in a substantial loss of protease inhibitory activity. Furthermore, the potency enhancing effect of the Tp-THF ligand with various hydroxyethyl sulfonamide isosteres to give inhibitor 36 and 37 was examined. The 4-methoxy sulfonamide derivative 35a appears to be the most potent inhibitor in the series comparable to inhibitor 2. However, the 4-amino derivative 36 exhibited very comparable enzyme inhibitory and antiviral potency similar to la.

Inhibitor 35a was examined for its activity against a panel of multidrug-resistant HIV-1 variants and compared it with that of other clinically available Pis including la. The results are shown in Table 2. All inhibitors seem to show high antiviral activity against an HIV-1 clinical strain isolated from a drug-na^'ive patient (wild-type).¹⁹ Compound 35a appears to display the most potent activity with an IC₅₀ of 1.9 nM. When tested against multidrug-resistant HIV-1 virus, compound 35a seems to have retained high activity to all variants with IC₅₀ values ranging from 2.6-27.5 nM. In contrast, other inhibitors, except la, seem to exhibit loss of activity. Interestingly, la and 35a seem to show similar fold-change of IC₅₀ against most multidrug-resistant HIV strains. The results may indicate that 35a is highly active against multidrug-resistant HIV-1 variants. This inhibitor outperformed the clinically available Pis with high antiviral activity and seems to compare well with la, which currently stands as the leading PI for the treatment of drug-resistant HIV infection.

Table 2. Comparison of the antiviral activity of 35a and other Pis against multidrug resistant clinical isolates in PHA-PBMs cells

Viras 35a ATV LPV DRV

0.0019 ± 0.0015 0.0027 ± 0.0006 0.03 1 ± 0.004 0.004 ± 0.001

HIV- l ERS104pre (X4)

0.0145 ± 0.0001 (8) 0.470 ± 0.007 (174) >1 (>32) 0.034 ± 0.008 (9) 0.0037 ± 0.0018 (2) 0.039 ± 0.003 (14) 0.437 ± 0.004 (14) 0.009 ± 0.005 (2)

HIV- 1MDR/G (X4) 0.0026 ± 0.0004 (1) 0.019 ± 0.008 (7) 0.181 ± 0.023 (6) 0.026 ± 0.009 (7) 0.0275 ± 0.0055 (14) 0.075 ± 0.003 (28) 0.423 ± 0.082 (14) 0.022 ± 0.015 (6) 0.0050 ± 0.0023 (3) 0.205 ± 0.024 (76) 0.762 ± 0.1 15 (25) 0.017 ± 0.005 (4)

0.0275 ± 0.0009 (14) 0.293 ± 0.099 (109) >1 (>32) 0.023 ± 0.005 (6) HIV- IMDR/JSL (R5) The amino acid substitutions identified in the protease-encoding region of HIV-l_E sio4_Pre, HIV- 1_B, HIV-1_c, HIV- 1_G, HIV-I_TM, HIV- 1 , HIV-1_JSL compared to the consensus type B sequence cited from the Los Alamos database include L63P; LIOI, K14R, L33I, M36I, M46I, F53I, K55R, I62V, L63P, A71V, G73S, V82A, L90M, I93L; LIOI, I15V, K20R, L24I, M36I, M46L, I54V, I62V, L63P, K70Q,V82A, L89M; LIOI, VI II, T12E, 115V, LI 91, R41K, M46L, L63P, A71T, V82A, L90M; LIOI, K14R, R41K, M46L, I54V, L63P, A71V, V82A, L90M; I93L; LIOI, K43T, M46L, I54V, L63P, A71V, V82A, L90M, Q92K; and LIOI, L24I, I33F, E35D, M36I, N37S, M46L, I54V, R57K, I62V, L63P, A71V, G73S, V82A, respectively. HrV-l_ERsio4pre served as a source of wild-type HIV-1. The EC₅₀ values were determined by using PHA-PBMs as target cells and the inhibition of p24 Gag protein production by each drug was used as an endpoint. The numbers in parentheses represent the fold changes of EC₅₀ values for each isolate compared to the EC₅₀ values for wild-type HIV- l_ERsio4_Pre- All assays were conducted in duplicate, and the data shown represent mean values (± 1 standard deviations) derived from the results of two or three independent experiments.

In order to obtain molecular insights into the enzyme-inhibitor interactions of 35a in the protease active site, an active model of35a was created. Inhibitor 35a was modeled starting from the X-ray crystal structure of lb. The conformation of35a was optimized using the MMFF94 force field,³⁷ as implemented in Molecular Operating Environment (version 2009.10, Chemical Computing Group, Montreal). The modeled structure maintains the important binding interactions (hydroxyl group with Asp25 and Asp25' carboxylates; cyclic ether oxygens with Asp29 and Asp30 backbone NH groups; methoxy oxygen with the Asp30' backbone NH bond; carbonyl oxygen and sulfonamide oxygen with a water molecule binding to Ile50 and Ile50') that are observed in the crystal structure of lb-bound HIV-1 protease.

Thus, in one embodiment, described herein is structure-based design of novel HIV-1 protease inhibitors incorporating a stereochemically defined 4-hexahydrofuropyranol- derived urethanes as the P2-ligand. In one aspect, the inhibitors were designed to make extensive interactions including hydrogen bonding with the protein backbone of the HIV-1 protease active site. In another embodiment, described herein are inhibitors that appear to show excellent enzyme inhibitory activity and antiviral potency. In one aspect, this antiviral potency may be comparable to that of approved protease inhibitors. In another embodiment, the inhibitors described herein appear to show excellent activity against multi-PI-resistant variants. In another embodiment, structure activity studies are described herein, which may indicate that the stereochemistry of the Tp-THF ligand and position of its oxygens may be important to the ligand's high enzyme affinity. Without being bound by theory, it seems from the data herein that both oxygens of the hexahydro-7/?-THF ligand appear to interact with the Asp29 and Asp30 backbone NH's similar to the bis-THF ligand oxygens, and that the extra methylene unit in the Tp-THF ligand appears to fill in the hydrophobic pocket in the S2-site more effectively in comparison with the bis-THF in la. While certain embodiments of the present invention have been described and/or exemplified above, it is contemplated that considerable variation and modification thereof are possible. Accordingly, the present invention is not limited to the particular embodiments described and/or exemplified herein. The following publications, and each additional publication cited herein, are incorporated herein by reference in their entirety.

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5. Palella, F. J. Jr.; Delaney, K. M.; Moorman, A. C; Loveless, M. O.; Fuhrer, J.; Satten, G. A.; Aschman, D. J.; Holmberg, S. D. Declining Morbidity and Mortality among Patients with Advanced Human Immunodeficiency Virus Infection. N. Engl. J. Med. 1998, 338, 853-860.

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Claims

WHAT IS CLAIMED IS:

1. A compound of the following formula

R¹ OR³ R⁴ w x. _R2

and pharmaceutically acceptable salts thereof, wherein

A is the following group, wherein (*) denotes point of attachment:

W is oxygen or sulfur;

R1 is hydrogen, a nitrogen protecting group, or a pro-drug substituent;

R^ is hydrogen, an oxygen protecting group, or a pro-drug substituent;

providing that the compound is not of the formula

or a pharmaceutically acceptable salts thereof.

2. The compound of claim 1, wherein R^A and R^B are both hydrogen.

The com ound of claim 1, where the compound has the formula:

wherein Q and R² are as described in any of the preceding claims; Ar is aryl or heteroaryl, each of which is optionally substituted; and wherein A is selected from the following group, wherein (*) denotes point of attachment:

4. The compound of claim 1, wherein A is selected from the following group, wherein (*) denotes point of attachment:

5. The compound of claim 1, wherein the compound has the following relative and/or absolute stereochemistry:

wherein Ar is aryl or heteroaryl, each of which is optionally substituted.

6. The compound of claim 1, wherein the compound has the following formula:

wherein Ar is aryl or heteroaryl, each of which is optionally substituted; and where Ar² is substituted aryl or substituted heteroaryl having one or more of the following illustrative substituents; halo, amino, hydroxy, alkyl, alkenyl, alkoxy, arylalkyl, arylalkyloxy,

hydroxyalkyl, hydroxyalkenyl, alkylene dioxy, aminoalkyl, where the amino group may also be substituted with one or two alkyl groups, arylalkylgroups, and/or acylgroups, nitro, acyl and derivatives thereof including oximes, hydrazones, and the like, cyano, alkylsulfonyl, alkylsulfonylamino, and the like.

7. The compound of claim 6, wherein the compound has the following formula:

wherein X^a and X are each independently selected from halo, amino, hydroxy, alkyl, alkenyl, alkoxy, arylalkyl, arylalkyloxy, hydroxyalkyl, hydroxyalkenyl, alkylene dioxy, aminoalkyl, where the amino group may also be substituted with one or two alkyl groups, arylalkylgroups, and/or acylgroups, nitro, acyl and derivatives thereof including oximes, hydrazones, and the like, cyano, alkylsulfonyl, alkylsulfonylamino, and the like.

8. The compound of claim 6, wherein the compound has the following formula:

and pharmaceutically acceptable salts thereof, wherein

Z is C(R^cR^d) where each of R^c and R^d is independently selected in each instance from the group consisting of hydrogen, alkyl, and arylalkyl; R^4A, R^4B and R^4C are independently selected in each instance from the group consisting of hydrogen, alkyl, and arylalkyl, each of which may be optionally substituted, or R^4A, R^4B and the atoms to which they are attached form a ring, and R^4C is selected from the group consisting of hydrogen, alkyl, and arylalkyl, each of which may be optionally substituted.

9. The compound of claim 6, wherein the compound has the following formula:

harmaceutically acceptable salts thereof wherein X^a and X^b are independently selected from H, OH or OR⁶, where R⁶ is alkyl, alkylaryl, an oxygen protecting group or a pro-drug substituent.

10. The compound of claim 9, wherein the compound has the following formula:

and pharmaceutically acceptable salts thereof wherein

X^a and X^b are independently selected from H, OH or OR⁶, where R⁶ is alkyl, alkylaryl, an oxygen protecting group or a pro-drug substituent.

11. The compound of claim 6, wherein the compound has the following formula:

and pharmaceutically acceptable salts thereof.

12. The compound of claim 1, where:

γΐ is oxygen; or γΐ is C(R^AR^), where R^A is hydrogen, and R^ is hydrogen or alkoxy, such as methoxy; or Y^ is oxygen; or Y^ is C(R^AR^), where R^A is hydrogen, and R^ is hydrogen or alkoxy, such as methoxy; and/or

m is 1; and/or

R^C is hydrogen; and/or

R^ is hydrogen; and/or

Q is oxygen; and/or

W is oxygen; and/or

R1 is hydrogen; and/or

R^ is hydrogen; and/or

Z is S0₂; or Z is CO; or Z is NH; and/or

R^a and R^b are each hydrogen; and/or

m is 1; and/or

R^ is optionally substituted phenyl.

13. The compound of claim 1 , wherein when the integer m is 1 , the ring fusion is syn, or wherein when the integer m is 0, 2, or 3, the ring fusion may be syn or anti; and wherein each of the relative stereochemical configurations may include either or both of the two absolute stereochemical configurations.

14. The compound of claim 1, wherein the structures refer both individually to each enantiomer, as well as collectively to all possible mixtures of such enantiomers.

15. The compound of claim 1, wherein the cyclic ethers may be optionally substituted with one or more groups R^a and/or R^b, each of which is independently selected.

16. The compound of claim 1, wherein the group A is a cyclic ether or another structurally related group selected from the following structures:

and stereoisomers thereof and mixtures thereof, where (*) indicates the point of attachment of A to the group Q, which is oxygen, sulfur, nitrogen, or C(R^aR^b); where each of R^a and R^b is independently selected in each instance.

17. The compound of claim 1, wherein R³ is alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy, cycloalkoxy, heterocyclyloxy, heterocyclylalkoxy, amino, mono or dialkylamino, cycloalkylamino, heterocyclylamino, or heterocyclylalkylamino, each of which is optionally substituted.

18. The compound of claim 1, wherein R³ is amino substituted alkyl or heterocyclyl, or heterocyclylalkyl.

19. The compound of claim 1, wherein R³ is amino substituted alkyl or heterocyclyl, or heterocyclylalkyl in which the nitrogen atom of the amino group is mono or disubstituted with alkyl, cycloalkyl, or acyl, or is included in another heterocyclic group including a pyrrolidinyl, piperidinyl, or piperazinyl group.

20. The compound of claim 1 , wherein R³ is amino substituted alkyl or heterocyclyl, or heterocyclylalkyl in which the nitrogen atom of the hetetocylclyl group is substituted with alkyl, cycloalkyl, or acyl.

21. The compound of claim 1, wherein R³ is optionally substituted alkyl or cycloalkyl, including both linear and branched variations thereof, including methyl, ethyl, butyl, isobutyl, and the like, and cyclobutyl, cyclopentyl, 3-methylcyclopentyl, and the like.

22. The compound of claim 1, wherein R³ is optionally substituted heterocyclyl or heterocyclylalkyl, where the heterocyclic portions includes, but is not limited to, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and the like.

23. The compound of claim 1, wherein the group A is a cyclic ether, selected from the following structures

24. The compound of claim 23, wherein R^a and R^b are both hydrogen.

25. The compound of claim 23, wherein R^c and R^d are both hydrogen.

26. The compound of claim 23, wherein R^a, R^b, R^c, and R^d are each hydrogen.

27. The compound of claim 23, wherein one or more of R^c and R^d is alkoxy.

28. The compound of claim 1, wherein R² is alkyl, heteroalkyl, cycloalkyl, eye lo heteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is substituted, where at least one substituent is a hydrogen bond forming group.

29. A pharmaceutical composition comprising one or more compounds of any of claim 1 together with a diluent, excipient or carrier.

30. A method for treating patients with HIV-1/AIDS comprising administering a therapeutically effective amount of the one or more compounds of claim 1.

31. Use of one or more compounds and/or compositions of any of the preceding claims for treating patients with HIV-1/AIDS.

32. Use of one or more compounds and/or compositions of any of the preceding claims in the manufacture of a medicament for treating patients with HIV-1/AIDS.

33. The compound of claim 1, wherein the compound is optically pure, or includes any of a variety of stereoisomeric mixtures, including racemic and other mixtures of enantiomers, other mixtures of diastereomers, and the like; and/or including a single

stereochemical configuration at one or more chiral centers, while including mixtures of stereochemical configuration at one or more other chiral centers.