ALKENYLDIARYLMETHANES HAVING NITROGEN-CONTAINING CARBOXYLIC

ACID DERIVATIVES

CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. provisional patent application Serial No. 60/920,163 filed March 27, 2007, the disclosure of which is hereby incorporated by reference.

TECHNICALFIELD

The invention described herein relates to compositions useful for treating viral diseases. In particular, the compounds described herein are useful for treating acquired immunodeficiency syndrome (AIDS), and/or human immunodeficiency virus (HTV) infection.

BACKGROUND

The human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS), was identified in the early 1980s. The AIDS epidemic has spread throughout the world and today an estimated 39.5 million people are living with

HIV/AIDS (see, UNAIDS/World Health Organization 2006 AIDS Epidemic Update, December 2006, UNAIDS/World Health Organization, Geneva). The potent therapeutic agents that have been developed to combat the progression of ADDS are based on four classes of drugs: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and fusion inhibitors (enfuvirtide). Treatment with combinations of these antiviral agents that target the viral enzymes reverse transcriptase (RT) and protease, termed highly active anti-reteroviral therapy (HAART), has been more successful than monotherapeutic regimens (see, De Clercq, E. Highlights in the Development of New Antiviral Agents. Mini Rev. Med. Chem. 2:163-175 (2002)). However, complications with drug toxicity and multidrug resistance often result after prolonged therapy. In contrast, NNRTIs may have the advantage that they are minimally toxic. Even so, the risk of the development of NNRTI resistance remains as a potential issue.

As an essential viral enzyme, HIV-I RT is one of the major targets of the antiretro viral drug therapies that are used in the treatment of AIDS. It has been reported that NNRTIs inhibit the enzyme by occupation of an induced allosteric binding site very close to the active site (see generally, De Clercq, E. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Past, Present, and Future. Chem. Biodiversity 2004, 1, 44-64; Esnouf et al. Mechanism of Inhibition of Reverse Transcriptase by Nonnucleoside Inhibitors. Nat. Struct.

Biol. 1995, 2, 303-308). However, the emergence of resistant HIV viral strains is a limitation for all therapeutic classes. Cross-resistance has been reported among the approved drugs nevirapine, delavirdine, and efavirenz. Therefore, the development of new NNRTIs with fewer side effects and more favorable drug resistance profiles remains an unmet need for the future management of HIV infection.

Among NNRTIs, the alkenyldiarylmethanes (ADAMs) are highly active, may be used in combination with other drugs, such as AZT, and importantly show activity against AZT- resistant strains of HIV-I (see, Cushman etal. Synthesis and Biological Evaluation of Certain Alkenyldiarylmethanes as Anti-HIV-1 Agents Which Act as Non-Nucleoside Reverse Transcriptase Inhibitors. /. Med. Chem. 1996, 39, 3217-3227; Cushmanet al. New

Alkenyldiarylmethanes with Enhanced Potencies as Anti-HIV Agents Which Act as Non- Nucleoside Reverse Transcriptase Inhibitors. J. Med. Chem. 1998, 41, 2076-2089; Casimiro- Gracia et al. Novel Modifications in the Alkenyldiarylmethane (ADAM) Series of Non- Nucleoside Reverse Transcriptase Inhibitors. /. Med. Chem. 1999, 42, 4861-4874; and Xuet al. The Biological Effects of Structural Variation at the Meta Position of the Aromatic Rings and at the End of the Alkenyl Chain in the Alkenyldiarylmethane Series of Non-Nucleoside Reverse Transcriptase Inhibitors. J. Med. Chem. 2001, 44, 4092-4113; the disclosures of which are incorporated herein by reference).

For example, known compound Ia (see, Table 1 below) inhibited HIV-I RT with an IC ₅₀ value of <1.0 μM and displayed an EC ₅₀ value of 1.0 μM for inhibition of HIV-I ₁₁₁ B in MT-4 cells (see, Silestri et al. Design, Synthesis, Anti-HIV Activities, and Metabolic Stabilities of Alkenyldiarylmethane (ADAM) Non-nucleoside Reverse Transcriptase Inhibitors. J. Med. Chem. 2004, 47, 3149-3162; and Deng et al. Synthesis and Anti-HIV Activity of New Alkenyldiarylmethane (ADAM) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Incorporating Benzoxazolone and Benzisoxazole Rings. Bioorg. Med. Chem. 2006, 14, 2366- 2374; the disclosure of which are incorporated herein by reference). The more recently synthesized compound 2 includes an oxazolone replacement for one of the methyl esters and an adjacent methyl ether present in Ia (see, Cushman et al. Synthesis and Biological Evaluation of an Alkenyldiarylmethane (ADAM) Which Acts as a Novel Non-nucleoside HIV-I Reverse Transcriptase Inhibitor. Bioorg. Med. Chem. Lett. 1995, 5, 2713-2716). Compound 2 showed potent anti-fflV-1 activity, with EC ₅₀ values of 0.03 μM (fflV-l _RF in CEM-SS cells) and 0.09 μM (HIV-I πi _B in MT-4 cells). Also, compound 2 was active against HIV-I RT with an IC ₅₀ = 0.02 μM. However, the methyl ester moieties of currently known ADAM compounds may be hydrolyzed to biologically inactive acids by non-specific esterases present in blood plasma.

Therefore, a need remains for the discovery of more stable analogs and derivatives of these ADAM esters.

SUMMARY OF THE INVENTION

Described herein are compounds useful for treating viral diseases, and methods for treating viral diseases. In addition, described herein are processes for preparing the compounds useful for treating viral diseases. The compounds described herein include one or more pharmacologically active replacements for the methyl esters present on the aryl rings and side chains of known ADAM compounds. Such replacements may also be bioisosteres.

In one illustrative embodiment, alkenyldiarylmethanes of the general formula (I) are described

(D and pharmaceutically acceptable salts thereof; wherein

Ar ¹ and Ar ² are each independently selected from the group consisting of optionally substituted monocyclic aryl and optionally substituted bicyclic aryl; double bond (a) is a E-double bond or a Z-double bond; n is an integer in the range from 1 to about 5; and

Z is a nitrogen-containing carboxylic acid derivative, including a heteroaryl derivative. In one illustrative aspect of the compounds described herein, the groups Ar ¹ and

Ar ² are the same. In another aspect, the groups Ar ¹ ands Ar ² are different. In another aspect, the double bond in formula I has the E-geometry. In another aspect, the double bond in formula I has the Z-geometry. In another aspect, the group Z is an ester, such as an optionally substituted alkyl or optionally substituted aryl ester. In another aspect, when Z is a methyl ester, at least one of Ar ¹ and Ar ² are a monocyclic aryl substituted with an N-alkoxyimidoylhalo. In another aspect, the group Z is an optionally substituted heterocyclyl group, such as 3-methyl- 1,2,4- oxadiazol-5-yl, and the like. In another aspect, the groups Ar ¹ and Ar ² are different and the group Z is an N-alkoxyimidoyl halide. In another aspect, the integer n is 2 or 3.

In another illustrative embodiment, alkenyldiarylmethanes of the general formula (II) are described

(π) wherein Het is optionally substituted heterocyclyl, such as an oxadizaole, tetrazole, and the like, and including compounds of the following formulae wherein R is optionally substituted alkyl.

In another illustrative embodiment, alkenyldiarylmethanes where Z is a hydroxamic acid, or a derivative thereof are described, including compounds of the general formulae (III)

(III) wherein

Ar ¹ and Ar ² are each independently selected from optionally substituted monocyclic and bicyclic aryls, and aryls fused with other rings; double bond a is an E-double bond or a Z-double bond; n is an integer in the range from 1 to about 5;

X is a halo or optionally substituted alkoxy group; and R is optionally substituted alkyl.

In another embodiment, alkenyldiarylmethanes having the general formulae (V) are described

(V) wherein

Ar ¹ and Ar ² are each independently selected from optionally substituted monocyclic and bicyclic aryls; double bond a is an E-double bond or a Z-double bond; and

n is an integer in the range from 1 to about 5; and

Z' is a carboxylic acid, or an analog or derivative thereof; providing that at least one of Ar ¹ or Ar ² includes a hydroxamic acid or a derivative thereof. In another illustrative embodiment, compounds of formulae I-V described herein may be useful for treating viral diseases, such as acquired immunodeficiency syndrome (ADDS), human immunodeficiency virus (HIV) infection, and the like. In another aspect, compounds of formulae I - IV described herein may be efficacious against viral strains, such as HIV viral strains, that have become resistant to other drugs, including other alkenyldiarylmethanes, azidothymidine (AZT), nevirapine, delavirdine, efavirenz, and the like. In another aspect, compounds of formulae I-V described herein have improved metabolic stability, such as improved metabolic stability in plasma as determined by the half-life of the compounds in rat blood plasma. In another aspect, compounds of formulae I-V described herein inhibit the cytopathic effect of HIV-I reverse transcriptase. In another illustrative embodiment, methods for treating viral diseases are described. In one aspect of the methods described herein, the viral disease is attributable to HIV. In another aspect, the viral disease is responsive to enzyme inhibition, such as inhibition of HIV-I reverse transcriptase. In another aspect, compounds of formulae I-V described herein may be combined with known or conventional compounds or therapies, such as drug combinations that include one or more of the compounds described herein and other alkenyldiarylmethanes, azidothymidine (AZT), nevirapine, delavirdine, efavirenz, and the like.

In another illustrative embodiment, processes for preparing the compounds of formulae I-V are described. In one aspect, the processes include the step of preparing an aromatic methyl ether, such as a methyl ether of a phenolic hydroxyl, where the step comprises contacting the corresponding aryl alcohol with dimethylsulfate, an inorganic base, and a phase- transfer catalyst, in a biphasic solvent. In another aspect, the processes include the step of preparing a methyl ester, where the step comprises contacting the corresponding carboxylic acid with a methylating agent, in a biphasic solvent. In yet another aspect, the processes include the step of incorporating an optionally substituted heterocycle, where the step comprises contacting the corresponding carboxylic acid with acetamide oxime, a tertiary amine, an acylation catalyst, and a coupling reagent, in a solvent comprising dimethylformamide (DMF). In another aspect, the processes include the step of preparing an O-alkyl hydroxamic acid derivative, where the step comprises contacting the corresponding carboxylic acid with methoxyamine, an acylation catalyst, and a coupling reagent, in a solvent comprising DCM at room temperature. In still

another aspect, the processes include the step of preparing an N-alkoxyimidoyl halide, where the step comprises contacting the corresponding O-methyl hydroxamic acid, triphenyl phosphine (PPh ₃ ), and CCl ₄ in a solvent comprising acetonitrile at reflux. In yet another aspect, the processes include the step of preparing an N-alkoxyimidoyl halide, where the step comprises contacting the corresponding O-methyl hydroxamic acid, triphenyl phosphine (PPh ₃ ), and CBr ₄ in a solvent comprising acetonitrile at reflux.

DETAILED DESCRIPTION

In one illustrative embodiment, alkenyldiarylmethane compounds having the general formula (I) are described

I wherein Ar ¹ and Ar ² , double bond (a), integer n, and Z are as described herein.

It has been discovered that when Z in the compounds of formula I is an ester, such as a methyl ester, and/or when one or more methyl esters are present as substituents on Ar ¹ and Ar ² , such compounds exhibit short half -lives in vivo, such as in plasma due to the presence of esterase. Hydrolysis of such methyl esters gives the corresponding carboxylic acid, which has been observed to show less potency and activity than the parent esters. For example, illustrative compounds 1-3, which have a plurality of methyl esters

1c: R=Br show a short plasma half life of less than 10 minutes, and in some cases less than 1 minute.

Accordingly, described herein are compounds that include one or more replacement groups for such esters, including bioisosteres of ester groups. Such replacement groups are analogs and derivatives of esters, including heteroaryl derivatives of esters. It is appreciated that such replacement groups in the form of analogs and derivatives of esters, including heteroaryl derivatives of esters, may have longer half-lives in vivo. Such longer half-

lives are illustrated by the longer plasma half-life as described herein. In one embodiment, compounds are described herein that show a plasma half life of at least about 10 minutes, or at least about 100 minutes. In another embodiment, compounds are described herein that show a plasma half life that is about 10 times or greater than the plasma half -life of the corresponding methyl ester. In other words, where one or more methyl esters have been replaced by analogs and derivatives of esters, including heteroaryl derivatives of esters, as described herein, those compounds show such increased half-lives.

In one variation, the ester replacement is an ester analog, such as a cyclic carbamate, and the like. In another variation, the ester replacement is a hydroxamic acid or derivative thereof, such as a bromo, chloro, or fluoro N-methoxyiminyl group, and the like. In another variation, the ester replacement is a heteroaryl, such as a l,2,4-oxadiazol-5-yl, 1,3,4- oxadiazol-5-yl, or tetrazol-5yl group, and the like, each of which is optionally substituted. In another variation, the ester replacement is a ring fusion on Ar ¹ and/or Ar ² to form the corresponding oxazolone, isoxazolone, oxazole, alkoxyoxazole, or alkoxyisoxazole group, and the like. In another variation, the ester replacement is a thio derivative of an ester, including thioesters, thionoesters, and dithioesters. In another variation, the ester replacement is a cyano derivative.

Accordingly, in another embodiment, the compounds described herein include more metabolically stable inhibitors. In another embodiment, the groups Ar ¹ and Ar ² are the same. In one variation, the groups Ar ¹ ands Ar ² are different. In another embodiment, the double bond in formula I has the E-geometry. In one variation, the double bond in formula I has the Z-geometry. In another embodiment, the group Z is an ester, such as an optionally substituted alkyl or optionally substituted aryl ester, and one or both of Ar ¹ and Ar ² include at least one hydroxamic acid or derivative thereof. In one variation, Ar ¹ and/or Ar ² is a monocyclic aryl substituted with the hydroxamic acid or derivative thereof. In another embodiment, Z is not an alkyl ester. In another embodiment, the group Z is an analog of a carboxylic acid or derivative thereof, such as an optionally substituted heterocyclyl group. Illustrative optionally substituted heterocyclyl groups include oxazolidinonyl and oxazolidinon-2-yl, and the like. In another embodiment, the groups Ar ¹ and Ar ² are different and the group Z is an optionally substituted heterocyclyl group, or a hydroxamic acid or derivative thereof. In another embodiment, the integer n is 2 or 3. In another embodiment, the compounds described herein include Z that is a heteroaryl, such as a heteroaryl derivative of a carboxylic acid of the following formulae

and the like.

In another embodiment, the compounds described herein include Z that is a hydroxamic acid or derivative thereof, such as a hydroxamic acid compounds of the following formulae

in and the like, wherein Ar ¹ and Ar ² , n, and (a) are as defined herein; and X is a halo or optionally substituted alkoxy group; and R is optionally substituted alkyl.

In another illustrative embodiment, Ar ¹ and/or Ar ² are bicyclic,such as a fused phenyl compound of the formulae where W is independently selected in each instance from N, O, and S, and where each of the above formulae is optionally substituted, vsuch as a substituent at a carbon, nitrogen, oxygen, or sulfur atom.

In another illustrative embodiment, alkenyldiarylmethanes of the general formulae (IV) are described

wherein (a) and n are as described herein; and

Z is a nitrogen-containing carboxylic acid derivative;

R ^a represents 1, 2, or 3 substituents each independently selected from the group consisting of halo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, hydroxy, nitro, carboxylate

and derivatives thereof, thioesters, thionoesters, xanthates, cyano, carbamoyl, carboxamido, amino, alkylamino, dialkylamino, alkylalkylamino, sulfonamide, and alkylsulfonylamino;

R ^d represents 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of halo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, hydroxy, nitro, carboxylate and derivatives thereof, thioesters, thionoesters, xanthates, cyano, carbamoyl, carboxamido, amino, alkylamino, dialkylamino, alkylalkylamino, sulfonamide, alkylsulfonylamino, O-alkylhydroxamoyl, iV-alkoxyimidoylhalo; and one of bond b or bond c is a double bond, and the other of bond b or bond c is a single bond; and R ^b and R ^c are each an optionally substituted alkyl; providing that when bond b is a double bond, R ^b is absent; and when bond c is a double bond, R ^c is absent.

In one variation, R ^a represents 1 or 2 substituents, or only 1 substituent. In another variation, R ^d represents 1, 2, or 3 substituents. In another variation, R ^d represents cyano. In another variation, R ^d represents 3 substituents.

In another embodiment, alkenyldiarylmethanes having the general formulae (V) are described

(Va) wherein Ar ¹ , Ar ² , (a), and n are as defined herein; providing that at least one of Ar ¹ or Ar ² includes a hydroxamic acid or a derivative thereof.

In another aspect, geometrically isomeric compounds are described, wherein Ar ¹ and Ar ² are different. Illustratively, separate isomers may be prepared, as is illustrated for (E)-5 and (Z)-5.

As used herein, the term "optionally substituted monocyclic and bicyclic aryls" includes an aromatic mono or bicyclic ring of carbon atoms, such as phenyl, naphthyl, and the

like, and to an aromatic mono or bicyclic ring of carbon atoms and at least one heteroatom selected from nitrogen, oxygen, and sulfur, such as pyridinyl, pyrimidinyl, indolyl, benzoxazolyl, benzisoxazolyl, benzoxazolinonyl, benzisoxazolinonyl, and the like, which may be optionally substituted with one or more independently selected substituents, such halo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, hydroxy, nitro, carboxylate and derivatives thereof, cyano, carbamoyl, carboxamido, amino, alkylamino, dialkylamino, alkylalkylamino, sulfonamide, and alkylsulfonylamino. In one aspect, substituted monocyclic and substituted bicyclic aryls include those compounds having at least one halo (e.g., fluoro) group, haloalkyl group, or halalkoxy group. In another aspect, substituted monocyclic and substituted bicyclic aryls do not include a carboxylate or derivative thereof. In another aspect, substituted monocyclic and substituted bicyclic aryls include those compounds having a cyano group.

As used herein, the term "alkyl" includes a saturated monovalent chain of carbon atoms, which may be optionally branched. It is understood that in embodiments that include alkyl, illustrative variations of those embodiments include lower alkyl, such as C ₁ -C ₆ , Ci-C ₄ alkyl, methyl, ethyl, propyl, 3-methylpentyl, and the like.

As used herein, the term "hydroxamic acid derivative" includes radicals of the general formula -CONH-OR ¹ , -CONR'-OH, -CONR'-OR', -C(OR')=N-OH, and -C(OR')=N- OR', and -C(X)=N-OR', where R' is in each instance an independently selected optionally substituted alkyl, and X is halo. As used herein, the terms "iV-alkoxyiminylhalo" and 'W-alkoxyiminyl halide" include the general formula -C(X)=N-OR', wherein R' is optionally substituted alkyl, and X is halo.

As used herein, the term term "heterocyclyl" includes a monovalent chain of carbon and heteroatoms, wherein the heteroatoms are selected from nitrogen, oxygen, and sulfur, a portion of which, including at least one heteroatom, form a ring.

As used herein, the term "alkylamino" includes monoalkylamino and dialkylamino, where the amino group is in each instance independently selected. Accordingly, it is to be understood that dialkylamino includes alkylalkylamino where the amino is substituted with two different alkyl groups, and illustratively includes methylamino, dimethylamino, methylethylamino, and the like.

In another illustrative embodiment, processes for preparing the compounds of formulae I-V are described. In one aspect, the processes include the step of preparing an aromatic methyl ether, such as a methyl ether of a phenolic hydroxyl, where the step comprises contacting the corresponding aryl alcohol with dimethylsulfate, an inorganic base such as

potassium carbonate, sodium hydroxide, and the like, and a phase-transfer catalyst, such as a tetraalkylammoniura halide, in a biphasic solvent comprising dichloromethane (DCM) and water.

In another embodiment, the processes include the step of preparing a methyl ester, where the step comprises contacting the corresponding carboxylic acid with a methylating agent, such as (trimethylsilyl)diazomethane (TMSCHN ₂ ), in a biphasic solvent comprising toluene and methanol. In another embodiment, the processes include the step of incorporating an optionally substituted heterocycle, such as 3-methyl-l,2,4-oxadiazole, where the step comprises contacting the corresponding carboxylic acid with acetamide oxime, a tertiary amine, such as diisopropylethylamine (DIPEA), an acylation catalyst, such as N-hydroxybenzotriazole (HOBt), and a coupling reagent, such as TBTU, in a solvent comprising dimethylformamide (DMF).

In another embodiment, the processes include the step of preparing an O-alkyl hydroxamic acid derivative, such as an O-methyl hydroxamic acid, where the step comprises contacting the corresponding carboxylic acid with methoxyamine, an acylation catalyst, such as N,N-dimethylaminopyridine (DMAP), and a coupling reagent, such as EDCI, in a solvent comprising DCM at room temperature. In another embodiment, the processes include the step of preparing an N-alkoxyiminyl halide, such as an N-methoxyimidoyl chloride, where the step comprises contacting the corresponding 0-methyl hydroxamic acid, triphenyl phosphine (PPh ₃ ), and CCl ₄ in a solvent comprsing acetonitrile at reflux. In another embodiment, the processes include the step of preparing an N-alkoxyimidoyl halide, such as an N-methoxyimidoyl bromide, where the step comprises contacting the corresponding O-methyl hydroxamic acid, triphenyl phosphine (PPh ₃ ), and CBr ₄ in a solvent comprsing acetonitrile at reflux.

In another embodiment, the processes include the step of preparing a compound of the formula

wherein n is an integer in the range from 1 to about 5; Ar ¹ is selected from optionally substituted monocyclic and bicyclic aryls; R is an alkyl group, such as n-butyl, and Z is a carboxylic acid derivative or an analog thereof, where the step comprises slowly contacting a dilute solution of a metal catalyst, such as Pd(PPh ₃ ) ₄ , Pd(PPh ₃ ^Cl ₂ , and the like, and a compound of the formula

with a trialkyltin hydride. The step proceeds with high regioselectivity and high geometric or stereoselectivity.

In another embodiment, the processes include the step of preparing a compound of the formula

wherein n is an integer in the range from 1 to about 5; Ar ¹ and Ar ² are each independently selected from optionally substituted monocyclic and bicyclic aryls, and Z is a carboxylic acid derivative or an analog thereof, where the step comprises contacting a solution comprising toluene at reflux, a compound of the formula Ar ² -L, where L is a leaving group such as a halo, trialkylstannnyl, boronyl, and the like, a metal catalyst, such as Pd(P(t-Bu) ₃ ) ₂ , and the like, CsF, and a compound of the formula

wherein n is an integer in the range from 1 to about 5; Ar ¹ is selected from optionally substituted monocyclic and bicyclic aryls; R is an alkyl group, such as n-butyl, and Z is a carboxylic acid derivative or an analog thereof.

It is to be understood that each of these aspects and variations of the various illustrative embodiments described herein may be combined as additional illustrative embodiments. For example, illustrative embodiments of the compounds of formulae I-V may include those aspects wherein the double bond has the E-geometry and Z is a iV-alkoxyimidoyl halide. In addition, illustrative embodiments of the compounds of formulae I - IV may include those aspects wherein the double bond has the Z-geometry, and Z is an optionally substituted heterocyclyl group. In addition, illustrative embodiments of the methods described herein may include those aspects wherein the viral disease is AIDS, and the method also includes the step of adding another protease inhibitor, such as AZT. It is to be understood that the additional step may be separate in time from the step of adding a compound of formulae I-V; or may be contemporaneous or simultaneous. Further, it is to be understood that in the contemporaneous

or simultaneous variation the compounds may be combined. In addition, illustrative embodiments of the processes described herein may include those aspects wherein the step of preparing a compound of the formula

is followed by the step of preparing a compound of the formula

wherein Ar ¹ , Ar ² , n, R, and Z are as defined herein.

In another illustrative embodiment, processes for preparing alkenyldiarylmethane compounds of formulae I-V are described. Illustratively, compounds of formulae I-V may be prepared by the general synthesis shown in the following scheme, and illustrated for the preparation of compounds of formula I where n is 3 and Z is as defined herein, such as a carboxylic acid analog or derivative, or a heteroaryl group.

75 76 77 79

(a) Ar ¹ J (74), Sonogashira coupling (cat. PdCl ₂ (PPh ₃ ) ₂ , cat. CuI, Et ₃ N, THF, it); (b) Bu ₃ SnH, Pd(PPh ₃ ) ₄ , 0 ⁰ C to rt; (c) Ar ² -I (78), Stille coupling (cat. CuI or 1 equiv. CuI, cat. Pd(PPh ₃ ) ₄ ,

CsF, DMF, 60 ⁰ C).

Sonogashira coupling of a terminal alkyne 75 with an aryl halide, Ar ¹ -X (74), yields the disubstituted alkyne 76. Hydrostannylation of alkyne 76 with tri-n-butyltin hydride in the presence of Pd(PPh ₃ ) ₄ affords the regiochemically and stereochemically defined vinylstannane 77, that undergoes a Stille cross-coupling with an aryl halide, Ar ² -X (78), to give the desired target compounds of formula I (79). It is appreciated that other compounds described herein may be prepared in an analogous manner, such as compounds wherein n is other than 3.

The conditions reported for all reactions in the above scheme are general and provide the desired products in good yields (typically >70% in most cases), regardless of the substrates used. With respect to the Stille coupling, it was found that the cross-coupling could

be performed in the presence of copper(I) iodide in either catalytic or stoichiometric amounts; however, the two conditions required reaction times of 4-24 hours (depending on the substrates) or 15 minutes, respectively. Although copper is a heavy metal and use of its associated reagents in excess amounts should be avoided due to toxicity concerns, the Stille couplings were performed on sufficiently small scale that using stoichiometric amounts of the metal did not present a significant hazard. As such, the majority of the Stille couplings utilized a full equivalent of copper(I) iodide in an effort to enhance coupling yields and reaction times.

Additional details regarding Sonogashira coupling, hydrostannylation, and Still cross-coupling are found in Deng et al. Synthesis, Anti-HIV Activity, and Metabolic Stability of New Alkenyldiarylmethane HIV-I Non-Nucleoside Reverse Transcriptase Inhibitors. /. Med. Chem. 2005, 48, 6140-6155; Deng et al. Bioorg. Med. Chem. 2006, 14, 2366-231 A; and Deng et al. Replacement of the Metabolically Labile Methyl Esters in the Alkenyldiarylmethane Series of Non-Nucleoside Reverse Transcriptase Inhibitors with Isoxazolone, Isoxazole, Oxazolone, or Cyano Substituents. J. Med. Chem. 2006, 49, 5319-5323, the disclosure of each of which is incorporated herein by reference.

Illustrative groups Ar-I (which may be used as Ar ¹ -I or Ar ² -I) include:

80 81 82 83

84 85 86 87 where the syntheses of intermediates 80, 82, 83, and 85 have been previously reported and benzonitriles 86 and 87 are commercially available. Details regarding the syntheses of intermediates 80, 82, 83, and 85 are found in Deng et al. J. Med. Chem. 2005, 48, 6140-6155, and Deng et al. Bioorg. Med. Chem. 2006, 14, 2366-231 '4, the disclosure of each of which is incorporated herein by reference. The syntheses of aryl intermediates 81 and 84 and the alkyne intermediates 95-98, are described in the following scheme.

80 88 81

89 90 84

(a) KOH, MeOH, reflux; (b) 1: SOCl ₂ , reflux, 2: NaSMe, PhH, rt; (c) H ₂ NOH-HCl, KOH,

EtOH, reflux; (d) PPh ₃ , DIAD.

Thioester 81 was achieved through another aryl building block, ester 80. Saponification of 80 was effected through heating a mixture of the ester and potassium hydroxide in methanol at reflux to afford benzoic acid 88. Treatment of acid 88 with thionyl chloride to obtain the corresponding acyl chloride intermediate, followed by esterification with sodium thiomethoxide in benzene afforded thioester 81. Synthesis of isoxazole 84 began with formation of oxime 90 from salicylic aldehyde 89 via condensation with hydroxylamine. Cyclization of oxime intermediate 90 was accomplished with triphenylphosphine and DIAD to afford isoxazole 84. Alkynes 97-100 were synthesized from their corresponding nitriles, 91 and 92, via tetrazole intermediates, as shown in the following scheme

(C) 99: n=1 100: n=2

(a) NaN ₃ , Et ₃ N-HCl, PhMe, reflux; (b) cat Bu ₄ NBr, Na ₂ CO ₃ , Me ₂ SO ₄ , EtOAc'H ₂ O; (c) Ac ₂ O, reflux. by treatment of commercially available nitriles 91 and 92 with triethylamine hydrochloride and sodium azide to give the cycloaddition products 93 and 94, respectively. The tetrazole

intermediates 93 and 94 served as common precursors for both the methylated tetrazole and oxadiazole-bearing side chains via application of different reaction conditions. Alkylation of tetrazoles 93 and 94 proceeded with dimethyl sulfide and potassium carbonate under biphasic catalysis conditions to afford mixtures of the IH and 2H methylated products (95 mixed with 97 and 96 mixed with 98), which were separated via chromatography on silica and distinguished by η NMR shifts of the methyl groups. Alternatively, a mixture of acetic anhydride and tetrazole 93 or 94 could be heated at reflux to obtain the desired oxadiazole intermediates 99 and 100, respectively.

In another illustrative embodiment, alkenyldiarylmethane compounds of formulae I-V may be prepared by the general synthesis shown in the following scheme, and illustrated for compounds 4 and 5.

(a) PdCl ₂ (PPh ₃ ) ₂ , CuI, TEA, THF, room temperature, 12 h; (b) Bu ₃ SnH, Pd(PPh ₃ ) ₄ , THF, room temperature, 2 h; (c) LiOH, dioxane-H ₂ O (6:1), 60 ⁰ C, 22 h; (d) H ₂ NOMe, EDCI, DMAP, CH ₂ Cl ₂ , room temperature, 15 h; (e) Pd(PPh ₃ ) ₄ , CuI, CsF, DMF, 60 ⁰ C, 0.5 h; (f) TFA-CH ₂ Cl ₂ (1 : 1), O ⁰ C, 3 h; (g) H ₂ NOMe, EDCI, DMAP, CH ₂ Cl ₂ , room temperature, 24 h; (h) PPh ₃ , CCl ₄ ,

CH ₃ CN, reflux 3.5 h; (i) PPh ₃ , CBr ₄ , CH ₃ CN, reflux, 2 h.

The functional groups, N-methoxy iminyl chloride and bromide, are introduced after the construction of the compound framework in order to avoid the risk of Pd-catalyzed reactions with the iminyl halides. The syntheses of intermediates 16 and 21, which are the precursors of the two aromatic rings of compounds 4 and 5, have been previously reported. Details regarding the syntheses of intermediates 16 and 21 are found in Deng et al. /. Med. Chem. 2005, 48, 6140- 6155; and Deng et al. Bioorg. Med. Chem. 2006, 14, 2366-2374, the disclosure of each of which is incorporated herein by reference. The Sonogashira coupling of starting materials 15 with 16 and the hydrostannation of 17 were carried out on large scale. Chemoselective cleavage of methyl ester 18 with LiOH in dioxane-H ₂ O afforded the corresponding carboxylic acid 19.

Subsequent EDCI-promoted coupling of 19 with methoxyamine gave 0-methylhydroxamic acid 20.

In the next step, the Stille coupling of 20 with 21 was attempted using the reaction conditions previously described by Mee et al. The significant feature of their conditions is that addition of a catalytic amount of cuprous iodide accelerates the reaction rate in a highly polar solvent, such as DMF. However, in the case of the reaction of 20 with 21, no reaction was

observed, probably due to the chelation of the 0-methylhydroxamic acid group of 20 and the neighboring methoxy group to Pd ^π -complexes. In this case, the Omethylhydroxamic acid group could be deprotonated by cesium fluoride and act as a ligand for palladium. Additional details regarding the use of palladium are found in Trost & Dong New Class of Nucleophiles for Palladium-Catalyzed Asymmetric Allylic Alkylation. Total Synthesis of Agelastatin A. J. Am. Chem. Soc. 2006, 128, 6054-6055, the disclosure of which is incorporated herein by reference. In order to improve this reaction, 1.2 equivalents of cuprous iodide were used. Surprisingly, addition of a large amount of cuprous iodide afforded the coupling product 22 quantitatively. The tert-butyl protecting group of 22 was removed with trifluoroacetic acid to give carboxylic acid 23. EDCI-coupling of 23 with methoxyamine provided di-0- methylhydroxamic acid 24. Finally, chlorination of 24 with PPh ₃ -CCl ₄ afforded compound 4 in 71% yield. Similarly, bromination of 24 with PPh ₃ -CBr ₄ was attempted. However, the reaction unfortunately afforded a nearly equimolar mixture of mixture of Z and E isomers of compound 5 in 75% yield. The isomeric mixture was tested for anti-HTV activity because its separation by column chromatography was unsuccessful.

In another illustrative embodiment, alkenyldiarylmethane compounds of formulae I-V may be prepared by the general synthesis shown in the following scheme, and illustrated for compounds 6 and 7.

(a) DAST, CH ₂ Cl ₂ , 0 ⁰ C, 0.5 h; (b) TMSOTf, TEA, dioxane, room temperature, 2 h; (c) acetamide oxime, TBTU, HOBt, DIPEA, DMF, room temperature, 0.5 h, then heated at 110 ⁰ C,

3 h (d) TMSCHN ₂ , toluene-MeOH (2:1), room temperature.

Fluorination of 22 with DAST afforded imidoyl fluoride 25. Cleavage of the tert-butyl ester of 25 was achieved using TMSOTf-Et ₃ N to give carboxylic acid 26. Details regarding the use of TMSOTf-Et ₃ N are found in Trzexciak, A.; Bannworth, W. Selective Cleavage of tert-Butyl Esters in the Presence of tert-Butyl Ethers. Application to the Synthesis of tert-Butoxy Amino Acids. Synthesis, 1996, 1433-1434, the disclosure of which is incorporated herein by reference. Compound 6, incorporating the 3-methyl-l,2,4-oxadiazole system, was synthesized in 46% yield from carboxylic acid 26 and acetamide oxime using TBTU. Details regarding the use of TBTU are found in Poulain et al. Parallel Synthesis of 1,2,4-Oxadiazoles from Carboxylic Acids Using an Improved, Uronium-Based, Activation. Tetrahedron Lett. 2001, 42, 1495-1498, the disclosure of which is incorporated herein by reference. Acid 26 was converted into compound 7 with TMSCHN ₂ in 82% yield.

In another embodiment, processes for preparing compounds of formula V are described. In one aspect, compounds of formula V may be prepared by the general synthesis shown in the following scheme.

(a) TsCl/pyridine, <20 ⁰ C; or KOH, THF-H ₂ O, room temperature; (b) 2-oxazolidinone, K ₂ CO ₃ ,

Bu ₄ NBr, toluene, reflux; (c) TMSCHN ₂ , MeOH, benzene, room temperature; or dimethyl sulfate, K ₂ CO ₃ , Bu ₄ NBr, CH ₂ Cl ₂ -H ₂ O, room temperature; (d) NaI, NaOH, NaOCl, 0-3 ⁰ C; (e)

Ar ¹ -I, PdCl ₂ (PPh ₃ ) ₂ , Cu(I)I, Et ₃ N, THF, room temperature. Commercially available 3-butyn-l-ol was converted to the corresponding tosylate, which reacted with 2-oxazolidinone to afford the alkylated intermediate. The Sonogashira coupling of the terminal alkyne with an aryl halides Ar ¹ -X yields the disubstituted alkyne. The hydrostannylation of the dialkyne with tri-n-butyltin hydride in the presence of Pd(PPh ₃ ) ₄ affords the regiochemically and stereochemically defined vinylstannane, that undergoes a Stille cross-coupling with the aryl halides Ar ² -X to give the desired target compounds of formula V. Additional synthetic details are described in PCT international Pub. No. WO 2007/005531, the disclosure of which is incorporated herein by reference. The following illustrative compounds

were prepared as described herein, where n is 2 or 3, where Ar ¹ and Ar ² are selected from:

A1 A2 A3 A4

A10 A11 A12 A13

A14 A15 and where Z is selected from CO ₂ H, CO ₂ Me, and CO ₂ (tBu), and from radicals of the formula:

I

N^CI N^Br HN 0

OMe OMe OMe OMe

Z1 Z2 Z3 Z10

Z4 Z5 Z6 Z7 Z8 Z9

In another embodiment, the following compounds of formula (I) may be prepared according to the processes described herein:

In another embodiment, the following compounds of formula (V) may be prepared according to the processes described herein:

In another illustrative embodiment, combination therapies are described, wherein the compounds described herein are combined with other known or conventional drugs or therapies. A number of HIV-I strains containing AZT resistance mutations have shown increased sensitivity to alkenyldiarylmethane compounds, such as those compounds described herein, indicating a possible therapeutic role for those compounds in combination with AZT (see, Cushman et al. J. Med. Chem. 1998, 41, 2076-2089, the disclosure of which is incorporated herein by reference). Alkenyldiarylmethane compounds have been found to inhibit the cytopathic effect of HIV-I in cell culture at low nanomolar concentrations, some with EC ₅₀ values of about 0.02 μM to about 0.21 μM for inhibition of the cytopathic effect of HTV-I _RF in CEM-SS cells, and IC ₅₀ values of from about 0.074 μM to about 0.499 μM for HIV-I RT with rCdG as the template primer.

EXAMPLES

Unless noted otherwise, ¹ H and ¹³ C NMR spectra were recorded using CDCl ₃ as the solvent and internal standard at 300 MHz and 75 MHz, respectively. In the cases where a solvent other than CDCl ₃ was utilized the alternative solvent was used as the internal standard, with the calibration set according to the residual solvent peak. ¹⁹ F NMR spectra were obtained at 282 MHz in CDCl ₃ , and chemical shifts are reported in δ values, relative to CF ₃ CO ₂ H at δ 0.00 ppm. IR spectra were recorded using a Perkin-Elmer 1600 series FT-IR. Flash chromatography was performed with 230-400 mesh silica gel and TLC was carried out using Baker-flex silica gel IB2-F plates of 0.25 mm thickness. Preparative TLC separations utilized Analtech Uniplates with glass supported silica (20 x20 cm, 2000 micron thickness) and UV indicator (254 nm). Melting points are uncorrected. Unless otherwise stated, chemicals and solvents were of reagent grade and used as obtained from commercial sources without further purification. Anhydrous tetrahydrofuran was prepared by distillation from sodium ketyl. Lyophilized rat plasma (lot 065K7555) was obtained from Sigma Chemical Co., St. Louis, MO. Microanalyses were performed at the Purdue Microanalysis Laboratory. All yields refer to yields of isolated compounds. The hydrolytic stability assay utilized lyophilized rat plasma (LOTs 052K7609 and 065K7555) from Sigma Chemical Co., St. Louis, MO. High resolution mass spectra for all ionization techniques were obtained from a FinniganMAT XL95. Analytical HPLC analyses performed to aide in the establishment of compound purity were completed on a Waters binary HPLC system (Model 1525, 20 μL injection loop) equipped with a Waters dual wavelength absorbance UV detector (Model 2487) set for 254 nM. The mobile phases consisted of 8:2 (v/v) acetonitrile-water or and the Symmetry ^® HPLC column (4.6 mm x

150 mm) was packed with C ₁₈ Silica from Waters. The structures of all of the intermediates for the general synthetic schemes that are referenced in experimental procedures, but are not explicitly shown in the body of the application, can be found in published literature.

General Procedure for the Synthesis of Alkenyldiarylmethanes via Stille Cross- Coupling of Stannanes with Aryl Halides. A mixture of stannane 77 (1 equiv) and aryl halide 78 (1.2 equiv) in anhydrous DMF (2-3 mL) was sparged with argon for 10 min and maintained under an argon atmosphere. Cesium fluoride (3.5 equiv), Pd(PPh ₃ ) ₄ (0.1 equiv), and copper(I) iodide (0.2-1 equiv) were quickly added to the reaction mixture, which was again placed under an argon atmosphere. The reaction mixture was allowed to stir at 60 ⁰ C, under an argon atmosphere, for 1-24 h until the stannane starting material had been consumed. The system was allowed to cool to room temperature and the reaction mixture was sonicated at room temperature for 30 sec, after being diluted with a mixture of ethyl acetate (5 mL), methanol (1 mL), and water (1 mL). The reaction mixture was loaded onto a short column of silica (10-20 mL) and the products were eluted with ethyl acetate (50-75 mL). The eluate was then washed with a basic, aqueous solution (pH = 10) of 1 M EDTA (2 x 20 mL) and an aqueous solution saturated with ammonium chloride (2 x 20 mL). The phases were separated and the organic phase was dried over magnesium sulfate, filtered, and condensed in vacuo to afford the crude products. The crude products were separated by column chromatography to obtain the desired product and, if necessary, additional purification methods were applied. General Procedure for the Synthesis of Stannane Intermediates via Palladium-

Catalyzed Hydrostannation of Alkynes. A solution of alkyne 76 (1 equiv) in anhydrous THF (0.02-0.05 M) was cooled in an ice bath, sparged with argon for 15 min, and maintained under an inert atmosphere at 0 ⁰ C. The catalyst, Pd(PPh ₃ ) ₄ (0.01 equiv), was added to the THF solution, followed by tributyltin hydride (1.2-1.5 equiv). The heterogeneous reaction mixture was allowed to stir at 0 ⁰ C, under an argon atmosphere, for 30 min to 2 h. If the reaction had not reached completion after approximately 2 h, the reaction mixture was allowed to warm to room temperature and stir for an additional 1-24 h. The reaction mixture was concentrated in vacuo and the remaining residue was absorbed onto silica. The products were separated by column chromatography to obtain the stannane product and, if necessary, additional purification methods were applied.

General Procedure for the Synthesis of Functionalized Alkyne Intermediates via the Sonogashira Coupling Reaction of Aryl Halides with Terminal Alkynes. A mixture of alkyne 75 (1.2-1.5 equiv), aryl halide 74 (1 equiv), and triethylamine (2.5 equiv) in anhydrous THF (0.1-0.5 M) was cooled in an ice bath, sparged with argon for 15 min, and maintained

under an inert atmosphere. After being allowed to warm back to room temperature, PdCl ₂ (PPh ₃ ) ₂ (0.1 equiv) and copper(I) iodide (0.2 equiv) were added. The heterogeneous reaction mixture was allowed to stir at room temperature, under an argon atmosphere, for 3-24 h. The reaction mixture was concentrated in vacuo, the remaining residue was absorbed onto silica. The products were separated by column chromatography to obtain the desired alkyne product and, if necessary, additional purification methods were applied. tert-Butyl 5-Hexynate (15). Di-tert-butyl-dicarbonate (29.2 g, 134 mmol) was added portionwise over 1 h to a solution of 5-hexynoic acid (5.00 g, 44.6 mmol) and 4- dimethylaminopyridine (0.550 g, 4.46 mmol) in t-BuOH (100 mL), and the reaction mixture was stirred for 2 h at room temperature. The mixture was evaporated and diluted with ethyl acetate (80 mL). The organic solvent was washed with 5% HCl (2 x 30 mL), 5% aq NaHCO ₃ (2 x 30 mL), brine (2 x 20 mL), and dried over sodium sulfate. After removal of solvent in vacuo, the residue was purified by column chromatography on silica gel using an ethyl acetate-hexanes gradient (0-10%) to afford the product 15 (4.65 g, 62%) as a colorless oil: IR (Neat) 3306, 1730, 1149 cm ^'1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.33 (t, J = 7.2 Hz, 2 H) 2.25 (dt, 7 = 7.2, 2.4 Hz, 2 H), 1.94 (t, J = 2.4 Hz, 1 H), 1.78 (q, / = 7.2 Hz, 2 H), 1.42 (s, 9 H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.31, 83.38, 80.16, 68.86, 34.11, 28.00, 27.79, 23.72, 21.36, 17.37; GC-CMS m/z (rel intensity) 169 (3, MH ⁺ ), 113 (100). Anal. Calcd for C ₁₀ Hj ₆ O ₂ : C, H.

Methyl 5-(5-tert-Butoxycarbonyl-pent-l-ynyl)-2-methoxy-3-methylbenz onate (17). A solution of alkyne 15 (1.648 g, 9.800 mmol), iodide 16 (2.500 g, 8.167 mmol), cuprous iodide (0.156 g, 0.817 mmol), and triethylamine (2.30 mL, 16.3 mmol) in THF (50 mL) was cooled to 0 ⁰ C and degassed for 10 min with argon. PdCl ₂ (PPh ₃ ) ₂ (0.585 g, 0.817 mmol) was added to the solution. After stirring for 12 h at room temperature under argon, the mixture was evaporated and diluted with ethyl acetate (15 mL). The mixture was filtered through a small pad of silica gel, concentrated, and purified by column chromatography on silica gel using an ethyl acetate-hexanes gradient (2-5%) to afford the product 17 (2.23 g, 79%) as a pale yellow oil: IR (Neat) 2973, 1731, 1256, 1215, 1148 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.65 (d, J = 2.0 Hz, 1 H), 7.34 (d, J = 2.0 Hz, 1 H), 3.88 (s, 3 H), 3.79 (s, 3 H), 2.34-2.25 (m, 4 H), 2.25 (s, 3 H), 1.84 (q, /= 7.2 Hz, 2 H), 1.43 (s, 9 H); ¹³ C NMR (75 MHz, CDCl ₃ ) δl72.43, 166.13, 157.80, 137.77, 132.84, 132.31, 124.41, 119.13, 88.99, 80.24, 79.91, 61.51, 52.16, 34.34, 28.04, 23.99, 18.70, 15.83; ESBVIS m/z (rel intensity) 369 (100, MNa ⁺ ). Anal. Calcd for C ₂₀ H ₂₆ O ₅ : C, H.

(E)-Methyl 5-(6-fert-Butoxy-6-oxo-l-(tributylstannyl)hex-l-enyl)-2-meth oxy-3- methylbenzoate (18). A solution of alkyne 17 (2.55 g, 7.36 mmol) in THF (90 mL) was cooled to 0 ⁰ C and degassed for 10 min with argon, and Pd(PPh ₃ ) ₄ (0.850 g, 0.736 mmol) was added.

Tributyltin hydride (2.93 mL, 11.0 mmol) was added dropwise to the mixture at room temperature and the reaction mixture was stirred for 2 h under argon. The mixture was evaporated and diluted with ethyl acetate (50 mL). The mixture was filtered through a small pad of silica gel, concentrated, and purified by column chromatography on silica gel using an ethyl acetate-hexanes gradient (2-4%) to afford the product 18 (4.15 g, 89%) as a colorless oil: IR (Neat) 2928, 2871, 1732, 1148, 1014 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) 5 7.16 (d, J= 2.0 Hz, 1 H), 6.85 (d, J = 2.0 Hz, 1 H), 5.70 (t, J = 6.6 Hz, 1 H), 3.87 (s, 3 H), 3.79 (s, 3 H), 2.26 (s, 3 H), 2.13 (t, J = 7.3 Hz, 2 H), 1.98-2.08 (m, 2 H), 1.36 (s, 9 H), 1.16-1.68 (m, 14 H), 0.83 (t, J= 7.4 Hz, 9 H), 0.71-0.96 (m, 6 H); ¹³ C NMR (75 MHz, CDCl ₃ ) 5172.89, 166.83, 155.68, 144.69, 141.52, 140.13, 133.63, 132.09, 127.39, 123.81, 77.86, 61.37, 51.92, 34.98, 29.31, 28.91, 27.94, 27.21, 25.11, 16.04, 13.60, 9.87; ESMS m/z (rel intensity) 657/659/661 (41/78/100, MNa ⁺ ). Anal. Calcd for C ₃₂ H ₅₄ O ₅ Sn: C, H.

(E)-5-(6-tert-Butoxy-6-oxo- 1 -(tributylstannyl)hex- 1 -enyl)-2-methoxy-3- methylbenzoic Acid (19). Lithium hydroxide monohydrate (0.328 g, 7.86 mmol) was added to a solution of methyl ester 18 (4.152 g, 6.513 mmol) in dioxane-H ₂ O (6:1, 60 mL). The reaction mixture was stirred for 22 h at 60 ⁰ C. The mixture was concentrated in vacuo and acidified with 5% HCl, and diluted with water (60 mL). The mixture was extracted with ethyl acetate (2 x 40 mL). The combined organic solvent was washed with brine (2 x 40 mL), dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel using 30% ethyl acetate-hexanes to give the product 19 (2.56 g, 63.0%) as an oil: IR (Neat) 2967, 2928, 1732, 1696, 1255, 1149 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.78 (br s, 1 H), 7.48 (d, J = 2.1 Hz, 1 H), 6.94 (d, J= 2.1 Hz, 1 H), 5.72 (t, J = 7.4 Hz, 1 H), 3.89 (s, 3 H), 2.31 (s, 3 H), 2.11 (t, J = 7.4 Hz, 2 H), 2.00 (t, /= 7.4 Hz, 2 H), 1.61 (quint, / = 7.4 Hz, 2 H), 1.36 (s, 9 H), 1.14-1.46 (m, 12 H), 0.83 (t, J = 7.2 Hz, 9 H), 0.71-0.97 (m, 6 H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.89, 167.15, 155.19, 144.30, 141.87, 141.73, 135.23, 131.12, 128.65, 121.48, 79.93, 62.00, 34.95, 29.35, 28.89, 27.94, 26.99, 25.04, 16.47, 13.60, 9.90; ESIMS m/z (rel intensity) 643/645/647 (15/28/35, MNa ⁺ ); negative ion ESMS m/z (rel intensity) 619/621/623 (39/76/100, M-H ⁺ ). Anal. Calcd for C ₃₁ H ₅₂ O ₅ Sn: C, H.

(E)-tgrt-Butyl 6-(4-Methoxy-3-(methoxycarbamoyl)-5-methylphenyl)-6- (tributylstannyl)hex-5-enoate (20). EDCI (2.26 g, 11.8 mmol) was added to a mixture of carboxylic acid 19 (2.45 g, 3.92 mmol), methoxyamine hydrochloride (0.983 g, 11.8 mmol), 4- dimethylaminopyridine (0.240 g, 1.96 mmol), and triethylamine (2.20 mL, 15.7 mmol) in dichloromethane (50 mL). The reaction mixture was stirred for 15 h at room temperature. After the reaction was complete, the mixture was diluted with ethyl acetate (100 mL). The organic

solution was washed with 5% HCl (2 x 30 niL), 5% aq NaHCO ₃ (2 x 30 mL), and brine (2 x 30 mL), and dried over sodium sulfate. After removal of solvent in vacuo, the residue was purified by column chromatography on silica gel using 30% ethyl acetate-hexanes to give the product 20 (1.56 g, 61%) as an oil: ER (Neat) 3340, 1730, 1683, 1464, 1148 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.15 (br s, 1 H), 7.37 (d, J = 2.3 Hz, 1 H), 6.82 (d, J = 2.3 Hz, 1 H), 5.70 (t, J = 7.4 Hz, 1 H), 3.87 (s, 3 H), 3.75 (s, 3 H), 2.26 (s, 3 H), 2.12 (t, J = 7.4 Hz, 2 H), 2.10 (q, J = 7.4 Hz, 2 H), 1.60 (quint, J = 7.4 Hz, 2 H), 1.36 (s, 9 H), 1.14-1.46 (m, 12 H), 0.83 (t, J= 7.2 Hz, 9 H), 0.71-0.95 (m, 6 H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.99, 164.37, 153.38, 144.62, 141.56, 133.37, 130.85, 127.23, 124.03, 79.93, 64.31, 61.37, 34.97, 29.36, 28.90, 27.95, 27.20, 25.08, 15.95, 13.62, 9.89; ESMS m/z (rel intensity) 672/674/676 (42/94/100, MNa ⁺ ). Anal. Calcd for C ₃₂ H ₅₅ NO ₅ Sn: C, H, N.

(E)-tert-Butyl 6-(3,7-Dimethyl-2-oxo-2,3-dihydrobenzo[<loxazol-5-yl)-6-( 4- methoxy-3-(methoxycarbamoyl)-5-methylphenyl)hex-5-enoate (22). A mixture of aryl iodide 21 (56 mg, 0.188 mmol), organostannane 20 (147 mg, 0.225 mmol), and cesium fluoride (104 mg, 0.675 mmol) in DMF (5 mL) was cooled to 0 ⁰ C and degassed for 10 min with argon. Pd(PPh ₃ ) ₄ (22 mg, 0.019 mmol) and cuprous iodide (43 mg, 0.255 mmol) were added to the mixture. The reaction mixture was stirred for 0.5 h at 60 ⁰ C under argon. After the reaction was complete, the reaction mixture was diluted with dichloromethane (20 mL) and water (10 mL). After vigorous shaking, the mixture was filtered through celite with ethyl acetate (80 mL). The organic layer was separated, washed with brine (3 x 30 mL), dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel using 30% ethyl acetate-hexanes to give the product 22 (100 mg, 100%) as an oil: IR (Neat) 3308, 2975, 2934, 1777, 1726, 167, 1470, 1151, 1001, 750 cm ^'1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.02 (br s, 1 H), 7.61 (d, J = 1.2 Hz, 1 H), 7.05 (d, J= 1.2 Hz, 1 H), 6.70 (d, J = 1.0 Hz, 1 H), 6.55 (d, J = 1.0 Hz, 1 H), 5.92 (t, J = 7.5 Hz, 1 H), 3.88 (s, 3 H), 3.83 (s, 3 H), 3.32 (s, 3 H), 2.29 (s, 6 H), 2.20 (t, J = 7.5 Hz, 2 H), 2.08 (q, J = 7.5 Hz, 2 H), 1.70 (quint, J = 7.5 Hz, 2 H), 1.37 (s, 9 H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.81, 164.10, 155.15, 154.97, 140.59, 140.40, 138.76, 136.33, 135.98, 131.54, 131.16, 129.98, 124.52, 123.62, 119.77, 104.60, 80.11, 64.33, 61.37, 34.95, 29.14, 28.13, 27.93, 25.13, 16.00, 14.36; ESIMS m/z (rel intensity) 547 (100, MNa ⁺ ); negative ion ESIMS m/z (rel intensity) 523 [100, (M - H ⁺ ) ^" ] . Anal. Calcd for C ₂₉ H ₃₆ NO ₇ : C, H, N.

(E)-6-(3,7-Dimethyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-6- (4-methoxy-3- (methoxycarbamoyl)-5-methylphenyl)hex-5-enoic Acid (23). Trifluoroacetic acid (2 mL) was added to a solution of the tert-butyl ester 22 (99 mg, 0.189 mmol) in dichloromethane (2 mL). The reaction mixture was stirred for 3 h at 0 ⁰ C. After the reaction was complete, the solvent was

evaporated at room temperature and the residue was diluted with ethyl acetate (40 mL). The organic solution was washed with brine (2 x 20 mL) and dried over sodium sulfate. After removal of solvent in vacuo, the residue was purified by column chromatography on silica gel using 75% ethyl acetate-hexanes to give the product 23 (71 mg, 80%) as an oil: IR (Neat) 3271, 1771, 1645, 1471, 731 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.22 (s, 1 H), 8.65 (br s, 1 H), 7.63 (d, J = 1.6 Hz, 1 H), 7.04 (d, J= 1.6 Hz, 1 H), 6.69 (d, J = 1.0 Hz, 1 H), 6.56 (d, J= 1.0 Hz, 1 H), 5.92 (t, J = 7.4 Hz, 1 H), 3.86 (s, 3 H), 3.82 (s, 3 H), 3.31 (s, 3 H), 2.32 (t, / = 7.4 Hz, 2 H), 2.28 (s, 6 H), 2.12 (q, J = 7.4 Hz, 2 H), 1.76 (quint, J = 7.4 Hz, 2 H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 177.82, 164.12, 155.09, 154.95, 140.74, 140.33, 138.62, 136.24, 136.05, 131.57, 131.07, 129.95, 129.61, 124.19, 123.55, 119.70, 104.55, 64.24, 61.31, 33.18, 28.84, 28.05, 24.55, 15.90, 14.26; ESIMS m/z (rel intensity) 491 (100, MNa ⁺ ); negative ion ESMS m/z (rel intensity) 467 [100, (M - H ⁺ ) ^" ]- Anal. Calcd for C ₂₅ H ₂₈ N ₂ O ₇ : C, H, N.

(E)-5-(l-(3,7-Dimethyl-2-oxo-2,3-dihydrobenzo[c0oxazol-5-yl) -6- (methoxyamino)-6-oxohex-l-enyl)-N,2-dimethoxy-3-methylbenzam ide (24). εDCI (58 mg, 0.304 mmol) was added to a solution of carboxylic acid 23 (71 mg, 0.152 mmol), methoxyamine hydrochloride (25 mg, 0.304 mmol), 4-dimethylaminopyridine (4 mg, 0.030 mmol), and triethylamine (0.06 mL, 0.456 mmol) in dichloromethane (4 mL). The reaction mixture was stirred for 24 h at room temperature. After the reaction was complete, the mixture was diluted with ethyl acetate (40 mL). The organic solution was washed with 2% HCl (2 x 15 mL), 5% aq NaHCO ₃ (2 x 15 mL), brine (2 x 15 mL), and dried over sodium sulfate. After removal of solvent in vacuo, the residue was purified by column chromatography on silica gel using 3% methanol-ethyl acetate to give the product 24 (40 mg, 53%) as an oil: IR (Neat) 3435, 1772, 1648, 1471, 1064 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.34 (br s, 1 H), 8.76 (br s, 1 H), 7.61 (s, 1 H), 7.02 (s, 1 H), 6.69 (s, 1 H), 6.56 (s, 1 H), 5.94 (t, J = 7.6 Hz, 1 H), 3.89 (s, 3 H), 3.83 (s, 3 H), 3.67 (s, 3 H), 3.31 (s, 3 H), 2.28 (s, 6 H), 2.14-1.99 (m, 4 H), 1.73-1.87 (m, 2 H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 170.40, 164.30, 155.25, 154.97, 140.65, 140.36, 138.60, 136.06, 135.93, 131.80, 131.12, 129.80, 129.59, 124.43, 123.56, 119.73, 104.58, 64.21, 63.90, 61.32, 32.31, 29.11, 28.10, 25.26, 15.97, 14.30; εSεVIS m/z (rel intensity) 498 (100, MH ⁺ ), 520 (70, MNa ⁺ ); negative ion εSεVIS m/z (rel intensity) 496 [86, (M -H ⁺ ) ^" ]. Anal. Calcd for C ₂₆ H ₃₁ N ₃ O ₇ : C, H, N.

(Z)-5-((lE,6Z)-6-Chloro-l-(3,7-dimethyl-2-oxo-2,3-dihydro benzo[d]oxazol-5- yl)-6-(methoxyimino)hex-l-enyl)-N,2-dimethoxy-3-methylbenzim idoyl Chloride (4). Carbon tetrachloride (0.16 mL, 1.61 mmol) was added to a solution of di-N-methoxyamide 24 (40 mg, 0.080 mmol) and triphenylphosphine (84 mg, 0.322 mmol) in acetonitrile (5 mL). The reaction

mixture was stirred for 0.5 h at room temperature and for 3.5 h at reflux. Additional triphenylphosphine (42 mg, 0.161 mol) and carbon tetrachloride (0.1 mL, 1.01 mmol) were added and the mixture was stirred for 1 h at reflux. After the reaction was complete, the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel using 20% ethyl acetate-hexanes to give the product 4 (30 mg, 71 %) as an oil: IR (Neat) 2938, 1779, 1464, 1025 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.08 (d, J = 2.0 Hz, 1 H), 6.99 (d, J = 2.0 Hz, 1 H), 6.76 (d, J = 1.1 Hz, 1 H), 6.57 (d, J = 1.1 Hz, 1 H), 5.93 (t, J = 7.4 Hz, 1 H), 4.07 (s, 3 H), 3.88 (s, 3 H), 3.83 (s, 3 H), 3.33 (s, 3 H), 2.47 (t, /= 7.4 Hz, 2 H), 2.31 (s, 3 H), 2.29 (s, 3 H), 2.16 (q, J = 7.4 Hz, 2 H), 1.79 (quint, J = 7.4 Hz, 2 H); ESMS m/z (rel intensity) 556/558/560 (100/65/11, MNa ⁺ ). Anal. Calcd for C ₂₆ H ₂₉ Cl ₂ N ₃ O ₅ : C, H, N.

A Stereoisomeric Mixture of (Z)-5-((lE,6Z)-6-Bromo-l-(3,7-dimethyl-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)-6-(methoxyimino)hex-l-enyl)-/V,2 -demethoxy-3- methylbenzimidoyl Bromide (E-5) and (Z)-5-((lZ,6Z)-6-Bromo-l-(3,7-dimethyl-2-oxo-2,3- dihydrobenzo[<i]oxazol-5-yl)-6-(methoxyimino)hex-l-enyl)- N,2-demethoxy-3- methylbenzimidoyl Bromide (Z-5). Carbon tetrabromide (893 mg, 2.47 mmol) was added to a solution of di-iV-methoxyamide 24 (123 mg, 0.247 mmol) and triphenylphosphine (342 mg, 1.24 mmol) in acetonitrile (15 mL). The reaction mixture was stirred for 0.5 h at room temperature and for 2 h at reflux. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel using 25% ethyl acetate-hexanes to give a equimolar mixture of E and Z isomers of compound 5 (115 mg, 75%) as an oil: IR (Neat) 2936, 1778,

1757, 1640, 1469, 1063 cm ^"1 ; ¹ R NMR (300 MHz, CDCl ₃ ) δ 7.05 (s, 2 H), 7.00 (s, 1 H), 6.97 (s, 1 H), 6.77 (s, 1 H), 6.71 (s, 1 H), 6.58 (s, 1 H), 6.52 (s, 1 H), 5.99 (t, J = 7.4 Hz, 1 H), 5.93 (t, J = 7.5 Hz, 1 H), 4.11 (s, 3 H), 4.09 (s, 3 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.82 (s, 3 H), 3.76 (s, 3 H), 3.35 (s, 3 H), 3.33 (s, 3 H), 2.94-2.64 (m, 4 H), 2.38 (s, 3 H), 2.31 (s, 3 H), 2.29 (s, 3 H), 2.23 (s, 3 H), 2.22-2.05 (m, 4 H), 1.87-1.69 (m, 4 H); εSMS m/z (rel intensity) 644/646/648 (47/100/49, MNa ⁺ ).

(F)-^rt-Butyl 6-(3,7-Dimethyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-6-(3-( (Z)- fluoro(methoxyimino)methyl)-4-methoxy-5-methylphenyl)hex-5-e noate (25). (Diethylamino)sulfur trifluoride (0.07 mL, 0.510 mmol) was added to a solution of N- methoxyamide 22 (134 mg, 0.255 mmol) in dichloromethane (7 mL) at 0 ⁰ C under argon and the mixture was stirred for 0.5 h. After quenching the reaction with 5% aq NaHCO ₃ , the mixture was extracted with ethyl acetate (2 x 25 mL). The combined organic solvent was washed with brine (2 x 25 mL) and dried over sodium sulfate. After removal of solvent in vacuo, the residue was purified by column chromatography on silica gel using an ethyl acetate-hexanes gradient

(10-13%) to give the product 25 (80 mg, 60%) as an oil: IR (Neat) 2939, 1779, 1727, 1472, 1149, 1051 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.19 (d, J = 2.0 Hz, 1 H), 7.04 (s, 1 H), 6.73 (s, 1 H), 6.56 (s, 1 H), 5.93 (t, J = IA Hz, 1 H), 3.94 (s, 3 H), 3.84 (s, 3 H), 3.32 (s, 3 H), 2.31 (s, 3 H), 2.29 (s, 3 H), 2.21 (t, 7 = 7.5 Hz, 2 H), 2.12 (t, J = 7.5 Hz, 2 H), 1.72 (quint, J = 7.5 Hz, 2 H), 1.38 (s, 9 H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 170.70, 156.16 (d, J = 75.2 Hz), 151.65, 147.35, 140.46, 138.72, 135.40, 132.56, 131.22, 129.97, 128.76, 128.75, 123.58, 120.22, 119.84, 104.56, 80.07, 63.06, 60.92, 35.00, 29.16, 28.15, 27.96, 25.19, 16.09, 14.40; ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ 10.95 (s, 1 F); ESMS m/z (rel intensity) 494 (100, M-methanol), 495 (30). Anal. Calcd for C ₂₉ H ₃₅ FN ₂ O ₅ : C, H, N. (F)-6-(3,7-Dimethyl-2-oxo-2,3-dihydrobenzoMoxazol-5-yl)-6-(3 -((Z)- fluoro(methoxy-imino)methyl)-4-methoxy-5-methylphenyl)hex-5- enoic Acid (26). Trimethylsilyl trifluoromethanesulfonate (0.59 mL, 3.27 mmol) was added to a solution of tert- butyl ester 25 (862 mg, 1.64 mmol) and triethylamine (0.46 mL, 3.27 mmol) in dioxane (25 mL) at room temperature under argon. The reaction mixture was stirred for 2 h at room temperature. After the reaction was complete, water (50 mL) was added to the mixture. The mixture was extracted with ethyl acetate (2 x 35 mL). The combined organic solvent was washed with brine (2 x 35 mL) and dried over sodium sulfate. After removal of solvent in vacuo, the residue was purified by column chromatography on silica gel using an ethyl acetate-hexanes gradient (30- 70%) to give the product 26 (626 mg, 81%) as an oil: IR (Neat) 3200, 2941, 1778, 1708, 1471, 1051 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.19 (d, J = 1.4 Hz, 1 H), 7.03 (d, J = 1.4 Hz, 1 H), 6.73 (d, / = 1.1 Hz, 1 H), 6.55 (d, J= 1.1 Hz, 1 H), 5.93 (t, J = 7.4 Hz, 1 H), 3.94 (s, 3 H), 3.84 (s, 3 H), 3.32 (s, 3 H), 2.34 (t, J = 7.3 Hz, 2 H), 2.30 (s, 3 H), 2.29 (s, 3 H), 2.15 (q, J = 13 Hz, 2 H), 1.77 (quint, / = 7.3 Hz, 2 H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 179.02, 155.67 (J = 89.9 Hz,), 151.80, 147.80, 140.94, 140.40, 138.64, 135.35, 135.33, 132.69, 131.27, 129.47, 128.71, 123.62, 120.10, 119.97, 140.85, 63.12, 60.98, 33.35, 29.06, 28.21, 24.69, 16.14, 14.46; ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ 11.29; ESIMS m/z (rel intensity) 470.97 (100, MH ⁺ ); negative ion ESMS m/z (rel intensity) 469 [100, (M - H ⁺ ) ^" ] • Anal. Calcd for C ₂₅ H ₂₇ FN ₂ O ₅ : C, H, N.

(Z)-5-((£)-l-(3,7-Dimethyl-2-oxo-2,3-dihydrobenzo[rf]oxazol -5-yl)-5-(3-methyl- l,2,4-oxadiazol-5-yl)pent-l-enyl)-N,2-dimethoxy-3-methylbenz imidoyl fluoride (6). TBTU (2- (lH-benzotriazol-l-yl)-l,l,3,3,-tetramethyluronium hexafluorophosphate) (71 mg, 0.213 mmol) was added to a mixture of carboxylic acid 26 (100 mg, 0.213 mmol), acetamide oxime (16 mg, 0.213 mmol), ηOBt (6 mg, 0.043 mmol), DIPEA (0.19 mL, 1.07 mmol) in DMF (4 mL). The mixture was stirred for 0.5 h at room temperature and for 3 h 110 ⁰ C. The mixture was diluted with ethyl acetate (50 mL) and the organic solution was washed with brine (4 x 20 mL), dried

over sodium sulfate, and concentrated. The residue was purified by preparative TLC using 50% ethyl acetate-hexanes to give the product 6 (50 mg, 46%) as an oil. IR (Neat) 2956, 1778, 1051 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.18 (d, J= 2.0 Hz, 1 H), 7.10 (d, J = 2.0 Hz, 1 H), 6.71 (d, J = 0.8 Hz, 1 H), 6.54 (d, / = 0.8 Hz, 1 H), 5.93 (t, J = 7.4 Hz, 1 H), 3.94 (s, 3 H), 3.85 (s, 3 H), 3.32 (s, 3 H), 2.83 (t, J = 7.7 Hz, 2 H), 2.33 (s, 3 H), 2.31 (s, 3 H), 2.29 (s, 3 H), 2.21 (q, J = 7.4 Hz, 2 H), 1.95 (quint, /= 7.5 Hz, 2 H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 179.12, 166.91, 155.61 (d, 7 = 98.3 Hz), 151.60, 147.30, 141.34, 140.56, 138.44, 135.25, 135.16, 132.72, 131.26, 128.76, 128.65, 123.56, 120.28, 119.92, 104.52, 63.10, 60.95, 28.93, 28.17, 26.47, 16.13, 14.42, 11.44; ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ 10.99 (s, 1 F); ESIMS m/z (rel intensity) 509 (100, MH ⁺ ). Anal. Calcd for C ₂₇ H ₂₉ FN ₄ O ₅ : C, H, N.

(£)-Methyl 6-(3,7-Dimethyl-2-oxo-2,3-dihydrobenzo[<f|oxazol-5-yl)-6- (3-(Z)- fluoro-(methoxyimino)methyl)-4-methoxy-5-methylphenyl)hex-5- enoate (7). (Trimethylsilyl)diazomethane (0.17 mL of 2 M solution in hexanes, 0.340 mmol) was added to a solution of the carboxylic acid 26 (80 mg, 0.170 mmol) in toluene-Methanol (2:1, 4.5 mL). After stirring for 10 min at room temperature, the excess (trimethylsilyl)diazomethane was quenched by dropwise addition of acetic acid. The solvent was evaporated and the residue was purified by column chromatography using an ethyl acetate-hexanes gradient (20-40%) to give the product 7 (67 mg, 82%) as an oil: IR (Neat) 2944, 1778, 1737, 1471, 1050 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.18 (d, J = 1.8 Hz, 1 H), 7.03 (d, J = 1.8 Hz, 1 H), 6.72 (s, 1 H), 6.55 (s, 1 H), 5.92 (t, J = 7.4 Hz, 1 H), 3.94 (s, 3 H), 3.84 (s, 3 H), 3.61 (s, 3 H), 3.32 (s, 3 H), 2.32 (s, 3 H), 2.29 (s, 3 H), 2.28 (t, J = 7.4 Hz, 2 H), 2.12 (q, J = 7.4 Hz, 2 H), 1.77 (quint, J = 7.4 Hz, 2 H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 173.74, 155.56 (d, J = 93.2 Hz), 151.62, 147.31, 140.70, 140.46, 138.64, 135.35, 132.57, 131.22, 129.64, 128.70, 123.55, 120.20, 119.89, 104.53, 63.04, 60.92, 51.41, 33.38, 29.90, 28.13, 24.92, 16.08, 14.38; ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ 10.86 (s, 1 F); ESIMS m/z (rel intensity) 485 (100, MH ⁺ ). Anal. Calcd for C ₂₆ H ₂₉ FN ₂ O ₆ : C, H, N.

Methyl 2-Methoxy-5-[ 1 -(4-methoxy-3-methyl-5-methoxycarbonyl-phenyl)-4-(2- methyl-2H-tetrazol-5-yl)-but-l-enyl]-3-methylbenzoate (40). The general Stille coupling procedure was followed using stannane 105 (375 mg, 0.619 mmol), iodide 80 (255 mg, 0.833 mmol), cesium fluoride (338 mg, 2.23 mmol), Pd(PPh ₃ ) ₄ (75 mg, 0.065 mmol), and copper(I) iodide (26 mg, 0.137 mmol) in anhydrous DMF (6 mL). The reaction mixture was allowed to stir for 17 h. The crude products were separated by column chromatography (100 mL silica gel, 2 in diameter) using an ethyl acetate-hexanes gradient (50-80%). The product was isolated and purified again by column chromatography (80 mL silica gel, 2 in diameter) using an ethyl acetate-hexanes gradient (20-66%). The desired product was isolated as a clear oil (255 mg,

83%): ER (neat) 2951, 2862, 2004, 1729, 1600, 1577, 1480, 1436, 1379, 1298, 1260, 1228, 1173, 1135, 1123, 1008 cm ^"1 ; ¹ H HMR (300 MHz, CDCl ₃ ) δ 7.44 (d, /= 2.4 Hz, 1 H), 7.37 (d, J = 2.4 Hz, 1 H), 7.08 (d, J= 1.8 Hz, 1 H), 7.06 (d, J= 1.8 Hz, 1 H), 6.01 (t, J = 7.5 Hz, 1 H), 4.30 (s, 3 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.80 (s, 3 H), 3.00 (t, J = 7.5 Hz, 2 H), 2.57 (q, J = 7.5 Hz, 2 H), 2.30 (s, 3 H), 2.25 (s, 3 H); ESMS m/z (relative intensity) 517 (MNa ⁺ , 100). Anal. (C ₂₆ H ₃₀ N ₄ O ₆ ) C, H, N.

2-Methoxy-5-[l-(4-methoxy-3-methyl-5-methylsulfanylcarbonyl- phenyl)-4-(2- methyl-2H-tetrazol-5-yl)-but-l-enyl]-3-methyl-thiobenzoic acid S-Methyl Ester (41). The general Stille coupling procedure was followed using stannane 109 (144 mg, 0.232 mmol), iodide 81 (95 mg, 0.299 mmol), cesium fluoride (135 mg, 0.889 mmol), Pd(PPh ₃ ) ₄ (27 mg, 0.023 mmol), and copper(I) iodide (15 mg, 0.079 mmol) in anhydrous DMF (2 mL). The reaction mixture was allowed to stir for 15 h. The crude products were absorbed onto silica gel (2 mL) and separated by column chromatography (80 mL silica gel, 2 in diameter) using an ethyl acetate-hexanes gradient (33-66%). The desired product was isolated as a highly viscous, pale yellow oil (57 mg, 47%): IR (neat) 2298, 2857, 2824, 1673, 1644, 1593, 1574, 1478, 1417, 1379, 1307, 1244, 1199, 1156, 1133, 1039, 1001 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.37 (d, 7 = 2.4 Hz, 1 H), 7.32 (d, J = 2.1 Hz, 1 H), 7.08 (dd, /= 2.1, 0.6 Hz, 1 H), 7.05 (dd, J = 2.1, 0.6 Hz, 1 H), 6.02 (t, J = 7.2 Hz, 1 H), 4.30 (s, 3 H), 3.86 (s, 3 H), 3.80 (s, 3 H), 3.02 (t, J = 7.5 Hz, 2 H), 2.59 (q, / = 7.5 Hz, 2 H), 2.44 (s, 3 H), 2.43 (s, 3 H), 2.32 (s, 3 H), 2.26 (s, 3 H); ESMS m/z (relative intensity) 549 (MNa ⁺ , 9), 526 (MH ⁺ , 37), 497 (MH ⁺ - SCH ₃ + H ₂ O, 100), 479 (MH ⁺ - SCH ₃ , 24). Anal. (C ₂₆ H ₃₀ N ₄ O ₄ S ₂ ) C, H, N.

(Z)-Methyl 2-Methoxy-5-[l-(4-methoxy-3-methyl-5-methylsulfanylcarbonyl- phenyl)-4-(2-methyl-2H-tetrazol-5-yl)-but-l-enyl]-3-methyl benzoate (42). The general Stille Coupling procedure was followed using stannane 105 (225 mg, 0.372 mmol), iodide 81 (183 mg, 0.568 mmol), cesium fluoride (199 mg, 1.30 mmol), Pd(PPh ₃ ) ₄ (50 mg, 0.043 mmol), and copper(I) iodide (18 mg, 0.096 mmol) in anhydrous DMF (4 mL). The reaction mixture was allowed to stir for 16 h. The crude products were absorbed onto silica (3 mL) and separated by column chromatography (100 mL silica, 2 in diameter) using an ethyl acetate-hexanes gradient (20-50%). The product was isolated as a yellow oil (141 mg, 74%): IR (neat) 3642, 2950, 2004, 1729, 1675, 1646, 1594, 1575, 1479, 1435, 1379, 1296, 1253, 1229, 1208, 1150, 1125, 1051, 1005 cm ^'1 ; ¹ H ηMR (300 MHz, CDCl ₃ ) δ 7.38 (s, 1 H), 7.37 (s, 1 H), 7.08 (d, J = 1.8 Hz, 1 H), 7.06 (d, J = 1.8 Hz, 1 H), 6.02 (t, J = 7.2 Hz, 1 H), 4.30 (s, 3 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 3.80 (s, 3 H), 3.00 (t, / = 7.2 Hz, 2 H), 2.58 (q, J = 7.2 Hz, 2 H), 2.43 (s, 3 H), 2.31 (s, 3 H), 2.26 (s, 3

H); ESI HRMS m/z Calcd for C ₂₆ H ₃₀ N ₄ O ₅ S [MNa ⁺ ]: 533.1835, found: 533.1840; ESIMS m/z (relative intensity) 533 (MNa ⁺ , 100), 481 (MH ⁺ - SCH ₃ + H ₂ O, 76).

(2)-5-[l-(3-Cyano-phenyl)-4-(2-methyl-2H-tetrazol-5-yl)-but- l-enyl]-2- methoxy-3-methylbenzoic Acid Methyl Ester (43). The general Stille Coupling procedure was followed using stannane 105 (155 mg, 0.256 mmol), bromide 86 (65 mg, 0.357 mmol), cesium fluoride (161 mg, 1.06 mmol), Pd(PPh ₃ ) ₄ (32 mg, 0.028 mmol), and copper(I) iodide (11 mg, 0.058 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 13.5 h. The crude products were absorbed onto silica (5 mL) and separated by column chromatography (100 mL silica, 2 in diameter) using an ethyl acetate-hexanes gradient (33-50%). The product was isolated as a clear oil (94 mg, 88%): IR (neat) 3063, 2951, 2858, 2229, 1728, 1597, 1575, 1480, 1436, 1418, 1396, 1380, 1300, 1256, 1231, 1199, 1154, 1125, 1008 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.51 (dt, / = 7.2, 1.5 Hz, 1 H), 7.44-7.34 (m, 4 H), 7.04 (d, /= 1.8 Hz, 1 H), 6.14 (t, / = 7.5 Hz, 1 H), 4.30 (s, 3 H), 3.91 (s, 3 H), 3.89 (s, 3 H), 3.02 (t, J = 7.5 Hz, 2 H), 2.61 (q, J = 7.5 Hz, 2 H), 2.32 (s, 3 H); ESIMS m/z (relative intensity) 440 (MNa ⁺ , 100), 364 (MH ⁺ - C ₂ H ₂ N ₂ , 67). Anal. (C ₂₃ H ₂₃ N ₅ O ₃ ) C, H, N.

Methyl 2-Methoxy-5-[l-(4-methoxy-3-methyl-5-methoxycarbonyl-phenyl) -4-(5- methyl-[l,3,4]oxadiazol-2-yl)-but-l-enyl]-3-methylbenzoate (44). The general Stille coupling procedure was followed using stannane 107 (522 mg, 0.862 mmol), iodide 80 (356 mg, 1.16 mmol), cesium fluoride (461 mg, 3.03 mmol), Pd(PPh ₃ ) ₄ (99 mg, 0.086 mmol), and copper(I) iodide (47 mg, 0.247 mmol) in anhydrous DMF (6 mL). The reaction mixture was allowed to for 17 h. The crude products were separated by column chromatography (125 mL silica, 2 in diameter) using an ethyl acetate-hexanes gradient (20-100%). The desired product was further purified by preparative thin layer chromatography using 50% ethyl acetate-hexanes as the eluant (developed 4 times). The desired product was isolated as a pale, yellow oil (284 mg, 67%): IR (neat) 3000, 2950, 2851, 1729, 1596, 1570, 1480, 1436, 1298, 1260, 1228, 1173, 1135, 1123, 1007 cm ^'1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.42 (d, J = 2.4 Hz, 1 H), 7.38 (d, J = 2.1 Hz, 1 H), 7.08 (d, J = 2.1 Hz, 1 H), 7.05 (d, J = 2.1 Hz, 1 H), 5.98 (t, J = 7.2 Hz, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.86 (s, 3 H), 3.80 (s, 3 H), 2.91 (t, J = 7.5 Hz, 2 H), 2.56 (dt, / = 7.5, 7.2 Hz, 2 H), 2.47 (s, 3 H), 2.30 (s, 3 H), 2.24 (s, 3 H); CMS m/z (relative intensity) 495 (MH ⁺ , 100), 463 (MH ⁺ - HOCH ₃ , 73). Anal. (C ₂₇ H ₃₀ N ₂ O ₇ ) C, H, N.

(2)-Methyl 2-Methoxy-5-[l-(4-methoxy-3-methyl-5-methylsulfanylcarbonyl- phenyl)-4-(5-methyl-[l,3,4]oxadiazol-2-yl)-but-l-enyl]-3-met hylbenzoate (45). The general Stille coupling procedure was followed using stannane 107 (433 mg, 0.715 mmol), iodide 81 (312 mg, 1.02 mmol), cesium fluoride (383 mg, 2.52 mmol), Pd(PPh ₃ ) ₄ (85 mg, 0.074 mmol),

and copper(I) iodide (28 mg, 0.143 mmol) in anhydrous DMF (7 mL). The reaction mixture was allowed to stir for 21 h. The crude products were separated by column chromatography (110 mL silica gel, 2 in diameter) using an ethyl acetate-hexanes gradient (50-100%) and the desired product was further purified by preparative thin layer chromatography using 50% ethyl acetate- hexanes as the eluant (developed twice). The product was isolated as a very viscous, opaque oil (239 mg, 65%): IR (neat) 2930, 2866, 2004, 1730, 1679, 1645, 1595, 1570, 1479, 1435, 1379, 1296, 1253, 1229, 1125, 1049, 1004 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.39 (d, J = 2.1 Hz, 1 H), 7.36 (d, J = 2.4 Hz, 1 H), 7.09 (d, 7 = 2.1 Hz, 1 H), 7.06 (d, J = 2.4 Hz, 1 H), 6.00 (t, J = 7.5 Hz, 1 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.80 (s, 3 H), 2.92 (t, / = 7.5 Hz, 2 H), 2.57 (q, J = 7.5 Hz, 2 H), 2.48 (s, 3 H), 2.43 (s, 3 H), 2.32 (s, 3 H), 2.27 (s, 3 H); ESIMS m/z (relative intensity) 511 (MH ⁺ , 94), 481 (MH ⁺ - SCH ₃ + H ₂ O, 100). Anal. (C ₂₇ H ₃₀ N ₂ O ₆ S) C, H, N.

(Z)-Methyl 5-[l-(3-Cyano-phenyl)-4-(5-methyl-[l,3,4]oxadiazol-2-yl)-but -l- enyl]-2-methoxy-3-methyl benzoate (46). The general Stille coupling procedure was followed using stannane 107 (200 mg, 0.330 mmol), bromide 86 (83 mg, 0.429 mmol), cesium fluoride (177 mg, 1.17 mmol), Pd(PPh ₃ ) ₄ (6 mg, 0.033 mmol), and copper(I) iodide (13 mg, 0.066 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 16 h. The crude products were absorbed onto silica (2 mL) and purified by column chromatography (100 mL silica, 2 in diameter) using an ethyl acetate-hexanes gradient (50-100%). The product was isolated as a clear oil (103 mg, 75%): IR (neat) 3065, 2950, 2851, 2229, 2003, 1728, 1596, 1571, 1480, 1436, 1379, 1299, 1256, 1230, 1199, 1154, 1125, 1007 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.52 (dt, J = 7.2, 1.5 Hz, 1 H), 7.46-7.35 (m, 4 H), 7.05 (d, J = 1.8 Hz, 1 H), 6.12 (t, J = 7.2 Hz, 1 H), 3.97 (s, 3 H), 3.90 (s, 3 H), 2.94 (t, J = 7.2 Hz, 2 H), 2.61 (q, J = 7.2 Hz, 2 H), 2.48 (s, 3 H), 2.33 (s, 3 H); ESI HRMS m/z Calcd for C ₂₄ H ₂₃ N ₃ O ₄ [MNa ⁺ ]: 440.1586, found: 440.1580; ESIMS m/z (relative intensity) 440 (MNa ⁺ , 100). (Z)-Methyl 5-[l-(4-Cyano-phenyl)-4-(5-methyl-[l,3,4]oxadiazol-2-yl)-but -l- enyl]-2-methoxy-3-methylbenzoate (47). The general Stille coupling procedure was followed using stannane 107 (541 mg, 0.894 mmol), bromide 87 (213 mg, 1.17 mmol), cesium fluoride (481 mg, 3.17 mmol), Pd(PPh ₃ ) ₄ (104 mg, 0.090 mmol), and copper(I) iodide (34 mg, 0.178 mmol) in anhydrous DMF (6 mL). The reaction mixture was allowed to stir for 15 h. The crude products were purified by column chromatography (100 mL silica gel, 2 in diameter) using an ethyl acetate-hexanes gradient (50-100%) and the desired product was isolated as a very viscous, pale yellow oil (363 mg, 87%): IR (neat) 2950, 2868, 2225, 1731, 1599, 1570, 1503, 1480, 1435, 1409, 1380, 1300, 1258, 1230, 1195, 1169, 1126, 1007 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.62 (dt, J = 8.4, 1.8 Hz, 2 H), 7.33 (dt, J = 8.7, 1.8 Hz, 2 H), 7.27 (d, J = 2.4 Hz, 1 H), 7.13 (d,

J = 1.8 Hz, 1 H), 3.87 (s, 3 H), 3.83 (s, 3 H), 2.99 (t, J = 7.2 Hz, 2 H), 2.59 (dt, J = 7.5, 7.2 Hz, 2 H), 2.44 (s, 3 H), 2.31 (s, 3 H); CIMS m/z (relative intensity) 418 (MH ⁺ , 100), 386 (MH ⁺ - OCH ₃ , 69). Anal (C ₂₄ H ₂₃ N ₃ O ₄ ) C, H, N.

(Z)-5-[l-(2,7-Dimethyl-3-oxo-2,3-dihydro-benzo[<i]isoxazo l-5-yl)-4-(5-methyl- [l,3,4]oxadiazol-2-yl)-but-l-enyl]-2-methoxy-3-methylbenzoic Acid Methyl Ester (48). The general Stille coupling procedure was followed using stannane 107 (160 mg, 0.264 mmol), iodide 85 (98 mg, 0.339 mmol), cesium fluoride (154 mg, 1.01 mmol), Pd(PPh ₃ ) ₄ (31 mg, 0.027 mmol), and copper(I) iodide (13 mg, 0.068 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 20 h. The crude products were absorbed onto silica (4 mL) and separated by column chromatography (80 mL silica, 2 in diameter) using an ethyl acetate- hexanes gradient (50-100%). The product was isolated as an off-white solid (76 mg, 60%): mp 135-136 °C. IR (CHCl ₃ ) 3469, 2949, 2862, 2236, 1997, 1729, 1690, 1614, 1596, 1570, 1490, 1437, 1399, 1378, 1298, 1257, 1227, 1168, 1147, 1121, 1008 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) 57.38 (d, J = 2.1 Hz, 1 H), 7.36 (d, J= 1.8 Hz, 1 H), 7.28 (s, 1 H), 7.05 (d, J = 1.5 Hz, 1 H), 6.02 (t, J = 7.2 Hz, 1 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 3.66 (s, 3 H), 2.92 (t, J = 7.5 Hz, 2 H), 2.59 (q, J = 7.5 Hz, 2 H), 2.48 (s, 3 H), 2.35 (s, 3 H), 2.31 (s, 3 H); ESI HRMS m/z Calcd for C ₂₆ H ₂₇ N ₃ O ₆ [MNa ⁺ ]: 500.1798, found: 500.1797; ESIMS m/z (relative intensity) 500 (MNa ⁺ , 100), 464 (MH ⁺ - OCH ₃ + OH, 33). Anal. (C ₂₆ H ₂₇ N ₃ O ₆ ) C, H, N: calcd. C, 65.40; found C, 64.66. (Z)-2-Methoxy-5-[l-(3-methoxy-7-methyl-benzo[rf]isoxazol-5-y l)-4-(5-methyl-

[l,3,4]oxadiazol-2-yl)-but-l-enyl]-3-methylbenzoic Acid Methyl Ester (49). The general Stille coupling procedure was followed using stannane 107 (144 mg, 0.238 mmol), iodide 83 (106 mg, 0.367 mmol), cesium fluoride (142 mg, 0.935 mmol), Pd(PPh ₃ ) ₄ (29 mg, 0.024 mmol), and copper(I) iodide (13 mg, 0.068 mmol) in anhydrous DMF (2 mL). The reaction mixture was allowed to stir for 20 h. The crude products were absorbed onto silica (3 mL) and separated by column chromatography (100 mL silica, 2 in diameter) using an ethyl acetate-hexanes gradient (33-100%). The product was isolated as a clear oil (106 mg, 93%): IR (neat) 2948, 1730, 1596, 1570, 1547, 1495, 1436, 1395, 1318, 1284, 1256, 1202, 1143, 1120, 1048, 1008 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.39 (d, J = 2.1 Hz, 1 H), 7.17 (s, 1 H), 7.15 (s, 1 H), 7.06 (d, J = 2.1 Hz, 1 H), 6.01 (t, J= 7.2 Hz, 1 H), 4.13 (s, 3 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 2.93 (t, J = 7.2 Hz, 2 H), 2.59 (q, J = 7.5 Hz, 2 H), 2.48 (s, 3 H), 2.45 (s, 3 H), 2.31 (s, 3 H); ESMS m/z (relative intensity) 500 (MNa ⁺ , 100). Anal. (C ₂₆ H ₂₇ N ₃ O ₆ ) C, H, N.

(E)-5-[l-(3,7-Dimethyl-2-oxo-2,3-dihydro-benzooxazol-5-yl )-4-(5-methyl- [l,3,4]oxadiazol-2-yl)-but-2-enyl]-2-methoxy-3-methylbenzoic Acid Methyl Ester (50). The

general Stille coupling procedure was followed using stannane 107 (197 mg, 0.325 mmol), iodide 82 (136 mg, 0.470 mmol), cesium fluoride (178 mg, 1.17 mmol), Pd(PPh ₃ ) ₄ (42 mg, 0.036 mmol), and copper(I) iodide (14 mg, 0.066 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 22 h. The crude products were absorbed onto silica (5 mL) and purified by column chromatography (60 mL silica, 1 in diameter) using ethyl acetate as the eluant. The desired product was further purified by preparative thin layer chromatography using ethyl acetate as the eluant (developed twice). The product was isolated from the plate and purified again by preparative thin layer chromatography using 66% ethyl acetate-hexanes as the eluant (developed three times). The pure product was isolated as a glassy, amber solid (80 mg, 52%): mp 43-47 ⁰ C. IR (CHCl ₃ ) 2949, 1776, 1728, 1641, 1619, 1596, 1570, 1475, 1437, 1368, 1334, 1299, 1229, 1196, 1141, 1120, 1064, 1008 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.39 (d, J = 2.1 Hz, 1 H), 7.06 (d, / = 2.4 Hz, 1 H), 6.73 (s, 1 H), 6.56 (d, / = 2.0 Hz, 1 H), 5.98 (t, J = 7.2 Hz, 1 H), 3.92 (s, 3 H), 3.88 (s, 3 H), 3.34 (s, 3 H), 2.94 (t, J = 7.2 Hz, 2 H), 2.59 (q, J = 7.2 Hz, 2 H), 2.47 (s, 3 H), 2.32 (s, 6 H); ESI HRMS m/z Calcd for C ₂₆ H ₂₇ N ₃ O ₆ [MNa ⁺ ]: 500.1798, found: 500.1794; ESIMS m/z (relative intensity) 500 (MNa ⁺ , 100).

5, _l S'-Dimethyl 5,5'-(4-(5-Methyl-l,3,4-oxadiazol-2-yl)but-l-ene-l,l-diyl)bi s(2- methoxy-3-methylbenzothioate) (51). The general Stille coupling procedure was followed using stannane 111 (165 mg, 0.266 mmol), iodide 81 (114 mg, 0.354 mmol), cesium fluoride (160 mg, 1.05 mmol), Pd(PPh ₃ ) ₄ (32 mg, 0.029 mmol), and copper(I) iodide (17 mg, 0.089 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 18.5 h. The crude products were purified by column chromatography (100 mL silica, 1.5 in diameter) using an ethyl acetate-hexanes gradient (50-66%). The product was isolated as a beige oil (81 mg, 59%): IR (neat) 2928, 2867, 1995, 1793, 1674, 1644, 1595, 1570, 1476, 1419, 1378, 1362, 1307, 1244, 1193, 1159, 1133, 1045, 1001 cm ⁴ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.35 (dd, J = 6.6, 2.4 Hz, 2 H), 7.09 (m, 1 H), 7.06 (m, 1 H), 6.01 (t, J = 7.5 Hz, 1 H), 3.87 (s, 3 H), 3.80 (s, 3 H), 2.93 (t, J = 7.5 Hz, 2 H), 2.58 (q, J = 7.5 Hz, 2 H), 2.49 (s, 3 H), 2.43 (s, 3 H), 2.39 (s, 3 H), 2.33 (s, 3 H), 2.27 (s, 3 H); ESIMS m/z (relative intensity) 549 (MNa ⁺ , 100), 497 (MH ⁺ - SCH ₃ + H ₂ O, 59). Anal. (C ₂₇ H ₃₀ N ₂ O ₅ S ₂ ) C, H, N.

(Z)-S-Methyl 2-Methoxy-5-(l-(3-methoxy-7-methylbenzo[rf]isoxazol-5-yl)-4- (5- methyl-l,3,4-oxadiazol-2-yl)but-l-enyl)-3-methylbenzothioate (52). The general Stille coupling procedure was followed using stannane 111 (140 mg, 0.225 mmol), iodide 83 (84 mg, 0.291 mmol), cesium fluoride (127 mg, 0.836 mmol), Pd(PPh ₃ ) ₄ (28 mg, 0.024 mmol), and copper(I) iodide (13 mg, 0.068 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 14 h. The crude products were purified by column chromatography (60 mL silica, 1.5 in

diameter) using an ethyl acetate-hexanes gradient (50-100%). The desired product was isolated as a pale, yellow oil (67 mg, 62%): IR (neat) 2929, 2862, 2230, 1775, 1675, 1641, 1610, 1596, 1570, 1547, 1495, 1477, 1448, 1418, 1394, 1316, 1284, 1240 cm- ¹ ; ¹ B NMR (300 MHz, CDCl ₃ ) δ 7.35 (d, J = 2.1 Hz, 1 H), 7.17 (s, 1 H), 7.16 (s, 1 H), 7.05 (d, / = 2.1 Hz, 1 H), 6.01 (t, J= 7.5 Hz, 1 H), 4.13 (s, 3 H), 3.87 (s, 3 H), 2.95 (t, J = 7.5 Hz, 2 H), 2.61 (q, J = 7.5 Hz, 2 H), 2.48 (s, 3 H), 2.45 (s, 3 H), 2.44 (s, 3 H), 2.32 (s, 3 H); ESIMS m/z (relative intensity) 516 (MNa ⁺ , 100). Anal. (C ₂₆ H ₂₇ N ₃ O ₅ S) C, H, N.

(Z)-S-Methyl 5-( 1 -(2,7-Dimethyl-3-oxo-2,3-dihydrobenzo[d]isoxazol-5-yl)-4-(5- methyl-l,3,4-oxadiazol-2-yl)but-l-enyl)-2-methoxy-3-methylbe nzothioate (53). The general Stille coupling procedure was followed using stannane 111 (162 mg, 0.261 mmol), iodide 85 (99 mg, 0.342 mmol), cesium fluoride (150 mg, 0.987 mmol), Pd(PPh ₃ ) ₄ (29 mg, 0.024 mmol), and copper(I) iodide (16 mg, 0.084 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 15 h. The crude products were purified by column chromatography (60 mL silica, 1.5 in diameter) using ethyl acetate as the eluant. The desired product was recrystallized from acetone-hexanes (1:3) to afford an off-white solid (84 mg, 65%): mp 123-124 °C. IR

(CHCl ₃ ) 2929, 2868, 2238, 1689, 1643, 1615, 1596, 1592, 1490, 1436, 1377, 1308, 1243, 1226, 1192, 1155, 1126, 1042, 1000 cm ^"1 ; ¹ H NMR (300 MHz, methanol-^) δ 7.47 (s, 1 H), 7.29 (s, 1 H), 7.24 (d, J = 1.8 Hz, 1 H), 7.16 (s, 1 H), 6.19 (t, J = 7.5 Hz, 1 H), 3.85 (s, 3 H), 3.68 (s, 3 H), 3.01 (t, J = 7.2 Hz, 2 H), 2.60 (q, / = 7.5 Hz, 2 H), 2.46 (s, 3 H), 2.43 (s, 3 H), 2.38 (s, 3 H), 2.34 (s, 3 H); ESIMS m/z (relative intensity) 516 (MNa ⁺ , 100), 464 (MH ⁺ - SCH ₃ + H ₂ O, 81). Anal. (C ₂₆ H ₂₇ N ₃ O ₅ S) C, H, N.

(E)-5-Methyl 5-(l-(3,7-Dimethyl-2-oxo-2,3-dihydrobenzo[6rioxazol-5-yl)-4- (5- methyl-l,3,4-oxadiazol-2-yl)but-l-enyl)-2-methoxy-3-methylbe nzothioate (54). The general Stille coupling procedure was followed using stannane 111 (118 mg, 0.190 mmol), iodide 82 (68 mg, 0.235 mmol), cesium fluoride (107 mg, 0.704 mmol), Pd(PPh ₃ ) ₄ (23 mg, 0.020 mmol), and copper(I) iodide (8 mg, 0.042 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 14 h. The crude products were purified by preparative thin layer chromatography using 66% ethyl acetate-hexanes as the eluant (developed 4 times). The product was isolated as a clear oil (39 mg, 43%): IR (CHCl ₃ ) 2925, 2853, 2252, 1772, 1641, 1597, 1571, 1463, 1376, 1318, 1246, 1153, 1045 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.35 (d, J = 2.1 Hz, 1 H), 7.05 (d, J = 1.8 Hz, 1 H), 6.73 (s, 1 H), 6.56 (d, J = 1.5 Hz, 1 H), 5.98 (t, J = 7.5 Hz, 1 H), 3.87 (s, 3 H), 3.34 (s, 3 H), 2.95 (t, J = 7.5 Hz, 2 H), 2.61 (q, J = 7.5 Hz, 2 H), 2.48 (s, 3 H), 2.45 (s, 3 H), 2.32 (s, 6 H); ESMS m/z (relative intensity) 516 (MNa ⁺ , 100). Anal. (C ₂₆ H ₂₇ N ₃ O ₅ S) C H ₁ N.

(Z)-5-Methyl 5-(l-(3-Cyanophenyl)-4-(5-methyl-l,3,4-oxadiazol-2-yl)but-l- enyl)-2-methoxy-3-methylbenzothioate (55). The general Stille coupling procedure was followed using stannane 111 (138 mg, 0.222 mmol), bromide 86 (61 mg, 0.340 mmol), cesium fluoride (132 mg, 0.869 mmol), Pd(PPh ₃ ) ₄ (90 mg, 0.078 mmol), and copper(I) iodide (33 mg, 0.173 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 14 h. The crude products were purified by column chromatography (100 mL silica, 1.5 in diameter) using an ethyl acetate-hexanes gradient (50-100%) and the desired product was further purified by preparative thin layer chromatography using 2: 1 ethyl acetate-hexanes as the eluant. The product was isolated as a clear film (21 mg, 22%): IR (neat) 3065, 2928, 2851, 2229, 1674, 1643, 1596, 1570, 1478, 1416, 1390, 1374, 1313, 1278, 1239, 1178, 1133, 1041, 1000 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.54-7.32 (m, 5 H), 7.04 (d, J= 1.8 Hz, 1 H), 6.12 (t, J = 7.5 Hz, 1 H), 3.88 (s, 3 H), 2.95 (t, / = 7.5 Hz, 2 H), 2.62 (q, J = 7.5 Hz, 2 H), 2.49 (s, 3 H), 2.43 (s, 3 H), 2.34 (s, 3 H); ESIMS m/z (relative intensity) 456 (MNa ⁺ , 100), 404 (MH ⁺ - SCH ₃ + H ₂ O, 23). Anal. (C ₂₄ H ₂₃ N ₃ O ₃ S) C, H, N. (Z)-S-Methyl 5-( 1 -(4-Cyanophenyl)-4-(5-methyl- 1 ,3 ,4-oxadiazol-2-yl)but- 1 - enyl)-2-methoxy-3-methylbenzothioate (56). The general Stille coupling procedure was followed using stannane 111 (162 mg, 0.261 mmol), bromide 87 (64 mg, 0.340 mmol), cesium fluoride (179 mg, 1.18 mmol), Pd(PPh ₃ ) ₄ (33 mg, 0.031 mmol), and coρper(I) iodide (18 mg, 0.091 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 24 h. The crude products were purified by column chromatography (80 mL silica, 1.5 in. diameter) using an ethyl acetate-hexanes gradient (50-66%) and the desired product was further purified by preparative thin layer chromatography using 50% ethyl acetate-hexanes as the eluant. The product was isolated as colorless, opaque oil (20 mg, 17%): IR (neat) 2929, 2226, 1674, 1641, 1597, 1570, 1502, 1476, 1409, 1312, 1231, 1136, 1040, 1001 cm ^"1 ; ¹ H NMR (SOO MHZ ₅ CDCI ₃ ) δ 7.55 (d, J = 8.4 Hz, 2 H), 7.32-7.25 (m, 3 H), 7.04 (d, J = 2.1 Hz, 1 H), 6.19 (t, J= 7.5 Hz, 1 H), 3.87 (s, 3 H), 2.95 (t, J = 7.5 Hz, 2 H), 2.63 (q, / = 7.5 Hz, 2 H), 2.48 (s, 3 H), 2.45 (s, 3 H), 2.33 (s, 3 H); ESI HRMS m/z Calcd for C ₂₄ H ₂₃ N ₃ O ₃ S [MNa ⁺ ]: 456.1358, found: 456.1362; ESMS m/z (relative intensity) 456 (MNa ⁺ , 100), 404 (MH ⁺ - SCH ₃ + H ₂ O, 21).

(Z)-5-Methyl 5-(l-(Benzo[d]isoxazol-5-yl)-4-(5-methyl-l,3,4-oxadiazol-2-y l)but- l-enyl)-2-methoxy-3-methylbenzothioate (57). The general Stille coupling procedure was followed using stannane 111 (118 mg, 0.190 mmol), iodide 84 (75 mg, 0.306 mmol), cesium fluoride (112 mg, 0.737 mmol), Pd(PPh ₃ ) ₄ (24 mg, 0.021 mmol), and copper(I) iodide (40 mg, 0.210 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 45 min. The crude products were purified by column chromatography (60 mL silica, 1.5 in diameter)

using an ethyl acetate-hexanes gradient (50-100%). The product was isolated as yellow oil (20 mg, 23%): IR (CDCl ₃ ) 2928, 2862, 2227, 1672, 1643, 1598, 1569, 1508, 1473, 1416, 1301, 1244, 1226, 1139 cm ^"1 ; ¹ U NMR (300 MHz, ^-methanol) δ 7.30 (d, J = 2.1 Hz, 1 H), 7.28 (d, J = 2.4 Hz, 1 H), 7.24 (d, J = 2.4 Hz, 2.4 Hz), 7.21 (d, J = 1.8 Hz, 1 H), 7.12 (dd, J = 2.1, 0.6 Hz, 1 H), 6.86 (d, J = 8.7 Hz, 1 H), 6.08 (t, J = 7.5 Hz, 1 H), 3.84 (s, 3 H), 2.98 (t, J = 7.2 Hz, 2 H), 2.55 (q, J = 7.2 Hz, 2 H), 2.45 (s, 3 H), 2.43 (s, 3 H), 2.33 (s, 3 H); ESI HRMS m/z Calcd for C ₂₄ H ₂₃ N ₃ O ₄ S [MH ⁺ ]: 450.1488, found: 450.1490; ESMS m/z (relative intensity) 450 (MH ⁺ , 51), 420 (MH ⁺ - SCH ₃ + H ₂ O, 100).

(Z)-5-Methyl 5-(l-(3,7-Dimethyl-2-oxo-2,3-dihydrobenzo[J]oxazol-5-yl)-4-( 5- methyl-l,3,4-oxadiazol-2-yl)but-l-enyl)-2-methoxy-3-methylbe nzothioate (58). The general Stille coupling procedure was followed using stannane 115 (213 mg, 0.362 mmol), iodide 81 (139 mg, 0.434 mmol), cesium fluoride (202 mg, 1.33 mmol), Pd(PPh ₃ ) ₄ (46 mg, 0.040 mmol), and copper(I) iodide (15 mg, 0.070 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 3.5 h. The crude products were absorbed onto silica (15 mL) and purified by column chromatography (60 mL silica, 1.5 in diameter) using an ethyl acetate-hexanes gradient (50-100%). The desired product was further purified by preparative thin layer chromatography using 70% ethyl acetate-toluene as the eluant. The product was isolated as a white, microcrystalline solid after being exposed to hi vacuum conditions (92 mg, 51%): mp: 50-53 ⁰ C. IR (neat) 2928, 2857, 1779, 1674, 1640, 1618, 1595, 1473, 1420, 1375, 1350, 1298, 1248, 1220, 1177, 1156, 1121, 1057, 1030, 1000 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) 57.35 (d, J= 2.4 Hz, 1 H), 7.12 (d, J = 2.4 Hz, 1 H), 6.68 (s, 1 H), 6.52 (s, 1 H), 6.04 (t, J = 7.5 Hz, 1 H), 3.80 (s, 3 H), 3.37 (s, 3 H), 2.92 (t, J = 7.5 Hz, 2 H), 2.57 (q, 7 = 7.5 Hz, 2 H), 2.43 (s, 3 H), 2.39 (s, 3 H), 2.27 (s, 3 H); ESEVIS m/z (relative intensity) 516 (MNa ⁺ , 100), 494 (MH ⁺ , 29), 464 (MH ⁺ - SCH ₃ + H ₂ O, 81). Anal. (C ₂₆ H ₂₇ N ₃ O ₅ S) C, H, N. (E)-5'-Methyl 2-Methoxy-5-(l-(3-methoxy-7-methylbenzo[if]isoxazol-5-yl)-4- (5- methyl-l,3,4-oxadiazol-2-yl)but-l-enyl)-3-methylbenzothioate (59). The general Stille coupling procedure was followed using stannane 119(164 mg, 0.278 mmol), iodide 81 (178 mg, 0.553 mmol), cesium fluoride (153 mg, 1.01 mmol), Pd(PPh ₃ ) ₄ (33 mg, 0.029 mmol), and copper(I) iodide (55 mg, 0.288 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 45 min. The crude products were purified by column chromatography (60 mL silica, 1.5 in diameter) using an ethyl acetate-hexanes gradient (55-66%). The product was isolated from the column as an orange, amorphous solid (115 mg, 84%): IR (neat) 2928, 2862, 1675, 1644, 1614, 1595, 1570, 1547, 1498, 1475, 1423, 1389, 1350, 1311, 1251, 1233, 1195, 1181, 1157, 1121, 1042, 1001 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.34 (d, J = 2.4 Hz, 1 H), 7.19 (s, 1 H),

7.10 (d, J = 1.5 Hz, 1 H), 7.00 (s, 1 H), 6.06 (t, J = 7.5 Hz, 1 H), 4.17 (s, 3 H), 3.80 (s, 3 H), 2.92 (t, J = 7.5 Hz, 2 H), 2.56 (q, / = 7.5 Hz, 2 H), 2.49 (s, 3 H), 2.47 (s, 3 H), 2.41 (s. 3 H), 2.26 (s, 3 H); ESI HRMS m/z Calcd for C ₂₆ H ₂₇ N ₃ O ₅ S [MH ⁺ ]: 494.1750, found: 494.1742; ESIMS m/z (relative intensity) 516 (MNa ⁺ , 13), 494 (MH ⁺ , 15), 464 (MH ⁺ - SCH ₃ + H ₂ 0, 100). (£)-S-Methyl 5-(l-(2,7-Dimethyl-3-oxo-2,3-dihydrobenzo[i]isoxazol-5-yl)-4 -(5- methyl-l,3,4-oxadiazol-2-yl)but-l-enyl)-2-methoxy-3-methylbe nzothioate (60). The general Stille coupling procedure was followed using stannane 123 (134 mg, 0.228 mmol), iodide 81 (88 mg, 0.273 mmol), cesium fluoride (123 mg, 0.810 mmol), Pd(PPh ₃ ) ₄ (27 mg, 0.023 mmol), and copper(I) iodide (49 mg, 0.257 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 1 h. The crude products were purified by column chromatography (40 mL silica, 1.5 in diameter) using ethyl acetate as the eluant. The product was isolated from the column as an orange oil (86 mg, 76%): IR (neat) 2926, 2855, 1778, 1692, 1615, 1595, 1570, 1493, 1477, 1438, 1376, 1301, 1251, 1224, 1193, 1121, 1047 1000 cm ¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.41 (d, J= 1.2 Hz, 1 H), 7.33 (d, /= 2.4 Hz, 1 H), 7.09 (d, J = 2.4 Hz, 2 H), 6.05 (t, / = 7.5 Hz, 1 H), 3.80 (s, 3 H), 3.70 (s, 3 H), 2.92 (t, / = 7.5 Hz, 2 H), 2.56 (q, / = 7.5 Hz, 2 H), 2.49 (s, 3 H), 2.42 (s, 3 H), 2.38 (s, 3 H), 2.26 (s, 3 H); ESIMS m/z (relative intensity) 516 (MNa ⁺ , 8), 494 (MH ⁺ , 48), 464 (MH ⁺ - SCH ₃ + H ₂ O, 100). Anal. (C ₂₆ H ₂₇ N ₃ O ₅ S) C, H, N.

(E)- _l S-Methyl 5-(l-(3-Cyanophenyl)-4-(5-methyl-l,3,4-oxadiazol-2-yl)but-l- enyl)-2-methoxy-3-methylbenzothioate (61). The general Stille coupling procedure was followed using stannane 127 (138 mg, 0.261 mmol), iodide 81 (128 mg, 0.397 mmol), cesium fluoride (157 mg, 1.03 mmol), Pd(PPh ₃ ) ₄ (37 mg, 0.032 mmol), and copper(I) iodide (54 mg, 0.284 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 1 h. The crude products were purified by column chromatography (50 mL silica, 1.5 in diameter) using an ethyl acetate-hexanes gradient (50-66%). The desired product was isolated as a yellow oil (85 mg, 75%): IR (neat) 3063, 2929, 2860, 2229, 1674, 1639, 1595, 1570, 1477, 1418, 1356,

1304, 1227, 1183, 1130, 1049, 999 cm ¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) 5 7.64 (dt, 7 = 7.8, 1.5 Hz, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 7.39 (tt, J = 7.8, 1.5 Hz, 2 H), 7.30 (d, J = 2.4 Hz, 1 H), 7.07 (d, J = 1.8 Hz, 1 H), 6.11 (t, / = 7.5 Hz, 1 H), 3.81 (s, 3 H), 2.94 (t, J = 7.5 Hz, 2 H), 2.55 (q, / = 7.5 Hz, 2 H), 2.50 (s, 3 H), 2.43 (s, 3 H), 2.27 (s, 3 H); ESMS m/z (relative intensity) 434 (MH ⁺ , 8), 404 (MH ⁺ - SCH ₃ + H ₂ 0, 100). Anal (C ₂₄ H ₂₃ N ₃ O ₃ S) C, H, N.

(E)-5-Methyl 5-(l-(4-Cyanophenyl)-4-(5-methyl-l,3,4-oxadiazol-2-yl)but-l- enyl)-2-methoxy-3-methylbenzothioate (62). The general Stille coupling procedure was followed using stannanel31 (118 mg, 0.223 mmol), iodide 81 (102 mg, 0.317 mmol), cesium fluoride (131 mg, 0.862 mmol), Pd(PPh ₃ ) ₄ (28 mg, 0.024 mmol), and coρρer(I) iodide (43 mg,

0.226 mmol) in anhydrous DMF (3 rnL). The reaction mixture was allowed to stir for 1 h. The crude products were purified by column chromatography (60 mL silica, 1.5 in diameter) using an ethyl acetate-hexanes gradient (50-66%). The desired product was isolated as an orange oil (74 mg, 77%): IR (neat) 2929, 2856, 2227, 1733, 1674, 1643, 1595, 1570, 1503, 1476, 1421, 1357, 1303, 1251, 1222, 1178, 1136, 1109, 1048, 999 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) 57.69 (d, J= 8.1 Hz, 2 H), 7.30 (d, J = 2.4 Hz, 1 H), 7.24 (d, J= 8.1 Hz, 2 H), 7.08 (d, J = 2.1 Hz, 1 H), 6.10 (t, J= 7.5 Hz, 1 H), 3.80 (s, 3 H), 2.93 (t, J= 7.5 Hz, 2 H), 2.56 (q, J = 7.5 Hz, 2 H), 2.48 (s, 3 H), 2.42 (s, 3 H), 2.27 (s, 3 H); ESI HRMS m/z Calcd for C ₂₄ H ₂₃ N ₃ O ₃ S [MH ⁺ ]: 434.1538, found: 434.1529; ESMS m/z (relative intensity) 434 (MH ⁺ , 16), 404 (MH ⁺ - SCH ₃ + H ₂ 0, 100).

5,5'-Dimethyl 5,5'-(5-(5-Methyl-l,3,4-oxadiazol-2-yl)pent-l-ene-l,l-diyl)b is(2- methoxy-3-methylbenzothioate) (63). The general Stille coupling procedure was followed using stannane 113 (213 mg, 0.335 mmol), iodide 81 (131 mg, 0.402 mmol), cesium fluoride (215 mg, 1.42 mmol), Pd(PPh ₃ ) ₄ (78 mg, 0.067 mmol), and copper(I) iodide (13 mg, 0.068 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 13.5 h. The crude products were purified by column chromatography (60 mL silica, 1.5 in diameter) using an ethyl acetate-hexanes gradient (50-66%). The product was isolated as an orange oil (126 mg, 70%): IR (neat) 2929, 2866, 1675, 1644, 1595, 1570, 1476, 1421, 1378, 1362, 1308, 1244, 1228, 1192, 1154, 1133, 1043, 1002 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.39 (d, J = 2.4 Hz, 1 H), 7.36 (d, J = 1.8 Hz, 1 H), 7.08 (m, 2 H), 5.99 (t, J = 7.5 Hz, 1 H), 3.87 (s, 3 H), 3.80 (s, 3 H), 2.80 (t, J = 7.5 Hz, 2 H), 2.47 (s, 3 H), 2.45 (s, 3 H), 2.43 (s, 3 H), 2.32 (s, 3 H), 2.27 (s, 3 H), 2.22 (q, / = 7.5 Hz, 2 H), 1.93 (p, J = 7.5 Hz, 2 H); ESIMS m/z (relative intensity) 563 (MNa ⁺ , 100), 533 (MH ⁺ , 9). Anal. (C ₂₈ H ₃₂ N ₂ O ₅ S ₂ ) C, H, N.

(Z)-5-Methyl 2-Methoxy-5-(l-(3-methoxy-7-methylbenzo[J]isoxazol-5-yl)-5-( 5- methyl-l,3,4-oxadiazol-2-yl)pent-l-enyl)-3-methylbenzothioat e (64). The general Stille coupling procedure was followed using stannane 113 (411 mg, 0.647 mmol), iodide 83 (231 mg, 0.779 mmol), cesium fluoride (443 mg, 2.92 mmol), Pd(PPh ₃ ) ₄ (78 mg, 0.067 mmol), and copper(I) iodide (29 mg, 0.152 mmol) in anhydrous DMF (6 mL). The reaction mixture was allowed to stir for 15 h. The crude products were absorbed onto silica (20 mL) and purified by column chromatography (100 mL silica, 1.5 in diameter) using an ethyl acetate-hexanes gradient (50-100%). The desired product was isolated as an amorphous, yellow solid (212 mg, 65%): IR (neat) 2930, 2867, 1675, 1642, 1614, 1596, 1570, 1547, 1494, 1477, 1455, 1424, 1394, 1315, 1275, 1240, 1223, 1042 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.38 (d, J = 2.1 Hz, 1 H), 7.19 (s, 1 H), 7.18 (s, 1 H), 7.09 (d, J = 2.1 Hz, 1 H), 6.01 (t, J = 7.5 Hz, 1 H), 4.15 (s, 3 H), 3.89 (s, 3 H),

2.83 (t, J = 7.5 Hz, 2 H), 2.48 (s, 3 H), 2.47 (s, 3 H), 2.46 (s, 3 H), 2.33 (s, 3 H), 2.26 (q, / = 7.5 Hz, 2 H), 1.95 (p, J = 7.5 Hz, 2 H); ESIMS m/z (relative intensity) 508 (MH ⁺ , 5), 478 (MH ⁺ - SCH ₃ + H ₂ 0, 100), 460 (MH ⁺ - SCH ₃ , 13). Anal. (C ₂₇ H ₂₉ N ₃ O ₅ S) C, H, N.

(Z)-5-Methyl 5-(l-(2,7-Dimethyl-3-oxo-2,3-dihydrobenzo[J]isoxazol-5-yl)-5 -(5- methyl-l,3,4-oxadiazol-2-yl)pent-l-enyl)-2-methoxy-3-methylb enzothioate (65). The general Stille coupling procedure was followed using stannane 113 (154 mg, 0.242 mmol), iodide 85 (90 mg, 0.311 mmol), cesium fluoride (134 mg, 0.882 mmol), Pd(PPh ₃ ) ₄ (32 mg, 0.028 mmol), and copper(I) iodide (50 mg, 0.263 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 1 h. The crude products were purified by column chromatography (60 mL silica, 1.5 in diameter) using an ethyl acetate-hexanes gradient (50-100%). The desired product was isolated as a yellow oil (90 mg, 73%): IR (neat) 3479, 2929, 2868, 1693, 1681, 1646, 1596, 1570, 1489, 1434, 1401, 1377, 1242, 1226, 1126, 1043 cm ^"1 ; ¹ H NMR (300 MHz, methanol-^) δ 7.47 (s, 1 H), 7.30 (s, 2 H), 7.18 (s, 1 H), 6.17 (t, J = 7.5 Hz, 1 H), 3.84 (s, 3 H), 3.70 (s, 3 H), 2.86 (t, / = 7.5 Hz, 2 H), 2.45 (s, 3 H), 2.42 (s, 3 H), 2.39 (s, 3 H), 2.33 (s, 3 H), 2.24 (q, J = 7.5 Hz, 2 H), 1.95 (p, J = 7.5 Hz, 2 H); ESI HRMS m/z Calcd for C ₂₇ H ₂₉ N ₃ O ₅ S [MH ⁺ ]: 508.1906, found: 508.1904; ESIMS m/z (relative intensity) 530 (MNa ⁺ , 100).

(E)-S-Methyl 5-(l-(3,7-Dimethyl-2-oxo-2,3-dihydrobenzo[<i]oxazol-5-yl) -5-(5- methyl-l,3,4-oxadiazol-2-yl)pent-l-enyl)-2-methoxy-3-methylb enzothioate (66). The general Stille coupling procedure was followed using stannane 113 (202 mg, 0.319 mmol), iodide 82 (140 mg, 0.533 mmol), cesium fluoride (195 mg, 1.28 mmol), Pd(PPh ₃ ) ₄ (38 mg, 0.033 mmol), and copper(I) iodide (16 mg, 0.084 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 14 h. The crude products were purified by preparative thin layer chromatography using ethyl acetate as the eluant. The desired was further purified two more times by preparative thin layer chromatography for which 66% ethyl acetate-hexanes was used as the developing solution for the first plate and 80% ethyl acetate-toluene was used for the second. The desired product was isolated as an opaque oil (6 mg, 4%). IR (neat) 2929, 2862, 1777, 1675, 1641, 1595, 1570, 1472, 1367, 1333, 1303, 1245, 1227, 1149, 1123, 1044, 1002 cm ^{" 1} 1 ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.37 (d, J = 2.1 Hz, 1 H), 7.08 (d, J = 2.1 Hz, 1 H), 6.74 (s, 1 H), 6.57 (s, 1 H), 5.97 (t, J = 7.5 Hz, 1 H), 3.88 (s, 3 H), 3.35 (s, 3 H), 2.82 (t, J = 7.5 Hz, 2 H), 2.47 (s, 3 H), 2.45 (s, 3 H), 2.33 (s, 6 H), 2.25 (q, / = 7.5 Hz, 2 H), 1.95 (p, /= 7.5 Hz, 2 H); ESEVIS m/z (relative intensity) 530 (MNa ⁺ , 24), 508 (MH ⁺ , 3), 478 (MH ⁺ - SCH ₃ + H ₂ 0, 100). Anal. (C ₂₇ H ₂₉ N ₃ O ₅ S) C, H, N.

(Z)-5-Methyl 5-(l-(3-Cyanophenyl)-5-(5-methyl-l,3,4-oxadiazol-2-yl)pent-l - enyl)-2-methoxy-3-methylbenzothioate (67). The general Stille coupling procedure was

followed using stannane 113 (92 mg, 0.145 mmol), bromide 86 (41 mg, 0.225 mmol), cesium fluoride (87 mg, 0.572 mmol), Pd(PPh ₃ ) ₄ (18 mg, 0.018 mmol), and copper© iodide (16 mg, 0.084 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 30 min. The crude products were purified by column chromatography (60 mL silica, 1 in diameter) using an ethyl acetate-hexanes gradient (50-66%) and the desired product was further purified via preparative thin layer chromatography using 66% ethyl acetate-hexanes as the eluant (developed twice). The pure product was obtained as a light, yellow oil (33 mg, 51%): IR (neat) 3063, 2930, 2866, 2228, 1995, 1726, 1675, 1643, 1595, 1570, 1478, 1416, 1394, 1378, 1239, 1175, 1133, 1043, 1000 cm ^'1 ; ¹ U NMR (300 MHz, methanol-^) δ 7.61-7.55 (m, 2 H), 7.47-7.45 (m, 2 H), 7.29 (s, 1 H), 7.18 (s, 1 H), 6.26 (t, J = 7.5 Hz, 1 H), 3.84 (s, 3 H), 2.85 (t, J = 7.5 Hz, 2 H), 2.45 (s, 3 H), 2.43 (s, 3 H), 2.33 (s, 3 H), 2.25 (q, J = 7.5 Hz, 2 H), 1.96 (p, / = 7.5 Hz, 2 H); ESIMS m/z (relative intensity) 470 (MNa ⁺ , 52), 418 (MH ⁺ - SCH ₃ + H ₂ 0, 100), 400 (MH ⁺ - SCH ₃ , 76). Anal. (C ₂₅ H ₂₅ N ₃ O ₃ S) C, H, N.

(Z)-5-Methyl 5-(l-(4-Cyanoρhenyl)-5-(5-methyl-l,3,4-oxadiazol-2-yl)pent- l- enyl)-2-methoxy-3-methylbenzothioate (68). The general Stille coupling procedure was followed using stannane 113 (171 mg, 0.269 mmol), bromide 87 (71 mg, 0.390 mmol), cesium fluoride (173 mg, 1.14 mmol), Pd(PPh ₃ ) ₄ (36 mg, 0.031 mmol), and copper(I) iodide (26 mg, 0.135 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 30 min. The crude products were purified by column chromatography (100 mL silica, 1.5 in diameter) using an ethyl acetate-hexanes gradient (50-66%). The product was isolated from the column as a yellow oil (71 mg, 59%): IR (neat) 2931, 2867, 2226, 1674, 1643, 1599, 1570, 1503, 1476, 1409, 1231, 1179, 1136, 1043, 1000 cm ^"1 ; ¹ H NMR (300 MHz, methanol-^) δ 7.64 (dd, J= 6.9, 1.8 Hz, 2 H), 7.37 (dd, J = 6.6, 1.8 Hz, 2 H), 7.28 (d, J = 2.1 Hz, 1 H), 7.17 (d, J = 2.1 Hz, 1 H), 6.33 (t, J = 7.5 Hz, 1 H), 3.84 (s, 3 H), 2.85 (t, J = 7.5 Hz, 2 H), 2.46 (s, 3 H), 2.42 (s, 3 H), 2.33 (s, 3 H), 2.25 (q, / = 7.5 Hz, 2 H), 1.96 (p, / = 7.5 Hz, 2 H); ESEvIS m/z (relative intensity) 448 (MH ⁺ , 11), 418 (MH ⁺ - SCH ₃ + H ₂ 0, 100). Anal. (C ₂₅ H ₂₅ N ₃ O ₃ S) C, H, N.

(Z)-S-Methyl 5-( 1 -(3 ,7-Dimethyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-(5- methyl-l,3,4-oxadiazol-2-yl)pent-l-enyl)-2-methoxy-3-methylb enzothioate (69). The general Stille coupling procedure was followed using stannane 117 (160 mg, 0.266 mmol), iodide 81 (127 mg, 0.394 mmol), cesium fluoride (144 mg, 0.948 mmol), Pd(PPh ₃ ) ₄ (38 mg, 0.033 mmol), and copper(I) iodide (56 mg, 0.294 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 1.5 h. The crude products were purified by column chromatography (60 mL silica, 1.5 in diameter) using an ethyl acetate-hexanes gradient (50-80%). The desired product was isolated as a yellow oil (81 mg, 60%): IR (neat) 3534, 2929, 2865, 1779, 1771, 1674, 1641,

1618, 1570, 1471, 1421, 1389, 1375, 1351, 1298, 1242, 1229, 1171, 1153, 1120 cm ¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.37 (d, J= 2.7 Hz, 1 H), 7.11 (d, /= 2.7 Hz, 1 H), 6.71 (s, 1 H), 6.55 (s, 1 H), 6.02 (t, J = 7.5 Hz, 1 H), 3.80 (s, 3 H), 3.38 (s, 3 H), 2.79 (t, J = 7.5 Hz, 2 H), 2.46 (s, 3 H), 2.43 (s, 3 H), 2.39 (s, 3 H), 2.27 (s, 3 H), 2.18 (q, J = 7.5 Hz, 2 H), 1.92 (p, J = 7.5 Hz, 2 H); ESI HRMS m/z Calcd for C ₂₇ H ₂₉ N ₃ O ₅ S [MH ⁺ ]: 508.1906, found: 508.1908; ESIMS m/z (relative intensity) 508 (MH ⁺ , 14), 478 (MH ⁺ - SCH ₃ + H ₂ O, 100), 460 (MH ⁺ - SCH ₃ , 33).

(E)-5-Methyl 2-Methoxy-5-(l-(3-methoxy-7-methylbenzo[J]isoxazol-5-yl)-5-( 5- methyl-l,3,4-oxadiazol-2-yl)pent-l-enyl)-3-methylbenzothioat e (70). The general Stille coupling procedure was followed using stannane 121 (123 mg, 0.204 mmol), iodide 81 (106 mg, 0.329 mmol), cesium fluoride (125 mg, 0.823 mmol), Pd(PPh ₃ ) ₄ (25 mg, 0.022 mmol), and copper(I) iodide (42 mg, 0.221 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 1 h. The crude products were purified by column chromatography (60 mL silica, 1.5 in diameter) using an ethyl acetate-hexanes gradient (50-66%). The desired product was isolated as a yellow, amorphous solid (81 mg, 60%): IR (neat) 2930, 1675, 1596, 1570, 1548, 1498, 1389, 1233, 1042 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.36 (d, J = 2.1 Hz, 1 H),

7.22 (s, 1 H), 7.09 (d, J = 2.1 Hz, 1 H), 7.04 (s, 1 H), 6.05 (t, J = 7.5 Hz, 1 H), 4.17 (s, 3 H), 3.80 (s, 3 H), 2.77 (t, J = 7.5 Hz, 2 H), 2.47 (s, 3 H), 2.45 (s, 3 H), 2.42 (s, 3 H), 2.26 (s, 3 H), 2.12 (q, / = 7.5 Hz, 2 H), 1.91 (p, J = 7.5 Hz, 2 H); ESI HRMS m/z Calcd for C ₂₇ H ₂₉ N ₃ O ₅ S [MH ⁺ ]: 508.1906, found: 508.1905; ESMS m/z (relative intensity) 508 (MH ⁺ , 8), 408 (MH ⁺ - SCH ₃ + H ₂ O, 100).

(E)-5-Methyl 5-(l-(2,7-Dimethyl-3-oxo-2,3-dihydrobenzo[J]isoxazol-5-yl)-5 -(5- methyl-l,3,4-oxadiazol-2-yl)pent-l-enyl)-2-memoxy-3-methylbe nzothioate (71). The general Stille coupling procedure was followed using stannane 125 (127 mg, 0.211 mmol), iodide 81 (116 mg, 0.360 mmol), cesium fluoride (138 mg, 0.908 mmol), Pd(PPh ₃ ) ₄ (27 mg, 0.023 mmol), and copper(I) iodide (45 mg, 0.236 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 45 min. The crude products were purified by column chromatography (60 mL silica, 1.5 in diameter) using an ethyl acetate-hexanes gradient (50-100%). The desired product was isolated as a yellow oil (80 mg, 75%): IR (neat) 2929, 2865, 1694, 1682, 1644, 1615, 1596, 1570, 1493, 1477, 1439, 1422, 1395, 1365, 1303, 1251, 1224, 1191, 1173, 1154, 1123 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.43 (d, J = 0.9 Hz, 1 H), 7.34 (d, J = 2.4 Hz, 1 H), 7.11 (s, 1 H), 7.08 (d, J= 1.8 Hz, 1 H), 6.03 (t, /= 7.5 Hz, 1 H), 3.80 (s, 3 H), 3.70 (s, 3 H), 2.77 (t, J = 7.5 Hz, 2 H), 2.42 (s, 3 H), 2.38 (s, 3 H), 2.35 (s, 3 H), 2.26 (s, 3 H), 2.19 (q, J = 7.5 Hz, 2 H), 1.91 (p, J = 7.5 Hz, 2 H); ESIMS m/z (relative intensity) 530 (MNa ⁺ , 27), 478 (MH ⁺ - SCH ₃ + H ₂ O, 100). Anal. (C ₂₇ H ₂₉ N ₃ O ₅ S) C, H, N.

(E)-5-Methyl 5-(l-(3-Cyanophenyl)-5-(5-methyl-l,3,4-oxadiazol-2-yl)pent-l - enyl)-2-methoxy-3-methylbenzothioate (72). The general Stille coupling procedure was followed using stannane 129 (86 mg, 0.159 mmol), iodide 81 (68 mg, 0.211 mmol), cesium fluoride (106 mg, 0.698 mmol), Pd(PPh ₃ ) ₄ (21 mg, 0.018 mmol), and copper(I) iodide (40 mg, 0.210 mmol) in anhydrous DMF (2 mL). The reaction mixture was allowed to stir for 1 h. The crude products were purified by column chromatography (60 mL silica, 1.5 in diameter) using an ethyl acetate-hexanes gradient (50-66%). The product was isolated from the column as an orange, viscous oil (51 mg, 72%): IR (neat) 3060, 2930, 2862, 2229, 1995, 1674, 1643, 1596, 1570, 1478, 1418, 1307, 1252, 1227, 1173, 1130, 1048, 1000 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.63 (dt, J = 7.5, 1.5 Hz, 1 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.43-7.38 (m, 2 H), 7.32 (d, J = 2.4 Hz, 1 H), 7.06 (d, J = 1.8 Hz, 1 H), 6.08 (t, 7 = 7.5 Hz, 1 H), 3.81 (s, 3 H), 2.79 (t, J = 7.5 Hz, 2 H), 2.77 (s, 3 H), 2.48 (s, 3 H), 2.27 (s, 3 H), 2.18 (q, J = 7.5 Hz, 2 H), 1.93 (p, J = 7.5 Hz, 2 H); ESIMS m/z (relative intensity) 470 (MNa ⁺ , 41), 448 (MH ⁺ , 18), 418 (MH ⁺ - SCH ₃ + H ₂ 0, 100). Anal. (C ₂₅ H ₂₅ N ₃ O ₃ S) C, H, N. (E)-5-Methyl 5-(l-(4-Cyanophenyl)-5-(5-methyl-l,3,4-oxadiazol-2-yl)ρent- l- enyl)-2-methoxy-3-rnethylbenzothioate (73). The general Stille coupling procedure was followed using stannane 133 (179 mg, 0.330 mmol), iodide 81 (158 mg, 0.490 mmol), cesium fluoride (222 mg, 1.46 mmol), Pd(PPh ₃ ) ₄ (42 mg, 0.036 mmol), and copper(I) iodide (50 mg, 0.352 mmol) in anhydrous DMF (3 mL). The reaction mixture was allowed to stir for 1 h. The crude products were purified by column chromatography (60 mL silica, 1.5 in diameter) using an ethyl acetate-hexanes gradient (50-66%) and the desired product was isolated as a highly viscous, yellow oil (103 mg, 70%): IR (neat) 2930, 2868, 2227, 1674, 1643, 1596, 1570, 1500, 1476, 1418, 1305, 1251, 1221, 1136, 1048 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.67 (dd, J = 6.6, 1.5 Hz, 2 H), 7.31 (d, J= 2.4 Hz, 1 H), 7.26 (dd, J= 6.6, 1.5 Hz, 2 H), 7.06 (d, J= 1.8 Hz, 1 H), 6.09 (t, J = 7.5 Hz, 1 H), 3.80 (s, 3 H), 2.79 (t, J = 7.5 Hz, 2 H), 2.47 (s, 3 H), 2.43 (s, 3 H), 2.26 (s, 3 H), 2.19 (q, J = 7.5 Hz, 2 H), 1.93 (p, J = 7.5 Hz, 2 H); εSIMS m/z (relative intensity) 448 (MH ⁺ , 42) 447 (M ⁺ , 51), 418 (MH ⁺ - SCH ₃ + H ₂ 0, 100), 400 (MH ⁺ - SCH ₃ , 37). Anal. (C ₂₅ H ₂₅ N ₃ O ₅ S) C, H, N.

5-Iodo-2-methoxy-3-methylthiobenzoic Acid S-Methyl Ester (81). A flask was charged with benzoic acid 88 (251 mg, 0.859 mmol) and thionyl chloride (3.4 mL). The flask was fitted with a condenser and the system heated at reflux, under argon, for 40 min. The system was allowed to cool to room temperature and the reaction mixture was azeotropically condensed in vacuo with benzene (2 mL). More benzene (3 mL) was added and the reaction mixture was concentrated again to azeotrope any remaining thionyl chloride (this step was

repeated two more times). A white solid was obtained after concentrating the reaction mixture (occasionally the material is a yellow oil). The solid was dissolved in benzene (3 mL) and sodium thiomethoxide (77 mg, 1.10 mmol) was added to the solution. The heterogeneous mixture was allowed to stir at room temperature for 15 h and was then diluted with ethyl acetate (5 mL) and water (5 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3 x 15 mL). Organic extracts were combined, dried over magnesium sulfate, filtered, and condensed in vacuo to afford an oil. The product was purified by column chromatography (30 mL silica, 0.5 in diameter) using 5% ethyl acetate-hexanes as the eluant. The product was isolated as a clear oil (215 mg, 78%): IR (Neat) 3066, 2926, 1995, 1674, 1642, 1565, 1465, 1414, 1255, 1173, 1039 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.83 (dd, J = 2.4, 0.6 Hz, 1 H), 7.65 (dd, J = 2.4, 0.6 Hz, 1 H), 3.80 (s, 3 H), 2.46 (s, 3 H), 2.28 (s, 3 H); EMS m/z (relative intensity) 322 (M ⁺ , 2), 275 (M ⁺ - SCH ₃ , 100). Anal. (C ₁₀ Hi iIO ₂ S) C, H.

5-Iodobenzo[<i]isoxazole (84). An oven-dried flask (25 mL) was charged with oxime 90 (180 mg, 0.684 mmol), triphenylphosphine (192 mg, 0.720 mmol), and anhydrous THF (4 mL). The flask was maintained under an argon atmosphere and diisopropylazodicarboxylate (DIAD) (0.14 mL, 0.719 mmol) was added dropwise. The reaction mixture was allowed to stir at room temperature for 1 h before more triphenylphosphine (30 mg) and DIAD (0.5 mL) were added. After the reaction mixture was allowed to stir for another hour, the mixture was condensed in vacuo and the remaining residue was loaded onto a short column of silica (20 mL, 0.5 in diameter). The product was eluted with 20% ethyl acetate-hexanes (80 mL) and the eluate was condensed in vacuo to afford a yellow solid. The material was recrystallized from acetone and hexanes to afford the product as a white, crystalline solid (77 mg, 46%): mp 102-103 ⁰ C. IR (CDCl ₃ ) 3085, 3056, 1995, 1896, 1782, 1755, 1724, 1621, 1597, 1506, 1435, 1417, 1269, 1254, 1224, 1167, 1133 cm ^'1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.65 (d, J = 0.9 Hz, 1 H), 8.10 (d, J = 1.8 Hz, 1 H), 7.82 (dd, J = 8.7, 1.5 Hz, 1 H), 7.42 (d, /= 8.7 Hz, 1 H); CIMS m/z (relative intensity) 246 (MH ⁺ , 100). Anal. (C ₇ H ₄ INO) C, H, N.

5-Iodo-2-methoxy-3-methylbenzoic Acid (88). A flask was charged with ester 80 ¹⁹ (266 mg, 0.869 mmol) and methanol (40 mL). Solid potassium hydroxide (506 mg, 9.02 mmol) was added and the reaction mixture was allowed to stir until all of the solids had dissolved. The flask was fitted with a condenser and the system was heated at reflux, under an argon atmosphere, for 19 h. The system was allowed to cool to room temperature and the reaction mixture was condensed in vacuo to afford a yellow oil. The oil was partitioned between water (10 mL) and ethyl acetate (20 mL), followed by separation of the two phases. The aqueous phase was cooled in an ice bath and acidified to a pH of 1, via slow addition of

concentrated hydrochloric acid, to produce a white precipitate. The precipitate was extracted with ethyl acetate (3 x 20 mL) and the combined organic phases were washed with brine (1 x 30 mL), dried over magnesium sulfate, filtered, and condensed in vacuo to afford a white, fluffy, solid (248 mg, 85%): mp 163-165 ⁰ C. IR (KBr) 3434, 2947, 2560, 1673, 1567, 1467, 1299, 1252, 1223, 1170, 996 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.27 (d, J = 2.4 Hz, 1 H), 7.76 (d, J = 1.8 Hz, 1 H), 3.92 (s, 3 H), 2.34 (s, 3 H); ESIMS m/z (relative intensity) 291 (M ^" - H, 100). Anal. (C ₉ H ₉ IO ₃ ) C, H.

2-Hydroxy-5-iodobenzaldehyde Oxime (90). A solution of aldehyde 89 (472 mg, 1.90 mmol) in ethanol (10 mL) was heated at 70 ⁰ C and an aqueous solution of hydroxylamine hydrochloride (3.70 g, 53.3 mmol in 15 mL of water) was added. The reaction mixture was allowed to stir for 1 h and then cooled to room temperature. The reaction mixture was diluted with water (50 mL) and the resulting heterogeneous mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and condensed in vacuo to afford the product as a white solid (489 mg, 98%): mp 134-135 °C. IR (CDCl ₃ ) 3416, 3137, 2945, 2225, 1873, 1769, 1640, 1616, 1555, 1477, 1429, 1359, 1288, 1255, 1181 cm ^"1 ; ¹ U NMR (300 MHz, CDCl ₃ ) δ 9.74 (s, 1 H), 8.14 (s, 1 H), 7.55 (dd, J = 8.7, 2.1 Hz, 1 H), 7.47 (d, J= 2.1 Hz, 1 H), 7.19 (s, 1 H), 6.76 (d, J = 8.7 Hz, 1 H); EIMS m/z (relative intensity) 263 (M ⁺ , 100), 245 (M ⁺ - H ₂ O, 27). Anal. (C ₇ H ₆ NIO ₂ ) C, H, N.

5-But-3-ynyl-lH-tetrazole (93). A flask was charged with nitrile 91 (8.449 g, 0.107 mol) and toluene (100 mL). Triethylamine hydrochloride (29.49 g, 0.214 mol) was added to the flask, followed by sodium azide (14.05 g, 0.216 mol). The flask was fitted with a condenser and the system was heated a reflux for 9.5 h. During the course of the reaction a second, black layer formed at the bottom of the flask. The system was allowed to cool to room temperature and the reaction mixture was diluted with water (35 mL). The phases were separated and the organic phase was extracted with water (3 x 10 mL). Aqueous extracts were combined and acidified to a pη of 1 through the addition of concentrated hydrochloric acid. The acidified extracts were stored at 5 ⁰ C for several hours to obtain a white precipitate. The precipitate was extracted with ethyl acetate (200 mL) and the organic phase was dried over magnesium sulfate, filtered, and condensed in vacuo to afford the product as an off-white solid (5.734 g, 49%). An analytical sample was prepared by recrystallization from ethyl acetate- hexanes (1:4): mp 59-61 ⁰ C. IR (CHCl ₃ ) 3684, 3617, 3412, 3308, 3020, 2978, 2897, 2400, 2243, 1885, 1602, 1520, 1476, 1423, 1219 1046, 929 cm ^"1 ; ¹ H NMR (300 MHz, acetone-d ₆ ) δ 3.20 (t, J = 7.2 Hz, 2 H), 2.73 (dt, J = 7.2, 2.7 Hz, 2 H), 2.41 (t, J = 2.7 Hz, 1 H); CMS m/z (relative intensity) 123 (MH ⁺ , 100). Anal. (C ₆ H ₆ N ₄ ) C, H, N.

5-Pent-4-ynyl-lH-tetrazole (94). A flask (100 mL) was charged with nitrile 92 (1.12 mL, 0.011 mol) and toluene (20 mL). Triethylamine hydrochloride (4.41 g, 0.032 mol) and sodium azide (2.06 g, 0.032 mol) were added to the solution and the resulting mixture was heated at reflux for 9 h. As the reaction progressed a black liquid formed at the bottom of the reaction vessel. The system was allowed to cool to room temperature and the reaction mixture was extracted with water (4 x 10 mL). Aqueous extracts were combined and acidified to a pη of 1 by adding concentrated hydrochloric acid. The aqueous phase was extracted with ethyl acetate (4 x 20 mL) and the combined organic extracts were dried over magnesium sulfate, filtered, and condensed in vacuo to afford a yellow oil that, when triturated with hexanes, solidified to low melting point solid (1.259 g, 84%): mp 24-26 ⁰ C. ¹ H NMR (300 MHz, DMSOd ₆ ) δ 3.31 (s, 1 H), 2.95 (t, J = 7.5 Hz, 2 H), 2.84 (t, J = 2.7 Hz, 1 H), 2.25 (dt, J = 7.2, 2.7 Hz, 2 H), 1.87 (p, J = 7.2 Hz, 2 H); CMS m/z (relative intensity) 137 (MH ⁺ , 100). Anal. (C ₆ H ₈ N ₄ ) C, H, N.

5-But-3-ynyl-l -methyl- lH-tetrazole (95) and 5-But-3-ynyl-2-methyl-2H- tetrazole (97). A flask was charged with tetrazole 93 (1.504 g, 12.3 mmol) and ethyl acetate (30 mL). Tetrabutylammonium bromide (419 mg, 1.30 mmol) and dimethyl sulfate (1.74 mL, 18.4 mmol) were added to the flask, followed by an aqueous solution (30 mL) saturated with potassium carbonate (14.40 g). The biphasic mixture was stirred vigorously for 16 h and then the phases were separated. The organic phase was dried over magnesium sulfate, filtered, and condensed in vacuo to afford a yellow oil. The products were separated by column chromatography (75 mL silica gel, 2 in diameter column) using 50% ethyl acetate-hexanes as eluant. Two methylated tetrazole products were isolated after column chromatography: solid 95 (553 mg, 33%) and liquid 97 (792 mg, 47%). The physical constants determined for 95: mp 47- 49 ⁰ C. IR (CHCl ₃ ) 3684, 3622, 3019, 2977, 2895, 2400, 1520, 1476, 1424, 1218, 1046, 928 cm ^{" l} ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.07 (s, 3 H), 3.10 (t, / = 7.2 Hz, 2 H), 2.78 (dt, J = 7.2, 2.7 Hz, 2 H), 2.02 (t, J = 2.7 Hz, 1 H); CMS m/z (relative intensity) 137 (MH ⁺ , 100). Anal. (C ₆ H ₈ N ₄ ) C, H, N.

5-But-3-ynyl-2-methyl-2H-tetrazole (97). IR (neat) 3290, 2958, 2925, 2119, 1497, 1440, 1395, 1330, 1194 1038 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.31 (s, 3 H), 3.12 (t, J = 7.5 Hz, 2 H), 2.69 (dt, J = 7.5, 2.7 Hz, 2 H), 1.98 (t, J = 2.7 Hz, 1 H); CIMS m/z (relative intensity) 137 (MH ⁺ , 100). Anal. (C ₆ H ₈ N ₄ ) C, H, N. l-Methyl-5-pent-4-ynyl-lH-tetrazole (96) and 2-Methyl-5-pentyl-4-ynyl-2H- tetrazole (98). A saturated aqueous solution of potassium carbonate (25 mL) was added to a mixture of tetrazole 94 (1.52 g, 0.011 mol), tetrabutylammonium bromide (373 mg, 1.16 mmol), and dimethyl sulfate (1.60 mL, 0.017 mol) in ethyl acetate (25 mL). The biphasic mixture was

stirred vigorously at room temperature for 7 h. The phases were separated and the Organic phase was washed with water (1 x 20 mL) and brine (1 x 20 mL), dried over magnesium sulfate, filtered, and condensed in vacuo to afford a brown oil. The products were purified by column chromatography (40 mL silica, 1 in diameter) using 50% ethyl acetate-hexanes as the eluant. Tetrazole 96 (593 mg, 36%) and 98 (825 mg, 50%) were isolated as clear oils. The physical constants determined for 96: IR (neat) 3920, 3465, 3285, 2955, 2873, 2116, 1633, 1526, 1468, 1455, 1434, 1415, 1349, 1332, 1286, 1239, 1152, 1095, 1034 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) 64.03 (s, 3 H), 3.00 (t, J = 7.5 Hz, 2 H), 2.35 (dt, J = 6.6, 2.7 Hz, 2 H), 2.06 (p, / = 6.6 Hz, 2 H), 2.02 (t, J = 2.7 Hz, 1 H); CMS m/z (relative intensity) 151 (MH ⁺ , 100). Anal. (C ₇ H ₁₀ N ₄ ) C, H, N.

2-Methyl-5-pentyl-4-ynyl-2H-tetrazole (98). IR (neat) 3921, 3291, 2957, 2870, 2116, 1496, 1435, 1395, 1348, 1329, 1295, 1191, 1078, 1032 cm ^'1 ; ¹ H NMR (300 MHz, CDCl ₃ ) 54.30 (s, 3 H), 3.01 (t, J = 7.5 Hz, 2 H), 2.31 (dt, 7 = 6.9, 2.7 Hz, 2 H), 2.01 (p, J = 7.2 Hz, 2 H), 1.99 (t, / = 2.7 Hz, 1 H); CMS m/z (relative intensity) 151 (MH ⁺ , 100). Anal. (C ₇ H ₁₀ N ₄ ) C, H, N.

2-But-3-ynyl-5-methyl-[l,3,4]oxadiazole (99). A flask was charged with tetrazole 93 (1.50 g, 12.3 mmol) and acetic anhydride (25 mL). The flask was fitted with a condenser and the system was heated at reflux for 20 h. The system was allowed to cool to room temperature and the reaction mixture was concentrated in vacuo to afford a black-yellow residue. The residue was dissolved in ethyl acetate (30 mL) and the organic solution was washed with an aqueous solution saturated with sodium bicarbonate (3 x 20 mL) and brine (I x 10 mL). The organic phase was dried over magnesium sulfate, filtered, and condensed in vacuo to afford a brown oil. The product was purified by column chromatography (100 mL silica, 2 in diameter) using an ethyl acetate-hexanes gradient (50-66%). The desired product was isolated as a clear oil (834 mg, 50%): IR (CHCl ₃ ) 3690, 3606, 3309, 3155, 2984, 2902, 2254, 1817,

1793, 1732, 1643, 1598, 1572, 1471, 1382, 1096, 912 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.03 (t, J = 7.3 Hz, 2 H), 2.67 (dt, / = 7.2, 2.7 Hz, 2 H), 2.46 (s, 3 H), 2.43 (t, J = 2.7 Hz, 1 H); CMS m/z (relative intensity) 137 (MH ⁺ , 100). Anal. (C ₇ H ₈ N ₂ O) C, H, N.

2-Methyl-5-pent-4-ynyl-[l,3,4]oxadiazole (100). A solution of tetrazole 94 (3.16 g, 0.023 mol) in acetic anhydride (22 mL) was heated at reflux for 24 h and then allowed to cool to room temperature. The mixture was diluted with water (30 mL) and basified to a pH of 8 through the addition of concentrated ammonium hydroxide. The mixture was extracted with ether (3 x 40 mL) and ethyl acetate (1 x 30 mL). The organic extracts were combined, washed with brine (1 x 40 mL), dried over magnesium sulfate, and condensed in vacuo to afford a

yellow oil. The crade products were purified by column chromatography (100 mL silica, 2 in diameter) using an ethyl acetate-hexanes gradient (33-50%). The product was isolated as a yellow oil (2.44 g, 91%): IR (neat) 3453, 3290, 2942, 2873, 2648, 2117, 1725, 1702, 1597, 1571, 1435, 1394, 1367, 1348, 1330, 1278, 1224, 1043 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.95 (t, J = 7.5 Hz, 2 H), 2.50 (s, 3 H), 2.34 (dt, J = 6.9, 2.7 Hz, 2 H), 2.06-1.99 (m, 3 H); CMS m/z (relative intensity) 151 (MH ⁺ , 100). Anal. (C ₈ H ₁₀ N ₂ ) C, H, N.

Molecular Modeling. Compounds 4-7, 22, and 24 are characterized by the presence of N-methoxyimidoyl halide, Omethylhydroxamic acid, and/or 3-methyl- 1,2,4- oxadiazole moieties. In order to visualize the size and electronic character of these methyl ester replacements, compounds 27-31 were modeled using Sybyl 7.1.

27 28

29, X = F 30, X = Cl 31, X = Br

The models were constructed and then energy minimized using the MMFF94s force field and MMFF94 charges, and the electrostatic potentials were mapped onto the Connolly surfaces. The results indicated a significant variation in the sizes and electronic characters of these replacements relative to a methyl ester itself, but in spite of this fact, the potencies of compounds 4, 5, 6, and 7 as inhibitors of HIV-I reverse transcriptase are all very close, with submicromolar IC ₅₀ values. This may reflect the well-known ability of the flexible NNRTI binding pocket to mold itself to the shape of the inhibitor.

RT Inhibition Assay. The ability of target compounds to inhibit the enzymatic activity of recombinant HIV-I RT (p66/51 dimer) was evaluated as described in Cushman et al. J. Med. Chem. 1996, 39, 3217-3227; Rice et al. Discovery and in Vitro Development of AIDS Antiviral Drugs as Biopharmaceuticals, Adv. Pharmacol. (San Diego) 1995, 33, 389-438; and Buckheit et al., Comparitive Anti-HIV Evaluation of Diverse HIV-I -Specific Reverse Transcriptase Inhibitor-Resistant Virus Isolates Demonstrates the Existence of Distinct Phenotypic Subgroups, Antiviral Res. 1995, 26 , 117-132; the disclosure of each of which is incorporated herein by refernece. Briefly, inhibition of purified HW-I reverse transcriptase was determined by the amount of ³² P labeled GTP incorporated into a nascent DNA strand, with a poly(rC)/oligo-(dG)(rCdG) homopolymer primer, in the presence of increasing concentrations of the target compounds.

In Vitro Anti-Viral Assays. The anti-viral activities of the compounds described herein were determined for the HIVstrains: HIV-I _RF , HIV-I _11IB , and HIV-2 _ROD - Evaluation of anti-viral activity against HIV-I _RF was determined in infected CEM-SS cells while using the MTS cytoprotection assay, as described in Rice et al. (1995), the disclosure of which is incorporated herein by reference. Evaluation of anti-viral activity against the HIV-I _111B and HIV-2 _ROD strains was performed in infected MT-4 cells using the MTT assay as described in Deng et al. J. Med. Chem. 2005, 48, 6140-6 P55; and Pauwels et al. Rapid and Automated Tetrazolium-based Colorimetric Assay for the Detection of Anti-HIV Compounds, J. Virol. Methods 1988, 20, 309-321; the disclosure of each of which is incorporated herein by reference. The biological data are listed in Table 1.

In the cellular assays for inhibition of the cytopathic effect of the virus, compounds 6 and 7 displayed anti-HIV- I _RF activity in the submicromolar range. Also, the compounds 4-7 produced EC ₅₀ values versus HIV-I _111B between 0.24-6.3 μM. Comparison between compounds 2 and 7 indicates that the N-methoxy imidoyl fluoride system retained the desired anti-HIV activity, although the potency of 7 was somewhat lower, both with regard to RT inhibition as well as prevention of the cytopathic effect of the virus. However, compounds 22 and 24, having N-methoxyamide groups, were inactive both in the enzymatic and cellular tests. Similar to other known NNRTIs, all of the compounds in this series were inactive against HIV-2. Of the 34 compounds under investigation, 74% of the compounds displayed IC ₅₀ values less than 50 μM. In addition, 53% of the array displayed RT IC ₅₀ values in the low micromolar to nanomolar range (less than 10 μM), with the lowest IC _5O of < 0.001 μM being assigned to compound 66. Athough 53% of the compounds in the array were potent inhibitors of HIV-I RT enzymatic activity in vitro, many suboptimally protected HIV-infected cells from the cytopathic effects of the virus because either they were less potent in a cellular system (example: compound 55) or possessed acute cytotoxicities, (example: compound 70), which caused the cells to die before a therapeutic effect could be observed. Compounds 64 and 66 exhibited anti-viral activities near those of two NNRTIs currently employed in HAART, nevirapine and efavirenz. As is typical of most NNRTIs, all of the target compounds were inactive against HIV-2, with the exception of compounds 54 and 58.

In Vitro Rat Plasma Assay. The compounds described herein were tested for their hydrolytic stability in solutions of reconstituted rat plasma using methods that have been reported in Silvestri et al. Design, Synthesis, Anti-HIV Activities, and Metabolic Stabilities of Alkenyldiarylmethane (ADAM) Non-nucleoside Reverse Transcriptase Inhibitors, /. Med.

Chem. 2004, 47, 3149-3162, the disclosure of which is incorporated herein by reference. The internal standard used was 1,1-diphenylethylene and two different batches of rat plasma had to be utilized for the experiments (LOT# 052K7609 and 065K7555). A control compound was tested in both batches of rat plasma to insure that the hydrolysis rates of the two batches were approximately equivalent. The aliquot supernatants were analyzed using a Waters binary HPLC system (Model 1525, 20 μL injection loop) and a Waters dual wavelength absorbance UV detector (Model 2487) set for 254 nM. Data were collected and processed using the Waters Breeze software (version 3.3) on a Dell Optiplex GX280 personal computer. The mobile phase consisted of 8:2 (v/v) acetonitrile/water and the SYMMETRY HPLC column (4.6 mm x 150 mm) was packed with C ₁₈ Silica from Waters. The column was maintained at room temperature during the analyses. The reported half-lives for the compounds are averages calculated from a minimum of two replicates. Half-lives for the individual replicates were calculated from regression curves fitted to plots of the compound concentration versus time.

The metabolism data indicate that the ester replacements were effective in increasing the metabolic half-lives of the analogues relative to the methyl ester parent compounds. Many of the compounds, and especially the more potent inhibitors such as compound 66, exhibited half-lives of at least three hours, which should translate into a longer half-life in a human system with similar metabolic processes.

The half-lives of compounds 4-6, in which the esters were replaced with N- methoxy imidoyl halide, 3-methyl-l,2,4-oxadiazole, or oxazolone moieties, increased in comparison with the previously reported compounds Ia and 2. The overall results revealed that N-methoxy imidoyl halide, especially N-methoxy imidoyl fluoride, and 3-methyl-l,2,4- oxadiazole systems were metabolically stable, biologically active bioisosteres for methyl esters in the compound series. Further, compound 6, displaying a 4791-fold and a 2801-fold increase in plasma half-life relative to compounds Ia and 2, respectively, maintains anti-HIV activities with submicromolar EC ₅₀ values.

The side chain ester SAR indicates this region of compounds is more flexible to change, relative to the rest of the molecule; however, conservation of electrostatic potential and hydrogen bond acceptor sites appears to be desirable for achieving high potency. It is appreciated that replacing the remaining side chain ester with a hydrolytically stable heterocycle (such as an alkylated tetrazole or 1,3,4-oxadiazole) that possesses a similar electrostatic potential surface, volume, and number of hydrogen bond acceptor sites as an ester may be advantageous.

Results for compounds described herein are presented in Table 1. AU data represent mean values of at least two separate experiments.

Table 1. Anti-viral activity and hydrolysis half-lives of compounds described herein compared to known compounds 1-3, Nevirapine (A), and Efavirenz (B).

No. IC ₅₀ EC ₅₀ (μM) ^b CC ₅₀ (μM) ^c Half-Life

(μM) ^a HIV-1 _RF HIV-IπIB fflV-2 _R0D CEM-SS MT-4 tie ± SD(min) ^d

Ia 1.0 0.25 1.0 NA ^e 6.0 6.1 0.76 ± 0.04

Ib 0.3 0.01 0.6 25.0 31.6 160 5.8 ± 0.9

Ic 0.3 0.001 0.3 N.A. ^e 13.0 91 6.2 ± 0.4

2 0.02 0.03 0.09 NA ^e 5.1 16.9 1.3 ± 0.09

3 0.91 0.04 0.02 N.A. ^e 0.5 1.1 N.T. ^f

(A) N.T. 0.015 0.053 N.A. ^e - 15.0 N.T. ^f

(B) N.T. 0.005 0.001 N.A. ^e - 6.0 N.T/

4 0.60 NA ^e 1.2 NA ^e 1.3 3.9 4970 ± 795

₅ (g) 0.85 NA ^e 6.3 NA ^e 2.1 13.3 156 ± 21

6 0.67 0.7 0.24 NA ^e 2.9 12.4 3641 ± 14.1

7 0.55 0.5 0.29 NA ^e 3.9 21.0 9.2 ± 1.5

22 >100 NA ^e NA ^e NA ^e 5.2 16.8 NT ^ε

24 >100 NA ^e NA ^e NA ^e 5.4 18.4 NT ^g

40 52.7 N.A. ^e N.A. ^e N.A. ^e 9.6 5.0 24 ± 3.2

41 66.5 2.9 N.A. ^e N.A. ^e 32.6 7.0 N.T/

42 95.3 N.Aλ N.A. ^e N.A. ^e 1.6 1.4 N.T/

43 7.7 2.4 1.5 N.A. ^e 7.4 34.0 42 ± 3.2

44 70.6 2.30 3.0 N.A. ^e 40.4 35.0 3.3 ± 0.07

45 31.9 N.A. ^e N.A. ^e N.A. ^e 13.2 4.0 78 ± 4.1

46 28.7 N.A. ^e N.A. ^e N.A. ^e 4.5 8.1 113.5 ± 0.7

47 23.5 3.0 2.0 N.A. ^e 27.9 13.0 45 ± 1.4

48 7.4 3.0 2.7 N.A. ^e 1.1 41.0 219.5 ± 9.2

49 0.39 0.36 0.42 N.A. ^e 2.8 6.4 331 ± 20

50 1.0 0.43 0.44 N.A. ^e 3.2 13.0 N.T/

51 > 100 N.A. ^e N.A. ^e N.A. ^e 8.1 5.9 N.T/

52 0.90 0.52 0.81 N.A. ^e 2.1 4.4 1,090 ± 302

53 9.2 6.4 3.7 N.A. ^e 17.6 18.9 N.T/

54 2.6 0.60 0.61 4.7 5.9 12.0 739 ± 25

55 9.3 N.A. ^e 1.4 N.A. ^e 2.7 8.4 221 ± 43

56 6.3 2.1 3.2 N.A. ^e 5.5 44.7 N.T/

57 1.1 2.6 N.T/ N.T. ^f 37.9 N.T. N.T/

58 90.4 N.A. ^e N.A. ^e 5.9 6.6 13.6 N.T/

59 32.7 N.A. ^e N.A. ^e N.A. ^e 1.2 1.6 N.T/

60 > 100 N.A. ^e N.A. ^e N.A. ^e 16.9 36.9 N.T/

61 54.7 N.A. ^e N.A. ^e N.A. ^e 1.3 3.8 N.T/

62 48.1 N.A. ^e N.A. ^e N.A. ^e 1.2 3.2 N.T/

63 6.7 2.2 1.3 N.A. ^e 5.3 4.4 76 ± 4.2

64 0.47 0.05 0.14 N.A. ^e 5.7 7.0 864 ± 29

65 > 100 0.97 0.76 N.A. ^e 6.0 9.9 N.T/

66 < 0.001 0.07 0.18 N.A. ^e 3.0 3.9 238 ± 8.5

67 0.52 0.50 0.83 N.A. ^e 12.2 35.5 221 ± 43

68 3.2 0.6 0.36 N.A. ^e 8.9 36.9 45 ± 7.1

69 35.6 N.A. ^e N.A. ^e N.A. ^e 5.5 7.7 N.T/

70 5.2 N.A. ^e N.A. ^e N.A. ^e 0.78 1.1 N.T/

71 > 100 N.A. ^e N.A. ^e N.A. ^e 12.4 24.8 N.T/

72 1.1 N.A. ^e N.A. ^e N.A. ^e 7.2 8.2 N.T/

73 0.45 N.A. ^e N.A. ^e N.A. ^e 4.8 7.6 41.5 ± 2.1

^α Inhibitory activity versus HIV-I RT with poly(rC).oligo(dG) as the template primer. ⁶ EC ₅₀ is the 50% inhibitory concentration for inhibition of the cytopathic effect of HIV-I _RF in CEM-SS cells, HTV-I _11IB in MT-4 cells, or HIV-2 _R0D in MT-4 cells. ^c CC ₅ o is the cytotoxic concentration required to induce cell death for 50% of the mock infected CEM-SS or MT-4 cells. ^The metabolic half-life of the compound when it was incubated with rat plasma; determined from a minimum of two replicates. ^e Not Active. ^Not Tested. ^(g) A mixture (1 : 1) of E- and Z-isomers.