WO2011097717A1 - Synthesis of bicyclic compounds and method for their use as therapeutic agents - Google Patents

Abstract

Disclosed embodiments concern the synthesis and use of therapeutic compounds that for treating emerging flu strains and minimizing resistance to such strains. Methods for making the disclosed compounds concern using a base-mediated addition/cyclization sequence followed by functional group manipulation to develop functionalized compounds that can target neuraminidase, which makes them ideal candidates for treating influenza. Pharmaceutical compositions comprising the therapeutic compounds and biologically-acceptable materials are also described. Methods of inhibiting neuraminidase in subjects that are suspected of containing neuraminidase are also described. The use of metabolites of the disclosed compounds can also be used in diagnostic assays for therapeutic dosing of the disclosed compounds.

Description

SYNTHESIS OF BICYCLIC COMPOUNDS

AND METHOD FOR THEIR USE AS THERAPEUTIC AGENTS

CROSS REFERENCE TO RELATED APPLICATION

This PCT application claims the benefit of the February 15, 2010, earlier filing date of U.S. provisional application No. 61/304,738, which is incorporated herein by reference in its entirety.

FIELD

The present invention relates to a method for making and using chemical compounds, structural analogues and derivatives thereof, for the treatment, prevention, or amelioration of diseases, particularly diseases with sialidase virulence factors.

BACKGROUND

Neuraminidase (also known as sialidase, acylneuraminyl hydrolase) is an enzyme common among animals and a number of microorganisms. It is a

glycohydrolase that cleaves terminal alpha-ketosidically linked sialic acids from glycoproteins, glycolipids and ogliosaccharides. Many of the microorganisms containing neuraminidase are pathogenic to man and other animals including fowl, horses, swine and seals. These pathogenic viruses include influenza.

Influenza is typically transmitted through aerosols as a result of coughing and sneezing by those infected. The virus can also be contracted by exposure to bird droppings, saliva, nasal secretions, feces and blood. The 80-120 nm viral particles consist of an outer envelope and a central core containing the RNA genome, along with various packaging proteins. The influenza genome is not a single piece of RNA, but instead is contained on 8 separate strands of negative-sense RNA, which together encode the 11 genes necessary for viral replication: hemagglutinin, neuraminidase, nucleoprotein, Ml, M2, NS1, NS2(NEP), PA, PB1, PB1-F2 and PB2.

Hemagglutinin and neuraminidase are glycoproteins that exist on the outside of the viral particle. During the infection of host cells, the hemagglutinin protein binds to sialic acid residues on the surface of epithelial cells located in the nose, throat, and lungs. The hemagglutinin is subsequently cleaved by host proteases, triggering importation of the viral particle into the host cell by endocytosis. Once inside the cell, the M2 ion channel transports protons from the acidic endosomal fluid into the core of the virus. This drop in internal pH triggers disassembly of the core and release of the viral RNA.

The negative-sense RNA is then transported into the host cell's nucleus, where it is transcribed to the corresponding positive-sense RNA before being exported to the cytoplasm and translated into viral proteins. These are assembled with negative-sense RNA into viral progeny that remain attached to the host cell via hemagglutinin-sialic acid interactions. Finally, the neuraminidase enzyme cleaves sialic acid from the host cell, allowing the newly formed viral particles to infect neighbouring cells.

Because of the absence of RNA proofreading enzymes, RNA transcription results in an error about once every 10,000 nucleotides. Since this is roughly the length of the total RNA present in the influenza genome, evolution is very rapid. Moreover, the separation of the genome into eight separate lengths of RNA permits shuffling of genetic sequences between viruses, if more than one strain of influenza infects a single cell. Together, these mechanisms of "antigenic drift" and "antigenic shift" lead to rapid evasion of established drug or vaccine protocols.

While the influenza virus mostly resides in the lungs, recent evidence that the swine flu strain of HlNl can penetrate to the gut in animal models raises concerns that drugs with low systemic availability (e.g. zanamivir) will promote reservoirs of the virus elsewhere in the body. These systemic viral reservoirs would be exposed to relatively low doses of the drug over time, providing ideal conditions to evolve further resistance.

Treatment of influenza infections relies on two classes of molecules. The first class includes the molecules amantadine and rimantadine, and works by blocking the M2 proton channel. However, resistance to amantadine and rimantadine is now widespread. The second class of drugs targets viral neuraminidase (also called sialidase). Zanamivir (Relenza™) was developed in 1989 as a structural mimic of the boat-shaped sialic acid-hydrolysis transition structure, and proved effective in limiting viral replication. However, the large number of heteroatoms within zanamivir' s structure limits its oral bioavailability. As a result, it must be administered by inhalation, and has therefore seen somewhat limited clinical use.

Oseltamivir (Tamiflu™) is a second-generation neuraminidase inhibitor developed by Gilead Sciences with substantially improved oral bioavailability. This molecule (marketed by Roche) dominates the influenza market, with sales of about $1 billion per year. Oseltamivir is a prodrug, which is hydro lyzed in the liver to form the biologically active carboxylate. The drug is made in a lengthy synthesis from (-)- shikimic acid, a natural product isolated from the Chinese star anise. Frequent global shortfalls in shikimic acid production threaten Roche's ability to provide large quantities of oseltamivir in response to influenza pandemics. Several alternative syntheses by prominent synthetic groups have appeared in the literature over the past few years, but so far none have been commercialized.

In an attempt to access neuraminidase inhibitors with a core structure distinct from oseltamivir, BioCryst pharmaceuticals developed the substituted cyclopentane peramivir (BCX-1812). This structure, containing a β-hydroxy acid function, is ten-fold more potent than oseltamivir - possibly due in part to the interaction of the hydroxyl group with the aspartic acid residue (Asp 151) present in the active site to recognize the a-hydroxyl group in sialic acid. Although originally intended as an oral antiviral agent, peramivir displayed poor bioavailability in early trials, and is now being studied in formulations suitable for intravenous and intramuscular injection. Other anti-influenza drugs are also in development, but these likewise suffer various disadvantages.

Because mutations in a key enzyme like neuraminidase are often toxic to the organism, resistance to oseltamivir or zanamivir was once thought to be less problematic than resistance to amantadine. Indeed, data prior to the 2007/2008 flu season showed resistance levels of -1%, with somewhat higher levels in children. Resistance increased dramatically in 2007, however, with oseltamivir-resistant H1N1 strains detected in the United States (10.9%), Canada (26%), Europe (25%) and Hong Kong (12%). Even more alarming, data from the first half of the 2008/2009 flu season (prior to the emergence of the swine flu H1N1 strain) showed that nearly all circulating cases of H1N1 influenza A were resistant to oseltamivir.

Both oseltamivir and peramivir were designed on the principle that the polar sidechain of sialic acid (and thus zanamivir) could be replaced by a large, lipophilic alkyl group. While this led to very active inhibitors (oseltamivir is effective at around 1 nM; peramivir is roughly ten-fold more potent), it provides an obvious mechanism for drug resistance. Indeed, influenza strains containing group 1 neuraminidases (Nl, N4, N5, N8) are susceptible to a second-shell mutation wherein histidine-274 of the enzyme is mutated to a tyrosine. This mutation results in the reorganization of a nearby glutamic acid residue (Glu276) such that it projects into the active site of the enzyme, where it suffers unfavourable interactions with the lipophilic alkyl group. The H274Y mutation is responsible for the majority of drug resistance described above, conferring resistance to both oseltamivir and peramivir. While strains of influenza expressing these variants remain susceptible to zanamivir (the polar sidechain engages in hydrogen-bonding with Glu276), the lack of oral bioavailability for this drug makes it a less desirable therapeutic.

Moreover, other neuraminidase mutations confer resistance to zanamivir. In addition to several zanamivir-resistant mutants generated in vitro (influenza A N2: El 19G/D/A, R292K; influenza A N9: El 19G, R292K; influenza B: El 19G/D), a recent sampling of Australian and South East Asian influenza A H1N1 viruses revealed a novel mutation (Q136K) which caused a 300-fold reduction in zanamivir susceptibility, as well as a 70-fold reduction in peramivir susceptibility. An earlier zanamivir-resistant strain of influenza B (containing the R152K mutation) was isolated from an

immunocompromised patient undergoing prolonged zanamivir treatment.

To effectively combat emerging flu strains and minimize the potential for resistance, novel therapeutic platforms that are effective against the H274Y variant and are sufficiently "plastic" to overcome new polymorphisms are essential.

SUMMARY

Disclosed embodiments concern compounds of the formula:

With reference to this general formula, V, V_a, V_b, and V_c are CR^UR¹², C(Rⁿ)₂, C(R¹³)₂, S0₂, SO, S, O, NR^{1 1}, CO, and Se; particularly, V is CHR¹², S0₂, SO, S, or CO;

W is nitrogen, CR¹⁰, or CR^{1 1};

R¹⁰ is H, alkyl or (CH₂)_nOH;

R¹¹ is H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, and any

combination thereof;

R¹² is H, (CH₂)_nZH, (CH₂)_nZR^u, (CH₂)_nZ(CO)R' ¹ , (CH₂)_nZ(S0₂)R¹¹,

(CH₂)_nZ(CO)NH₂, (CH₂)_nZ(CO)ORⁿ, or (CH₂)_nZ(CNH)NH₂, and Z = O, S, Se, or NR¹¹;

R¹³ is H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, a heteroatom- containing moiety, and any combination thereof. The heteroatom-containing moiety is selected from aldehyde, acyl halide, carbonate, carboxyl, carboxylate, ether, ester, hydroxyl, ketone, silyl ether, peroxy, hydroperoxy, phosphate, phosphoryl,

phosphodiester, phosphine, thiol, thioether/sulfide, disulfide, sulfinyl, sulfonyl, carbonothioyl, sulfino, sulfo, thiocyanate, isothiocyanate, oxazole, oxadiazole, imidazole, triazole, tetrazole, amine, amide, azide, azo, cyano, isocyanate, imide, nitrile, isonitrile, nitro, nitroso, nitromethyl, selenol, guanidino, and substituted guanidino; if V_a comprises CRⁿR¹², C(Rⁿ)₂, or C(R¹³)₂, then V_a and V_b together can comprise a lactone or a lactam; if V_c comprises CRⁿR¹², C(R^U)₂, or C(R¹³)₂ and has at least two substituents selected from R¹¹, R¹², or R¹³, or any combination thereof, then the two substituents together can form a cyclic alkyl group;

n = 0, 1 or 2;

m = 0, 1 or 2; and

pharmaceutically acceptable salts thereof.

Particular embodiments concern com ounds having a formula:

With reference to this general formula, V is CRⁿR¹², C(R^U)₂, S0₂, SO, S, O, NR¹¹, CO, and Se; particularly, V is CHR¹², S0₂, SO, S, or CO;

R¹ is C0₂H, (CH₂)_nC0₂H, (CH₂)_nOH, tetrazolyl, S0₂H, S0₃H, P0₃H₂, or esters, amides, anhydrides or other protected forms thereof;

R² is OH, H, (CH₂)_nZH, where Z = O, S, Se, or NR¹¹ ;

or where R¹ and R² together represent =0;

R³ and R⁴ independently are H, alkyl, branched alkyl, aryl or heteroaryl;

or R³ and R⁴ together represent a cyclic alkyl group or =0;

R⁵ is NH₂, (CH₂)_nN(Rⁿ)_m(H)_(2-m), (CH₂)_nNHC(0)(R^H),

(CH₂)_nNC(-NRⁿ)N(Rⁿ)_m(H)_(2-m), (CH₂)_nNHC(0)Z(R^u), (CH₂)_nZH, where Z = O, S, Se, or NR¹¹; guanidino, substituted guanidino, alkyl, branched alkyl, cyclic alkyl, aryl or heteroaryl;

or where R⁵ and R¹ together form a lactam or lactone;

R⁶ is H, alkyl or (CH₂)_nOH;

R⁷ and R⁸ independently are H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, (CH₂)_nY, (CH)₂ZH, [CH₂]_n[CH(ZH)]_mCH₂ZH, [CH₂]_n[CH(ZH)]_mCH₂Y, where Y is aryl, heteroaryl, alkyl or cyclic alkyl, amino or guanidino, and Z = 0, S, Se, or NR^{1 1};

or where R and R together represent a cyclic alkyl group; R⁹ is H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, 0(Rⁿ)_m, S(Rⁿ)_n N(Rⁿ)_m(H)_(2-m);

R¹⁰ is H, alkyl or (CH₂)_nOH;

R¹¹ is H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, and any combination thereof;

R¹² is H, (CH₂)_nZH, (CH₂)_nZRⁿ, (CH₂)_nZ(CO)R^{1 1}, (CH₂)_nZ(S0₂)Rⁿ, (CH₂)_nZ(CO)NH₂, (CH₂)_nZ(CO)ORⁿ, or (CH₂)_nZ(CNH)NH₂, and Z = O, S, Se, or NR^{1 1};

n = 0, 1 or 2;

m = 0, 1 or 2; and

pharmaceutically acceptable salts thereof.

Certain disclosed compounds further satisfy the following general formulae, where V is selected from CHR¹², S0₂, SO, S, or CO, where R¹² is selected from H, (CH₂)_nZH, (CH₂)_nZR^u, (CH₂)_nZ(CO)Rⁿ, (CH₂)_nZ(S0₂)Rⁿ, (CH₂)_nZ(CO)NH₂, (CH₂)_nZ(CO)OR^{1 !}, or (CH₂)_nZ(CNH)NH₂, and Z = O, S, Se, or NR¹¹; and the remaining substituents are as stated above.

and

Certain disclosed embodiments also relate to derivatives accessible from those above, for example by the method of Sellstedt and Almqvist, including those represented by the following formula:

V is selected from S0₂, SO, S, O, NR¹ CO, Se, and any combination thereof;

R¹ is C0₂H, (CH₂)_nC0₂H, (CH₂)_nOH, tetrazolyl, S0₂H, S0₃H, P0₃H₂, or esters, amides, anhydrides or other protected forms thereof;

R² is OH, H, (CH₂)_nZH, where Z = O, S, Se, or NR¹¹;

'y

or where R and R together represent =0;

R³ and R⁴ independently are H, alkyl, branched alkyl, aryl or heteroaryl;

or R³ and R⁴ together represent a cyclic alkyl group or =0;

R⁵ is NH₂, (CH₂)_nN(Rⁿ)_m(H)_(2-m), (CH₂)_nNHC(0)(Rⁿ),

(CH₂)_nNC NRⁿ)N(Rⁿ)_m(H)_(2-m), (CH₂)_nNHC(0)Z(Rⁿ), (CH₂)_nZH, where Z = O, S, Se, or NR¹¹; guanidino, substituted guanidino, alkyl, branched alkyl, cyclic alkyl, aryl or heteroaryl;

or where R⁵ and R¹ together form a lactam or lactone;

R⁶ is H, alkyl or (CH₂)_nOH;

R⁷ and R⁸ independently are H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, (CH₂)_nY, (CH)₂ZH, [CH₂]_n[CH(ZH)]_mCH₂ZH, [CH₂]_n[CH(ZH)]_mCH₂Y, where Y is aryl, heteroaryl, alkyl or cyclic alkyl, amino or guanidino, and Z = 0, S, Se, or NR^{1 1};

or where R⁷ and R⁸ together represent a cyclic alkyl group;

R⁹ is H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, 0(Rⁿ)_m, S(Rⁿ)_m, or N(Rⁿ)_m(H)_(2-m);

R¹⁰ is H, alkyl or (CH₂)_nOH; R^{1 1} is H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, and any

combination thereof;

n = 0, 1 or 2;

m = 0, 1 or 2; and

pharmaceutically acceptable salts thereof.

In particular embodiments, disclosed compounds have the following formulae, where the substituents are as stated above:

Certain disclosed embodiments also relate to compositions for inhibiting influenza virus neuraminidase comprising a pharmaceutically acceptable carrier and an amount of a compound, as defined above, for effective inhibition of viral

neuraminidase.

A further aspect of the disclosed embodiments concerns compositions for inhibiting bacterial sialidase virulence factors, including, but not limited to the S.

pneumonia sialidases NanA, NanB, and NanC, wherein a compound as defined above is combined with a pharmaceutically acceptable carrier. These may include physiologically acceptable powders, liquids, salves, creams and ointments as a delivery method.

A further aspect of the disclosed embodiments concerns compositions leading to the inhibition of both viral neuraminidase and bacterial sialidase(s), leading to treatments for influenza-associated bacterial infections.

A further aspect of the disclosed embodiments relates to the administration of any of these compounds for the purposes of prophylaxis against influenza.

Certain disclosed embodiments also concern using the following chemical reactions, or reactions similar thereto as would be understood by a person of ordinary skill in the art, for preparing neuraminidase/sialidase inhibitors:

With reference to this scheme and the general formulae:

V is S0₂, SO, S, or CO;

R⁵ represents a functional group known by those skilled in the art to be convertible to NH₂, (CH₂)_nN(Rⁿ)_m(H)_(2-m), (CH₂)_nNHC(0)(Rⁿ),

(CH₂)_nNC(=NR^{1 x})N(RⁿUH)₍₂._m), (CH₂)_nNC(=NR' 'MR¹ ')_m(H)₍₂._m)!

(CH₂)_nNHC(0)Z(Rⁿ), (CH₂)_nZH, where Z = O, S, Se, or NR^{1 1} ; guanidino, substituted guanidino, alkyl, alkenyl, branched alkyl, cyclic alkyl, aryl or heteroaryl;

R¹⁰ is H, alkyl or a protected form of (CH₂)_nOH;

R^{1 1} is H, alkyl, branched alkyl, cyclic alkyl, aryl or heteroaryl;

n = 0, 1 or 2; and

m = 0, 1 or 2. A further aspect of disclosed embodiments relates to the use of chemical reactions similar to the following, for the purposes of the preparation of neuraminidase / sialidase inhibitors:

With reference to this scheme and the general formulae:

R¹⁴ and R¹⁵ independently are H, OH, a suitably protected derivative thereof, and any combination thereof;

or where R¹⁴ and R¹⁵ together represent =0.

A further aspect of the disclosed embodiments relates to intermediates represented by the following formulae for the preparation of neuraminidase/sialidase inhibitors:

With reference to this scheme and the general formulae,

V is CHR¹², S0₂, SO, S, or CO;

R³ and R⁴ independently are H, alkyl, branched alkyl, aryl or heteroaryl;

or R³ and R⁴ together represent a cyclic alkyl group or =0;

R⁵ is NH₂, (CH₂)_nN(Rⁿ)_m(H)_(2-m), (CH₂)_nNHC(0)(R^u),

(CH₂)_nNC(=NRⁿ)N(R^{1 l} Hfo-_m), (CH₂)_nNC(=NR¹¹)N(R¹¹)_m(H)(2_-m),

(CH₂)_nNHC(0)Z(Rⁿ), (CH₂)_nZH, where Z = O, S, Se, or NR^{1 1} ; guanidino, substituted guanidino, alkyl, branched alkyl, cyclic alkyl, aryl or heteroaryl;

R⁶ is H, alkyl or (CH₂)_nOH;

R⁷ and R⁸ independently are H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, (CH₂)_nY, (CH)₂ZH, [CH₂]_n[CH(ZH)]_mCH₂ZH, [CH₂]_n[CH(ZH)]_mCH₂Y, where Y is aryl, heteroaryl, alkyl or cyclic alkyl, amino or guanidino, and Z = O, S, Se, or NR^{1 1}; or where R⁷ and R⁸ together represent a cyclic alkyl group;

R⁹ is H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, 0(Rⁿ)_m, S(Rⁿ)_m, or N(R")_m(H)_(2-m);

R¹⁰ is H, alkyl or (CH₂)_nOH;

R¹¹ is H, alkyl, branched alkyl, cyclic alkyl, aryl or heteroaryl;

R¹² is H, (CH₂)_nZH, (CH₂)ZRⁿ, (CH₂)_nZ(CO)Rⁿ, (CH₂)_nZ(S0₂)Rⁿ,

(CH₂)_nZ(CO)NH₂, (CH₂)_nZ(CO)ORⁿ, or (CH₂)_nZ(CNH)NH₂, and Z = O, S, Se, or NR¹¹;

n = 0, 1 or 2; and

m = 0, 1 or 2.

Disclosed embodiments also concern alternative ring systems accessible from those described above, using ring expansions or ring contractions (or other

transformations) familiar to those of ordinary skill in the art. These include, but are not limited to, structures represented by the followin formula:

With reference to this general formula, V, V_a, and V_c are CR^UR¹², C(Rⁿ)₂ )₂, SC-2, SO, S, O, NR^{1 1}, CO, and Se;

R³ and R⁴ independently are H, alkyl, branched alkyl, aryl or heteroaryl;

or R³ and R⁴ together represent a cyclic alkyl group or =0;

R⁵ is NH₂, (CH₂)_nN(R^u)_m(H)_(2-m), (CH₂)_nNHC(0)(Rⁿ),

(CH₂)_nNC(=NR¹¹)N(R¹¹)_m(H)_(2-m), (CH₂)_nNHC(0)Z(Rⁿ), (CH₂)_nZH, where Z = O, S, Se, or NR^{1 1}; guanidino, substituted guanidino, alkyl, branched alkyl, cyclic alkyl, aryl or heteroaryl;

or where V_a is CR^UR¹², C(Rⁿ)₂, or C(R¹³)₂, then R⁵ and any one of R¹¹, R¹², or R¹³ together form a lactam or lactone;

R⁶ is H, alkyl or (CH₂)_nOH; where V_c is CR^NR¹², C(R^U)₂, C(R¹³)₂, then any one of R^N, R¹², or R¹³ together can form a cyclic alkyl;

R⁹ is H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, 0(R^N)_M, S(R^U)_M, or N(R^N)_M(H)_(2-M);

R¹⁰ is H, alkyl or (CH₂)_NOH;

R^{1 1} is H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, and any

combination thereof;

R¹² is H, (CH₂)_NZH, (CH₂)_NZR^N , (CH₂)_NZ(CO)R^H , (CH₂)_NZ(S0₂)R^N ,

(CH₂)_NZ(CO)NH₂, (CH₂)_NZ(CO)OR^N, or (CH₂)_NZ(CNH)NH₂, and Z = O, S, Se, or NR^{1 1} ;

R¹³ is H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, a heteroatom- containing moiety, and any combination thereof. The heteroatom-containing moiety is selected from aldehyde, anhydride, acyl halide, carbonate, carboxyl, carboxylate, ether, ester, hydroxyl, ketone, silyl ether, peroxy, hydroperoxy, phosphate, phosphoryl, phosphodiester, phosphine, thiol, thioether/sulfide, disulfide, sulfinyl, sulfonyl, carbonothioyl, sulfmo, sulfo, thiocyanate, isothiocyanate, oxazole, oxadiazole, imidazole, triazole, tetrazole, amine, amide, azide, azo, cyano, isocyanate, imide, nitrile, isonitrile, nitro, nitroso, nitromethyl, selenol, guanidino, and substituted guanidino; n = 0, 1 or 2;

m = 0, 1 or 2; and

pharmaceutically acceptable salts thereof.

Particular embodiments of the disclosed compounds have the following general formulae:

With reference to these general formulae,

V is CHR¹², S0₂, SO, S, or CO;

U is 0, NR¹¹, CHR¹¹, or S;

R¹ is C0₂H, (CH₂)_nC0₂H, (CH₂)_nOH, tetrazolyl, S0₂H, S0₃H, P0₃H₂, or esters, amides, anhydrides or other protected forms thereof;

R² is OH, H, (CH₂)_nZH, where Z = O, S, Se, or NR¹¹;

or where R¹ and R² together represent =0;

R³ and R⁴ independently are H, alkyl, branched alkyl, aryl or heteroaryl;

or R³ and R⁴ together represent a cyclic alkyl group or =0;

R⁵ is NH₂, (CH₂)_nN(Rⁿ)_m(H)_(2-m), (CH₂)_nNHC(0)(Rⁿ),

(CH₂)_nNC(=NRⁿ)N(Rⁿ)_m(H)_(2-m), (CH₂)_nNHC(0)Z(Rⁿ), (CH₂)_nZH, where Z = O, S, Se, or NR^H; guanidino, substituted guanidino, alkyl, branched alkyl, cyclic alkyl, aryl or heteroaryl;

or where R⁵ and R¹ together form a lactam or lactone;

R⁶ is H, alkyl or (CH₂)_nOH;

R⁷ and R⁸ independently are H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, (CH₂)_nY, (CH)₂ZH, [CH₂]_n[CH(ZH)]_mCH₂ZH, [CH₂]„[CH(ZH)]_mCH₂Y, where Y is aryl, heteroaryl, alkyl or cyclic alkyl, amino or guanidino, and Z = O, S, Se, or NR^{1 1};

or where R⁷ and R⁸ together represent a cyclic alkyl group;

R⁹ is H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, O(R^! ')_m, S(R^] ')_m, or

N(Rⁿ)_m(H)_(2-m);

R¹⁰ is H, alkyl or (C¾)_nOH;

R^{1 1} is H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, (CH₂)_nY, (CH)₂ZH, [CH₂]_n[CH(ZH)]_mCH₂ZH, [CH₂]_n[CH(ZH)]_mCH₂Y, where Y is aryl, heteroaryl, alkyl or cyclic alkyl, amino or guanidino, and Z = O, S, Se, or NR¹¹ ;

R¹² is H, (CH₂)_nZH, (CH₂)ZR^U, (CH₂)_nZ(CO)Rⁿ, (CH₂)_nZ(SO₂)Rⁿ,

(CH₂)Z(CO)NH₂, (CH₂)Z(CO)ORⁿ, or (CH₂)_nZ(CNH)NH₂, and Z = O, S, Se, or NR^{1 1}; n = 0, 1 or 2;

m = 0, 1 or 2; and

pharmaceutically acceptable salts thereof.

Disclosed embodiments also concern heteroatom-substituted variants of those compounds described above. These include, but are not limited to, structures represented by the following formulae:

With respect to this general formula, V, V_b, and V_c are CR¹ V², C(R^U)₂,

C(R¹³)₂, SO₂, SO, S, O, NR¹¹ , CO, and Se; and W is CHR¹⁰, CR^{1 1}, nitrogen, and any combination thereof; R¹ is C0₂H, (CH₂)_nC0₂H, (CH₂)_nOH, tetrazolyl, S0₂H, S0₃H, P0₃H₂, or esters, amides, anhydrides or other protected forms thereof;

R² is OH, H, (CH₂)_nZH, where Z = 0, S, Se, or NR¹¹;

or where R¹ and R² together represent =0;

R¹⁰ is H, alkyl or (CH₂)_nOH;

R¹¹ is H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, and any

combination thereof;

R¹² is H, (CH₂)_nZH, (CH₂)_nZRⁿ, (CH₂)_nZ(CO)Rⁿ, (CH₂)_nZ(S0₂)Rⁿ,

(CH₂)_nZ(CO)NH₂, (CH₂)_nZ(CO)ORⁿ, or (CH₂)_nZ(CNH)NH₂, and Z = O, S, Se, or NR^{1 1} ;

R¹³ is H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, a heteroatom- containing moiety, and any combination thereof. The heteroatom-containing moiety is selected from aldehyde, acyl halide, carbonate, carboxyl, carboxylate, ether, ester, hydroxyl, ketone, silyl ether, peroxy, hydroperoxy, phosphate, phosphoryl,

phosphodiester, phosphine, thiol, thioether/sulfide, disulfide, sulfinyl, sulfonyl, carbonothioyl, sulfino, sulfo, thiocyanate, isothiocyanate, oxazole, oxadiazole, imidazole, triazole, tetrazole, amine, amide, azide, azo, cyano, isocyanate, imide, nitrile, isonitrile, nitro, nitroso, nitromethyl, selenol, guanidino, and substituted guanidino; or where V_b is CR^UR¹², C(Rⁿ)₂, or C(R¹³)₂, then R¹ and any one of R¹¹, R¹², or R together form a lactam or lactone;

or where V_c is CRⁿR¹², C(Rⁿ)₂, C(R¹³)₂, then any one of R¹¹, R¹², or R¹³ together can form a cyclic alkyl;

n = 0, 1 or 2;

m = 0, 1 or 2; and

pharmaceutically acceptable salts thereof;

Particular embodiments have the following formulae:

With reference to these general formulae,

V is CHR¹², S0₂, SO, S, or CO;

Z is O, S, Se, or NR¹¹ ;

R¹ is C0₂H, (CH₂)_nC0₂H, (CH₂)_nOH, tetrazolyl, S0₂H, S0₃H, P0₃H₂, or esters, amides, anhydrides or other protected forms thereof;

R² is OH, H, (CH₂)_nZH, where Z = O, S, Se, or NR¹¹;

or where R¹ and R² together represent =0;

R³ and R⁴ independently are H, alkyl, branched alkyl, aryl or heteroaryl;

or R³ and R⁴ together represent a cyclic alkyl group or =0; R⁵ is NH₂, (CH₂)_nN(Rⁿ)_m(H)_(2-ni), (CH₂)_nNHC(0)(R^u),

(CH₂)_nNC(=NRⁿ)N(Rⁿ)_m(H)₍₂._m), (CH₂)_nNHC(0)Z(R^H), (CH₂)_nZH, where Z = O, S, Se, or NR¹¹; guanidino, substituted guanidino, alkyl, branched alkyl, cyclic alkyl, aryl or heteroaryl;

or where R⁵ and R¹ together form a lactam or lactone;

R⁶ is H, alkyl or (CH₂)_nOH;

R⁷ and R⁸ independently are H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, (CH₂)_nY, (CH)₂ZH, [CH₂]_n[CH(ZH)]_mCH₂ZH, [CH₂]_n[CH(ZH)]_mCH₂Y, where Y is aryl, heteroaryl, alkyl or cyclic alkyl, amino or guanidino, and Z = O, S, Se, or NR^{1 1};

or where R⁷ and R⁸ together represent a cyclic alkyl group;

R⁹ is H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, OCR¹¹)™, S(R^u)_m, or

R¹⁰ is H, alkyl or (CH₂)_nOH;

R¹¹ is H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, (CH₂)_nY, (CH)₂ZH, [CH₂]_n[CH(ZH)]_mCH₂ZH, [CH₂]_n[CH(ZH)]_mCH₂Y, where Y is aryl, heteroaryl, alkyl or cyclic alkyl, amino or guanidino, and Z = O, S, Se, or NR¹¹;

R¹² is H, (CH₂)_nZH, (CH₂)ZR^U, (CH₂)_nZ(CO)Rⁿ, (CH₂)_nZ(S0₂)Rⁿ,

(CH₂)Z(CO)NH₂, (CH₂)Z(CO)ORⁿ, or (CH₂)_nZ(CNH)NH₂, and Z = O, S, Se, or NR¹¹; n = 0, 1 or 2;

m = 0, 1 or 2; and

pharmaceutically acceptable salts thereof.

Exemplary compounds having structures within the scope of the disclosed embodiments are represented by the following:

wherein R = H, alkyl, aryl, heteroaryl, or acyl.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an image of the X-ray structure of bicyclic sulfone 14 from Example

2.

FIG. 2 is a graph illustrating neuraminidase inhibition by compound 19 shown in Scheme 4. Compound 19 showed dose-dependent inhibition of commercially available recombinant H1N1 neuraminidase.

FIG. 3 is an image of the X-ray structure of the ethyl ester of compound 31

(crystallized as the hydrochloride salt) from Example 16.

FIG. 4 is an image of the X-ray structure of the benzyl-substituted product from Example 5.

DETAILED DESCRIPTION

I. Terms

The following explanations of terms and methods are provided to better describe the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. The singular forms "a," "an," and "the" refer to one or more than one, unless the context clearly dictates otherwise. For example, the term "comprising the compound" includes single or plural molecules and is considered equivalent to the phrase "comprising at least one compound." The term "or" refers to a single element of stated alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise. As used herein, "comprises" means "includes." Thus, "comprising A or B," means "including A, B, or A and B," without excluding additional elements. A wavy line "), is used to indicate a bond disconnection, and a dashed line ("- - -") is used to illustrate that a bond may or may not be formed at a particular position.

Unless explained otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting.

In order to facilitate review of the various examples of this disclosure, the following explanations of specific terms are provided:

Aldehyde: Is a carbonyl-bearing functional group having a formula

O

where the line drawn through the bond i Λndicates that the functional group can be attached to any other moiety, but that such moiety simply is not indicated.

Aliphatic: A substantially hydrocarbon-based compound, or a radical thereof

(e.g., C₆Hi3, for a hexane radical), including alkanes, alkenes and alkynes, and further including straight- and branched-chain arrangements, and all stereo and position isomers as well.

Analog, Derivative or Mimetic: An analog is a molecule that differs in chemical structure from a parent compound, for example a homolog (differing by an increment in the chemical structure, such as a difference in the length of an alkyl chain), a molecular fragment, a structure that differs by one or more functional groups, a change in ionization. Structural analogs are often found using quantitative structure activity relationships (QSAR), with techniques such as those disclosed in Remington (The Science and Practice of Pharmacology, 19th Edition (1995), chapter 28). A derivative is a biologically active molecule derived from the base structure. A mimetic is a molecule that mimics the activity of another molecule, such as a biologically active molecule. Biologically active molecules can include chemical structures that mimic the biological activities of a compound.

Animal: Living multi-cellular vertebrate organisms, a category that includes, for example, mammals and birds. The term mammal includes both human and non- human mammals. Similarly, the term "subject" includes both human and veterinary subjects, for example, humans, non-human primates, dogs, cats, horses, and cows.

Aryl: A substantially hydrocarbon-based aromatic compound, or a radical thereof (e.g. C₆H₅) as a substituent bonded to another group, particularly other organic groups, having a ring structure as exemplified by benzene, naphthalene, phenanthrene, anthracene, etc.

Arylalkyl: A compound, or a radical thereof (C₇H₇ for toluene) as a substituent bonded to another group, particularly other organic groups, containing both aliphatic and aromatic structures.

Carboxylic Acid: Refers to a carbonyl-bearing functional group having a formula

Cyclic: Designates a substantially hydrocarbon, closed-ring compound, or a radical thereof. Cyclic compounds or substituents also can include one or more sites of unsaturation, but does not include aromatic compounds. One example of such a cyclic compound is cyclopentadienone.

Dialkylidene: A compound having at least two carbon-carbon double bonds joined to the carbon atom of a carbonyl or sulfoxide group. This term also encompasses compounds having multiple conjugated carbon-carbon double bonds. Examples of dialkylidenes can have a formula

Where X is selected from oxygen and sulfur, R⁵ can be a functional group known by those skilled in the art to be convertible to NH_2i guanidino, substituted guanidino, alkyl, alkenyl, branched alkyl, cyclic alkyl, aryl or heteroaryl, (CH₂)_nN(Rⁿ)_m(H)_(2-m), (CH₂)_nNHC(0)(R¹

(CH₂)_nNHC(0)Z(R^u), (CH₂)_nZH; where Z is O, S, Se, or NR¹¹; where n and m independently are 1-10; R¹¹ is H, alkyl, branched alkyl, cyclic alkyl, aryl or heteroaryl, and n is 1-10.

Diene: A diene, for purposes of the present invention, is any compound having at least two double bonds.

Ester: A carbonyl-bearing substituent having a formula

where R is virtually any group, including aliphatic, substituted aliphatic, aryl, arylalkyl, heteroaryl, etc.

Heteroaryl: Refers to an aromatic, closed-ring compound, or radical thereof as a substituent bonded to another group, particularly other organic groups, where at least one atom in the ring structure is other than carbon, and typically is oxygen, sulfur and/or nitrogen.

Heterocyclic: Refers to a closed-ring compound, or radical thereof as a substituent bonded to another group, particularly other organic groups, where at least one atom in the ring structure is other than carbon, and typically is oxygen, sulfur and/or nitrogen.

Ketone: A carbonyl-bearing substituent having a formula

where R is virtually any group, including aliphatic, substituted aliphatic, aryl, arylalkyl, heteroaryl, etc.

Lower: Refers to organic compounds having 10 or fewer carbon atoms in a chain, including all branched and stereochemical variations, particularly including methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

Inhibiting or Treating a Disease: Inhibiting the full development of a disease or condition, for example, in a subject who is at risk for a disease such as anthrax. "Treatment" refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop. As used herein, the term "ameliorating," with reference to a disease, pathological condition or symptom, refers to any observable beneficial effect of the treatment. The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, a reduction in the number of relapses of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease.

Mammal: This term includes both human and non-human mammals.

Similarly, the term "subject" includes both human and veterinary subjects.

Pharmaceutically Acceptable Carriers: The pharmaceutically acceptable carriers (vehicles) useful in this disclosure are conventional. Remington 's

Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, PA, 15th Edition (1975), describes compositions and formulations suitable for pharmaceutical delivery of one or more therapeutic compounds or molecules, such as one or more S ARS-CoV nucleic acid molecules, proteins or antibodies that bind these proteins, and additional pharmaceutical agents. The term "pharmaceutically acceptable carrier" should be distinguished from "carrier" as described above in connection with a hapten/carrier conjugate or an antigen/carrier conjugate.

In general, the nature of the carrier will depend on the particular mode of administration being employed. For instance, parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. For solid compositions (for example, powder, pill, tablet, or capsule forms), conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically-neutral carriers, pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like., for example sodium acetate or sorbitan monolaurate.

Pharmaceutically Acceptable Salt: Typically, pharmaceutically acceptable salts are more soluble in aqueous solutions than the corresponding free acids and bases from which the salts are produced; however, salts having lower solubility than the corresponding free acids and bases from which the salts are produced may also be formed. Pharmaceutically acceptable salts are typically counterbalanced with an inorganic base, organic base, or basic amino acid if the salts are positively charged; or the salt is counterbalanced with an inorganic acid, organic acid, or acidic amino acid if they are negatively charged. Pharmaceutically acceptable salts can also be zwitterionic in form. Salts can be formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. Other elements capable of forming salts are well-known to those skilled in the art, e.g. all elements from the main groups I to V of the Periodic Table of the Elements, as well as the elements from the subgroups I to VIII. Any chemical compound recited in this specification may alternatively be administered as a pharmaceutically acceptable salt thereof. "Pharmaceutically acceptable salts" are also inclusive of the free acid or base. Descriptions of suitable pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts, Properties, Selection and Use, Wiley VCH (2002), which we herein incorporate by reference.

Substituted: A fundamental compound, such as an aryl or aliphatic compound, or a radical thereof, having coupled thereto, typically in place of a hydrogen atom, a second substituent. For example, substituted aryl compounds or substituents may have an aliphatic group coupled to the closed ring of the aryl base, such as with toluene. Again solely by way of example and without limitation, a long-chain hydrocarbon may have a substituent bonded thereto, such as an aryl group, a cyclic group, a heteroaryl group or a heterocyclic group.

Therapeutically Effective Amount: A quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent. For example, this may be the amount of a conjugate useful in increasing resistance to, preventing, ameliorating, and/or treating infection and disease. Ideally, a therapeutically effective amount of an agent is an amount sufficient to increase resistance to, prevent, ameliorate, and/or treat infection and without causing a substantial cytotoxic effect in the subject. The effective amount of an agent useful for increasing resistance to, preventing, ameliorating, and/or treating infection and disease in a subject will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the therapeutic composition.

II. Pharmaceutical Formulations

One aspect of the composition of the disclosed compounds comprises of one or more pharmaceutically acceptable carriers. One or more of the disclosed compounds are administered by any route appropriate to the condition to be treated.or sample to be tested. Examples include but are not limited to oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural).

In particular embodiments, the compounds are presented as pharmaceutical formulations. The formulations comprise at least one active ingredient, as described above, with one or more acceptable carriers therefore and optionally other therapeutic ingredients.

In other embodiments, acceptable carriers are defined as a compound or molecule compatible with the other ingredients of the formulation and substantially physiologically innocuous to the recipient thereof.

Biologically acceptable materials include, but are not limited to carriers, diluents, adjuvants, excipients, binders, fillers, lubricants, osmotic agents, flavoring agents, other active ingredients, and combinations thereof. Examples of carriers can include, without limitation, solvents, saline, buffered saline, dextrose, water, glycerol, ethanol, propylene glycol, polysorbate 80 (Tween-80.TM.), poly(ethylene)glycol 300 and 400 (PEG 300 and 400), PEGylated castor oil (E.g. Cremophor EL), poloxamer 407 and 188, hydrophobic carriers, fat emulsions, lipids, PEGylated phopholids, polymer matrices, biocompatible polymers, lipospheres, vesicles, particles, and liposomes, or combinations thereof. Examples of excipients include stabilizing agents, solubilizing agents, surfactants, buffers, antioxidants and preservatives, tonicity agents, bulking agents, lubricating agents, emulsifiers, suspending agents, viscosity agents, inert diluents, fillers, disintegrating agents, binding agents, wetting agents, lubricating agents, antibacterials, chelating agents, sweetners, perfuming agents, flavouring agents, coloring agents, administration aids, or combinations thereof. Examples of diluents include sodium carbonate, calcium carbonate, sodium phosphate, calcium phosphate, lactose, or combinations thereof. Examples of osmotic agents include sodium chloride, glycerol, sorbitol, xylitol, glucose, or combinations thereof. Binders can include acacia gum, starch, gelatin, sucrose, polyvinylpyrrolidone (Providone), sorbitol, or tragacanth methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, ethylcellulose, or combinations thereof. Examples of fillers can include calcium phosphate, glycine, lactose, maize-starch, sorbitol, sucrose, or combinations thereof. Exemplary lubricants include magnesium stearate or other metallic stearates, stearic acid, polyethylene glycol, waxes, oils, silica and colloical silica, silicon fluid, talc, or combinations thereof. Flavoring agents can be peppermint, oil of wintergreen, fruit flavoring, or combinations thereof.

An effective amount of the disclosed compounds can depend at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active influenza infection, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. Expected dosage amounts are to be from greater than 0 to about 1000 mg/kg body weight per day, typically, from about greater than 0 to about 10 mg/kg body weight per day, more typically, from about greater than 0 to about 5 mg/kg body weight per day, and even more typically, from about greater than 0 to about 0.5 mg/kg body weight per day. For example, for inhalation the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses.

In a further aspect, the pharmaceutical formulations are for both veterinary and human use.

In a further aspect, the pharmaceutical formulations may be presented in unit dosage form and may be prepared by any methods known to a person of ordinary skill in the art of pharmacy.

III. Methods of Inhibiting Neuraminidase

Another aspect concerning the disclosed embodiments relates to methods of inhibiting the activity of neuraminidase comprising treating a sample suspected of containing neuraminidase with a compound and/or composition of the disclosed compounds invention.

In a further aspect, samples suspected of containing neuraminidase include natural or man-made materials. Examples include but are not limited to; living organisms; tissue or cell cultures; biological samples such as living organisms; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like); laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a glycoprotein or any desired biological molecule.

In a further aspect, the sample contains an organism which produces

neuraminidase. Examples include but are not limited to a pathogenic organism such as a virus or bacterium. In a further aspect, the inhibitory activity of disclosed compound extends to neuraminidase molecules, including but not limited to, neuraminidase molecule variants such as the H274Y mutant.

In a further aspect, the inhibitory activity of the compound extends to neuraminidase molecules expressed by various pathogenic strains of influenza, including but not limited to HlNl, H3N2, H5N1, H1N2, H2N2, H7N7, N9N2, H7N2, H7N3, and H10N7.

In a further aspect, the samples are in any medium including water, organic solvent, and organic solvent/water mixtures. Examples include but are not limited to living organisms, such as humans and animals and any man made materials such as cell cultures.

In a further aspect, the activity of neuraminidase after administering a disclosed compound and/or composition can be observed or monitored by any quantitative, qualitative and semi-quantitative method. This includes but is not limited to observation of the physiological properties of a living organism.

IV. Compound Metabolites

Another aspect associated with disclosed embodiments is directed to in vivo metabolic products of the compounds described herein.

In other embodiments, the metabolic product of the compound described herein results from oxidation, reduction, hydrolysis, amidation, and/or esterfication of disclosed embodiments of the compounds, including but not limited to any product of enzymatic process of the administered compound. The products of the compound, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the disclosed compounds even if they possess no neuraminidase inhibitory activity of their own.

V. Compounds Derived from Alternative Methods In other particular embodiments ring expansions or ring contractions (or other transformations) familiar to those skilled in the art can be used to synthesize the disclosed compounds.

Other embodiments relate to heteroatom-substituted variants of the disclosed compounds, which are synthesized utilizing chemical synthesis methodologies known to those skilled in the art. The compounds are further considered to be additional embodiments of the disclosed compounds.

VI. Exemplary Methods for Making Disclosed Compounds Disclosed embodiments also concern making the disclosed compounds, and compositions comprising the compounds. The compounds and/or compositions are prepared by applicable variety of organic synthetic techniques, as will be understood by a person of ordinary skill in the art based on the following discussion. These include, but are not limited to, condensations, cycloadditions or alkylations from any applicable acyclic, monocyclic or bicyclic precursors. These also include degradations from compounds of higher molecular weight.

An exemplary method for preparing disclosed compounds is provided in Scheme 1 below.

1 2 3

Scheme 1

A method for making compounds having a general formula 4 is disclosed, wherein R⁵ can be a functional group known by those skilled in the art to be convertible to NH_2, guanidino, substituted guanidino, alkyl, alkenyl, branched alkyl, cyclic alkyl, aryl or heteroaryl, (CH₂)_nN(Rⁿ)_m(H)_(2-m), (CH₂)_nNHC(0)(Rⁿ),

(CH₂)_nNC(=NR¹ ^NCR¹ ')_m(H)₍₂._m), (CH₂)_nNHC(0)Z(Rⁿ), (CH₂)_nZH; where Z is O, S, Se, or NR^{1 1}; where n and m independently are 1-10; R¹¹ is H, alkyl, branched alkyl, cyclic alkyl, aryl or heteroaryl; R is H, alkyl or any protected form of (CH₂)_nOH; V is any heteroatom, carbonyl, sulfonyl, or sulfone; and X is any heteroatom, such as oxygen or sulfur, or any combination thereof. An acidic cyclic starting material 1 is added to compound 2 using a base, wherein the addition can occur directly or in a conjugate fashion. Compound 2 is typically selected to comprise a heteroatom- containing dialkylidene compound, such as, but not limited to, a dialkylidene ketone or dialkylidene sulfoxide. After addition, a second treatment of an intermediate with base induces rearrangement and cyclization to provide bicycle 3. Bicycle 3 can be reduced to saturated bicycle 4 using a reducing agent known to a person of ordinary skill in the art to be suitable for reducing olefins.

Another exemplary method for preparing disclosed compounds is provided in Scheme 2.

5 6 7 8

Scheme 2

A method for making compounds having a general formula 8 is disclosed, wherein R¹⁴ and R¹⁵ are independently H, OH, or a suitably protected derivative thereof, or else R¹⁴ and R¹⁵ together represent =0, and where:

R¹ is C0₂H, (CH₂)_nC0₂H, (CH₂)_nOH, tetrazolyl, S0₂H, S0₃H, P0₃H₂, or esters, amides, anhydrides or other protected forms thereof;

R² is OH, H, (CH₂)_nZH, where Z = O, S, Se, or NR^{1 1};

R⁵ is NH₂, (CH₂)_nN(Rⁿ)_m(H)_(2-m), (CH₂)_nNHC(0)(R^u),

(CH₂)_nNC(=NRⁿ)N(Rⁿ)_m(H)_(2-m), (C¾)_nNHC(0)Z(Rⁿ), (CH₂)_nZH, where Z - O, S, Se, or NR¹¹; guanidino, substituted guanidino, alkyl, branched alkyl, cyclic alkyl, aryl or heteroaryl; R⁷ and R⁸ independently are H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, (CH₂)_nY, (CH)₂ZH, [CH₂]_n[CH(ZH)]_mCH₂ZH, [CH₂]_n[CH(ZH)]_mCH₂Y, where Y is aryl, heteroaryl, alkyl or cyclic alkyl, amino or guanidino, and Z = O, S, Se, or NR¹¹, or where R⁷ and R⁸ together represent a cyclic alkyl group;

Rⁿ is H, alkyl, branched alkyl, cyclic alkyl, aryl or heteroaryl;

R¹² is H, (CH₂)_nZH, (CH₂)ZRⁿ, (CH₂)_nZ(CO)Rⁿ, (CH₂)_nZ(S0₂)Rⁿ,

(CH₂)_nZ(CO)NH₂, (CH₂)_nZ(CO)ORⁿ, or (CH₂)_nZ(CNH)NH₂, and Z = O, S, Se, or NR^{1 1};

n = 0, 1 or 2;

m = 0, 1 or 2;

In the method illustrated in Scheme 2, a cyclic diene, such as cyclooctadiene 5, can be oxidized using reagents known to a person of ordinary skill in the art, such as, but not limited to, peracids and peroxides. Rearrangement can be induced by treating the oxidized intermediate with a base to make bicycle 6. Both steps can be carried out using the method of Oger, Brinkmann, Bouazzaoui, Durand and Galeno, or by other means known to a person of ordinary skill in the art. Particular embodiments concern using resolution methods of individual enantiomers of compound 6, such as enzymatic resolution, crystallographic resolution to obtain enantiomerically pure forms of compound 6. Further oxidative transformations of the kind familiar to those skilled in the art are sufficient to make 7, after which derealization can make functionalized bicycle 8. Methods leading to tricyclic or polycyclic analogues of 8 are also contemplated by the disclosed methods.

A particular working embodiment is illustrated in Scheme 3. This embodiment concerned a base-induced addition of diene 9 to commercially available 10, making isomeric sulfones 12 or 13, depending upon the temperature at which the reaction was quenched. In other embodiments, compound 12 was converted to 13 by treatment with base. Bicycle 14 was made by treating 13 with lithium hexamethyldisilazide.

Reduction of 14 was carried out using an appropriate reducing agent, such as lithium aluminium hydride or sodium bis(2-methoxyethoxy)aluminumhydride, to make bicyclic

cheme 3

With reference to Scheme 3, a more particular process comprised treating a solution of ketone 9 and sulfone 10 with LiHMDS at -78 °C. This resulted in attack from the γ-position of the sulfone anion directly to the ketone of 9. The reaction was quenched at low temperature, and the major isolated product was the tertiary alcohol 12. Treating 12 with a second equivalent of LiHMDS initiated an anionic oxy-Cope rearrangement, affording keto-sulfone 13 as a single diastereomer. Molecule 13 was also accessed in a single step, when a mixture of 9, 10 and LiHMDS was warmed to room temperature prior to aqueous workup. By either preparation, sulfone 13 was prepared as a single diastereomer. Reaction of keto-sulfone 13 with more LiHMDS resulted in a second attack from the γ-position of the sulfone to the ketone, leading to the formation of alcohol 14, again as a single diastereomer. An image of the X-ray structure of alcohol 14 is illustrated in FIG. 1. The electrophilic vinyl sulfone function was reduced with L1AIH4, affording 15 in a 50% yield over 3 steps (average of 79% per step).

Scheme 4 illustrates another general method for making disclosed compounds.

Oxidative degradation

Scheme 4

With reference to the general method of Scheme 4, the functional groups of bicycle 4 can be manipulated through many different reaction conditions. Certain disclosed embodiments concern using an oxidative cleavage of the exocyclic olefin, followed by oxidation to make bicycle 16. With reference to bicycle 16, R⁵ can be a functional group known by those or ordinary skill in the art to be convertible to NH₂, guanidino, substituted guanidino, alkyl, alkenyl, branched alkyl, cyclic alkyl, aryl or heteroaryl, (CH₂)_nN(R^{l l} H)_i2-_m), (CH₂)_nNHC(0)(R¹ '),

(CH₂)_nNC(=NR^{1 ,})N(R^{1 1})_m(H)_(2-m), (CH₂)_nNHC(0)Z(Rⁿ), (CH₂)_nZH, where Z is O, S, Se, or NR¹¹; where n and m independently are 1-10; R^u is H, alkyl, branched alkyl, cyclic alkyl, aryl or heteroaryl; R is H, alkyl or any protected form of (CH₂)_nOH; V is any heteroatom, particularly oxygen or sulphur, and carbonyl, sulfonyl, or sulfone; and X is any heteroatom, such as oxygen or sulphur; and any and all combinations thereof. Another method concerns alkylation of the bicycle using alkylation conditions known to a person of ordinary skill in the art, such as a base and an appropriate alkylating reagent. After alkylation, the same oxidative cleavage and oxidation steps can be used to obtain bicycle 17. Other embodiments of the disclosed method concern an oxidative degradation step to remove the exocylic olefin to provide bicycle 18. Any of the disclosed methods can be employed in the stated sequence, or any combination thereof. Scheme 5 provides exemplary reaction conditions to implement the general concepts of Scheme 4.

21

Scheme 5

In particular working embodiments, sulfone 15 was converted through the steps stated above to various products. Cleavage of the exocyclic olefin was accomplished following a two-step ozonolysis/Pinnick procedure to provide 19, which exhibited dose- dependent inhibition of commercially available recombinant H1N1 neuraminidase, as shown in FIG. 2. Alternatively, alkylation at the position adjacent to the sulfone using benzyl bromide prior to oxidative cleavage resulted in forming 20, as a single diastereomer. In cases where the C-4 ketone is required, either as an inhibitor or a synthetic intermediate, the exocyclic olefin can by completely cleaved by treatment with RuCl₃ and oxone. Treating 15 with RuCl₃ and oxone led to the formation of ketone 21.

Further exemplary reactions are provided in Scheme 6. An image of the X-ray structure of the ethyl ester of compound 31, which was crystallized as the hydrochloride salt, is illustrated in FIG. 3.

Scheme 6

Scheme 7 illustrates another general method for making the disclosed compounds.

37 36 35

Scheme 7

With reference to the general method of Scheme 7, oxidation and rearrangement of diene 5 using the method of Oger, Brinkmann, Bouazzaoui, Durand and Galeno can afford alcohol 32. Using a modified method to that of Bedekar et al, acetylation and allylic oxidation of 32 can provide 33. Reagents for allylic oxidation include those known to a person of ordinary skill in the art, such as, but not limited to, a metal- containing oxidant or an organic oxidant. Examples of metal-containing oxidants include, but are not limited to, chromium oxidants, manganese oxidants, rhodium oxidants, and copper oxidants. An example of an organic oxidant is selenium dioxide. Chemoselective derivatization using methodology familiar to those skilled in the art can provide access to compounds 34 - 37, each of which may be useful as an inhibitor of viral or bacterial sialidases, or may be a synthetic precursor for other inhibitors. Those skilled in the art will recognize that some or all of the intermediates shown in Scheme 7 may require additional deprotection steps or other manipulations prior to their use as inhibitors.

With reference to this general formulae in Scheme 7, R¹ is C0₂H, (CH₂)_nC0₂H, (CH₂)_nOH, tetrazolyl, S0₂H, S0₃H, P0₃H₂, or esters, amides, anhydrides or other protected forms thereof; R² is OH, H, (CH₂)_nZH, or protected forms thereof, where Z = O, S, Se, or NR^{1 1} ; R⁵ is N¾, (CH₂)_nN(R^u)_m(H)_(2-m), (CH^NHCCOXR^{1 x}),

(CH₂)_nNC(=NRⁿ)N(R (H)_(2-m), (CH₂)_nNHC(0)Z(Rⁿ), (CH₂)_nZH, or protected forms thereof, where Z = O, S, Se, or NRⁿ; guanidino, substituted guanidino, alkyl, branched alkyl, cyclic alkyl, aryl or heteroaryl; R is alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, (CH₂)_nY, (CH)₂ZH, [CH₂]_n[CH(ZH)]_mCH₂ZH, [CH₂]_n[CH(ZH)]_mCH₂Y, where Y is aryl, heteroaryl, alkyl or cyclic alkyl, amino or guanidino, and Z = O, S, Se, or NR¹¹; R^{1 1} is H, alkyl, branched alkyl, cyclic alkyl, aryl or heteroaryl; R¹² is H, (CH₂)_nZH, (CH₂)ZR^U, (CH₂)_nZ(CO)R^M, (CH₂)_nZ(S0₂)Rⁿ, (CH₂)Z(CO)NH₂,

(CH₂)Z(CO)OR^u, or (CH₂)_nZ(CNH)NH₂, and Z = O, S, Se, or NR^{1 1}; n - 0, 1 or 2; and m = 0, 1 or 2.

Exemplary methods for preparing the disclosed compounds as shown in Schemes 3, 5, and 6 are provided in the experimental section below. In each of the schemes provided herein it may be advantageous to separate reaction products from one another and/or starting materials. The desired products of each step or series of steps are separated and/or purified to the desired degree of homogeneity by the techniques common in the art. Examples include but are not limited to multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.

VII. EXAMPLES

The following examples are provided to illustrate certain features of working embodiments of the present invention. A person of ordinary skill in the art will appreciate that the invention is not limited to such features. All examples refer to the schemes. All compounds are numbered as found in the schemes.

Exam le 1

As shown in Scheme 3: Hexamethyldisilazane (8.80 mL, 42.2 mmol) was dissolved in tetrahydrofuran (60 mL). The solution was cooled to -78 °C, and «-butyllithium (17.8 mL, 2.20 M, 39.2 mmol) was slowly added. The solution was stirred at -78 °C for 15 min, then warmed to room temperature for 45 min. Butadiene sulfone (10) (4.20 g, 35.6 mmol) and ketone 9 (4.80 g, 43.6 mmol) were dissolved in tetrahydrofuran (300 mL), and the solution was cooled to -78 °C. The prepared solution of LiHMDS was added via cannula. The reaction mixture was stirred for 30 min at -78 °C, then removed from the cooling bath and stirred 1 hour at room temperature. The reaction was quenched by the addition of 10% aqueous HC1 (50 mL), and the mixture was partially concentrated in vacuo at 30 °C. The resulting yellow solution was partitioned between 10% aqueous HC1 and chloroform. The organic fraction was washed with brine and dried with

Na₂S0₄ then concentrated in vacuo at 30 °C to provide 7.80 g of sulfone 13 as a yellow oil. The crude product was carried to the next step with no further purification. IR (film) 1694, 1303, 1 133, 971 cm ¹; Ή NMR (500 MHz) 5 6.89 (dq, J=16, 7 Hz, 1 H, H9), 6.12 (dq, J= 16, 2 Hz, 1 H, H8) 6.11-6.00 (m, 2 H, H3, H2), 3.78-3.63 (m, 3 H, HI, H4), 2.92 (dd, J= 16, 5 Hz, 1 H, H6), 2.74-2.65 (m, 1 H, H5), 2.55 (dd, J= 16, 8 Hz, 1 H, H6), 1.89 (dd, J= 7, 2 Hz, 3 H, H10), 1.14 (d, J= 7 Hz, 3 H, Hl l); ¹³C NMR (125 MHz) δ 198.6 (C), 144.0 (CH), 132.1 (CH), 129.1 (CH), 124.2 (CH), 69.1 (CH), 56.6 (CH₂), 43.1 (CH₂), 29.9 (CH), 18.5 (CH₃), 16.8 (CH₃); MS (ES+) m/z 253 (4), 251 (100); HRMS calcd for CnHi₆0₃S (M+Na): 251.0718. Found: 251.0715.

Exam le 2

14

As shown in Scheme 3: Hexamethyldisilazane (8.54 mL, 41.0 mmol) was dissolved in tetrahydrofuran (60 mL). The solution was cooled to -78 °C, and n-butyllithium (15.1 mL, 2.50 M, 37.6 mmol) was slowly added. The solution was stirred at -78 °C for 15 minutes then warmed to room temperature for 45 minutes. Compound 13 (crude, 7.80 g, 34.2 mmol) was dissolved in tetrahydrofuran (400 mL), and the solution was cooled to -78 °C. The prepared solution of LiHMDS was added via cannula. The reaction mixture was stirred for 30 minutes at -78 °C then removed from the cooling bath and stirred 5 hours at room temperature. The reaction was quenched by the addition of 10% aqueous HC1 (100 mL), and the mixture was partially concentrated in vacuo. The resulting red solution was partitioned between 10% aqueous HC1 and chloroform. The organic fraction was washed with brine, dried with Na₂S0₄ and concentrated in vacuo at 30 °C to provide 8.20 g of crude vinylsulfone 14 as a yellow oil. The crude product was typically carried to the next step with no further purification. Alternatively, an analytically pure sample could be obtained through flash-column chromatography

(dichloromethane:ethyl acetate 10: 1) followed by recrystallization from a minimum amount of ethyl acetate and diethyl ether. Mp 107-110 °C; IR (film) 3485 (br), 1282,

1 132 cm^"1; Ή NMR (500 MHz) δ 6.52 (dd, J- 7, 2 Hz, 1 H, H2), 6.49 (dd, J= 7, 3 Hz, 1 H, H3), 5.79 (dq, J=15, 6 Hz, 1 H, H9), 5.58 (dq, J= 15, 2 Hz, 1 H, H8), 3.53 (ddd, J = 10, 3, 2 Hz, 1 H, H3a), 3.19 (dd, J= 10, 8 Hz, 1 H, H6a), 2.97-2.85 (m, 1 H, H6), 2.02 (dd, J= 13, 6 Hz, 1 H, H5_eq), 1.71 (dd, J= 6, 2 Hz, 3 H, H10), 1.70 (t, J= 13 Hz, 1 H, H5_ax), 1.24 (d, J = 6 Hz, 3 H, H7); ^,3C NMR (125 MHz) δ 137.1 (CH), 133.7 (CH), 132.7 (CH), 125.9 (CH), 80.6 (C), 67.8 (CH), 57.8 (CH), 51.6 (CH₂), 33.6 (CH), 19.6 (CH₃), 17.8 (CH₃); MS (ES+) mlz 253 (4), 251 (100); HRMS calcd for CnH₁₆0₃S (M+Na): 251.0718. Found: 251.0715.

Example 3

10

As shown in Scheme 3: Compound 14 (crude, 4.50 g, 19.7 mmol) was dissolved in tetrahydrofuran (300 mL). The solution was cooled to 0 °C and LiAlH₄ (1.87 g, 49.3 mmol) was added in three portions over 5 minutes. The solution was warmed to room temperature and stirred for 2.5 hours. Wet sodium sulfate was added in small portions over 5 minutes until gas evolution desisted. The reaction mixture was filtered and washed with ethyl acetate and methanol. The filtrate was concentrated in vacuo to provide 4.20 g of crude sulfone 15 as yellow residue. Flash-column chromatography of a 1.10 g sample of crude material (ethyl acetate-dichloromethane:methanol 20:20:1) afforded 600 mg (50% over 3 steps) of 15 as a thick yellow oil. IR (film) 3484 (br), 1290, 1102, 972 cm^"1 ; 1H NMR (500 MHz) δ 5.72 (dq, J= 15, 6 Hz, 1 H, H9), 5.44 (dq,

J= 15, 2 Hz, 1 H, H8), 3.28 (ddd, J= 13, 13, 7 Hz, 1 H, H2), 2.93 (dd, J = 10, 10 Hz, 1

H, H6a), 2.87 (ddt, J= 13, 7, 2 Hz, 1 H, H2), 2.82-2.76 (m, 2H, H6 and H3a), 2.11 (dd,

J= 13, 7 Hz, 1 H, H3), 1.97 (dddd, J - 13, 13, 8, 7 Hz, 1 H, H3), 1.83 (dd, J- 13, 6 Hz,

1 H, H5), 1.68 (dd, J= 6, 2 Hz, 3 H, H10), 1.45 (t, J= 13 Hz, 1 H, H5), 1.18 (d, J= 7 Hz, 3 H, H7); ¹³C NMR (125 MHz) δ 134.4 (CH), 125.1 (CH), 82.3 (C), 69.4 (CH), 50.8 (CH₂), 50.5 (CH), 49.9 (CH₂), 35.9 (CH), 19.5 (CH₃), 19.4 (CH₂), 17.8 (CH₃); MS (ES+) m/z 253 (4), 251 (100); HRMS (ES+) calcd for C_nH₁₈0₃S (M+Na): 253.0874. Found: 253.0869.

Example 4

19

As shown in Scheme 5: Compound 15 (390 mg, 1.70 mmol) was dissolved in dichloromethane (70 mL). The solution was cooled to -78 °C, then ozone was bubbled through until a light blue color persisted. The solution was purged with argon for 10 minutes, then dimethylsulfide (1.7 mL) was added at -78 °C. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated in vacuo, and the crude product was carried on to the next step with no further purification. The crude aldehyde was dissolved in t-butanol (15 mL) and water (7.5 mL). Potassium phosphate (1.06 g, 7.8 mmol) was added, followed by 2-methyl-2- butene (7.8 mL, 2.0 M in THF, 16 mmol). The reaction mixture was stirred for 5 minutes, then sodium chlorite (208 mg, 2.3 mmol) in water (1.5 mL) was added drop- wise. The reaction mixture was stirred for a further 80 minutes at room temperature then partitioned between ethyl acetate and 10% aqueous HC1. The aqueous layer was washed with ethyl acetate, and the combined organic fractions were dried with sodium sulfate and concentrated in vacuo. Flash column chromatography

(dichloromethane:methanol:acetic acid 100:5:1) afforded 150 mg (25% over 2 steps) of

19 as a thick colorless oil. IR (film) 3473 (br), 1727, 1288, 1115 cm^"1; Ή NMR (500 MHz) δ 3.52-3.45 (m, 1 H, H3a), 3.26 (ddd, J = 13, 10, 10 Hz, 1 H, H2), 3.07 (t, J= 10 Hz, 1 H, H6a), 2.93 (dt, J= 13, 4 Hz, 1 H, H2), 2.88-2.75 (m, 1 H, H6), 2.13-2.09 (m, 2 H, H3), 2.06 (dd, J= 13, 6 Hz, 1 H, H5_eq), 1.87 (t, J= 13 Hz, 1 H, H5_ax), 1.25 (d, J= 7 Hz, 3H, H7); ¹³C NMR (125 MHz) δ 178.7 (C), 82.3 (C), 68.6 (CH), 50.2 (CH₂), 49.7 (CH), 47.7 (CH₂), 37.2 (CH), 20.5 (CH₂), 18.9 (CH₃); MS (ES-) mlz 235 (4), 233 (100); HRMS calcd for C₉Hi₄0₅S (M-H): 233.0477. Found: 233.0480.

Example 5

As shown in Scheme 5: Compound 15 (265 mg, 1.2 mmol) was dissolved in tetrahydrofuran (15 mL). The solution was cooled to -78 °C. NaHMDS (2.65 mL, 1M in THF, 2.65 mmol) was added in one portion. The solution was warmed to room temperature over 30 minutes. The reaction mixture was cooled to -78 °C whereupon benzyl bromide (175 μί, 1.5 mmol) was added. The solution was stirred for 2 hours at -78 °C then warmed to room temperature and stirred for 16 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NH₄C1. The aqueous layer was washed with ethyl acetate, and the combined organic fractions were washed with brine then dried with sodium sulfate and concentrated in vacuo. Flash- column chromatography (hexanes-ethyl acetate 2:1) afforded 316 mg (83%) of the C2- benzyl sulfone as a white solid. An image of the X-ray structure of this compound is illustrated in FIG. 4. Mp 129-132 °C; IR (film) 3502 (br), 1288, 1114, 967 cm^"1; 1H NMR (500 MHz) δ 7.27-7.15 (m, 5 H, Ph), 5.58 (dq, J= 15, 7 Hz, 1 H, H9), 5.40 (dq, J = 15, 2 Hz, 1 H, H8), 3.66 (dddd, J- 13, 9, 7, 6 Hz, 1 H, H2), 3.18 (dd , J= 14, 5 Hz, 1 H, HI 1), 2.99 (dd, J= 11, 9 Hz, 1 H, H6a), 2.83-2.73 (m, 1 H, H6), 2.71 (dd, J- 14, 9 Hz, 1 H, HI 1), 2.65 (dd, J = 10, 9 Hz, 1 H, H3a), 2.02 (dd, J= 13, 7 Hz, 1 H, H3), 1.80 (d, J= 1.5 Hz, 1 H, OH), 1.78 (dd, J= 13, 6 Hz, 1 H, H5), 1.66 (ddd, J= 13, 13, 7 Hz, 1 H, H3), 1.62 (dd, J= 7, 2 Hz, 3 H, H10), 1.42 (t, J= 13 Hz, 1H, H5), 1.17 (d, J= 6 Hz, 3 H, H7); ¹³C NMR (125 MHz) δ 137.6 (C), 134.3 (CH), 129.0 (CH), 128.7 (CH), 126.7 (CH), 124.8 (CH), 81.8 (C), 69.8 (CH), 60.4 (CH), 49.3 (CH₂), 47.7 (CH), 36.1 (CH), 32.4 (C¾), 26.0 (CH₂), 19.2 (CH₃), 17.7 (CH₃); MS (ES+) m/z 345 (4), 343 (100); HRMS calcd for C₁₈H₂₄0₃S (M+Na): 343.1344. Found: 343.1342.

Example 6

20

As shown in Scheme 5: The alkene from Example 5 (220 mg, 0.69 mmol) was dissolved in dichloromethane (60 mL). The solution was cooled to -78 °C, then ozone was bubbled through until a light blue color persisted. The solution was purged with argon for 10 minutes, then dimethylsulfide (0.7 mL) was added at -78 °C. The reaction mixture was warmed to room temperature and stirred for 16 hourse. The reaction mixture was concentrated in vacuo, and the crude product was carried on to the next step with no further purification. The crude aldehyde was dissolved in i-butanol (15 mL) and water (7.5 mL). Potassium phosphate (554 mg, 4.1 mmol) was added followed by 2-methyl-2-butene (4.1 mL, 2.0 M in THF, 8.2 mmol). The reaction mixture was stirred for 5 minutes then sodium chlorite (111 mg, 1.2 mmol) in water (1.5 mL) was added drop-wise. The reaction mixture was stirred for 80 minutes at room temperature then partitioned between ethyl acetate and 10% HC1. The aqueous layer was washed with ethyl acetate, and the combined organic fractions were dried with sodium sulfate and concentrated in vacuo. Flash column chromatography

(dichloromethane:methanol:acetic acid 100:5: 1) afforded 180 mg (80% over 2-steps) of 20 as a thick oil. IR (film) 3467 (br), 1731, 1288, 1114 cm^"1; 1H NMR (500 MHz): δ 7.31-7.16 (m, 5 H, Ph), 3.59 (m, 1 H, H2), 3.35 (dd, J= 11 , 8 Hz, 1 H, H3a), 3.24 (dd, J = 14, 5 Hz, 1 H, H9), 3.14 (dd, J= 11 , 9 Hz, 1 H, H6a), 2.87-2.76 (m, 1 H, H6), 2.72 (dd, J = 14, 10 Hz, 1 H, H9), 2.00 (dd, 7= 13, 6 Hz, 1 H, H3), 1.91 (dd, J= 14, 6, 1 H, H5), 1.84-1.72 (m, 2 H, H3, H5), 1.26 (d, J= 7 Hz, 3 H, H7); ¹³C NMR (125 MHz) δ 178.8 (C), 137.2 (C), 129.0 (CH), 128.9 (CH), 127.1 (CH), 82.1 (C), 69.9 (CH), 60.0 (CH), 47.4 (CH₂), 47.0 (CH), 37.7 (CH), 32.0 (CH₂), 26.8 (CH₂), 18.8 (CH₃); MS (ES-) mlz 325 (4), 323 (100); HRMS calcd for Ci₆H₂₀O₅S (M-H): 323.0953. Found:

323.0957.

Exam le 7

12

As shown in Scheme 3: Hexamethyldisilazane (2.10 mL, 10.2 mmol) was dissolved in tetrahydrofuran (10 mL). The solution was cooled to -78 °C and w-butyllithium (4.50 mL, 2.06 M, 9.35 mmol) was slowly added. The solution was stirred for 15 minutes, then warmed to room temperature for 45 minutes. Butadiene sulfone 10 (1.00 g, 8.5 mmol) and ketone 9 (1.20 g, 10.9 mmol) were dissolved in tetrahydrofuran (60 mL), and the solution cooled to -78 °C. The prepared solution of LiHMDS was added via cannula. The mixture was stirred for 10 minutes at -78 °C, then acetic acid (2 mL) was added. The reaction mixture was diluted with 10% aqueous HCl (50 mL), then partially concentrated in vacuo at 30 °C. The resulting yellow solution was partitioned between

10% HCl and chloroform, and the organic fraction was dried with Na₂S0₄ and concentrated in vacuo at 30 °C to provide a crude mixture of sulfone 13 and

intermediate 12. Extensive flash column chromatography (hexanes: ethyl acetate 1 :1) afforded 131 mg of 12 as a thick colorless oil. IR (film) 3479 (br), 1289, 1 135, 973 cm^" '; 1H NMR (500 MHz): δ 6.67 (dd, J= 7, 3 Hz, 1 H, HI), 6.67 (dd, J= 7, 2 Hz, 1 H, H2), 5.75 (dq, J= 15, 7 Hz, 1 H, H10 or H7), 5.72 (dq, J= 15, 7 Hz, 1 H, H10 or H7), 5.47 (dq, J= 15, 2 Hz, 1 H, H6 or H9), 5.44 (dq, J= 15, 2 Hz, 1 H, H6.or H9), 3.27- 3.19 (m, 1 H, H3), 3.18-3.05 (m, 2 H, H4), 2.13 (s, 1 H, OH), 1.71 (dd, J= 7, 2 Hz, 3 H, H8 or Hl l), 1.67 (dd, J= 7, 2 Hz, 3 H, H8 or Hl l); ¹³C NMR (125 MHz) 6 140.2 (CH), 133.1 (CH), 132.0 (CH), 127.5 (CH), 127.3 (CH), 75.4 (C), 50.0 (CH₂), 49.2 (CH), 17.7 (CH₃); MS (ES+) m/z 253 (4), 251 (100); HRMS calcd for C_nH₁₆0₃S (M+Na):

251.0718. Found: 251.0712.

Example 8

21

As shown in Scheme 5: Compound 15 (50 mg, 0.22 mmol) was dissolved in

acetonitrile (5 mL) and water (3 mL). Ruthenium trichloride (2 mg, 0.01 mmol) was added followed by a mixture of Oxone (270 mg, 0.44 mmol) and sodium bicarbonate (85 mg, 1.0 mmol) in three portions over 10 min. After 1 hour the reaction mixture was partitioned between 10% aqueous sodium thiosulfate and dichloromethane. The aqueous layer was washed with dichloromethane then the combined organic extracts were dried (Na₂S0₄) and concentrated in vacuo. Crystallization from a minimum amount of ether and hexanes provided 42 mg (82%) of 21 as a white solid. IR (film) 1746, 1298, 1115 cm^"1; Ή NMR (500 MHz): δ 3.34 (dd, J= 10, 5 Hz, 1 H, H6a), 3.17 (td, J = 10, 4 Hz, 1 H, H3a), 3.10-3.02 (m, 1 H, H2), 2.83-2.70 (m, 2 H, H6, H2), 2.62 (dd, J= 18, 8 Hz, 1 H, H5), 2.38-2.28 (m, 2 H, H3), 2.16 (dd, J = 18, 7 Hz, 1 H, H5), 1.29 (d, J= 7 Hz, 3 H, H7) ¹³C NMR (125 MHz) δ 215.1 (C), 66.7 (CH), 49.7 (CH₂), 48.1 (CH), 45.8 (CH₂), 30.8 (CH), 22.1 (CH₂), 21.4 (CH); MS (ES+) m/z 213 (4), 211 (100), 152 (13); HRMS calcd for C₈H,₄0₃S (M+Na): 211.0405. Found: 211.0407.

Exam le 9

As shown in Scheme 6: Hexamethyldisilazane (432 μΐ,, 2.08 mmol) was dissolved in tetrahydrofuran (5 mL). The solution was cooled to -78 °C, and n-butyllithium (1.25 mL, 1.54 M, 1.92 mmol) was slowly added. The solution was stirred at -78 °C for 15 minutes, then warmed to room temperature for 45 minutes. Butadiene sulfone (10) (188 mg, 1.60 mmol) and ketone 22 (458 mg, 1.60 mmol) were dissolved in tetrahydrofuran (20 mL), and the solution was cooled to -78 °C. The prepared solution of LiHMDS was added via cannula. The reaction mixture was stirred for 40 min at -78 °C, then removed from the cooling bath and stirred 1 hour at room temperature. The reaction was quenched by the addition of 10% aqueous HC1 (10 mL), and the mixture was partially concentrated in vacuo at 30 °C. The resulting yellow solution was partitioned between 10% aqueous HC1 and dichloromethane. The organic fraction was washed with brine and dried with Na₂S0₄ then concentrated in vacuo at 30 °C to provide 701 mg of crude keto-sulfone as a red oil. The crude product was carried to the next step with no further purification.

Hexamethyldisilazane (362 μί, 1.74 mmol) was dissolved in tetrahydrofuran (10 mL). The solution was cooled to -78 °C, and n-butyllithium (1.06 mL, 1.54 M, 1.59 mmol) was slowly added. The solution was stirred at -78 °C for 15 minutes then warmed to room temperature for 45 minutes. The crude keto-sulfone (573 mg, 1.31 mmol) was dissolved in tetrahydrofuran (20 mL), and the solution was cooled to -78 °C. The prepared solution of LiHMDS was added via cannula. The reaction mixture was stirred for 30 minutes at -78 °C then removed from the cooling bath and stirred 5 hours at room temperature. The reaction was quenched by the addition of 10% aqueous HCl (10 mL), and the mixture was partially concentrated in vacuo. The resulting yellow solution was partitioned between 10% aqueous HCl and dichloromethane. The organic fraction was washed with brine, dried with Na₂S0₄ and concentrated in vacuo at 30 °C. Flash- column chromatography (dichloromethane-ethyl acetate 10:1) afforded 201 mg (38% over 2 steps) of vinyl sulfone 23 as a yellow oil; IR (film) 3479 (br), 1284, 1 132 cm^"1; 1H NMR (500 MHz) δ 7.50-7.16 (m, 10 H), 6.78 (dd, J = 16, 10 Hz), 6.64-6.53 (m, 5 H), 6.23 (dd, J = 16, 7 Hz), 5.91 (d, J = 16 Hz, 1 H), 3.78 (ddt, J = 13, 8, 7 Hz, 1 H), 3.65 (ddd, 10, 3, 2 Hz, 1 H), 3.57 (dd, J = 10, 8 Hz, 1 H), 2.23 (dd, J - 13, 7 Hz, 1 H), 2.11 (t, J= 13 Hz, 1 H); ¹³C NMR (125 MHz) δ 137.0 (C), 136.7 (C), 136.4 (CH), 135.0 (CH), 134.3 (CH), 133.4 (CH), 132.2 (CH), 130.7 (CH), 129.0 (CH), 128.9 (CH), 128.8 (CH), 128.2 (CH), 127.9 (CH), 127.4 (CH), 126.7 (CH), 126.6 (CH), 80.6 (C), 66.0 (CH), 57.8 (CH), 50.0 (CH₂), 41.8 (CH); MS (ES+) mlz 429 (4), 427 (100); HRMS calcd for C₂₅H₂₄0₃S (M+Na): 427.1344. Found: 427.1350.

Exam le 10

As shown in Scheme 6: Butadiene sulfone (10) (2.81 g, 23.8 mmol) and ketone 24 (7.00 mg, 23.8 mmol) were dissolved in tetrahydrofuran (200 mL), and the solution was cooled to -78 °C. LiHMDS (28.6 mL, 1M in THF, 28.6 mmol) was added in one portion. The reaction mixture was stirred for 1 hour at -78 °C, then removed from the cooling bath and stirred 1 hour at room temperature. The reaction was quenched by the addition of 10% aqueous HC1 (50 mL), and the mixture was partially concentrated in vacuo at 30 °C. The resulting orange solution was partitioned between 10% aqueous HC1 and dichloromethane. The organic fraction was washed with brine and dried with Na₂S0₄ then concentrated in vacuo at 30 °C to provide 9.82 g of the crude keto-sulfone intermediate as a light yellow solid.

The crude intermediate (9.82 g, 23.8 mmol) was dissolved in tetrahydrofuran (250 mL), and the solution was cooled to -78 °C. LiHMDS (28.6 mL, 1M in THF, 28.6 mmol) was added in one portion. The reaction mixture was stirred for 30 minutes at -78 °C then removed from the cooling bath and stirred 2.5 hours at room temperature. The reaction was quenched by the addition of saturated aqueous NH₄C1 and the mixture was partially concentrated in vacuo. The resulting red solution was partitioned between saturated aqueous NH₄C1 and dichloromethane. The organic fraction was washed with brine, dried with Na₂S0₄ and concentrated in vacuo at 30 °C to provide 9.90 g of crude vinyl-sulfone 25 as a brick red solid. 1H NMR (300 MHz) δ 7.19 (d, J = 8 Hz, 2 H), ^' 7.12 (d, J= 8 Hz, 2 H), 6.73 (d, J = 8 Hz, 2 H), 6.72 (d, J= 8 Hz, 2 H), 6.58 (d, J = 16 Hz, 1 H), 6.50 (dd, J = 7, 2 Hz, 1 H), 6.43 (dd, J = 7, 3 Hz, 1 H), 6.07 (d, J- 16 Hz, 1 H), 4.15-3.95 (m, 1 H), 3.66 (s, 3 H), 3.64 (s, 3 H), 3.63-3.52 (m, 2 H), 2.30-2.23 (m, 2 H).

Exam le 11

As shown in Scheme 6: Compound 25 (crude, 5.16 g, 12.5 mmol) was dissolved in tetrahydrofuran (40 mL). The solution was cooled to 0 °C and Red-Al (7.8 mL, 65% in toluene) was added in one portion. The solution was stirred at 0 °C for 0.5 hours. A 10% aqueous solution of Rochelle's salt was added in small portions over 5 minutes until gas evolution desisted. The reaction mixture was partitioned between EtOAc and water. The organic fraction was dried with Na₂S0₄ and concentrated in vacuo. Flash- column chromatography (dichloromethane-ethyl acetate 25:1) afforded 900 mg (17% over 3 steps) of reduced sulfone 26. 1H NMR (300 MHz) δ 7.27 (d, J= 8 Hz, 2 H), 7.20 (d, J= 8 Hz, 2 H), 6.81 (d, J= 8 Hz, 2 H), 6.80 (d, J= 8 Hz, 2 H), 6.62 (d, J= 16 Hz, 1 H), 6.07 (d, J= 16 Hz, 1 H), 4.08-3.94 (m, 1 H), 3.75 (s, 3 H), 3.72 (s, 3 H), 3.50-3.35 (m, 2 H), 3.06-2.89 (m, 2 H), 2.13-1.95 (m, 2 H), 2.26-2.13 (m, 2 H). ¹³C NMR (125 MHz) δ 159.5, 158.5, 133.2, 129.5, 129.0, 128.8, 128.4, 127.8, 114.2, 1 14.1, 82.4, 70.0, 55.3, 51.2, 50.9, 49.2, 44.7, 19.2. Exam le 12

As shown in Scheme 6: Compound 26 (672 mg, 1.62 mmol) was dissolved in dichloromethane (80 niL). The solution was cooled to -78 °C, then ozone was bubbled through until a light blue color persisted. The solution was purged with argon for 10 minutes, then dimethylsulfide (1.62 mL) was added at -78 °C. The reaction mixture was warmed to room temperature and stirred for 16 hours. The mixture was concentrated in vacuo, and the crude product was carried on to the next step with no further purification.

The crude aldehyde was dissolved in t-butanol (15 mL), tetrahydrofuran (10 mL) and water (7 mL). Potassium phosphate (2.28 g, 16.4 mmol) was added, followed by 2- methyl-2-butene (16 mL, 2.0 M in THF, 32 mmol). The mixture was stirred for 5 minutes, then sodium chlorite (446 mg, 4.93 mmol) in water (2 mL) was added drop- wise. The reaction mixture was stirred for a further 60 minutes at room temperature then partitioned between ethyl acetate and 10% aqueous HC1. The aqueous layer was washed with ethyl acetate, and the combined organic fractions were dried with Na₂S0₄ and concentrated in vacuo. Flash column chromatography (dichloromethane :EtO Ac 5:1 to dichloromethane:methanol:acetic acid 100:5:1) afforded 360 mg (62% over 2 steps) of carboxylic acid intermediate as a white solid. 1H NMR (300 MHz) δ 7.20 (d, J= 9 Hz, 2 H), 6.80 (d, J= 9 Hz, 2 H), 4.00-3.88 (m, 1 H), 3.73 (s, 3 H), 3.60-3.28 (m, 3 H), 2.98-2.87 (m, 1 H), 2.39 (t, J= 13 Hz, 1 H), 2.23 (dd, J= 13, 7 Hz, 1 H), 2.16-2.05 (m, 2 H). The acid (188 mg, 0.576 mmol) was dissolved in benzene (30 mL) and ethanol (5 mL). /7-Toylsulfonic acid (4 mg, 0.023 mmol) was added and the solution was heated at 80 °C using a dean-stark apparatus for 16 hours. The reaction mixture was partitioned between water and EtOAc. The organic fraction was dried with Na₂S0₄ and concentrated in vacuo to provide 178 mg of ethyl ester 27. 1H NMR (300 MHz) δ 7.20 (d, J= 8 Hz, 2 H), 6.80 (d, J= 2 Hz, 2 H), 4.25 (dq, J= 10 , 7Hz, 2 H), 3.99-3.86 (m, 1 H), 3.72 (s, 3 H), 3.51-3.43 (m, 2 H), 3.41-3.25 (m, 1 H), 2.97-2.85 (m, 1 H), 2.29 (t, J- 13 Hz, 1 H), 2.17 (dd, J= 13, 7 Hz, 1 H), 2.12-2.03 (m, 2 H), 1.27 (t, J= 7 Hz, 3 H), ¹³C NMR (125 MHz) δ 174.2, 158.7, 132.2, 128.5, 114.2, 82.3, 68.9, 63.0, 55.3, 50.5, 49.5, 46.7, 45.9, 21.5, 14.1.

Exam le 13

As shown in Scheme 6: Ester 27 (crude, 123 mg, 0.347 mmol) was dissolved in CC1₄ (2 mL), acetonitrile (2 mL) and water (4 mL). NaHC0₃ (3 mg) was added, followed by NaI0₄ (1.11 g, 5.19 mmol). RuCl₃ (6 mg, 0.014 mmol) was added and the reaction mixture was stirred 16 hours. The reaction mixture was quenched with saturated aqueous Na₂S₂0₃ then partitioned between 10% aqueous HC1 and EtOAc. The organic fraction was washed with saturated aqueous Na₂S₂0_3> dried with Na₂S0₄ then concentrated in vacuo at 30 °C to provide 99 mg of crude acid-sulfone 28 as a white solid. 1H NMR (300 MHz) δ 4.23 (dq, J= 10 , 7 Hz, 2 H), 3.92-3.84 (m, 1 H), 3.89 (s, 3 H), 3.67 (dt, J= 11, 8 Hz, 1 H), 3.54-3.44 (m, 1 H), 3.33-3.18 (m, 1 H), 3.02-2.90 (m, 1 H), 2.41-2.23 (m, 2 H), 2.20-2.00 (m, 2 H), 1.26 (t, J= 7 Hz, 3 H). ¹³C NMR (125 MHz) δ 176.6, 173.5, 82.3, 63.8, 63.3, 50.6, 49.0, 45.5, 42.5, 29.7, 20.7, 14.0.

Exam le 14

As shown in Scheme 6: Compound 28 (crude, 160 mg, 0.548 mmol) was dissolved in benzene (20 mL). Triethylamine (153 μί, 1.1 1 mmol) was added, followed by DPPA

(120 μί, 0.548 mmol). Benzyl alcohol (173 μΐ-, 0.822 mmol) was added and the reaction mixture was stirred at 80 °C for 16 hours. The reaction was quenched with saturated aqueous NH₄C1 then partitioned between saturated aqueous NH₄C1 and

EtOAc. The organic fraction was dried with Na₂S0₄ and then concentrated in vacuo.

Flash column chromatography (dichloromethane:EtOAc 20:1 to

dichloromethane: EtOAc 2: 1) afforded 82 mg (29% over 3 steps) of 29 as a brown solid.

1H NMR (300 MHz) δ 7.33-7.24 (m, 5 H), 5.31-5.20 (m, 1 H), 5.06-4.99 (m, 2 H), 4.46- 4.29 (m, 1 H), 4.23 (q, J= 7 Hz, 2 H), 3.84-3.71 (m, 1 H), 3.55-3.40 (m, 1 H), 3.31-3.17

(m, 1 H), 2.94-2.85 (m, 1 H), 2.75-2.58 (m, 1 H), 2.18-1.93 (m, 3 H), 1.25 (t, J= 7 Hz,

3 H).

Exam le 15

As shown in Scheme 6: Compound 29 (61 mg, 0.15 mmol) was dissolved in methanol (8 mL) in a glass 20 mL scintillation vial. Acetic acid (~ 100 μί) was added, followed by Pd/C 10% (- 10 mg). The reaction mixture was stirred inside a Parr reactor pressurized to 300 PSI H₂ for 16 hours. The resulting suspension was filtered through cotton, and the filtrate was diluted with cyclohexane (10 mL) then concentrated in vacuo to provide 47 mg of the acetic acid salt of amino- sulfone 30. 1H NMR (300 MHz) δ 4.50 (dt, J= 1 1 , 7 Hz, 1 H), 4.08 (dq, J= 10, 7 Hz, 2 H), 3.52-3.32 (m, 2 H), 3.18- 3.05 (m, 1 H), 2.83-2.73 (m, 1 H), 2.15-1.90 (m, 4 H), 1.14 (t, J= 7 Hz, 3 H); ¹³C NMR (125 MHz) δ 173.9, 82.8, 70.0, 63.0, 62.3, 51.6, 49.6, 45.8, 21.2, 14.4. MS (ES+) m/z 266 (4), 264 (100).

31

As shown in Scheme 6: Compound 30 (crude, 30 mg, 0.0929 mmol) was dissolved in DMF (3 mL). Triethylamine (65 μί, 0.464 mmol) was added, followed by HgCl₂ (25 mg, 0.0929 mmol). l,3-bis(benzyloxycarbonyl)-2-methylisothiourea (33 mg, 0.0929 mmol) was added and the reaction mixture was stirred 16 hours. The reaction mixture was diluted with EtOAc, filtered through celite, then concentrated in vacuo. Flash column chromatography (dichlorome thane :EtO Ac 25:1 to dichloromethane:EtOAc 10:1) afforded 30 mg (54% over 2 steps) of crude protected guanidine as a solid.Ή NMR (300 MHz) δ 8.99 (s, 1 H), 8.19 (s, 1 H), 7.46-7.30 (m, 10 H), 5.22-5.18 (m, 4 H), 4.93-4.83 (m, 1 H), 4.20 (q, J= 7 Hz, 2 H), 3.83-3.75 (m, 1 H), 3.65-3.55 (m, 1 H), 3.33-3.21 (m, 1 H), 3.00-2.89 (m, 1 H), 2.43 (t, J= 12 Hz, 1 H), 2.31-2.08 (m, 3 H), 1.26 (t, J = 7 Hz, 3 H). MS (ES+) mlz 508 (4), 506 (100).

The protected guanidine (30 mg, 0.052 mmol) was dissolved in methanol (8 mL) in a glass 20 mL scintillation vial. Acetic acid (~ 100 μί) was added, followed by Pd/C 10% (10 mg). The reaction mixture was stirred inside a Parr reactor pressurized to 300 PSI H₂ and was stirred for 16 hours. The resulting suspension was filtered through cotton, diluted with cyclohexane (10 mL) then concentrated in vacuo to provide 15 mg of the ethyl ester of 31, as the acetic acid salt. 1H NMR (300 MHz) δ 5.94 (d, J= 5 Hz, 1 H), 5.10 (s, 2 H), 4.53-4.38 (m, 1 H), 4.09 (q, J= 7 Hz), 3.59-3.35 (m, 2 H), 3.17-3.06 (m, 1 H), 2.83-2.73 (m, 1 H), 2.29 (t, J= 12 Hz, 1 H), 2.13-1.89 (m, 3 H), 1.13 (t, J= 7 Hz, 3 H). MS (ES+) mlz 308 (4), 306 (100).

The invention has been described in detail sufficient to allow a person of ordinary skill in the art to make and use claimed invention. A person of ordinary skill in the art also will appreciate that certain modifications of the methods and

compositions of the claims can be made and still be within the scope of the claimed invention.

Claims

WE CLAIM:

1. A compound, having a first formula

a second formula

a third formula

or a fourth formula

where V, V_a, V_b, and V_c are selected from CR^UR¹², C(Rⁿ)₂, C(R¹³)₂, SO₂, SO, S, O,

NRⁿ, CO, and Se; W is selected from CR¹⁰, CR^{1 1}, nitrogen, and any combination thereof; R¹ is selected from CO₂H, (CH₂)_nCO₂H, (CH₂)_nOH, tetrazolyl, SO₂H, SO₃H, PO₃H₂, esters, amides, anhydrides and other protected forms thereof; R² is selected from OH, H, (CH₂)_nZH, where Z is selected from O, S, Se, and NR^{1 1}; R³ and R⁴ independently are selected from hydrogen, alkyl, branched alkyl, aryl or heteroaryl; R⁵ is selected from NH₂, (CH₂)_nN(R^u)_m(H)_(2-m), (CH₂)_nNHC(O)(R^u),

(CH₂)_nNC(=NRⁿ)N(Rⁿ)_m(H)_(2-m), (CH₂)_nNHC(O)Z(Rⁿ), (CH₂)_nZH, where Z is selected from O, S, Se, and N ^{1 1} ; guanidino, substituted guanidino, alkyl, branched alkyl, cyclic alkyl, aryl and heteroaryl; R⁶ is H, alkyl and (CH₂)_nOH; R⁷ and R⁸ independently are selected from H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, (CH₂)_nY, (CH)₂ZH, [CH₂]_n[CH(ZH)]_mCH₂ZH, [CH₂]_n[CH(ZH)]_mCH₂Y, where Y is selected from aryl, heteroaryl, alkyl, cyclic alkyl, amino and guanidino, and Z is selected from O, S, Se, or NR^{1 1}; R⁹ is selected from H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, 0(Rⁿ)_m, S(Rⁿ)_m, and N(Rⁿ)_m(H)(_2-m); R¹⁰ is selected from H, alkyl and (CH₂)_nOH; R^{1 1} is selected from H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, and any combination thereof; R¹² is selected from H, (CH₂)_nZH,

(CH₂)_nZRⁿ, (CH₂)_nZ(CO)Rⁿ, (CH₂)_nZ(S0₂)Rⁿ, (CH₂)_nZ(CO)NH₂, (CH₂)_nZ(CO)OR^u, or (CH₂)_nZ(CNH)NH₂, and Z is selected from O, S, Se, or NR¹¹; R¹³ is selected from H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, a heteroatom-containing moiety, and any combination thereof; n = 0, 1 or 2; and m = 0, 1 or 2. 2. The compound according to claim 1 where the heteroatom-containing moiety is selected from aldehyde, anhydride, acyl halide, carbonate, carboxyl, carboxylate, ether, ester, hydroxyl, ketone, silyl ether, peroxy, hydroperoxy, phosphate, phosphoryl, phosphodiester, phosphine, thiol, thioether/sulfide, disulfide, sulfinyl, sulfonyl, carbonothioyl, sulfino, sulfo, thiocyanate, isothiocyanate, oxazole, oxadiazole, imidazole, triazole, tetrazole, amine, amide, azide, azo, cyano, isocyanate, imide, nitrile, isonitrile, nitro, nitroso, nitromethyl, selenol, guanidino, and substituted guanidino;

3. The compound according to claim 1 where R and R together represent carbonyl.

4. The compound according to claim 1 where R³ and R⁴ together represent cyclic alkyl group or a carbonyl.

5. The compound according to claim 1 where R⁵ and R¹ together form a lactam or lactone.

6. The compound according to claim 1 where R and R together represent a cyclic alkyl group.

7. The compound according to claim 1 where V_a is CRⁿR¹², C(Rⁿ)₂, or C(R¹³)₂, and any one of R¹ ', R¹², or R¹³ together with R⁵ form a lactam or lactone.

8. The compound according to claim 1 where V_c is CR^{1 !}R¹², C(R^] ')₂, C(R¹³)₂, and any one of Rⁿ, R¹², or R¹³ together form a cyclic alkyl.

9. The compound according to claim 1 where V_b is CR¹ 'R¹², CiR^{1 1})₂, or C(R^I3)₂, and any one of R^{1 1}, R¹², or R¹³ together with R¹ form a lactam or lactone.

10. The compound according claim 1 formulated as a pharmaceutically acceptable salt.

11. The compound accordin to claim 1 where the compound has a formula

or

or

The compoun the compound has a formula or

61

62

63

The compound according to claim 1 having a formula

16. The compound according to claim 1 where the compound i

17. A composition, comprising: a compound having a first formula

a second formula

a third formula Vc

I

R 0-1 or a fourth formula

where V, V_a, V_b, and V_c are selected from CRⁿR¹², C(Rⁿ)₂, C(R¹³)₂, S0₂, SO, S, O, NR^{1 1}, CO, and Se; W is selected from CR¹⁰, CR¹¹, nitrogen, and any combination thereof; R¹ is selected from CO₂H, (C¾)_nCO₂H, (CH₂)_nOH, tetrazolyl,- SO₂H, SO₃H,

2

PO3H2, esters, amides, anhydrides and other protected forms thereof; R is selected from OH, H, (CH₂)_nZH, where Z is selected from O, S, Se, and NR¹¹; R³ and R⁴ independently are selected from hydrogen, alkyl, branched alkyl, aryl or heteroaryl; R⁵ is selected from NH₂, (CH₂)_nN(R^{1 1})_m(H)_(2-m), (CH₂)_nNHC(O)(Rⁿ),

(CH₂)„NC(= R^{1 1})N(R^{1 ,})_m(H)₍2-_III), (CH₂)_nNHC(O)Z(Rⁿ), (CH₂)_nZH, where Z selected from O, S, Se, and NR^{1 1} ; guanidino, substituted guanidino, alkyl, branched alkyl, cyclic alkyl, aryl and heteroaryl; R⁶ is H, alkyl and (CH₂)_nOH; R⁷ and R⁸ independently are selected from H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, (CH₂)_nY, (CH)₂ZH, [CH₂]_n[CH(ZH)]_mCH₂ZH, [CH₂]_n[CH(ZH)]_mCH₂Y, where Y is selected from aryl, heteroaryl, alkyl, cyclic alkyl, amino and guanidino, and Z is selected from O, S, Se, or NR¹¹; R⁹ is selected from H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, O(Rⁿ)_m, S(R^u)_m, and N(Rⁿ)_m(H)_(2-m); R¹⁰ is selected from H, alkyl and (CH₂)_nOH; R^{1 1} is selected from H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, and any combination thereof; R is selected from H, (CH₂)_nZH,

(CH₂)_nZRⁿ, (C¾)_nZ(CO)Rⁿ, (CH₂)_nZ(SO₂)R^u, (CH₂)_nZ(CO)NH₂, (CH₂)_nZ(CO)OR^u, or (CH₂)_nZ(CNH)NH₂, and Z is selected from O, S, Se, or NR^{1 1}; R¹³ is selected from H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, a heteroatom-containing moiety, and any combination thereof; n = 0, 1 or 2; and m = 0, 1 or 2; and at least one biologically acceptable material.

18. The composition according to claim 17 where the heteroatom-containing moiety is selected from aldehyde, anhydride, acyl halide, carbonate, carboxyl, carboxylate, ether, ester, hydroxyl, ketone, silyl ether, peroxy, hydroperoxy, phosphate, phosphoryl, phosphodiester, phosphine, thiol, thioether/sulfide, disulfide, sulfmyl, sulfonyl, carbonothioyl, sulfino, sulfo, thiocyanate, isothiocyanate, oxazole, oxadiazole, imidazole, triazole, tetrazole, amine, amide, azide, azo, cyano, isocyanate, imide, nitrile, isonitrile, nitro, nitroso, nitromethyl, selenol, guanidino, and substituted guanidino;

19. The composition according to claim 17 where R and R together represent a carbonyl.

20. The composition according to claim 17 where R³ and R⁴ together represent a cyclic alkyl group or a carbonyl.

21. The composition according to claim 17 where R⁵ and R¹ together form a lactam or lactone. 22. The composition according to claim 17 where R and R together represent a cyclic alkyl group.

23. The composition according to claim 17 where V_a is CRⁿR¹², C(R^H)₂, or C(R¹³)₂, and any one of R^{1 1}, R'², or R¹³ together with R⁵ form a lactam or lactone.

24. The composition according to claim 17 where V_c is CR^{1 !}R¹², C(R^J ')₂, C(R¹³)₂, and any one of Rⁿ, R¹², or R¹³ together form a cyclic alkyl.

25. The composition according to claim 17 where V_b is CRⁿR¹², C(R^U)₂, or C(R¹³)₂, and any one of Rⁿ, R¹², or R¹³ together with R¹ form a lactam or lactone.

26. The composition according claim 17 formulated as a pharmaceutically acceptable salt.

27. The composition according to claim 17 where the compound has a formula

or

28. The composition according to claim 17 where the compound has a formula

29. The composition according to claim 17 where the compound has a formula

formula

72

31. The composition according to claim 17 where the compound has a formula

32. The composition according to claim 17 where the compound is

33. The composition according to claim 17 where the least one biologically acceptable material is selected from carriers, diluents, adjuvants, excipients, binders, fillers, lubricants, osmotic agents, flavoring agents, other active ingredients, and combinations thereof.

34. The composition according to claim 32 where the carrier is selected from solvents, saline, buffered saline, dextrose, water, glycerol, ethanol, propylene glycol, polysorbate 80 (Tween-80.TM.), poly(ethylene)glycol 300 and 400 (PEG 300 and 400), PEGylated castor oil (E.g. Cremophor EL), poloxamer 407 and 188, hydrophobic carriers, fat emulsions, lipids, PEGylated phopholids, polymer matrices, biocompatible polymers, lipospheres, vesicles, particles, and liposomes, or combinations thereof.

35. The composition according to claim 32 where the excipient is selected from stabilizing agents, solubilizing agents, surfactants, buffers, antioxidants and preservatives, tonicity agents, bulking agents, lubricating agents, emulsifiers, suspending agents, viscosity agents, inert diluents, fillers, disintegrating agents, binding agents, wetting agents, lubricating agents, antibactenals, chelating agents, sweetners, perfuming agents, flavouring agents, coloring agents, administration aids, or combinations thereof.

36. The composition according to claim 32 where the diluent is selected from sodium carbonate, calcium carbonate, sodium phosphate, calcium phosphate, lactose, or combinations thereof.

37. The composition according to claim 32 where the osmotic agent is selected from sodium chloride, glycerol, sorbitol, xylitol, glucose, or combinations thereof.

38. The composition according to claim 32 where the binder is selected from acacia gum, starch, gelatin, sucrose, polyvinylpyrrolidone (Providone), sorbitol, or tragacanth methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, ethylcellulose, or combinations thereof.

39. The composition according to claim 32 where the filler is selected from calcium phosphate, glycine, lactose, maize-starch, sorbitol, sucrose, or combinations thereof.

40. The composition according to claim 32 where the lubricant is selected from magnesium stearate or other metallic stearates, stearic acid, polyethylene glycol, waxes, oils, silica and colloical silica, silicon fluid, talc, or combinations thereof.

41. The biologically acceptable material according to claim 32 where the flavoring agent can be peppermint, oil of wintergreen, fruit flavoring, or combinations thereof. 42. A method for treating a subject, comprising,

providing an effective amount of a compound according to claim 1, or a composition comprising the compound; and

administering the compound or composition to the subject. 43. The method according to claim 42 where the subject is a human.

44. The method according to claim 42 where the compound or composition is administered prophylactically. 45. The method according to claim 42 where the effective amount is from greater than 0 to about 1000 mg/kg body weight per day.

46. The method according to claim 42 where the effective amount is from greater than 0 to about 10 mg kg body weight per day.

47. The method according to claim 42 where the effective amount is from greater than 0 to about 5 mg/kg body weight per day.

48. The method according to claim 42 where the effective amount is from greater than 0 to about 0.5 mg kg body weight per day.

49. The method according to claim 42 where the compound or composition is administered in single or multiple doses.

50. The method according to claim 42 where administering comprises oral, rectal, nasal, topical (including buccal and sublingual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration, or combinations thereof.

51. A method of making a bicyclic compound, comprising:

providing a starting material; and

converting the starting material to a roduct having a first formula

a second formula

a third formula

or a fourth formula

where V, V_a, V_b, and V_c are selected from CRⁿR¹², C(R^H)₂, C(R¹³)₂, SO₂, SO, S, O, NR^{1 1}, CO, and Se; W is selected from CR¹⁰, CRⁿ, nitrogen, and any combination thereof; R¹ is selected from CO₂H, (CH₂)_nCO₂H, (CH₂)_nOH, tetrazolyl, SO₂H, SO₃H,

PO₃H₂, esters, amides, anhydrides and other protected forms thereof; R² is selected from OH, H, (CH₂)_nZH, where Z is selected from O, S, Se, and NR¹¹; R³ and R⁴ independently are selected from hydrogen, alkyl, branched alkyl, aryl or heteroaryl; R⁵ is selected from N¾, (CH₂)_nN(Rⁿ)_m(H)_(2-m), (CH₂)nNHC(0)(Rⁿ),

(CH₂)_nNC(=NRⁿ)N(R^u)_m(H)₍₂._m), (CH₂)_nNHC(0)Z(R^u), (CH₂)_nZH, where Z is selected from O, S, Se, and NR¹¹; guanidino, substituted guanidino, alkyl, branched alkyl, cyclic alkyl, aryl and heteroaryl; R⁶ is H, alkyl and (CH₂)_nOH; R⁷ and R⁸ independently are selected from H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, (CH₂)_nY, (CH)₂ZH, [CH₂]_n[CH(ZH)]_mCH₂ZH, [CH₂]_n[CH(ZH)]_mCH₂Y, where Y is selected from aryl, heteroaryl, alkyl, cyclic alkyl, amino and guanidino, and Z is selected from O, S, Se, or NR^{1 x}; R⁹ is selected from H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, 0(Rⁿ)_m, S(Rⁿ)_m, and N(Rⁿ)_m(H)_(2-m); R¹⁰ is selected from H, alkyl and (CH₂)_nOH; R^{1 1} is selected from H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, and any combination thereof; R¹² is selected from H, (CH₂)_nZH,

(CH₂)_nZRⁿ, (CH₂)_nZ(CO)Rⁿ, (CH₂)_nZ(S0₂)Rⁿ, (CH₂)_nZ(CO)NH₂, (CH₂)_nZ(CO)ORⁿ, or (CH₂)_nZ(CNH)NH₂, and Z is selected from O, S, Se, or NR^{1 1} ; R¹³ is selected from H, alkyl, branched alkyl, cyclic alkyl, aryl, heteroaryl, a heteroatom-containing moiety, and any combination thereof; n = 0, 1 or 2; and m = 0, 1 or 2.

52. The composition according to claim 50 where the heteroatom-containing moiety is selected from aldehyde, anhydride, acyl halide, carbonate, carboxyl, carboxylate, ether, ester, hydroxyl, ketone, silyl ether, peroxy, hydroperoxy, phosphate, phosphoryl, phosphodiester, phosphine, thiol, thioether/sulfide, disulfide, sulfinyl, sulfonyl, carbonothioyl, sulfmo, sulfo, thiocyanate, isothiocyanate, oxazole, oxadiazole, imidazole, triazole, tetrazole, amine, amide, azide, azo, cyano, isocyanate, imide, nitrile, isonitrile, nitro, nitroso, nitromethyl, selenol, guanidino, and substituted guanidino;

53. The method according to claim 51 where R¹ and R² together represent a carbonyl.

54. The method according to claim 51 where R³ and R⁴ together represent a cyclic alkyl group or a carbonyl.

55. The method according to claim 51 where R⁵ and R¹ together form a lactam or lactone.

56. The method according to claim 51 where R⁷ and R⁸ together represent a cyclic alkyl group. 57. The method according to claim 51 where V_a is CR¹ 'R¹², C(R^{J 1})₂, or

C(R¹³)₂, and any one of R^{1 1} , R¹², or R¹³ together with R⁵ form a lactam or lactone.

58. The method according to claim 51 where V_c is CR^{1 2}, C(R^! ')₂, C(R¹³)₂, and any one of R^U , R¹², or R¹³ together form a cyclic alkyl.

59. The method according to claim 51 where V_b is CR^{1 ]}R¹², C(R^{] ]})₂, or C(R¹³)₂, and any one of R¹ ', R¹², or R¹³ together with R¹ form a lactam or lactone.

60. The method according claim 51 formulated as a pharmaceutically acceptable salt.

61. The method according to claim 51 where converting comprises:

oxidizing a cyclic diene with a first oxidant to produce a first intermediate; exposing the first intermediate to a base to make the bicyclic intermediate having a formula

oxidizing the bicyclic intermediate with a second oxidant.

62. The method according to claim 61 where the cyclic diene comprises at least eight carbon atoms.

63. The method according to claim 61 where the cyclic diene is

cyclooctadiene.

64. The method according to claim 61 where the first oxidant is selected from a peracid.

65. The method according to claim 61 where the second oxidant is a metal- containing oxidant or an organic oxidant. 66. The method according to claim 51 where converting comprises:

exposing an acidic cyclic compound comprising an olefin, and a cyclic or acyclic, heteroatom-containing dialkylidene to a base to make the bicyclic intermediate.

67. The method according to claim 66 where the acidic cyclic compound comprises a sulfone.

68. The method according to claim 66 where the heteroatom-containing dialkylidene is selected from a dialkylidene ketone or a dialkylidene sulfoxide. 69. The method according to claim 66 where the acidic cyclic compound is a sulfone, and further comprising:

alkylating the bicyclic intermediate at a position alpha to a sulfone moiety; oxidatively cleaving an exocyclic olefin to form an aldehyde; and

oxidizing the aldehyde to the carboxylic acid.

70. The method according to claim 69 where oxidatively cleaving comprises using ozonolysis.

71. The method according to claim 66 where the acidic cyclic compound is a sulfone, and further comprising:

oxidatively cleaving an exocyclic olefin to form an aldehyde; and

oxidizing the adlehyde to a carboxylic acid.

72. The method according to claim 51 where the bicyclic compound is

73. A method for making a bicyclic compound, comprising:

oxidizing cyclooctadiene with peracetic acid to make an oxidized

cyclooctadiene; treating the oxidized cyclooctadiene with a base to form a bicyclic intermediate having a structure

oxidizing the bicyclic intermediate with selenium dioxide or C0₃-pyridine.

74. A method for making a bicyclic compound, comprising:

exposing butadiene sulfone and a dialkylidene ketone to a base to form a bicyclic intermediate having a structure