WO2002096359A2 - Piperazine pentanamide hiv protease inhibitors - Google Patents

Abstract

Piperazine pentanamide compounds of formula (1): wherein A, R?1, R2, R3, and R4¿ are defined herein, are inhibitors of HIV protease and inhibitors of HIV replication. These compounds are useful in the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described. These compounds are effective against HIV viral mutants which are resistant to HIV protease inhibitors currently used for treating AIDS and HIV infection.

Description

TITLE OF THE INVENTION

PIPERAZENE PENTANA VHDE H PROTEASE INHIBITORS

This application claims the benefit of U.S. Provisonal Application No. 60/294,370, filed May 30, 2001 , the disclosure of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to a class of N-[(3,4-dihydro-3- hydroxy-2H- 1 -benzopyran-4-yl] -γ-hydroxy-4- [ [5-(halophenyl)-2-(f uranyl or oxazolyl)] alkyl] - -(arylmethyl or heteroarylmethyl)-2-[[(2,2,2- trifluoroethyl)amino]carbonyl]-l-piperazinepentanamides which are Η protease inhibitors. The present invention is also directed to pharmaceutical compositions containing these protease inhibitors and methods of using the protease inhibitors.

BACKGROUND OF THE INVENTION

The HTV retrovirus is the causative agent for AIDS. The HIV-1 retrovirus primarily uses the CD4 receptor (a 58 kDa transmembrane protein) to gain entry into cells, through high- affinity interactions between the viral envelope glycoprotein (gp 120) and a specific region of the CD4 molecule found in

T-lymphocytes and CD4 (+) T-helper cells (Lasky L.A. et al., Cell 1987, 50: 975- 985). HTV infection is characterized by an asymptomatic period immediately following infection that is devoid of clinical manifestations in the patient. Progressive HTV-induced destruction of the immune system then leads to increased susceptibility to opportunistic infections, which eventually produces a syndrome called AJDS- related complex (ARC) characterized by symptoms such as persistent generalized lymphadenopathy, fever, and weight loss, followed itself by full blown AIDS.

After entry of the retrovirus into a cell, viral RNA is converted into DNA, which is then integrated into the host cell DNA. The reverse transcriptase encoded by the virus genome catalyzes the first of these reactions (Haseltine W. A. FASEB J. 1991, 5: 2349-2360). At least three functions have been attributed to the reverse transcriptase: RNA-dependent DNA polymerase activity which catalyzes the synthesis of the minus strand DNA from viral RNA, ribonuclease H (RNase H) activity which cleaves the RNA template from RNA-DNA hybrids and DNA- dependent DNA polymerase activity which catalyzes the synthesis of a second DNA strand from the minus strand DNA template (Goff S. P., J. Acq. Imm. Defic. Syndr. 1990, 3: 817-831). The double stranded DNA produced by reverse transcriptase, now called provirus, is then able to be inserted into host genomic DNA.

At the end of reverse transcription, the viral genome in the form of DNA is integrated into host genomic DNA and serves as a template for viral gene expression by the host transcription system, which leads eventually to virus replication (Sakai, H al., J. Virol. 1993, 67: 1169-1174). The preintegration complex consists of integrase, reverse transcriptase, pl7 and proviral DNA (Bukrinsky et al., Proc. Nat. Acad. Sci. USA 1992, 89: 6580-6584). The phosphorylated pl7 protein plays a key role in targeting the preintegration complex into the nucleus of host cell (Gallay et al., Cell 1995, 80:, 379-388).

As in the case of several other retroviruses, HTV encodes the production of a protease which carries out post-translational cleavage of precursor polypeptides in a process necessary for the formation of infectious virions (S. Crawford et al., J. Virol. 1985, 53: 899). These gene products include pol — which encodes the virion RNA- dependent DNA polymerase (reverse transcriptase), an endonuclease, and HTV protease — and gag — which encodes the core-proteins of the virion. (H. Toh et al., EMBO J. 1985, 4: 1267; L.H. Pearl et al., Nature 1987, 329- 351; M.D. Power et al, Science 1986, 231: 1567). A number of synthetic anti-viral agents targeted to various stages in the replication cycle of HTV have been disclosed. These agents include inhibitors of HTV cellular fusion (Turpin et al., Expert Opinion on Therapeutic Patents 2000, 10: 1899- 1909), reverse transcriptase inhibitors (e.g., didanosine, zidovudine (AZT), and efavirenz), integrase inhibitors (Neamati, Expert Opinion on Investigational Drugs 2000, 10: 281-296), and protease inhibitors. Protease inhibitors inhibit the formation of infectious virions by interfering with the processing of viral polyprotein precursors. Processing of these precursor proteins requires the action of virus-encoded proteases which are essential for replication (Kohl, N.E. et al., Proc. Natl. Acad. Sci. USA 1988, 85: 4686). Several HTV protease inhibitors are presently in clinical use for the treatment of AIDS and HTV infection, including indinavir (see US 5413999), nelfinavir (US 5484926), saquinavir (US 5196438), and ritonavir (US 5484801). Each of these protease inhibitors is a peptidomimetic, competitive inhibitor of the viral protease which prevents cleavage of the HTV gag-pol polyprotein precursor. Indinavir, for example, has been found to be highly effective in reducing HTV viral loads and increasing CD4 cell counts in HTV-infected patients, when used in combination with nucleoside reverse transcriptase inhibitors. See, for example, Hammer et al, New England J. Med. 1997, 337: 725-733 and Gulick et al., New England J. Med. 1997, 337: 734-739. A substantial and persistent problem in the treatment of AIDS has been the ability of the HTV virus to develop resistance to the therapeutic agents employed to treat the disease. Resistance to HTV-1 protease inhibitors has been associated with 25 or more amino acid substitutions in both the protease and the cleavage sites. Many of these viral variants are resistant to all of the HTV protease inhibitors currently in clinical use. See Condra et al., Drug Resistance Updates 1998, 1: 1-7; Condra et al, Nature 1995, 374: 569-571; Condra et al., J. Virol. 1996, 70: 8270-8276; Patrick et al., Antiviral Ther. 1996, Suppl. 1: 17-18; and Tisdale et al., Antimicrob. Agents Chemother. 1995, 39: 1704-1710.

Attempts to address the resistance issue with "salvage therapy" consisting of high doses of multiple protease inhibitors have only been moderately successful due to the high level of cross resistance and toxicities associated with these protease inhibitors. Accordingly, there remains a need for new protease inhibitors having improved effectiveness against the viral variants.

SUMMARY OF THE INVENTION

The present invention provides a novel class of N-[(3,4-dihydro-3- hydroxy-2H-l-benzopyran-4-yl]-γ-hydroxy-4-[[5-(halophenyl)-2-(furanyl or oxazolyl)] alkyl] -α-(arylmethyl or heteroarylmethyl)-2-[[(2,2,2- trifluoroethyl)amino]carbonyl]-l-piperazinepentanamides which are potent inhibitors of ΗTV protease including mutant forms thereof that are resistant to known protease inhibitors. A feature of the piperazinepentanamides in this class is that they exhibit little or no inhibition of either or both the CYP 2D6 and 2C9 enzymes relative to their inhibition of CYP 3A4. These compounds are useful in the inhibition of ΗTV protease, the prevention of infection by ΗTV, the treatment of infection by ΗTV and in the treatment of AIDS and/or ARC, when employed as compounds or pharmaceutically acceptable salts or hydrates (when appropriate) thereof, optionally as pharmaceutical composition ingredients, and optionally in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. More particularly, the present invention includes a compound of Formula (I):

wherein

A is CH or N;

Rl i_s _p or -Cl;

R2 and R3 are each independently -H or methyl; and

R4 IS

X is O or S;

Y is pyridyl which is optionally substituted with from 1 to 3 substituents each of which is independently halogen, cyano, Cχ-C6 alkyl, or C1-C6 alkoxy;

each Z is independently hydrogen, halogen, cyano, C1-C6 alkyl, or C1-C6 alkoxy; and

q is an integer from zero to 2; and with the proviso that when A is N and R4 is:

, then R2 and R3 are both -H;

or a pharmaceutically acceptable salt thereof.

The present invention also includes pharmaceutical compositions containing a compound of the present invention and methods of preparing such pharmaceutical compositions. The present invention further includes processes for preparing the compounds of the invention, and also includes methods of inhibiting HIV protease, delaying the onset of AIDS, treating AIDS, preventing infection by HTV, and treating infection by HTV.

The foregoing embodiments as well as other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples, and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes the compounds of Formula (I) above. These compounds and their pharmaceutically acceptable salts are HTV protease inhibitors.

A first embodiment of the present invention is a compound of Formula

wherein each of the variables is as originally defined above; or a pharmaceutically acceptable salt thereof.

A second embodiment of the invention is a compound of Formula (I), wherein

AisCHorN;

Rl is -F or -Cl;

R2 and R are either both -H or both methyl;

R is

Y is pyridyl which is optionally substituted with from 1 to 3 substituents each of which is independently halogen, cyano, C1-C4 alkyl, or C1-C4 alkoxy;

or a pharmaceutically acceptable salt thereof.

An aspect of the second embodiment is a compound of Formula (I), wherein

AisCHorN;

Rlis-For-Cl;

R2 and R3 are either both -H or both methyl;

R4is

Q is -H, -F, -Cl, -Br, C1-C4 alkyl, or C1-C4 alkoxy;

and all other variables are as defined in the second embodiment;

or a pharmaceutically acceptable salt thereof.

A third embodiment of the present invention is a compound of Formula (I), wherein

A is CH or N;

Rl is -F or -Cl;

R2 and R are either both -H or both methyl;

X is S or O;

each Z is independently -H, -F, -Cl, -Br, C1-C4 alkyl, or C1-C4 alkoxy; and

q is an integer from zero to 2;

or a pharmaceutically acceptable salt thereof. An aspect of the third embodiment is a compound of Formula (I), wherein

A is CH or N;

Rl is -F or -Cl;

R2 and R3 are either both -H or both methyl;

R i is

Z is -H, C1-C4 alkyl, or C1-C4 alkoxy;

or a pharmaceutically acceptable salt thereof.

A fourth embodiment of the present invention is a compound of Formula (I), wherein

A is CH or N;

Rl is -F or -Cl;

R2 and R3 are either both -H or both methyl;

R i is

each Z is independently -H, -F, -Cl, -Br, C1-C4 alkyl, or C1-C4 alkoxy; and

q is an integer from zero to 2; and with the proviso that when A is N and R4 is:

, then R2 and R3 are both -H;

or a pharmaceutically acceptable salt thereof.

An aspect of the fourth embodiment is a compound of Formula (I), wherein

A is CH or N;

Rl is -F or -Cl;

R2 and R3 are either both -H or both methyl; and

R4 is

and with the proviso that when A is N and R4 is:

or , then R2 and R3 are both -H;

or a pharmaceutically acceptable salt thereof.

A fifth embodiment of the present invention is a compound of Formula (I), wherein

A is CH or N;

Rl is -F or -Cl; R2 and R3 are either both -H or both methyl;

R is

each Z is independently -H, -F, -Cl, -Br, C1-C4 alkyl, or C1-C4 alkoxy; and

q is an integer from zero to 2;

or a pharmaceutically acceptable salt thereof.

An aspect of the fifth embodiment is a compound of Formula (I), wherein

A is CH or N;

Rl is -F or -Cl;

R and R3 are either both -H or both methyl;

R is

Z is -H, C 1-C4 alkyl, or C1-C4 alkoxy;

or a pharmaceutically acceptable salt thereof.

Additional embodiments and aspects of the present invention include a compound of Formula (II) whose variables are as defined in any one of the second, third, fourth, and fifth embodiments set forth above, or in any one of the aspects thereof as set forth above.

Additional embodiments and aspects of the present invention include a compound of Formula (I) or of Formula (II), in which A is CH and all other variables are as originally defined above or as defined in any one of the foregoing embodiments and aspects. Still other embodiments and aspects of the present invention include a compound of Formula (I) or of Formula (II), in which A is N and all other variables are as originally defined above or as defined in any one of the foregoing embodiments and aspects.

Further embodiments and aspects of the present invention include a compound of Formula (I) or of Formula (II), in which Rl is -F and all other variables are as originally defined above or as defined in any one of the foregoing embodiments and aspects. Still further embodiments and aspects of the present invention include a compound of Formula (I) or of Formula (II), in which Rl is -Cl and all other variables are as originally defined above or as defined in any one of the foregoing embodiments and aspects.

Exemplifying the invention are compounds selected from the group consisting of

and pharmaceutically acceptable salts thereof.

Other embodiments of the present invention include the following: (a) A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier. (b) A pharmaceutical composition which comprises the product prepared (i.e., made) by combining (e.g., mixing) a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier.

(c) The pharmaceutical composition of (a) or (b), wherein the composition further comprises a therapeutically effective amount of at least one AIDS treatment agent selected from the group consisting of AIDS antiviral agents, immunomodulators, and anti-infective agents.

(d) The pharmaceutical composition of (a) or (b), wherein the composition further comprises a therapeutically effective amount of at least one antiviral agent selected from the group consisting of non-nucleoside HTV reverse transcriptase inhibitors, nucleoside HTV reverse transcriptase inhibitors, HTV integrase inhibitors, and CCR5 receptor antagonists.

(e) The pharmaceutical composition of (d), further comprising a therapeutically effective amount of an additional HTV protease inhibitor. (g) The pharmaceutical composition of (a) or (b), wherein the composition further comprises a therapeutically effective amount of at least one antiviral agent which is a CCR5 receptor antagonist.

(h) The pharmaceutical composition of (a) or (b), wherein the composition further comprises a therapeutically effective amount of at least one antiviral agent which is an HTV integrase inhibitor.

(i) The pharmaceutical composition of (a) or (b), further comprising a cytochrome P450 monooxygenase inhibitor (e.g., ritonavir or a pharmaceutically acceptable salt thereof) in an amount effective to improve the pharmacokinetics of the compound. (j) A combination which comprises a therapeutically effective amount of a compound of Formula (I) and a therapeutically effective amount of an HTV infection/ AIDS treatment agent selected from the group consisting of HTV/ AIDS antiviral agents, immunomodulators, and anti-infective agents.

(k) The combination of (j), wherein the HTV infection/ AIDS treatment agent is an antiviral selected from the group consisting of non-nucleoside HTV reverse transcriptase inhibitors, nucleoside HTV reverse transcriptase inhibitors, HTV integrase inhibitors, and CCR5 receptor antagonists.

(1) A method of inhibiting HTV protease in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of Formula (I). (m) A method of preventing or treating infection by HTV in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of Formula (I).

(n) A method of delaying the onset of or treating AIDS in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of Formula (I).

(o) The method of (1) or (m) or (n), wherein the compound of Formula (I) is administered in combination with a therapeutically effective amount of at least one AIDS treatment agent selected from the group consisting of AIDS antiviral agents, immunomodulators, and anti-infective agents.

(p) The method of (1) or (m) or (n), wherein the compound of Formula (I) is administered in combination with a therapeutically effective amount of at least one antiviral agent selected from the group consisting of non-nucleoside HTV reverse transcriptase inhibitors and nucleoside HTV reverse transcriptase inhibitors. (q) The method of (1) or (m) or (n), wherein the compound is administered in combination with a cytochrome P450 monooxygenase inhibitor in an amount effective to improve the pharmacokinetics of the compound.

(r) A method of inhibiting HTV protease in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any one of the compositions set forth in (a) to (i).

(s) A method of preventing or treating infection by HTV in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any one of the compositions set forth in (a) to (i).

(t) A method of delaying the onset of or treating AIDS in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any one of the compositions set forth in (a) to (i).

Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(t) above, wherein the compound employed therein is a compound of one of the embodiments or aspects of the compounds described above. It is to be understood that, unless expressly stated to the contrary, the compound of the present invention can be employed in the above- described pharmaceutical compositions, combinations, and methods in its free form or as a pharmaceutically acceptable salt.

As used herein, the term "C1-C6 alkyl" refers to a linear or branched chain alkyl group having from 1 to 6 carbon atoms, and is selected from the hexyl alkyl and pentyl alkyl isomers, n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. "C1-C4 alkyl" refers to a linear or branched chain alkyl group having from 1 to 4 carbon atoms, and is selected from n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. The term "Cχ-C6 alkoxy" means an -O-alkyl group wherein alkyl is Cl to C6 alkyl as defined above. "C1-C4 alkoxy" has an analogous meaning; i.e., it is an alkoxy group selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and sec-butoxy. Similarly, "C1-C3 alkoxy" is selected from methoxy, ethoxy, n-propoxy, and isopropoxy. The term "aryl" refers to aromatic mono- and poly-carbocyclic ring systems, wherein the carbocyclic rings in the polyring systems may be fused or attached to each other via a single ring carbon. Exemplary aryl groups are phenyl and naphthyl.

The term "heteroaryl" refers to (i) a 5- or 6-membered aromatic ring consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, S, and O or (ii) an 8- to 10-membered bicyclic ring system consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, S, and O, wherein at least one of the rings in the bicyclic system is an aromatic ring.

The term "substituted" refers to mono- and poly-substitution by a named substituent to the extent such single and multiple substitution is chemically allowed and results in a chemically stable compound.

The symbol " ^fU ' " in front of an open bond in the structural formula of a group marks the point of attachment of the group to the rest of the molecule. When any variable or term occurs more than one time in any constituent or formulas set forth herein (e.g., Formula (I)), its definition on each occurrence is independent of its definition at every other occurrence.

Combinations of substituents and/or variables are permitted only to the extent such combinations result in stable compounds.

The compounds of the present invention are potent inhibitors of HTV protease including mutant forms thereof that are resistant to known protease inhibitors, as may be seen by reference to Examples 12 - 14 below. At the same, the compounds of the instant invention are significantly less potent inhibitors of CYP 2D6 and CYP 2C9 than structurally related piperazinepentanamide protease inhibitors. Accordingly, the compounds of the invention can be expected to avoid and/or have fewer drug-drug interactions compared to their structurally related counterparts. Inhibition of CYP 2D6 and 2C9 can be determined by many methods such as those detailed in Chiba et al., Drug metabolism and Disposition 1997, 25, No. 9: 1022-1031.

The present invention includes pharmaceutical compositions useful for inhibiting HTV protease, comprising an effective amount of a compound of this invention, and a pharmaceutically acceptable carrier. Pharmaceutical compositions useful for preventing or treating infection by HTV, for delaying the onset of AIDS, or for treating AIDS, are also encompassed by the present invention, as well as a method of inhibiting HTV protease, and a method of preventing or treating infection by HTV, of delaying the onset of AIDS, or of treating AIDS. An aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of an agent useful for treating HTV infection and/or AIDS (alternatively referred to as an HTV/ AIDS treatment agent) selected from: (1) an HTV/ATDS antiviral agent,

(2) an anti-infective agent, and

(3) an immunomodulator.

The present invention also includes the use of a compound of the present invention as described above as a medicament for (a) inhibiting HTV protease, (b) preventing or treating infection by HTV, or (c) treating AIDS. The present invention further includes the use of a compound of the present invention as described above in the preparation of a medicament for (a) inhibiting HTV protease, (b) preventing or treating infection by HTV, (c) delaying the onset of AIDS, or (d) treating AIDS. The present invention also includes the use of any of the HTV protease inhibiting compounds of the present invention as described above in combination with one or more HTV/ATDS treatment agents selected from an HTV/ATDS antiviral agent, an anti-infective agent, and an immunomodulator for use as a medicament for (a) inhibiting HTV protease, (b) preventing or treating infection by HTV, (c) delaying the onset of AIDS, or (d) treating AIDS, said medicament comprising an effective amount of the HTV protease inhibitor compound and an effective amount of the one or more treatment agents.

The present invention further includes the use of any of the HTV protease inhibiting compounds of the present invention as described above in combination with one or more HTV/ AIDS treatment agents selected from an HTV/ATDS antiviral agent, an anti-infective agent, and an immunomodulator for the manufacture of a medicament for (a) inhibiting HTV protease, (b) preventing or treating infection by HTV, (c) delaying the onset of ADDS, or (d) treating ADDS, said medicament comprising an effective amount of the HTV protease inhibitor compound and an effective amount of the one or more treatment agents.

The present invention also includes a compound of the present invention for use in (a) inhibiting HTV protease, (b) preventing or treating infection by HTV, or (c) preventing, treating or delaying the onset of ADDS. In this use, the compound of the present invention can optionally be employed in combination with one or more HTV/ATDS treatment agents selected from HTV/ATDS antiviral agents, anti-infective agents, and immunomodulators.

The compounds of the present invention have asymmetric centers and can have additional centers (e.g., where one of R and R3 is -H and the other is methyl), in which event the compound of the present invention may occur as a mixture of stereoisomers or as individual diastereomers, with all isomeric forms being included in the present invention.

A therapeutically effective amount of the compounds of the present invention are useful in the inhibition of HTV protease, the prevention or treatment of infection by HTV and the delay in the onset of or treatment of consequent pathological conditions such as ADDS. Treating or delaying the onset of ADDS or preventing or treating infection by HTV is defined as including, but not limited to, treating a wide range of states of HTV infection: ADDS, ARC, both symptomatic and asymptomatic, and actual or potential exposure to HTV. For example, the compounds of this invention are useful in treating infection by HTV after suspected past exposure to HTV by e.g., blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery. The compounds of the invention can also be used in "salvage" therapy; i.e., the compounds can be used to treat HTV infection, ADDS, or ARC in HIV-positive subjects whose viral load achieved undetectable levels via conventional therapies employing known protease inhibitors, and then rebounded due to the emergence of HTV mutants resistant to the known inhibitors.

The compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HTV protease, e.g., by competitive inhibition. Thus the compounds of this invention are commercial products to be sold for these purposes.

The present invention also provides for the use of a compound of structural formula (I) to make a pharmaceutical composition useful for inhibiting HTV protease, treating or preventing HTV infection, delaying the onset of ADDS, and for treating ADDS.

The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to all acceptable salts of the compounds of Formula (I) (in the form of water- or oil-soluble or dispersible products) and includes the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. The salt can be used as a dosage form for modifying the solubility or hydrolysis characteristics of the compound or can be used in sustained release or pro-drug formulations.

The compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically- acceptable carriers, adjuvants and vehicles.

The term "administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention each mean providing the compound or a prodrug of the compound to the individual in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., ADDS antivirals), "administration" and its variants are each understood to include concunent and sequential provision of the compound or prodrug thereof and other agents.

The present invention further provides for preventing or treating HTV infection and for delaying the onset of or treating ADDS by administering to a subject in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of the present invention.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The expression "pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The term "subject," (alternatively referred to herein as "patient") as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.

These pharmaceutical compositions may be in the form of orally- administrable suspensions or tablets or capsules, nasal sprays, sterile injectible preparations, for example, as sterile injectible aqueous or oleagenous suspensions or suppositories.

When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners/flavoring agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.

When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.

The injectible solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid. When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.

The compounds of this invention can be administered orally to humans in a dosage range of 0.01 to 1000 mg/kg body weight per day in a single dose or in divided doses. One preferred dosage range is 0.1 to 200 mg/kg body weight per day orally in a single dose or in divided doses. Another preferred dosage range is 0.5 to 100 mg/kg body weight per day orally in single or divided doses. For oral administration, the compositions are preferably provided in the form of tablets containing 1 to 1000 milligrams of the active ingredient, particularly 1, 5, 10, 15. 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. The present invention is also directed to combinations of the HTV protease inhibitor compounds with one or more agents useful in the treatment of HTV infection and/or ADDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the HIV/ ADDS antivirals, imunomodulators, antiinfectives, or vaccines, such as those in Table 1 as follows:

TABLE 1 - HTV/ATDS ANTTVIRALS, TMUNOMODULATORS, ANTDNFECTTVES, AND OTHER TREATMENTS

ANTΓVΓRALS

Drug Name Manufacturer Indication (Tradename and/or Location)

Amprenavir Glaxo Wellcome HTV infection, ADDS, 141 W94 (AGENERASE®) ARC GW 141 (protease inhibitor)

Abacavir Glaxo Welcome HTV infection, ADDS, ARC GW 1592 (ZIAGEN®) (reverse transcriptase 1592U89 inhibitor)

Acemannan Carrington Labs ARC (Irving, TX)

Acyclovir Burroughs Wellcome HTV infection, ADDS, ARC in combination with AZT

AD-439 Tanox Biosystems HTV infection, ADDS, ARC

AD-519 Tanox Biosystems HTV infection, ADDS, ARC

Adefovir dipivoxil Gilead Sciences HTV infection

AL-721 Ethigen ARC, PGL, HTV positive,

(Los Angeles, CA) ADDS

Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HTV, in combination w/Retrovir

Ansamycin Adria Laboratories ARC LM 427 (Dublin, OH) Erbamont (Stamford, CT)

Antibody which Advanced Biotherapy ADDS, ARC neutralizes pH labile alpha Concepts (Rockville, aberrant Interferon MD)

AR177 Aronex Pharm HTV infection, ADDS, ARC beta-fluoro-ddA Nat'l Cancer Institute ADDS -associated diseases

BMS-232623 Bristol-Myers Squibb/ HTV infection, ADDS, (CGP-73547) Novartis ARC

(protease inhibitor) BMS-234475 Bristol-Myers Squibb/ HTV infection, ADDS, (CGP-61755) Novartis ARC (protease inhibitor)

CI-1012 Warner-Lambert HΓV-1 infection

Cidofovir Gilead Science CMV retinitis, herpes, papillomavirus

Curdlan sulfate AJI Pharma USA HTV infection

Cytomegalovirus immune Medlmmune CMV retinitis globin

Cytovene Syntex sight threatening CMV Ganciclovir peripheral CMV retinitis

Delavirdine Pharmacia-Upjohn HTV infection, ADDS, (RESCRIPTOR®) ARC (nonnucleoside reverse transcriptase inhibitor)

Dextran Sulfate Ueno Fine Chem. Did. ADDS, ARC, HTV Ltd. (Osaka, Japan) positive asymptomatic ddC Hoffman-La Roche HTV infection, ADDS, ARC

Dideoxycytidine (HJVDD®) ddl Bristol-Myers Squibb HTV infection, ADDS, ARC; Dideoxyinosine (VDDEX®) combination with AZT/d4T

mozenavir AVDD (Camden, NJ) HTV infection, ADDS, ARC (DMP-450) (protease inhibitor)

EL10 Elan Corp, PLC HTV infection (Gainesville, GA)

Efavirenz DuPont HTV infection, ADDS, (DMP 266) (SUSTΓVA®) ARC (non-nucleoside RT

Merck (STOCRTN®) inhibitor)

Famciclovir Smith Kline herpes zoster, herpes simplex

FTC Emory University HIV infection, ADDS, ARC (reverse transcriptase inhibitor)

GS 840 Gilead HTV infection, ADDS, ARC (reverse transcriptase inhibitor) HBY097 Hoechst Marion Roussel HTV infection, ADDS, ARC (non-nucleoside reverse transcriptase inhibitor)

Hypericin VTMRx Pharm. HTV infection, ADDS, ARC

Recombinant Human Triton Biosciences ADDS, Kaposi's sarcoma, Interferon Beta (Almeda, CA) ARC

Interferon alfa-n3 Interferon Sciences ARC, ADDS

Indinavir Merck (CRTXTVAN®) HTV infection, ADDS, ARC, asymptomatic HTV positive, also in combination with AZT/ddl/ddC

ISIS 2922 ISIS Pharmaceuticals CMV retinitis KNI-272 Nat'l Cancer Institute HTV-assoc. diseases Lamivudine, 3TC Glaxo Wellcome HTV infection, ADDS,

(EPTVIR®) ARC (reverse transcriptase inhibitor); also with AZT

Lobucavir Bristol-Myers Squibb CMV infection Nelfinavir Agouron HTV infection, ADDS, (VIRACEPT®) ARC (protease inhibitor)

Nevirapine Boeheringer HTV infection, ADDS,

Ingleheim ARC (non-nucleoside

(VIRAMUNE®) reverse transcriptase inhibitor)

Novapren Novaferon Labs, Inc. HTV inhibitor (Akron, OH)

Peptide T Peninsula Labs ADDS

Octapeptide (Belmont, CA)

Sequence

Trisodium Astra Pharm. Products, CMV retinitis, HTV infection, Phosphonoformate Inc other CMV infections

PNU-140690 Pharmacia Upjohn HTV infection, ADDS, ARC (protease inhibitor)

Probucol Vyrex HTV infection, ADDS RBC-CD4 Sheffield Med. Tech HTV infection, ADDS, (Houston TX) ARC Ritonavir Abbott HTV infection, ADDS, (ABT-538) (RΠΌNAVIJR®) ARC (protease inhibitor)

Saquinavir Hoffmann-LaRoche HTV infection, ADDS, (FORTOVASE®) ARC (protease inhibitor)

Stavudine; d4T Bristol-Myers Squibb HTV infection, ADDS, ARC

Didehydrodeoxy- (ZERIT®) thymidine

Valaciclovir Glaxo Wellcome genital HSV & CMV infections

Virazole Viratek/ICN (Costa asymptomatic HTV positive, Ribavirin Mesa, CA) LAS, ARC

VX-478 Vertex HTV infection, ADDS, ARC

Zalcitabine Hoffmann-La Roche HTV infection, ADDS, ARC, with AZT

Zidovudine; AZT Glaxo Wellcome HTV infection, ADDS, ARC, (RETROVTR®) Kaposi's sarcoma in combination with other therapies (reverse transcriptase inhibitor)

Lopinavir (ABT-378) Abbott HTV infection, ADDS, ARC (protease inhibitor)

Lopinavir + ritonavir Abbott (KALETRA®) HTV infection, ADDS, ARC (ABT-378/r); Kaletra (protease inhibitor)

JE2147/AG1776 Agouron HTV infection, ADDS, ARC (protease inhibitor)

T-20 Trimeris HTV infection, ADDS, ARC (fusion inhibitor)

T-1249 Trimeris HTV infection, ADDS, ARC (fusion inhibitor) atazanavir (BMS 232632); Bristol-Myers-Squibb HTV infection, ADDS, ARC Zrivada (ZRIVADA®) (protease inhibitor)

PRO 542 Progenies HIV infection, ADDS, ARC (attachment inhibitor)

PRO 140 Progenies HTV infection, ADDS, ARC (CCR5 co-receptor inhibitor) TAK-779 Takeda HTV infection, ADDS, ARC (injectable CCR5 receptor antagonist)

DPC 681 & DPC 684 DuPont HTV infection, ADDS, ARC (protease inhibitors)

DPC 961 & DPC 083 DuPont HTV infection ADDS, ARC (nonnucleoside reverse transcriptase inhibitors) abacavir + lamivudine + GlaxoSmithKline HTV infection, ADDS, ARC zidovudine (TRIZTVTR®) (reverse transcriptase inhibitors) tipranavir (PNU-140690) Boehringer Ingelheim HTV infection, ADDS, ARC (protease inhibitor) tenofovir Gilead (VTREAD®) HTV infection, ADDS, ARC (nucleotide reverse transcriptase inhibitor)

TMC-120 & TMC-125 Tibotec HTV infections, ADDS, ARC (non-nucleoside reverse transcriptase inhibitors)

TMC-126 Tibotec HTV infection, ADDS, ARC (protease inhibitor)

IMMUNO-MODULATORS

Drug Name Manufacturer Indication AS-101 Wyeth-Ayerst ADDS Bropirimine Pharmacia Upjohn advanced ADDS Acemannan Carrington Labs, Inc. ADDS, ARC (Irving, TX)

CL246/738 American Cyanamid ADDS, Kaposi's sarcoma Lederle Labs

EL10 Elan Corp, PLC HTV infection (Gainesville, GA)

FP-21399 Fuki ImmunoPharm blocks HTV fusion with CD4+ cells

Gamma Interferon Genentech ARC, in combination w/TNF (tumor necrosis factor) Granulocyte Macrophage Genetics Institute ADDS Colony Stimulating Factor Sandoz

Granulocyte Macrophage Hoeschst-Roussel ADDS Colony Stimulating Factor Immunex

Granulocyte Macrophage Schering-Plough ADDS, combination w/AZT Colony Stimulating Factor

HTV Core Particle Rorer seropositive HTV Immunostimulant

TL-2 Cetus ADDS, in combination

Interleukin-2 w/AZT

IL-2 Hoffman-La Roche ADDS, ARC, HTV, in Interleukin-2 Immunex combination w/AZT

D_-2 Chiron ADDS, increase in CD4 cell

Interleukin-2 (aldeslukin) counts

Immune Globulin Cutter Biological pediatric ADDS, in ntravenous (human) (Berkeley, CA) combination w/AZT

ΓMREG-1 Imreg (New Orleans, ADDS, Kaposi's sarcoma, LA) ARC, PGL

TMREG-2 Imreg (New Orleans, ADDS, Kaposi's sarcoma, LA) ARC, PGL

Lmuthiol Diethyl Dithio Merieux Institute ADDS, ARC Carbamate

Alpha-2 Interferon Schering Plough Kaposi's sarcoma w/AZT, ADDS

Methionine- Enkephalin TNI Pharmaceutical ADDS, ARC (Chicago, TL)

MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma Muramyl-Tripeptide

Granulocyte Colony Amgen ADDS, in combination Stimulating Factor w/AZT

Remune Immune Response Corp. immunotherapeutic rCD4 Recombinant Genentech ADDS, ARC Soluble Human CD4 rCD4-IgG hybrids ADDS, ARC

Recombinant Soluble Biogen ADDS, ARC Human CD4 Interferon Alfa 2a Hoffman-La Roche Kaposi's sarcoma, ADDS, ARC, in combination w/AZT

SK&F106528 Smith Kline HTV infection Soluble T4

Thymopentin Immunobiology HTV infection Research Institute

Tumor Necrosis Factor; Genentech ARC, in combination

TNF w/gamma Interferon etanercept Immunex Corp rheumatoid arthritis (ENBREL®) infliximab Centocor rheumatoid arthritis and

(REMICADE®) Crohn's disease

ANTI-ΓNFECTΓVΈS

Drug Name Manufacturer Indication

Clindamycin with Pharmacia Upjohn PCP Primaquine

Fluconazole Pfizer cryptococcal meningitis, candidiasis

Pastille Nystatin Pastille Squibb Corp. prevention of oral candidiasis

Ornidyl Eflornithine Menell Dow PCP

Pentamidine Isethionate LyphoMed PCP treatment (TM & TV) (Rosemont, TL)

Trimethoprim antibacterial

Trimethoprim/sulfa antibacterial

Piritrexim Burroughs Wellcome PCP treatment

Pentamidine isethionate Fisons Corporation PCP prophylaxis for inhalation

Spiramycin Rhone-Poulenc cryptosporidia diarrhea

Intraconazole-R51211 Janssen Pharm. histoplasmosis; cryptococcal meningitis

Trimetrexate Warner-Lambert PCP OTHER

Drug Name Manufacturer Indication

Daunorubicin NeXstar, Sequus Karposi's sarcoma

Recombinant Human Ortho Pharm. Corp. severe anemia assoc. with Erythropoietin AZT therapy

Recombinant Human Serono ADDS-related wasting, Growth Hormone cachexia

Leukotriene B4 Receptor HTV infection Antagonist

Megestrol Acetate Bristol-Myers Squibb treatment of anorexia assoc. w/ATDS

Soluble CD4 Protein and HTV infection Derivatives

Testosterone Alza, Smith Kline ADDS-related wasting

Total Enteral Nutrition Norwich Eaton diarrhea and malabsorption, Pharmaceuticals related to ADDS

It will be understood that the scope of combinations of the compounds of this invention with HTV/ATDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in Table 1 above, but includes in principle any combination with any pharmaceutical composition useful for the treatment of HTV infection and/or ADDS. When employed in combination with the compounds of the invention, the HTV/ATDS antivirals and other agents are typically employed in their conventional dosage ranges and regimens as reported in the art, including the dosages described in the Physicians' Desk Reference, 54^th edition, Medical Economics Company, 2000. The dosage ranges for a compound of the invention in these combinations are the same as those set forth above just before Table 1.

One suitable combination is a compound of the present mvention and a nucleoside inhibitor of HTV reverse transcriptase such as AZT, 3TC, ddC, or ddl. Another suitable combination is a compound of the present invention and a non- nucleoside inhibitor of HTV reverse transcriptase, such as efavirenz, and optionally a nucleoside inhibitor of HTV reverse transcriptase, such as AZT, 3TC, ddC or ddl. Still another suitable combination is any one of the combinations in the preceding paragraph, further comprising an additional HTV protease inhibitor such as indinavir, Compound A, nelfinavir, ritonavir, saquinavir, amprenavir, or abacavir. An aspect of this combination is the combination wherein the additional inhibitor of HTV protease is the sulfate salt of indinavir. Another aspect of this combination is the combination in which the additional protease inhibitor is selected from nelfinavir and ritonavir. Still another aspect of this combination is the combination in which the additional inhibitor of HTV protease is saquinavir, which is typically administered in a dosage of 600 or 1200 mg tid. Other suitable combinations include a compound of the present invention with the following (1) efavirenz, optionally with AZT and/or 3TC and/or ddl and/or ddC, and optionally with indinavir; (2) any of AZT and or ddl and/or ddC and/or 3TC, and optionally with indinavir; (3) d4T and 3TC and/or AZT; (4) AZT and 3TC; and (5) AZT and d4T. Another aspect of the present invention is co-administration of a compound of the present invention with an inhibitor of cytochrome P450 monooxygenase in an amount effective to improve the pharmacokinetics of the compound. Compounds of the invention can be metabolized, at least in part, by cytochrome P450 (CYP3A4). Co-administration of compounds of the invention with a cytcochrome P450 inhibitor can improve the pharmacokinetic profile of the compound in subjects (e.g., humans); i.e., co-administration can increase C _aχ (the maximum plasma concentration of the compound), AUC (area under the curve of plasma concentration of the compound versus time), and/or the half -life of the compound. A suitable P450 inhibitor is ritonavir. It is to be understood that the primary role of ritonavir in this circumstance is as a pharmacokinetic modulator and not as a protease inhibitor; i.e., an amount of ritonavir which is effective for improving the pharmacokinetics of the compound can provide a secondary or even negligible contribution to the antiviral effect.

A compound of the present invention can also be administered in combination with an HTV integrase inhibitor such as a compound described in WO 99/62520, WO 99/62513, or WO 99/62897. A compound of the present invention can also be administered in combination with a CCR5 receptor antagonist, such as a compound described in WO 00/59502, WO 00/59503, WO 00/59497, WO 00/59498, WO 00/76511, WO 00/76512, WO 00/76513, WO 00/76514, WO 00/76972, or WO 00/76793. In the above-described combinations, the compound of the present invention and other active agents may be administered together or separately. In addition, the administration of one agent may be prior to, concunent with, or subsequent to the administration of other agent(s). These combinations may have unexpected or synergistic effects on limiting the spread and degree of infection of HTV.

Efavirenz is (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-l ,4- dihydro-2H-3,l-benzoxazin-2-one, also known as DMP-266 or SUSTTVA® (DuPont) or STOCRTN® (Merck). Efavirenz and its utility as an HTV reverse transcriptase inhibitor is described in US 5519021 and in the corresponding PCT published application, WO 95/20389. Efavirenz can be synthesized by the protocol of US 5633405. Additionally, the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition and cyclization sequence is described in Thompson et al., Tetrahedron Letters 1995, 36: 8937-40, as well as in the PCT publication, WO 96/37457.

AZT is 3'-azido-3'-deoxythymidine, is also known as zidovudine, and is available from Burroughs-Wellcome under the tradename RETROVTR®. Stavudine is 2',3'-didehydro-3'-deoxythymidine, is also known as 2',3'-dihydro-3'- deoxythymidine and d4T, and is available from Bristol-Myers Squibb under the tradename ZERIT®. 3TC is (2R-cis)-4-amino-l-[2-(hydroxymethyl)-l,3-oxathiolan- 5-yl]-2(lH)-pyrimidinone, is also known as (-)-l-[(2R,5S)-2-(hydroxymethyl)-l,3- oxathiolan-5-yl]cytosine and lamivudine, and is available from Glaxo Wellcome under the tradename EPTVTR®. ddC is 2',3'-dideoxycytidine, is also known as zalcitabine, and is available from Hoffman LaRoche under the tradename HΓVDD®. ddl is 2',3 '-dideoxyinosine, is also known as didanosine, and is available from Bristol- Myers-Squibb under the tradename VDDEX®. The preparation of ddC, ddl and AZT are also described in EPO 0,484,071.

Indinavir is N-(2(R)-hydroxy-l (S)-indanyl)-2(R)-phenylmethyl-4-(S)- hydroxy-5-(l-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))- pentaneamide, and can be prepared as described in US 5413999. Indinavir is generally administered as the sulfate salt at a dosage of 800 mg three times a day. Indinavir sulfate is available from Merck under the tradename CRTXTVAN®.

Compound A is N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl- 4(S)-hydroxy-5-(l-(4-(2-benzo[b]furanylmethyl)-2(S)-N'-(t-butylcarboxamido)- piperazinyl))pentaneamide, preferably administered as the sulfate salt. Compound A can be prepared as described in US 5646148.

Ritonavir is [5S-(5R*,8R*,10R*, HR*)]-10-hydroxy-2-methyl-5-(l- methylethyl)-l -[2-( 1 -methylethyl)-4-thiazolyl]-3 ,6-dioxo-8 , 11 -bis(phenylmethyl)-2, 4, 7, 12-tetraazatridecan-13-oic acid 5-thiazolylmethyl ester, also known as 5- thiazolylmethyl [(aS)-a-[(lS,3S)-l-hydroxy-3-[(2S)-2-[3-[(2-isopropyl-4- thiazolyl)methyl]-3-methylureido]-3-methylbutyramido]-4- phenylbutyl]phenethyl]carbamate. It is available from Abbott under the tradename NORVTR®. Ritonavir can be prepared as described in US 5484801. Nelfinavir is [3S-[2(2S*,3S*),3a,4ab,8ab]]-N-(l,l- dimethylethyl)decahydro-2- [2-hydroxy-3 - [(3 -hydroxy-2-methylbenzoyl)amino] -4- (phenylthio)butyl]-3-isoquinolinecarboxamide, also known as (3S,4aS,8aS)-N-tert- Butyl-2-[(2R,3R)-3-(3,2-crestoamido)-2-hydroxy-4-(phenylthio)butyl]decahydro-3- isoquinolinecarboxamide. VERACEPT®, the monomethanesulfonate salt of nelfinavir (nelfinavir mesylate) is commerically available from Agouron. Nelfinavir can be prepared as described in US 5484926.

Saquinavir is N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl- 3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)- isoquinoline-3(S)-carboxamide. Saquinavir can be prepared in accordance with procedures disclosed in US 5196438. TNVTRASE® (saquinavir mesylate) is available from Roche Laboratories.

Amprenavir is 4-amino-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)- tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide, also known as Compound 168 and 141 W94. Amprenavir is an aspartyl protease inhibitor that can be prepared by following the procedures described in

US 5585397. Amprenavir is available under the tradename AGENERASE® from Glaxo Wellcome. Amprenavir can be prepared as described in US 5783701.

Abacavir is (lS,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H- purin-9-yl]-2-cyclopentene-l-methanol, also known as 1592U89. Abacavir can be prepared by following the protocol of EP 0434450.

Abbreviations used in the instant specification include the following:

ACN = acetonitrile AcOH = acetic acid ADDS = acquired immune deficiency syndrome Alloc = allyloxycarbonyl

ARC = ADDS related complex

BOC or Boc = t-butyloxycarbonyl

BOC-ON = 2-(tert-butoxycarbonylamino)-2-phenyl acetonitrile 5 Bu = butyl

CBZ = carbobenzoxy (alternatively, benzyloxycarbonyl)

CSA = camphorsulfonic acid

DCE = dichloroethane

DCM = dichloromethane 10 DMF = dimethylformamide

DMSO = dimethylsulfoxide

DTEA = diisopropylethylamine

EDC = l-ethyl-3-(3-dimethylaminopropyl) carbodiimide

ES = electron spray (ionization) 15 Et = ethyl

Et2θ = diethyl ether

EtOAc = ethyl acetate

EtOH = ethanol

HBTU = 1-hydroxybenzotriazole 20 HTV = human immunodeficiency virus

HO AT = l-hydroxy-7-azabensotriazole

HOBT = 1-hydroxy benzotriazole hydrate

HPLC = high performance liquid chromatography

LC = liquid chromatography 25 LDA = lithium diisopropylamide

Me = methyl

MeOH = methanol

MS = mass spectrometry

NMP = N-methyl pynolidinone 30 NMR = nuclear magnetic resonance

Ph = phenyl

TB AF = tetrabutylammonium fluoride

TBDC = di t-butyl dicarbonate

TBSC1 = t-butyldimethylsilyl chloride 35 TBSOTf = t-butyldimethylsilyl triflate TEA = triethylamine TFA = trifluoroacetic acid TFEA = trifluoroethylamine Tf2θ = triflic anhydride THF = tetrahydrofuran

TLC = thin layer chromatgraphy TMSCN = trimethylsilyl cyanide TsOH = p-toluenesulfonic acid

The compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.

The preparation of the compounds of the present invention can be carried out in sequential or convergent synthetic routes, as shown in Schemes 1-7 below. A compound of Formula (I) can be prepared in accordance with Scheme 1, wherein Compound I is readily prepared via literature procedures described in Dorsey et al., J. Med. Chem. 1994, 37: 3443-3451, and also in US 5413999. Treatment of the hydroxyl compound 1 with triflic anhydride and lutidine in an inert solvent such as dichloromethane provides triflate 2. Displacement of the triflate with piperazine 3 occurs on heating in an inert solvent such as isopropanol to give lactone 4. Hydrolysis of lactone 4 with an aqueous lithium hydroxide provides the hydroxy acid which is conveniently protected with a standard silyl protecting group such as t-butyldimethylsilyl by reaction with either t-butyldimethylsilyl chloride in the presence of imidazole in an inert solvent or the reaction with the silyl triflate and diisopropyl ethylamine in an inert solvent such as dichloromethane. Mild aqueous hydrolysis of the silyl ester provides the protected hydroxy-acid 5. Amide coupling of compound 5 with aminochromanol to obtain 6 is typically performed by the carbodiimide method with reagents such as l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and HOBT in an inert solvent such as dichloromethane. Other methods of forming the amide or peptide bond include, but are not limited to, the synthetic routes via an acid chloride, azide, mixed anhydride or activated ester. The silyl protecting group is removed with fluoride to arrive at compound 7. The BOC protecting group on the amine is then removed with a strong acid such as trifluoroacetic acid or hydrochloric acid in an alcoholic solvent such as methanol to give the penultimate intermediate 8. Penultimate 8 is then reacted with the desired aldehyde 9 and a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride in an inert solvent such as dichloromethane to give compound 10.

SCHEME 1

SCHEME 1 (continued)

SCHEME 1 (continued)

A more convergent route to compounds of the present invention is presented in Scheme 2, below. The orthogonally protected piperazine 11 can be selectively deprotected. The BOC protecting group can be removed by treatment with strong acids such as trifluoroacetic acid in dichloromethane or HCI in methanol. The resulting amine 12 can then be reacted with an aldehyde in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride to give piperazine 13. Removal of the Alloc protecting group is readily accomplished with a palladium catalyst in the presence of a nucleophilic trapping agent such as 1,3- dimethylbarbituric acid or as in J. Org. Chem. 1993, 58, 6109-6113. Displacement of the triflate of 2 with piperazine 14, as in Scheme 1 gives lactone 15 which is then converted into compounds of the present invention following the route depicted in Scheme 1. SCHEME 2

An alternative route to the instant compounds is presented in Scheme 3. Compound 16 can be easily prepared according to the procedures described in the literature including, but not limited to, those described in Tetrahedron Letters 1995, 36: 2195-2198, US 5646148, Tetrahedron Letters 1991, 32: 711-714, Tetrahedron Letters 1995, 36: 3993-3996 and Synthesis 1998, 938-961. A procedure for preparing czs-aminochromanols by the stereoselective hydrogen bromide-promoted hydrogenation of an α-hydroxyoxime is described in Davies et al., Tetrahedron Letters 2000, 41: 8021-8025.

As shown in Part A of Scheme 3, the epoxide opening can be carried out by heating piperazine 3 and the epoxide in an inert solvent. Acidic removal of the protecting groups can be accomplished by treatment with hydrochloric acid in an alcoholic solvent such as methanol, ethanol or isopropanol. The resulting intermediate 18 is then reductively aminated as in Scheme 1 to provide the compounds of the present invention. Alternatively, as shown in Part B of Scheme 3, the epoxide opening can be preformed with fully elaborated piperazine 14 to give 20. Once again the protecting group is removed with strong acid to give 19.

SCHEME 3

Piperazine intermediates are readily prepared from the known piperazine carboxylic acid 21, which can be prepared as described in He/. Chem. Acta. 1960, 43: 888-896. Selective monoprotection of the piperazine is carried out using BOC anhydride as described in Tetrahedron Letters 1989, 30: 5193-5196. The remaining unprotected amine can then be protected with any number of chloroformates including allyl chloroformate or benzyl chloroformate to give 23. Amide couplings of 23 with trifluoroethylamine to give 24 are performed using standard amide coupling reactions as described above. Acidic removal of the BOC protecting group as before gives 25. The Alloc group can be removed as before. The CBZ group is readily removed by hydrogenolysis with a palladium catalyst under a hydrogen atmosphere in an alcoholic solvent such as methanol or ethanol. Removal of the protecting groups can also be accomplished by a number of methods known in the art, such as those described in Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991. These deprotected intermediates are then carried onto compounds of the instant invention via the synthetic routes shown in Schemes 1, 2 and 3.

SCHEME 4

Alloc]

NH£ \

EDC, HOBT ^CF3

The desired aldehyde intermediates are, in many cases, commercially available (e.g., Aldrich Chemical). Other aldehydes of interest can be prepared by literature methods including classical methods familiar to those skilled in the art. Stille and Suzuki coupling of commercially and readily available aryl and heteroaryl halides, aryl trialkylstannanes, and arylboronic acids also provides the desired aldehydes as exemplified for bromofuran in Scheme 5 below. Aldehyde 27 can be reacted with trialkylarylstannane 26 in the presence of a palladium catalyst by the method of Gronowitz et al. , J. Heterocyclic Chem. 1995, 35: 771, to give 28. Alternatively, trialkylstannane 30 can be coupled with arylhalides such as 29 to give 31 which can be deprotected under mild conditions with dilute hydrochloric acid to give aldehyde 28. Other aldehydes are available via metal halogen exchange followed by anion quenching with DMF as described by Vogel et al., J. Chem. Soc. Perkin Trans I, 1974, 37. Metalation of a biaryl or heterobiaryl compound such as 32 with a strong base such as n-butyllithium at low temperature in an inert solvent such as THF followed by anion trapping with DMF also provides aldehydes such as 28.

SCHEME 5

ArSnMθ₃

26 27 28

[Ar = aryl]

HCI

29 30 31

32 28

When R and R3 are alkyl, the necessary intermediates can be formed as shown in Scheme 6 below. Piperazine 12 can be treated with TMSCN and a ketone in acetic acid to give intermediate 34 according to the method described in J. Org. Chem. 1990, 55, 4207-4209. The Alloc protecting group is removed as described in Scheme 4 and the resulting intermediate, 35, is then treated with an excess of a Grignard to give the gem-dialkyl compound 14 A. This intermediate is then converted to the compounds of the present invention via chemistry described in Schemes 2 and 3 above. SCHEME 6

Oxazolyl piperazine intermediates such as 40 are available via the route shown in Scheme 7 below. Alkylation of piperazine 25 with bromo acid 36 in the presence of silver triflate in an inert solvent such as THF, according to methods detailed in J. Org. Chem. 1995, 60: 4013-4016, provides 37. Amide coupling of amine 38 to acid 37 to provide 39 can be carried out by any of the methods described above including the EDC /HOBT method. Amines such as 38 are prepared via chemistry described in Org. Synth. 1986, 64: 19-26 and Tetrahedron Letters 1999, 40: 6739-6743. Oxazole formation is accomplished by the action of a strong acid such as sulfuric acid on 39 in an inert solvent at elevated temperature, or as described in J. Med. Chem. 1996, 39: 2753-2763, to give intermediate 40. Again, intermediates such as these can be transformed into compounds of the instant invention via synthetic routes shown in Schemes 1,2, and 3. SCHEME 7

Oxazolyl piperazine intermediate 40 can also be obtained via the route shown in Scheme 8 below. Treatment of piperazine amide 41 with acetone at an elevated temperature will afford the acetonide which can be treated with acid HL (wherein L" is a non-nucleophilic anion such as OTf-) to afford the acid salt 42. Reaction of 42 with a dimethoxyalkane (e.g., 2,2-dimethoxypropane) will provide iminium salt 43, which can be coupled with a suitably metallated oxazole to provide coupled product 44. Suitable metallated oxazoles include those obtained by metallating the oxaole with an alkyllithium (e.g., n-butyllithium) or an alkylmagnesium halide (e.g., isopropylmagnesium bromide) in an inert solvent (e.g., an ether such as THF). Oxazolyl piperazine intermediate 40 can be obtained from 44 by treating 44 with acid (e.g., HCI, TFA, or an arylsulfonic acid). SCHEME 8

The following examples serve only to illustrate the invention and its practice. The examples are not to be construed as limitations on the scope or spirit of the invention.

EXAMPLE 1 (αR,γ_lS,25)-4-[[5-(4-chlorophenyl)-2-furanyl]methyl]-N-[(3₁S,4S)-2,3-dihydro-3- hydroxy-3H- 1 -benzopyran-4-yl] -γ-hydroxy-α- [ [4-(3 -pyridinyl)phenyl]methyl] -2- [ [(2,2,2-trifluoroethyl)amino]carbonyl]- 1 -piperazinepentanamide

Step A

To a solution of 4-chromanone (10 g, 67.49 mmol) in 400 mL dichloromethane at 0 °C was added bromine (4.45 mL, 86.39 mmol) dropwise slowly. The reaction was monitored by TLC. After half an hour the reaction mixture was diluted with methylene chloride (100 mL) and was washed with water (300 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting product was dissolved in HOAc (100 mL) and sodium sulfite (8 g) was added. The reaction mixture was st red at room temperature and reaction progress was monitored by TLC. After 48 hours the reaction mixture was poured into water and the product was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the titled compound as a white solid. lH NMR (CDCI3, 400 MHz): 7.93 (d, /= 8.8 Hz, IH), 7.54 (t, IH),

7.08 (t, IH), 7.02 (d, J = 8.0 Hz, IH), 4.63 (m, 4H)

Step B

To a solution of 3-bromo-4-chromanone (2 g, 8.81 mmol) in methanol (20 mL) was added sodium borohydride (0.4 g, 10.57 mmol). The reaction was stined at room temperature and monitored by TLC. After 2 hours the solvent was removed in vacuo and then diluted with ethyl acetate (50 mL). The resulting solution was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the titled compound as a white solid. lH NMR (CDCI3, 300 MHz): 7.32 (d, /= 7.2 Hz, IH), 7.23 (t, IH), 6.96 (t, IH), 6.84 (d, J =

9.0 Hz, IH), 4.82 (m, IH), 4.54 (m, IH), 4.38 (m, 2H).

To a solution of 3-bromo-4-chromanol (2 g, 8.72 mmol) in acetonitrile (20 mL) was added concentrated sulfuric acid (1 mL, 17.47 mmol). The reaction mixture was stirred at 45 °C - 50 °C for 18 hours. The solvent was removed in vacuo. Then water ( 10 mL) was added. The reaction mixture was heated to reflux. After 5 hours the reaction mixture was cooled to room temperature. The pH of the reaction mixture was adjusted to 12-13 by dropwise addition of aqueous 50% sodium hydroxide. The product was extracted with tetrahydrofuran three times. The organic layer were combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as a white solid. lH NMR (CDCI3,

300 MHz): 7.29 (d, J = 7.8 Hz, IH), 7.16 (t, IH), 6.93, (t, IH), 6.83 (d, J = 8.4 Hz, IH), 4.12 (m, IH), 3.99 (m, 2H), 3.84 (m, IH).

Step D

To a suspension of the racemic 4-amino-3-chromanol in ethanol (35 mL per gram of 4-amino-3-chromanol) was added 1.0 equivalent of (S)-(+) mandelic acid. The suspension was heated to 70 °C until forming a homogeneous solution. The solution was cooled to room temperature and white crystal was formed. After filtering the white crystal was dissolved in 3 N aqueous sodium hydroxide solution and the resolved product was extracted with ethyl acetate three times. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the titled compound as a white solid. The purity of the compound was verified by chiral HPLC with Crownpak CR+ column eluted with pH 1.0 perchloric acid solution. lH NMR (CDCI3, 300 MHz): 7.29 (d, J = 7.8 Hz, IH), 7.16 (t, IH),

6.93, (t, IH), 6.83 (d, J = 8.4 Hz, IH), 4.12 (m, IH), 3.99 (m, 2H), 3.84 (m, IH).

To a solution of 4-bromo-3-phenyl propionic acid (7.0g, 30.55 mmol) and amino chromanol from Step D (5.04 g, 30.33 mmol) in 300 mL of 1:1 NN- Dimethyl formamide and dichloromethane was added HOBt (5.37g, 39.72 mmol), NN-Diisopropyl ethyl amine (6.38 mL, 36.66 mmol) and EDC (7.6 g, 39.72 mmol). The resulting solution was stirred at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with IN HCI, sat. ΝaHCO₃ (2X). A white precipitate crashed out. This material was extracted with 10% methanol-dichloromethane (2X100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as a white solid.

To a solution of the intermediate from Step E (11.49g, 30.55 mmol) in NN-Dimethyl formamide and dichloromethane (500 mL) was added 2-methoxy propene (14.7 mL, 153 mmol) followed by camphor sulfonic acid (1.42 g, 6.11 mmol). The reaction was heated at 40° C for 6 hours. The reaction mixture was cooled to room temperature and washed with IN ΝaOH (2X), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 20% ethyl acetate-hexanes then 40% ethyl acetate-hexanes to give the desired compound as an off white solid.

To a solution of 3-bromopyridine in anhydrous THF (15 mL) cooled to 0° C under a nitrogen atmosphere was added drop wise a solution of isopropyl magnesium chloride. The reaction mixture was stirred at room temperature for 45 minutes. A solution of trimethyl tin chloride in THF (15 mL) was added. The reaction mixture was stirred for 45 minutes at room temperature. The reaction was quenched with saturated ammonium chloride solution and the resulting bi-phasic mixture extracted with ethyl acetate (3X). The organic layers were washed with brine, dried over anhydrous sodium sulfate filtered and concentrated in vacuo to give a light brown oil. This material was purified by flash chromatography using 20% ethyl acetate-hexanes the 40% ethyl acetate-hexanes to give the desired compound as a colorless oil. Step H

To a solution of the intermediate obtained from Step F (3.94 g, 9.46 mmol) and the intermediate obtained from Step G (2.3 g, 9.46 mmol) in NN- Dimethyl formamide (50 mL) was added Pd(PPh₃)₄ (110 mg, 0.09 mmol) and the reaction heated to 100° C for two hours. The reaction mixture was cooled to room temperature and quenched with saturated potassium fluoride solution (100 mL). After stirring vigorously for one hour the reaction mixture was filtered through celite and washed with ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (3X). The organic layer was washed with brine, dried over anhydrous sodium sulfate filtered and concentrated in vacuo. The residue was purified by flash chromatography using 40% ethyl acetate then 100% ethyl acetate and finally with 5% 2.0M ΝH3-MeOH-ethyl acetate to give the desired compound as a white solid.

To a solution of the intermediate from Step H (2.38g, 5.74 mmol) and allyl bromide (547 μL, 6.32 mmol) in THF (100 mL) cooled to -20° C was added drop-wise a solution of LHMDS (6.32 mL, 1.0 M in THF). The reaction mixture was stirred at —20° C for 45 minutes and quenched with saturated NaHCO solution. The resulting bi-phasic mixture was extracted with ethyl acetate (2X), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography with 60% ethyl acetate-hexanes to give the desired compound as a white solid.

To a solution of the intermediate obtained from Step I (1.9g, 4.18 mmol) in ethyl acetate (80 mL) was added NaHCO₃ solution (80 mL, 0.5 M) and the reaction cooled to 0°C. N-iodo-succinimide (1.975g, 8.77 mmol) was added and the reaction stined at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with a saturated solution of sodium thiosulfate (2X), water (IX), brine (IX) and dried over anhydrous sodium sulfate. The reaction mixture was filtered and concentrated in vacuo to give the desired compound as a light brown foam.

To a solution of the intermediate from Step J (2.5g, 4.18 mmol) in ethyl acetate (80 mL) was added a solution of sodium methoxide (1.43 mL, 6.27 mmol). After 15 minutes the reaction mixture was quenched with saturated with saturated NaHCO₃ solution and extracted with ethyl acetate(3X). The organic layer was washed with brine, dried over anhydrous sodium sulfate filtered and concentrated in vacuo. The residue was purified by flash chromatography with 60% ethyl acetate- hexanes to give the desired compound as an off-white solid.

To a solution of l,4-piperazine-2-(5)-carboxylic acid [bis(+)-CSA salt (30.0 g, 50.0 mmol) in 600 mL THF was added IN aqueous NaOH until the resulting solution was pH 9 (150 mL). The solution was cooled to 0 oc, and BOC-ON (12.3 g, 50.0) was added. The resulting solution was warmed to ambient temperature over 5 hours, then cooled again to 0 °C. Allyl chloroformate (5.31 mL, 50.0 mmol) was added via syringe, followed by an additional 60 mL of IN aqueous NaOH. The solution was warmed to ambient temperature overnight, then concentrated to minimum volume by rotary evaporator. The resulting mixture was acidified to pH 1 with IN aqueous HCI, and extracted with ethyl acetate (400 mL x 2). The organic layers were washed with brine (200 mL) dried (MgSO4) and concentrated in vacuo, affording 23.7 g of a yellow oil. This material was dissolved in 750 mL of dichloromethane, followed by the addition of triethylamine (35.0 mL, 250 mmol), trifluoroethylamine (9.95 mL, 125 mmol), HO AT (10.2 g, 75.0 mmol), and EDC

(14.4 g, 75.0 mmol). After 22 hours at ambient temperature the reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (500 mL). The organic layer was washed with an additional 500 mL of saturated aqueous NaHCO3, then IN aqueous NaHSO4 (500 mL), and additional saturated aqueous NaHCO3 (500 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. Purification by flash chromatography (40% ethyl acetate in hexane) afforded the title compound as a white solid. lH NMR (CDCI3, 400 MHz) 5.95 (m, IH), 5.35 (d, IH), 5.28 (d, IH),

4.75 (s, IH), 4.68 (d, IH), 4.53 (d, IH), 3.90 (m, 3H), 3.20 (dd, IH), 3.00 (m, IH), 1.45 (s, 9H).

To a solution of the intermediate obtained from Step L (following the removal of the Boc protecting group with trifluoro acetic acid) (890 mg, 3 mmol) in 1,2-dichloroethane (13 mL) was added 5-(4-chlorophenyl)-furan-aldehyde (623 mg, 3 mmol) and sodium triacetoxy borohydride (893 mg, 4.21 mmol). The reaction was quenched after one hour with saturated NaHCO₃ solution. The aqueous layer was extracted with dichloromethane(3X). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography with 50% ethyl acetate-hexanes to give the desired compound as a solid.

To a stined solution of the intermediate obtained from Step M (1.05 g,

2.16 mmol) in anhydrous THF (15 mL) was added 1,3-Dimethyl barbituric acid (405 mg, 2.59 mmol) and Pd(PPh₃) (250 mg, 0.22 mmol). After 45 minutes the reaction mixture was diluted with ethyl acetate (50 mL) and the organic layer was washed with IN HCI (6X15 mL). To the combined aqueous layers was added solid sodium carbonate until the pH=10. The aqueous layer was extracted with 5% methanol- dichloromethane (4X50 mL). The organic layer was dried over anhydrous sodium sulfate filtered and concentrated in vacuo to give the desired compound as a white solid.

To a solution of the intermediate obtained from Step K (65 mg, 0.13mmol) in 2-propanol (4 mL) was added the intermediate from Step N (50 mg, 0.12 mmol) and the resulting mixture heated to 85° C for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate then 5% 2.0M ammonia- methanol-ethyl acetate to give the title compound as an yellow oil.

Step P

(αR,γ5,2S)-4-[[5-(4-chlorophenyl)-2-furanyl]methyl]-N-[(3S,4S)-2,3-dihydro-3- hydroxy-3H-l-benzopyran-4-yl]-γ-hydroxy-α-[[4-(3-pyridinyl)phenyl]methyl]-2-

[[(2,2,2-trifluoroethyl)amino]carbonyl]-l-piperazinepentanamide

To a solution of the intermediate from Step O (55 mg, 0.063 mmol) in anhydrous methanol (3 mL) was added a solution of ΗC1 in ether (1 mL, l.OM solution). After 1 hour the reaction mixture was concentrated in vacuo. The residue was partitioned between IN ΝaOΗ (5 mL) and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3X). The organic layer was dried over anhydrous sodium sulfate filtered and concentrated in vacuo. The residue was purified by flash chromatography using 5% methanol-ethyl acetate to give the title compound as a white solid.

1H ΝMR(CD₃OD, 500 MHz): 8.77 (bs, IH), 8.5 (d, 7=4.6 Hz, IH), 8.08 (dd, 7=1.8, 8.0 Hz, IH), 7.65 (d, 7=8.7 Hz, 2H), 7.58 (d, 7=8.2 Hz, 2H), 7.52 (dd, 7=5.0, 7.8 Hz, IH), 7.4 (m, 5H), 7.15 (d, 7=7.6 Hz, IH), 7.08 (t, 7=8.2 Hz, IH), 6.84 (t, 7=7.6 Hz, IH), 6.74 (m, 2H), 6.4 (d, 7=3.2 Hz, IH), 5.19 (d, 7=4.1 Hz, IH), 3.9-4.25 (m, 4H), 3.8 (m, 3H), 3.6 (s, IH), 3.2 (m, 2H), 3.0 (m, 3H), 2.83 (dd, 7=6.6, 13.5 Hz, IH), 2.75 (bd, 7=11.9 Hz, IH), 2.6 (t, 7=8.4 Hz, IH), 2.54 (t, 7=8.7 Hz, IH), 2.45 (m, 2H), 2.4 (m, 2H), 2.12 (t, 7=11.2 Hz, IH), 1.47 (m, IH). LC-MS (M⁺+l) (El) 832.2.

EXAMPLE 2 (α5,γ5,2S)-4-[[5-(4-chlorophenyl)-2-furanyl]methyl]-N-[(3S,4,S)-2,3-dihydro- 3-hydroxy-3H-l-benzopyran-4-yl]-γ-hydroxy-α-[5-(3-pyridinyl)-2-furanyl]lmethyl]- 2-[[(2,2,2-trifluoroethyl)arnino]carbonyl]-l-piperazinepentanamide

To a solution of 5-bromo-furaldehyde (2.23 g, 12.74 mmol) and the intermediate from Example 1 Step G (3.7g, 15.3 mmol) in toluene (50 mL) was added Pd(PPh₃)₄ and the resulting mixture heated to reflux for 18 hours. The reaction mixture was cooled to room temperature and quenched with saturated potassium fluoride solution (100 mL). After stirring vigorously for one hour the reaction mixture was filtered through celite and washed with ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (3X). The organic layer was washed with brine, dried over anhydrous sodium sulfate filtered and concentrated in vacuo. The residue was purified by flash chromatography using 60% ethyl acetate then 80% ethyl acetate-hexanes to give the desired compound as an off-white solid.

To a solution of the intermediate from Step A (2.14 g, 12.35 mmol) and malonic acid (2.83 g, 27.18 mmol) in pyridine (12 mL) was added piperidine (95 μL, 0.95 mmol) and the reaction mixture heated to reflux for 4 hours. The reaction mixture was cooled to room temperature whereupon a yellow solid precipitated out. This material was suspended in dichloromethane (100 mL) and filtered. The residue was dried under vacuum to give the title compound as a yellow powder.

To a solution of the intermediate from Step B (2.3 g) in ethanol (60 mL) was added N,N-Diisopropyl ethyl amine (4.0 mL) followed by Pd/C. The reaction mixture was stined under a hydrogen balloon for 18 hours. The reaction mixture was filtered through celite and concentrated in vacuo to give the title compound as a yellow solid.

Ste D

To a solution of the intermediate from Step C (2.2g, 10.12 mmol) and amino chromanol (1.67 g, 10.12 mmol) in 100 mL of 1:1 N,N-Dimethyl formamide and dichloromethane was added HOBt (1.77 g, 13.15 mmol), NN-Diisopropyl ethyl amine (2.3 mL, 13.15 mmol) and EDC (2.51 g, 13.15 mmol). The resulting solution was stined at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with IN HCI, sat. NaHCO₃ (2X). A white precipitate crashed out. The organic layer was concentrated in vacuo and azeotropically dried with toluene (2X) to give the desired compound as a white solid.

To a solution of the intermediate from Step D (3.7 g, 10.12 mmol) in NN-Dimethyl formamide and dichloromethane (400 mL) was added 2-methoxy propene (4.86 mL, 50 mmol) followed by camphor sulfonic acid (2.82 g, 12.14 mmol). The reaction was stined at room temperature for 18 hours. The reaction mixture was quenched with IN ΝaOH (200 mL) and extracted with dichloromethane (2X), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 100% ethyl acetate to give the desired compound.

To a solution of the intermediate from Step E (3.39 g, 8.39 mmol) and allyl bromide (799 μL, 9.23 mmol) in THF (100 mL) cooled to -20° C was added drop wise a solution of LHMDS (9.23 mL, 1.0 M in THF). The reaction mixture was stined at -20° C for 45 minutes and quenched with saturated ΝaHCO₃ solution. The resulting bi-phasic mixture was extracted with ethyl acetate (2X), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography with 50% ethyl acetate-hexanes to give the desired compound as an off-white foam.

Step G

To a solution of the intermediate obtained from Step F(3.1 g, 6.97 mmol) in ethyl acetate (50 mL) was added NaHCO₃ solution (50 mL, 0.5 M) and the reaction cooled to 0 oC. N-iodo-succinimide (3.3 g, 14.64 mmol) was added and the reaction stined at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with a a saturated solution of sodium thiosulfate (2X), water (IX), brine (IX) and dried over anhydrous sodium sulfate. The reaction mixture was filtered and concentrated in vacuo to give the desired compound as a brown foam.

To a solution of the intermediate from Step G (4.1g, 6.97 mmol) in ethyl acetate (75 mL) was added a solution of sodium methoxide (2.39 mL). After 30 minutes the reaction mixture was quenched with saturated with saturated ΝaHCO₃ solution and extracted with ethyl acetate(3X). The organic layer was washed with brine, dried over anhydrous sodium sulfate filtered and concentrated in vacuo. The residue was purified by flash chromatography with 60% ethyl acetate-hexanes then 80% ethyl acetate-hexanes to give the title compound as a yellow solid.

To a solution of the intermediate obtained from Step H (63 mg, 0.13mmol) in 2-propanol (4 mL) was added the intermediate from Example 1 Step N (50 mg, 0.12 mmol) and the resulting mixture heated to 85° C for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate then 5% methanol- ethyl acetate to give the desired compound as an yellow solid.

Step J

(α₁S,γ5^,,25)-4-[[5-(4-chlorophenyl)-2-furanyl]methyl]-N-[(3,S,45)-2,3-dihydro-

3 -hydroxy-3H- 1 -benzopyran-4-yl] -γ-hydroxy-α- [5-(3 -pyridinyl)-2-f uranyl] lmethyl] -

2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-l-piperazmepentanamide

To a solution of the intermediate from Step I (37mg, 0.043 mmol) in anhydrous methanol (2 mL) was added a solution of ΗC1 in ether (1 mL, l.OM solution). After 1 hour the reaction mixture was concentrated in vacuo. The residue was partitioned between IN ΝaOΗ (5 mL) and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3X). The organic layer was dried over anhydrous sodium sulfate filtered and concentrated in vacuo. The residue was purified by flash chromatography using 5% methanol-ethyl acetate and then 5% 2.0 M ammonia in methanol-ethyl acetate to give the title compound as a white solid. 1H NMR (CD₃OD, 500 MHz): 8.83 (bs, IH), 8.37 (bd, 7=4.3 Hz, IH), 8.07 (d, 7=7.8 Hz, IH), 7.65 (d, 7=8.5 Hz, 2H), 7.43 (dd, 7=4.8, 7.7 Hz, IH), 7.37 (d, 7=8.5 Hz, 2H), 7.18 (d, 7=7.8 Hz, IH), 7.11 (t, 7=7.5 Hz, IH), 6.84 (m, 2H), 6.74 (m, 2H), 6.39 (d, 7=3.3 Hz, IH), 6.31 (d, 7=3.2 Hz, IH), 5.25 (d, 7=4.1 Hz, IH), 4.1 (bs, 2H), 3.9 (m, 3H), 3.65-3.85 (m, 3H), 3.6 (bs, 2H), 3.25 (m, IH), 3.0-3.2 (m, 3H), 2.9 (dd, 7=6.7, 14.9 Hz, IH), 2.82 (d, 7=9.9 Hz, IH), 2.73 (m, IH), 2.58 (t, 7=11.0 Hz, IH), 2.4 (m, 3H), 2.15 (t, 7=11.5 Hz, IH), 1.5 (m, IH). LC-MS (M^+l) (El) 822.2.

EXAMPLE 3 (α5,γS,2S)-4-[l-[5-(4-chlorophenyl)-2-oxazolyl]-l-methylethyl]-N-[(3.S,4S)-2,3- dihydro-3 -hydroxy-3H- 1 -benzopyran-4-yl] -γ-hydroxy-α- [5-(3 -pyridinyl)-2- thiazolyl]methyl]-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-l-piperazinepentanamide

Step A

To a solution of 2-formyl thiazole (6.0g, 53 mmol) in benzene placed in a round bottom flask (100 mL) was added ethylene glycol (7.4 mL, 132.5 mmol) and -toluene sulfonic acid (131 mg, 0.69 mmol). The flask was fitted with a Dean- Stark trap and the solution heated to 120° C for one hour. The reaction was cooled to room temperature and concentrated in vacuo. The residue was diluted with ethyl acetate washed with sat. NaHCO₃ and dried over anhydrous sodium sulfate. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography using 15% ethyl acetate-hexanes then 40% ethyl acetate- hexanes to give the desired compound as a light brown oil.

To a solution of the intermediate obtained from Step A (5.0g, 31.8 mmol) in THF (100 mL) cooled to -78° C was added a solution of n-Butyllithium (24 mL, 38.17 mmol). After 10 min a solution of trimethyl tin chloride (7.6 g, 38.17 mmol) in 10 mL of THF was added. The reaction was warmed to 0° C and quenched with saturated NH₄CI solution. The resulting bi-phasic layer was extracted with ethyl acetate (3x), washed with sat. NaCl and dried over anhydrous sodium sulfate. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography using 20% ethyl acetate-hexanes to give the desired compound as a light brown oil.

To a solution of the intermediate obtained from Step B (6.0g, 22.5 mmol) in toluene (100 mL) was added 3-bromopyridine (2.16 mL, 22.5 mmol) and Pd(PPh₃)₄ (1.08 g, 0.937 mmol) and the reaction mixture heated to 120° C for 18 hours. The reaction mixture was cooled to room-temperature and quenched with saturated potassium fluoride solution. The resulting mixture was stined vigorously for 1 hour. The reaction mixture was filtered through celite. The aqueous layer was extracted with ethyl acetate (2X). The combined organic layers were washed with water (2X) and brine (IX) and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 60% ethyl acetate-hexanes then 80% ethyl acetate-hexanes to give the desired compound as a light yellow solid.

To a solution of the intermediate obtained from Step C (3.2 g, 13.65 mmol) in THF (100 mL) was added HC1(47.8 mL, l.OM) and the resulting mixture refluxed for 4 hours. The reaction mixture was cooled to room temperature and washed with saturated solution of sodium carbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound.

To a solution of the intermediate from Step D(1.84g, 9.68 mmol) and malonic acid(2.21 g, 21.3 mmol) in pyridine (12 mL) was added piperidine (74 μL, 0.74 mmol) and the resulting mixture refluxed for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was azeotropically dried with toluene (3X) to give a dark brown solid. Thia material was suspended in dichloromethane and filtered to give the desired compound as a dark yellow solid.

To a solution of the intermediate from Step E (2.0 g) in ethanol (30 mL) was added NN-Diisopropyl ethyl amine (6.0 mL) followed by Pd C. The reaction mixture was stined under a hydrogen balloon for 18 hours. The reaction mixture was filtered through celite washed with methanol. The filtrate was concentrated in vacuo and azeotropically dried with toluene (3X) to give the desired compound as a light yellow solid.

To a solution of the intermediate from Step F (2.0g, 8.53 mmol) and amino chromanol from example 1 Step E (1.41 g, 8.53 mmol) in 100 mL of 1:1 NN- Dimethyl formamide and dichloromethane was added HOBt(1.5 g, 11.1 mmol), NN- Diisopropyl ethyl amine (1.93 mL, 11.1 mmol) and EDC (2.12 g, 11.1 mmol). The resulting solution was stined at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with IN HCI, saturated ΝaHCO₃ (2X). A white precipitate crashed out of the organic layer. The organic layer was concentrated in vacuo and azeotropically dried with toluene (2X) to give the desired compound as a white solid.

Step H

To a solution of the intermediate from Step G (2.8 g, 7.34 mmol) in N,N-Dimethyl formamide and dichloromethane (300 mL) was added 2-methoxy propene (3.52 mL, 37 mmol) followed by camphor sulfonic acid (2.1 g, 8.8mmol). The reaction was stined at room temperature for 18 hours. The reaction mixture was quenched with IN ΝaOH (200 mL) and extracted with dichloromethane (2X), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 100% ethyl acetate then 3% methanol-ethyl acetate to give the desired compound as a light brown solid.

To a solution of the intermediate from Step H (2.74 g, 6.5 mmol) and allyl bromide (675 μL, 7.8 mmol) in THF (100 mL) cooled to -60° C was added drop- wise a solution of LHMDS (7.8 mL, 1.0 M in THF). The reaction mixture was warmed slowly to -20° C and stined for 45 minutes. The reaction was quenched with saturated ΝaHCO₃ solution and the resulting bi-phasic mixture was extracted with ethyl acetate (2X), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography with 80% ethyl acetate- hexanes to give the desired compound as an off-white foam.

To a solution of the intermediate obtained from Step 1(2.29 g, 4.96 mmol) in ethyl acetate (50 mL) was added NaHCO₃ solution (50 mL, 0.5 M) and the reaction cooled to 0_o C. N-iodo-succinimide (2.34 g, 10.42 mmol) was added and the reaction stined at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with a saturated solution of sodium thiosulfate (2X), water (IX), brine (IX) and dried over anhydrous sodium sulfate. The reaction mixture was filtered and concentrated in vacuo to give the title compound as a brown foam.

Step K

To a solution of the intermediate from Step J (2.38 g, 3.93 mmol) in ethyl acetate (50 mL) was added a solution of sodium methoxide (1.34 mL, 5.9 mmol, 25% wt). After 30 minutes the reaction mixture was quenched with saturated with saturated ΝaHCO₃ solution and extracted with ethyl acetate(3X). The organic layer was washed with brine, dried over anhydrous sodium sulfate filtered and concentrated in vacuo. The residue was purified by flash chromatography with 60% ethyl acetate- hexanes to give the title compound as a brown solid. Step L

To a solution of the piperazine intermediate from Example 1, Step M

(1 g, 3.39 mmol following removal of the BOC group with trifluoroacetic acid) and silver trifluoromethane sulfonate (725 mg, 2.82 mmol) in THF (5 mL) was added triethylamine. While stirring, a solution of 2-bromo-2-methylpropionic acid (472 mg, 2.82 mmol) in 5 mL of THF was introduced slowly (within 1.5 hours) through a syringe pump. The reaction mixture was stined at room temperature for 2 hours after the additions. Then, it was filtered. The filtrate was concentrated and purified by flash column chromatography on silica gel with 10/1 ethyl acetate / methanol as eluant to give the title compound as a white solid. lH NMR (CDC13, 400 MHz): δ 9.02 (broad s, 1 H), 6.98 (broad s, 1 H), 5.90-6.00 (m, 1 H), 5.24-5.28 (m, 2 H), 5.65 ( broad s, 1 H), 4.16 ( broad s, 1 H), 2.90-2.93 (m, 1 H), 2.55-2.57 (m, 1 H), 2.40-2.41 (m, 1 H), 1.59-1.61 (m,lH).

Step M:

To a stirring solution of hexamethylenetetramine (12.0g; 85.7mmol) in

CH₂C1₂ (400mL) was added portionwise α-bromo-p-chloroacetophenone (20.0g;

85.7mmol). After 30 minutes the precipitate was filtered and then suspended in EtOH

(680mL). Cone. HCI was added (45mL) and the suspension stined at 90 °C 1.5hrs. Dissolution occuned followed by solution turning pale yellow and a new precipitate formed. This solid was filtered, washed with EtOH, and dried under vacuum to provide the desired compound. lH NMR (500 MHz, CD₃OD): δ 4.60 (s, 2H), 7.61 (d, J=8.7 Hz, 2H), 8.04 (d, J=8.4 Hz, 2H).

To a stined solution of carboxylic acid from Step L (4.96g; 13mmol) in dry NMP (75mL) under nitrogen was added DIEA (9.06 mL; 52 mmol). After cooling the solution to 0 °C, the following solids were added, allowing one to dissolve before adding the next: HOBt (3.95g; 29.3mmol), intermediate from Step M above (3.22g; 15.6mmol), and HBTU (7.4g; 19.5mmol). The reaction was allowed to reach ambient temperature, and the next morning the mixture was poured into EtOAc and washed with saturated NaHCO₃, water, brine, 3x dilute NaHCO₃, and brine. After drying (MgSO₄), filtration, and removal of solvent in vacuo, the residue was purified by flash column chromatography (50% EtOAc/hexane). Residual NMP which remained was removed by dissolution in EtOAc followed by washing with water (2x), brine, drying (MgSO ), filtration, and solvent removal in vacuo. The residue resulting after workup was purified by Biotage column chromatography (40M; 45% EtOAc/hexane) to provide the desired product. lH NMR (500 MHz, CDC1₃): δ 1.28 (s, 3H), 1.30 (s, 3H), 2.35 (apparent td, J=3.0, 11.6 Hz, IH), 2.45 (apparent dd, J=3.8, 11.8 Hz, IH), 2.86 (d, J=10.6 Hz, IH), 3.22-3.33 (broad, IH), 3.67 (d, J=11.7 Hz, IH), 3.74-4.30 (broad, 3H), 4.51 (d, J=18.6 Hz, IH), 4.70 (d, J=4.5 Hz, 2H), 4.83 (s, IH), 4.89 (1/2ABX, J=6.8, 18.7 Hz, IH), 5.30 (d, J=10.3 Hz, IH), 5.36 (d, J=17.1 Hz, IH), 5.92-6.02 (br s, IH), 6.60-6.72 (br s, IH), 7.49 (d, J=8.5 Hz, 2H), 7.93 (d, J=8.5 Hz, 2H), 8.20-8.30 (br s, IH) ; electrospray ionization mass spectrum: m/e 533.3 (MH+ calcd for C23H29CIF3N4O5, 533.2). Step O

To the amide obtained in Step N (139mg; 0.26mmol) was added

H₂SO₄ (2.75mL). Partial dissolution occuned. The reaction vessel was purged with nitrogen, P₂O₅ (HOmg; 0.39mmol) was added, and the mixture was stined at 65 °C for 20 minutes. After cooling to 0 °C, ice chips were added and the reaction adjusted to pH 9 with the addition of 50% NELOH, then cone. NH OH. Extraction with CHC1₃ (3x) was followed by drying (Na₂SO ), filtration and removal of the solvent in vacuo. Flash column chromatography (93:5:2 EtOAc: MeOH: TEA) provided the desired product. lH NMR (500 MHz, CDC1₃): δ 1.60 (s, 3H), 1.61 (s, 3H), 1.75-1.88 (broad s, IH), 2.56-2.60 (complex m, 2H), 2.77-2.81 (m, IH), 2.86-2.98 (complex m, 3H), 3.50-3.52 (m, IH), 3.93-4.00 (m, 2H), 7.26 (s, IH), 7.42 (d, J=8.5 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 8.10-8.18 (broad s, IH) ; electrospray ionization mass spectrum: m/e 431.3 (MH+ calcd for C19H23CIF3N4O2, 431.1).

Step P

To a solution of the intermediate from Step K (60 mg, 0.125 mmol) in 2-propanol (5 mL) was added the intermediate from Step O (250 mg, 0.54 mmol) and the resulting mixture heated at 85° C for 6 hours. The reaction mixture was concentrated in vacuo and purified by flash chromatography using 5% methanol-ethyl acetate. The product obtained was re-purified by reverse-phase HPLC using a

MetaChem 21X150mm Polaris C18-A5 micron column. The gradient used was 35% acetonitrile-water with 0.1% TFA to 60% acetonitrile-water. The product containing fractions were combined and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated sodium carbonate solution to give the desired compound as a white solid.

Step Q

(αS,γ5,2S)-4-[l-[5-(4-chlorophenyl)-2-oxazolyl]-l-methylethyl]-N-[(35,45)-2,3- dihydro-2-hydroxy-3H- 1 -benzopyran-4-yl] -γ-hydroxy-α- [5-(3 -pyridinyl)-2- thiazolyl]methyl]-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-l-piperazinepentanamide

To a solution of the intermediate from Step P (20 mg, 0.022 mmol) in anhydrous methanol (2 mL) was added a solution of ΗC1 in ether (1 mL, l.OM solution). After 1 hour the reaction mixture was concentrated in vacuo. The residue was partitioned between IN ΝaOΗ (5 mL) and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3X). The organic layer was dried over anhydrous sodium sulfate filtered and concentrated in vacuo. The residue was purified by flash chromatography using 5% methanol-ethyl acetate and then 5% 2.0 M ammonia in methanol-ethyl acetate to give the title compound as a white solid. ¹ΗΝMR (CD₃OD, 500 MHz): 8.77 (bs, 7=1.4 Hz, IH), 8.5 (d, 7=4.3 Hz, IH), 8.05 (m, IH), 8.0 (s, IH), 7.68 (d, 7=8.7 Hz, 2H), 7.48 (dd, 7=4.8 Hz, IH), 7.43 (m, 3H), 7.18 (d, 7=7.6 Hz, IH), 7.12 (t, 7=8.2 Hz, IH), 6.84 (t, 7=7.3 Hz, IH), 6.76 (d, 7=7.6 Hz, IH), 5.23 (d, 7=4.1 Hz, IH), 4.15 (m, 2H), 3.9-4.0 (m, 2H), 3.8 (m, 2H), 3.41 (dd, 7=8.3 Hz, IH), 3.25 (m, IH), 3.18 (dd, 7=5.8 Hz, IH), 3.09 (m, IH), 3.0 (m, IH), 2.89 (bd, 7=9.4 Hz, IH), 2.79 (m, IH), 2.64 (t, 7=7.8 Hz, IH), 2.45 (m, 4H), 2.13 (t, 7=10.9 Hz, IH), 1.59 (s, 6H), 1.46 (m, IH). ). LC-MS (M⁺+l) (El) 868.2. EXAMPLE 4 (α5,γ5,25)-4-[[5-(4-chlorophenyl)-2-furanyl]methyl]-N-[(3S,4S)-2,3-dihydro-3- hydroxy-3H- 1 -benzopyran-4-yl] -α-(furo [3 ,2-c]pyridin-2-ylmethyl)-γ-hydroxy-2- [[(2,2,2-trifluoroethyl)amino]carbonyl]-l-piperazinepentanamide

A suspension of 4-pentynoic acid (9.52 g, 99.89 mmol) and the intermediate from Example 1 Step D (15 g, 90.81 mmol) in TΗF (900 mL) was added EDC (26.1 g, 136.2 mmol), ΗOBt (18.2 g, 136.2) and DTEA (31.5 mL, 181.6 mmol). The reaction mixture was stined at room temperature for 3 days. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. This organic solution was washed with water, saturated ΝaΗCO₃, brine, then it was dried over Na^O^ filtered and concentrated. The resulting residue was dissolved in minimum amount of methylene chloride and hexane was added until white precipitate was formed. After filtration the title compound was obtained as a white solid.

To a solution of intermediate from Step A (3.5 g, 14.3 mmol) in methylene chloride (65 mL) at room temperature was added 2-methoxypropene (6.8 mL, 71.3 mmol) and camphorsulfonic acid (catalytic amt.). After 15 min the reaction was added to IN NaOH and extracted with methylene chloride three times. The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel with 3:2 ethyl acetate/hexane as eluant to give the title compound.

A suspension of intermediate from Step B (2.62 g, 9.2 mmol) and 4- hydroxy-3,5-diiodo-pyridine (3.51 g, 10.1 mmol) in pyridine (48 mL) was purged with nitrogen for 5 min, then Cu₂O (1.7 g, 11.94 mmol) was added. The resulting suspension was purged with nitrogen for another 5 min. The reaction mixture was heated at 120 °C for 1.5 h. The resulting suspension was filtered through celite and concentrated. The crude product was purified by flash column chromatography on silica gel with ethyl acetate as eluant to give the title compound.

To a solution of intermediate from Step C (2.22 g, 4.4 mmol) in ethanol (40 mL) was added Pd(OH)₂ (0.63 g, cat.) and DIEA (3.07 mL, 17.6 mmol). The suspension was stined under a hydrogen balloon at room temperature overnight. This reaction mixture was filtered through celite and concentrated. The crude product was purified by flash column chromatography on silica gel with ethyl acetate as eluant to afford the title compound.

A solution of intermediate from Step D (1.6 g, 4.2 mmol) in anhydrous THF was cooled to - 25 °C. To this solution, ally bromide (0.44 mL, 5.0 mmol) was added followed by addition of LHMDS in THF (1 M in THF, 5.0 mL, 5.0 mmol). After 1 h, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic layer was dried over Na_jSO,,, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel with 3:1 ethyl acetate/hexane as eluant to afford the title compound. Step F

A solution of intermediate from Step E (1.1 g, 2.7 mmol) in ethyl acetate (25 mL) and 0.5 M NaHCO₃ (25 mL) was cooled to 0 °C and NTS (1.53 g, 6.81 mmol) was added. After stirring from 0 °C to room temperature, the reaction mixture was poured into Na_jSO_j solution and extracted with ethyl acetate three times. The combined organic layer was dried over Na,SO₄, filtered and concentrated. The resulting residue was dissolved in ethyl acetate (47 mL) and NaOMe (2.52 mL, 25 % by wt in methanol) was added. The reaction mixture was stined at room temperature for 1.5 h, then it was poured into saturated NaHCO₃ solution and extracted with ethyl acetate three times. The combined organic layer was dried over Na^O,,, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel with 4: 1 ethyl acetate/ hexane as eluant to give the title compound.

A solution of the intermediate from Step F (80 mg, 0.184 mmol) and the intermediate from Example 1 Step N (111 mg, 0.276 mmol) in 2-propanol (2 ml) was heated to reflux overnight. The solvent was removed in vacuo. The crude reaction mixture was purified by flash column chromatography on silica gel with 70% ethyl acetate/acetone as eluant to give the titled compound as a white solid. LC-MS (M⁺+1) (El) 836.4.

Step H

(αS,γ5,2S)-4-[[5-(4-chlorophenyl)-2-furanyl]methyl]-N-[(35,45)-2,3-dihydro-3- hydroxy-3H- 1 -benzopyran-4-yl] -α-(furo [3 ,2-c]pyridin-2-ylmethyl)-γ-hydroxy-2- [[(2,2,2-trifluoroethyl)amino]carbonyl]-l-piperazinepentanamide

To a solution of the intermediate from Step G (75.8 mg, 0.091 mmol) in methanol (3.2 ml) was added 1 M ΗC1 in ethyl ether (1.4 ml, 1.4 mmol). The reaction mixture was stined at room temperature overnight. Then the reaction mixture was neutralized by 2 M ammonia in methanol. The solvent was removed in vacuo and the reaction mixture was diluted with methylene chloride and washed with 1 Ν ΝaOΗ. The aqueous layer was extracted with methylene chloride three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by reverse phase ΗPLC. 1H ΝMR (CDC1₃, 500 MHz): 9.15 (bs, ΝH, IH), 8.81 (m, IH), 8.43 (m, IH), 7.58-7.56 (m, 2H), 7.38-7.37 (m, 3H), 7.16-7.13 (m, 2H), 6.84-6.80 (m, 2H), 6.61-6.58 (m, 3H), 6.34 (d, 7 = 3.4 Hz, IH), 5.29-5.27 (m, IH), 4.17-4.10 (m, 2H), 4.01-3.97 (m, 2H), 3.82-3.78 (m, IH), 3.72-3.48 (m, 3H), 3.34-3.25 (m, 2H), 3.19-3.14 (m, IH), 3.04- 2.94 (m, 3H), 2.72-2.63 (m, 3H), 2.55-2.37 (m, 3H), 1.92-1.86 (m, IH), 1.68-1.58 (m, IH). LC-MS (M⁺+1) (ET) 796.3.

EXAMPLE 5 (2S)-4-[[5-(4-chlorophenyl)-2-furanyl]methyl]-l-[(2,S,45)-4-(furo[2,3-c]pyridin-2- ylmethyl)-2-hydroxy-5-[[(35,45)-3-hydroxy-3,4-dihydro-2H-chromen-4-yl]amino]-5- oxopentyl]-N-(2,2,2-trifluoroethyl)-2-piperazinecarboxamide

To a stined solution of DTPA (1.28mL; 9.74mmol) in dry THF (26mL) at 0 °C was added dropwise n-BuLi (3.54mL; 8.85mmol). After 15 minutes, the solution was cooled to -78 °C and a solution of (5')-(+)-dihydro-5-(t- butyldimethylsilylhydroxymethyl)-2(3H)-furanone (2.04g; 8.85mmol) in dry TΗF (8mL) was added dropwise. After an additional 30 minutes, propargyl bromide (1.56mL; lO.όmmol) was added dropwise. After 45 minutes the reaction was quenched with 10% citric acid, poured into Et₂O, and washed with Η₂O (2x) and brine, dried (MgSO₄), filtered, and solvents removed in vacuo. Purification by Biotage column chromatography (40M; 8% EtOAc/hexane) provided the desired compound.

To a stined solution of the intermediate from Step A above (903mg;

3.46mmol) in dry THF (21mL) was added HF-pyridine complex (1.2mL). The next morning, the reaction mixture was cooled to 0 °C and adjusted to pH 10 with NH4.OH/Η₂O (2:1). Much solvent was removed in vacuo and the residue was poured into EtOAc and washed with saturated NaHCO₃, 2x H₂O and brine. Drying (MgSO ), filtration, removal of solvent in vacuo, and purification by Biotage column chromatography (40M; 50% EtOAc/hexane) provided the desired product.

To a stined solution of intermediate from Step B above (720mg; 4.67mmol) in dry CH₂C1₂ (19mL) at 0 °C was added 2,6-lutidine (816uL; 7.0mmol) followed dropwise by trifluoromethanesulfonic anhydride (1.02mL; 6.07mmol).

After 1.75 hours, the reaction mixture was poured into 20mL ice/brine and stined 30 minutes. This mixture was poured into CH₂C1₂ and washed with 2x H O and 2x brine. After drying (MgSO₄), filtration, and removal of solvent in vacuo, the residue was purified by Biotage column chromatography (40M; 20% EtOAc/hexane) to provide the desired intermediate. lH NMR (500 MHz, CDC1₃): δ 2.08 (m, IH), 2.38- 2.44 (complex m, IH), 2.52-2.59 (complex m, IH), 2.67 (m, 2H), 2.94-2.98 (complex m, IH), 4.57 (1/2ABX, J=4.1, 11.2 Hz, IH), 4.71 (1/2ABX, J=3.0, 11.2 Hz, IH), 4.89 (m, IH).

To a stined solution of piperazine (lOOmg; 0.25mmol) from Step C above and triflate (72mg; 0.25mmol) from Step C above in dry iPrOH (1.25mL) was added DTEA (52uL; 0.30mmol). The next morning, the reaction mixture was poured into EtOAc and washed with saturated NaHCO₃, water, brine, water, and brine. Drying (MgSO₄), filtration, and removal of solvent in vacuo was followed by flash column chromatography (70% EtOAc/hexane) to provide the desired intermediate.

To a solution of acetylene (845mg; 1.9mmol) from Step D above and 4-iodo-3-hydroxypyridine (501mg; 2.23mmol) in dry pyridine (lOmL) was added Cu₂O (323mg; 2.3mmol). After 35 minutes at 120 °C, the mixture was cooled to ambient temperature and filtered through celite, washing with EtOAc. The organics were washed with aqueous Na₂SO , 2x water, brine, dried (Na₂SO ), filtered, and the solvents removed in vacuo. Purification by flash column chromatography (gradient elution 3% to 5% MeOH/CH₂Cl₂) provided the desired intermediate

To a solution of the lactone (565mg; 1.04mmol) obtained from Step E above in dry dimethoxyethane (lOmL) cooled to 0 °C under nitrogen was added aqueous LiOH (1.04mL;1.0M). The flask was allowed to warm to ambient temperature and stined for 3.5hr. The reaction was azeotroped from MeCN, MeCN/benzene, and benzene, taking care to keep the water bath below 35 °C. This salt was further dried under vacuum, then dissolved in dry DMF (lOmL) and imidazole (1.41g; 21.0mmol) was added. This solution was cooled to 0 °C and TBSC1 was added (1.56g; 10.4mmol). The flask was allowed to warm to ambient temperature and stined overnight. The next morning the reaction was quenched with pH 7 phosphate buffer and extracted 3x EtOAc. After drying (Na₂SO₄), filtration, and removal of solvent in vacuo, the residue was dissolved in 3mL THF/water (2: 1). After lhr the mixture was azeotroped from MeCN, benzene, and MeCN to provide the carboxylic acid, which was used without further purification.

To a stined solution of acid (672 mg; .296mmol) from Step F in dry NMP (3mL) at 0 °C was added DIEA (155uL; 0.89mmol) followed by the following solids, allowing one to dissolve before adding the next: HOBt (90mg; 0.66mmol), amino chromanol obtained from Example 1 Step D (68mg; 0.41mmol), and HBTU (168mg; 0.44mmol). The reaction was allowed to reach ambient temperature and the next morning the mixture was poured into EtOAc and washed with saturated NaHCO₃, water, brine, 3x dilute NaHCO₃, and brine. After drying (Na₂SO ), filtration, and removal of the solvent in vacuo, the residue was purified by flash chromatography (95% EtOAc/hexane) to provide the desired product.

The intermediate from the previous Step ( 48 mg) was stined in a mixture of 30% TFA in dichloromethane (1 mL) for 1.5 hours. The solution was then poured into EtOAc ( 40 mL) containing sat NaHCO3 solution. The aqueous layer was washed with water, brine, and then dried and filtered to give the desired product.

To a solution of the intermediate obtained from Step H (27mg, 0.037 mmol) in DMF (0.5 mL) was added 5-(4-chlorophenyl)-furan-aldehyde (10 mg, 0.048 mmol) and sodium triacetoxy borohydride (10.3 mg, 0.048 mmol). The reaction was quenched after one hour with saturated NaHCO3 solution. The aqueous layer was extracted with dichloromethane (3X). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography with 5% methanol-dichloromethane to give the title compound (17mg) . Step J

(25)-4-[[5-(4-chlorophenyl)-2-furanyl]methyl]-l-[(2_lS,45)-4-(furo[2,3-c]pyridin-2- ylmethyl)-2-hydroxy-5-[[(35,45)-3-hydiOxy-3,4-dihydiO-2H-chromen-4-yl]amino]-5- oxopentyl]-N-(2,2,2-trifluoroethyl)-2-piperazinecarboxamide

To a solution of the intermediate (17mg; 0.0187mmol) from Step I in dry TΗF (0.5mL) was added TBAF (56uL; 0.056mmol). The solution was stined at 55 °C for 2 hours. The reaction mixture was poured into EtOAc and washed with saturated ΝaΗCO₃, water, and brine. Drying (Na₂SO₄), filtration, and removal of the solvent in vacuo followed by purification by MPLC (Lobar column; linear gradient 10% to 90% MeCN/H₂O) provided the titled compound after lyophilization from MeCN/water (1:1). . 1H NMR (CD₃OD, 500 MHz): 8.70 (s, IH), 8.26 (d, 7= 5.2 Hz, IH), 7.65-7.63 (m, 2H), 7.59 (d, 7= 5.5 Hz, IH), 7.37-7.36 (m, 2H), 7.17 (d, 7 = 7.6 Hz, IH), 7.12-7.09 (m, IH), 6.84-6.81 (m, IH), 6.76-6.73 (m, 3H), 6.39 (d, 7= 3.2 Hz, IH), 5.23 (d, 7 = 4.1 Hz, IH), 4.84-3.70 (m, 6H), 3.64 (s, 2H), 3.28-3.23 (m, 2H), 3.11-3.00 (m, 3H), 2.82-2.71(m, 2H), 2.57-2.35 (m, 5H), 2.16-2.11 (m, IH), 1.51- 1.46(m, IH). LC-MS (M⁺+1) (El) 796.3.

EXAMPLE 6

(αS,γ5,2S)-4-[[5-(3-chlorophenyl)-2-furanyl]methyl]-N-[(35,45)-2,3-dihydro-3- hydroxy-3H- 1 -benzopyran-4-yl] -α-(f uro [3 ,2-c]pyridin-2-ylmethyl)-γ-hydroxy-2- [[(2,2,2-trifluoroethyl)amino]carbonyl]-l-piperazinepentanamide

A solution of the intermediate from Example 4 Step F (0.3 g, 0.7 mmol) and the Boc piperidine intermediate from Example 16 Step 5 (0.3 g, 1.0 mmol) in 2-propanol (8 mL) was refluxed overnight. Then the solvent was removed and the residue was purified by flash column chromatography on silica gel with ethyl acetate as eluant. The resulting product was dissolved in methanol (2 mL) and 4 N HCI in dioxane (1 mL) was added. After stirring at room temperature for 4 h, the solvent was removed and 1 N NaOH and methylene chloride was added to the resulting residue. The organic layer was separated, dried over Na₂SO₄, filtered and concentrated to give the title compound.

To a solution of 5-bromo-2-furaldehyde (5.6 g, 32.0 mmol) in DME (130 mL) was added tetrakis(triphenylphosphine)palladium (1.85 g, 1.6 mmol). The mixture was stined at room temperature for 10 min. Then 3-chloro-phenylboronic acid (5 g, 32 mmol) was added followed by 2 M Na₂CO₃ (32 mL). The reaction mixture was refluxed overnight. Then it was poured into 1 N NaOH and extracted with ethyl acetate three times. The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel with 1:9 ethyl acetate/hexane as eluant to give the title compound. Step C

(α5,γ5,2S)-4-[[5-(3-chlorophenyl)-2-furanyl]methyl]-N-[(3S,4₁S)-2,3-dihydro-3- hydroxy-3H- 1 -benzopyran-4-yl] -α-(furo [3 ,2-c]pyridin-2-ylmethyl)-γ-hydroxy-2- [[(2,2,2-trifluoroethyl)amino]carbonyl]-l-piperazinepentanamide

To a solution of intermediate from Step B (18.8 mg, 0.09 mmol) and intermediate from Step A (50 mg, 0.08 mmol) in 1,2-dichloroethane (0.4 mL) was added ΝaB(OAc)₃Η (26.3 mg, 0.12 mmol). The reaction mixture was stined at room temperature overnight. Then solvent was removed and the crude product was purified by flash column chromatography on silica gel with 7 % 2 M NH₃ in MeOH/ethyl acetate as eluant to give the title compound. 1H NMR (CD₃OD, 500 MHz): 8.75 (s, IH), 8.33 (d, 7 = 5.7 Hz, IH), 7.67 (m, IH), 7.58 (d, 7= 7.8 Hz, IH), 7.51 (d, 7 = 5.7 Hz, IH), 7.35 (t, 7= 8.0 Hz, 7= 7.7 Hz, IH), 7.24 (m, IH), 7.17 (d, 7= 4.8 Hz, IH), 7.10 (t, 7 = 8.0 Hz, 7 = 7.7 Hz, IH), 6.84-6.74 (m, 4H), 6.40 (d, 7= 3.4 Hz, IH), 5.24 (d, 7 = 4.1 Hz, 1 H), 4.84-3.71 (m, 6H), 3.65 (s, 2H), 3.28-3.20 (m, IH), 3.12-3.10 (M, IH), 3.03-2.98 (m, 2H), 2.82-2.70 (m, 2h), 2.58-2.36 (m, 6H), 2.15-2.09 (m, IH), 1.51-1.46 (m, IH). LC-MS (M⁺+l) (El) 796.3.

EXAMPLE 7 (αS,γS,2S)-4-[l-[5-(4-chlorophenyl)-2-oxazolyl]-l-methylethyl]-N-[(35,45)-2,3- dihydro-3-hydroxy-3H- 1 -benzopyran-4-yl] -γ-hydroxy-α-(5-thiazolylmethyl)-2- [ [(2,2,2-trifluoroethyl)amino]carbonyl]- 1 -piperazinepentanamide

Step A

To a solution of n-butyllithium (2.5 M in hexanes, 131 mL, 327.4

mmol) in dry ether (700 mL) was added, at -78 °C, a solution of 2- (trimethylsilyl)thiazole (50.0 g, 317.8 mmol) in dry ether (300 mL) slowly through a dropping funnel. After it was stined at -78 °C for 30 minutes, N-formyl morpholine (35.2 mL, 349.6 mmol) was dropped in slowly. The reaction solution was stined at - 78 °C for one hour. After it was washed with saturated aqueous sodium bicarbonate solution ( 500 ml), the organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash column chromatography on silica gel with hexanes / ethyl acetate = 2 / 1 as eluant to get the title compound as a slightly yellow solid. 1H ΝMR (CDC1₃, 500 MHz): δ 10.14 (s, 1 H), 9.13 (s, 1 H), 8.55 (s, I H).

A suspension of the aldehyde from the previous Step (21.4 g, 189.2 mmol) and malonic acid (43.3 g, 416.2 mmol) in pyridine (100 mL) and piperidine (1.9 mL) was refluxed for 2 hours. It was concentrated in vacuo. The residue was distributed between ether (1 L) and 1 Ν hydrochloric acid ( 200 mL). The organic layer was concentrated in vacuo to constant weight to get the title compound as a pale powder. 1H ΝMR (DMSO, 500 MHz): δ 9.15 (s, 1 H), 8.24 (s, 1 H), 7.80 (d, J=15.5 Hz, 1 H), 6.25 (d, J=15.5 Hz, 1 H).

To a suspension of the carboxylic acid obtained from the previous Step (5.0 g, 32.2 mmol) in a mixture of acetic acid and methanol ( 1 / 1, 330 mL) was added palladium on activated carbon ( 10 %, 2 g). After it was subjected to hydrogen gas (50 pci) for 24 hours, one more gram of palladium on activated carbon was added. It was subjected to hydrogen gas under the same pressure for 12 hours. Then, another gram of palladium on activated carbon was added. The reaction mixture was subjected to hydrogen gas under the same pressure for 10 more hours. It was filtered. The solid was washed with hot methanol for several times. The combined filtrate and washes was concentrated to get the title compound as pale solid. 1H NMR (DMSO_, 500 MHz): δ 8.89 (s, 1 H), 7.65 (s, 1 H), 3.05 (d, J=7.5 Hz, 2 H), 2.57 (d, J=7.5 Hz, 2 H).

To a solution of the carboxylic acid from the previous Step (4.5 g, 28.6 mmol) and aminochromanol from Example 1 Step D (4.73 g, 28.6 mmol) in DMF (20 mL) was added l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.2 g, 37.2 mmol), HOBt (5.1 g, 37.2 mmol) and diisopropylethylamine (15 mL, 85.9 mmol). After it was stined at room temperature for 3 hour, the solvent was removed in vacuo. The residue was washed with hot water (60 °C) to get the title compound as a pale solid. LC-MS (M⁺+1) (El) 305.0.

To a suspension of the amide from the previous Step (7.5 g, 24.6 mmol) and para-toluenesulfonic acid (1.17 g, 6.16 mmol) in THF (50 mL) was added 2-methoxypropene (11.8 mL, 123.2 mmol). After it was stined at 40 °C for 3 hours, ethyl acetate (500mL) was added. It was washed with IN NaOH solution. Organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash column chromatography on silica gel with ethyl acetate as eluant to get the title compound as a white oily solid LC-MS (M⁺+l) (El) 345.0.

To a solution of the protected amide from the previous Step (6.6 g, 19.2 mmol) and allyl bromide (1.83 ml, 21.1 mmol) in anhydrous THF (50 mL) was added dropwise of a solution of lithium bis(trimethylsilyl)amide in THF (1.0 M, 21.1 mL, 21.1 mmol) at -25 °C. The reaction solution was stined at -20 °C to -15 °C for 3 hours. Then, 500mL of ethyl acetate was added. It was washed with water. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash column chromatography on silica gel with hexanes / ethyl acetate =1 / 1 as eluant to get the title compound as a white solid. LC-MS (M⁺+1) (El) 385.1.

To a solution of the olefin from the previous Step (6.13 g, 15.9 mmol) in isopropyl acetate (30 mL) was added sodium bicarbonate (1.0 g, 12 mmol) and water (25 mL). After it was cooled to 5 °C, N-chlorosuccinimide (3.86 g, 28.9 mmol) and sodium iodide (4.33 g, 18.9 mmol) were added. It was stined at 6 °C ~ 11 °C for 15minutes and warmed to 25 °C, at which it was stined for 3 hours. The organic layer was washed with aqueous sodium bicarbonate solution and with a solution of sodium sulfite (2.2 g) in water (12 mL). It was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash column chromatography on silica gel with hexanes / ethyl acetate =1 / 1 as eluant to get the title compound as a slightly yellow solid LC-MS (M⁺+l) (El) 529.1.

To a solution of the intermediate from the previous Step (6.7 g, 12.7 mmol) in isopropyl acetate (20 mL) was added sodium methoxide in methanol ( 25 Wt %, 5.8 mL, 25.4 mmol) slowly. The reaction solution was stined at room temperature for 3 hours. After it was quenched with water, the organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash column chromatography on silica gel with ethyl acetate as eluant to get the title compound as a white solid. LC-MS Qs/ +1) (El) 401.5.

A solution of the epoxide from the previous Step (186 mg, 0.464 mmol) and the piperazine from Example 3, Step O (200 mg, 0.464 mmol) in ethanol (5 mL) was refluxed for 14 hours. After the solvent was removed, the residue was purified on a Biotage cartridge using ethyl acetate / methanol = 100 / 3 as eluent to get the title compound as a white solid. LC-MS (M⁺+l) (El) 831.1. Step J

(a5 5,2S)-4-[l-[5-(4-chlorophenyl)-2-oxazolyl]-l-methylethyl]-N-[(3.S,4S)-2,3- dihydro-3-hydroxy-3H-l-benzopyran-4-yl]-γ-hydroxy-α-(5-thiazolylmethyl)-2- [ [(2,2,2-trifluoroethyl)amino]carbonyl]- 1 -piperazinepentanamide

To a solution of the protected final product from the previous Step (348 mg, 0.42 mmol) was in methanol (10 mL) was added ΗC1 in ether (1 M, 2.1 mL). It was stined at room temperature for 10 hours. After the solvent was removed, the residue was purified on preparative reverse phase ΗPLC. After neutralized with ammonia in methanol the fraction collected was concentrated in vacuo and run through a short silica gel column to get the title compound as a white solid. 1H ΝMR (CD₃OD, 500 MHz): δ 8.80 (s, 1 H), 7.69 (d, J=8.5 Hz, 2 H), 7.65 ( s, 1 H), 7.47 ( d, J = 8.5 Hz, 2 H), 7.44 (s, 1 H), 7.08 - 7.13 ( m, 2 H), 6.82 (dt, J=7.5 Hz, 1.0 Hz, 1 H), 6.75 (dd, J=8.5 Hz, 1.0 Hz, 1 H), 5.20 (d, J=4.5 Hz, 1 H), 4.04-4.06 (m, 2 H), 3.92-3.98 ( m, 1 H), 3.78-3.82 (m, 1 H), 3.72-3.77 (m, 2 H), 3.06-3.10 (m, 1 H), 2.96- 3.03 (m, 2 H), 2.88-2.94 (m, IH), 2.85 (d, J=11.2 Hz, 1 H), 2.70-2.77 (m, 2 H), 2.63- 2.67 (m, 1 H), 2.44-2.50 (m, 1 H), 2.34-2.44 (m, 4 H), 2.00-2.04 (m, 1 H), 1.60 (s, 3 H), 1.59 (s, 3 H), 1.35-1.38 (m, 1 H). LC-MS (MM) (El) 791.4.

EXAMPLE 8 (α₁S,γS,2S)-4-[[5-(4-chlorophenyl)-2-furanyl]methyl]-N-[(3S,45)-2,3-dihydro- 3-hydroxy-3H-l-benzopyran-4-yl]-γ-hydroxy-α-(5-thiazolylmethyl)-2-[[(2,2,2- trifluoroethyl)amino]carbonyl] - 1 -piperazinepentanamide

A solution of the epoxide from Example 7, Step I (50 mg, 0.125 mmol) and the piperazine from Example 1, Step N ( 51mg, 0.125 mmol) in ethanol (5 mL) was refluxed for 12 hours. After the solvent was removed, the residue was purified on a Biotage cartridge using ethyl acetate / methanol = 100 / 3 as eluent to get the title compound as a white solid. LC-MS (MM) (El) 802.3.

Step B

(αS,γ5,25)-4-[[5-(4-chlorophenyl)-2-furanyl]methyl]-N-[(3S,45)-2,3-dihydro-

3-hydroxy-3H-l-benzopyran-4-yl]-γ-hydroxy-α-(5-thiazolylmethyl)-2-[[(2,2,2- trifluoroethyl)amino]carbonyl]-l-piperazinepentanamide

To a solution of the protected final product from the previous Step (74 mg, 0.09 mmol) was in methanol (10 mL) was added ΗC1 in ether (1 M, 0.5 mL). It was stined at room temperature for 36 hours. After the solvent was removed, the residue was purified on preparative reverse phase ΗPLC. After neutralized with ammonia in methanol the fraction collected was concentrated in vacuo and run through a short silica gel column to get the title compound as a white solid. 1H ΝMR (DMSO, 500 MHz): δ 8.86 (s, 1 H), 8.41-8.84 (m, 1 H), 7.91 (d, J=8.5 Hz, 2 H), 7.63- 7.66 ( m, 3 H), 7.44 ( d, J = 8.5 Hz, 2 H), 7.03-7.08 (m, 2 H), 6.91 - 6.92 ( m, 1 H), 6.76 (t, J=7.5 Hz, 1 H), 6.69 (d, J=8.5 Hz, 1 H), 6.40-6.41 (m, 1 H), 5.23 (s, 1 H), 5.12-5.14 (m, 1 H), 4.67 (d, J= 3 Hz, 1 H), 4.13-4.15 (m, 1 H), 4.05-4.08 (m, 1 H), 3.85-3.93 ( m, 1 H), 3.71-3.82 (m, 2 H), 3.62-3.68 (m, 1 H), 3.09-3.13 (m, 1 H), 2.91-2.97 (m, 4 H), 2.65-2.67 (m, 2 H), 2.37-2.49 (m, 1 H), 2.18-2.32 (m, 3 H), 1.97 (t, J=12 Hz, 3 H), 1.20 (t, J=12 Hz, 3 H), 1.35-1.38 (m, 1 H). LC-MS (MM) (El) 762.3. EXAMPLE 9 (aS^5,2S)-4-[l-[5-(4-chlorophenyl)-2-oxazolyl]-l-methylethyl]-N-[(3.S,4S)-2,3- dihydro-3 -hydroxy-3H- 1 -benzopyran-4-yl] -γ-hydroxy-α-(thieno [3 ,2-c]pyridin-2- ylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-l-piperazinepentanamide

TsCl (52.56 g, 0.275 mol) and triethylamine (41.89 mL, 0.298 mol) were added slowly to a solution of aminoacetaldehyde dimethyl acetal (24.12 g, 0.229 mol) in methylene chloride (100 mL) at 0°C. The resulting slurry was stined at 0°C and room temperature for 4 h. The mixture was diluted with methylene chloride (300 mL) and washed with water (100 mL), brine (100 mL), and dried over sodium sulfate. Biotage purification using EtOAc/Hexane (3:7) as the elute afforded the titled compound as a colorless oil.

To a solution of the titled compound from Step A (18.1 g, 69.8 mmol), triphenylphosphine (20.1 g, 76.9 mmol), and 3-thiophenemethanol (8.78 g, 76.9 mmol) in 150 mL of THF under N₂ at 0°C, diisopropyl azodicarboxylate was added dropwise. The solution was stined at 0°C for 30 min. The solution was then placed in a cold room (5°C) overnight. The reaction was quenched with saturated NaHCO₃ solution. THF was removed via vacuum. The mixture was extracted with EtOAc (3 x 150 mL). The combined EtOAc layers were washed with brine (100 mL), and dried over sodium sulfate. Biotage purification using EtOAc/Hexane (1:4) as the elute gave the titled compound as an oil.

Step C

^NCQ

The mixture of the titled compound from Step B (25.14 g, 74.9 mmol) and concentrated HCI (25 mL) in dioxane (100 mL) was heated to reflux overnight. The solvent was removed via a vacuum. The pH of the aqueous solution was adjusted to 9 with concentrated NH OH. The aqueous was extracted with methylene chloride (3x100 mL). The combined methylene chloride layers were washed with brine and dried over sodium sulfate. Biotage purification using EtOAc/Hexane (1:1) as the elute afforded the titled compound as an oil.

To a solution of the titled compound from Step C (5.41 g, 40.0 mmol) in THF (50 mL) at -78°C, LDA (22.0 mL, 44.0 mmol, 2M solution) was added dropwise. The resulting yellowish solution was stined at -78°C for 30 min. Ethyl formate (3.86 mL, 48 mmol) was added slowly. The solution turned into slurry and it was allowed to stir at -78°C for 3 h. Saturated ammonium chloride solution (50 mL) was added. The mixture was warmed up to room temperature and extracted with EtOAc (3x150 mL). The EtOAc layers were washed with brine and dried over sodium sulfate. Biotage purification using EtOAc/Hexane as the elute gave the titled compound a yellow solid.

To a solution of triethyl phosphonoacetate (4.68 mL, 23.6 mmol) in THF (50 mL) at 0°C, NaH (1.13 g, 28.36 mmol, 60%) was added. The mixture was stined at 0°C for 30 min until no hydrogen formed. A solution of the titled compound from Step D (3.21 g, 19.69 mmol) in THF (50 mL) was added. The solution was stined at 0°C for 2 h. Saturated ammonium chloride (50 mL) was added and the mixture was extracted with EtOAc (3x100 mL). The combined EtOAc layers were washed with brine and dried over sodium sulfate. The titled compound was obtained as a white solid after flash chromatography using EtOAc/Hexane (6:4) as the elute.

A solution of the titled compound from Step E (0.21 g, 0.90 mmol) in

MeOH was hydrogenated at 1 atm using Pd/C as the catalyst. The mixture was stined for 2 h and filtered through Celite. The filtrate was concentrated via vacuum. The residue was dissolved in MeOH (5 mL). An aqueous of NaOH (0.036 g, 0.91 mmol) was added. The solution was stined at room temperature for 2 h. The solvents were removed. Toluene was added to the solid and removed (2 x 5 mL). 1 mL of IN HCI solution was added and removed. The above process was repeated with toluene (2 x). To a mixture of the residue in methylene chloride (10 mL), aminochromanol from Example 1, Step D (0.19 g, 1.15 mmol), EDC (0.27 g, 1.43 mmol), HOBT (0.19 g, 1.43 mmol), and DTEA (0.83 mL, 4.75 mmol) were added. The mixture was stined at room temperature overnight. The resulting slurry was filtered and washed with methylene chloride (2 x 10 mL). The titled compound was obtained as a white solid.

To a solution of the titled compound from Step F (0.55 g, 1.55 mmol) and 2-methoxypropene (1.48 mL, 15.5 mmol) in methylene chloride (20 mL) at room temperature, 10-camphorsulfonic acid (0.27 g, 1.16 mmol) was added portionwise in a period of 1 h. The progress of the reaction was monitored by TLC (EtOAc). Upon completion of addition of the acid, color of the reaction turned to light brown. It was allowed to stir for another 30 min and TLC indicated that there was no starting material left. The solution was diluted with methylene chloride (100 mL). The solution was washed with saturated sodium bicarbonate, brine, and dried over sodium sulfate. Biotage purification using EtOAc Hexane (8:2) as the elute gave the titled compound as a white solid.

To a solution of the titled compound from Step G (0.55 g, 1.396 mmol) and allyl bromide (0.18 mL, 2.09 mmol) and THF at -25°C, LiN(TMS)₂ (1.67 mL, 1.67 mmol, IM THF solution) was added dropwise. The resulting yellow solution was stined at -25 °C for lh. TLC (EtOAc) showed no starting material left. The reaction was quenched with saturated ammonium chloride (5 mL) and extracted with EtOAc (3x50 mL). The combined EtOAc layers were washed brine and dried over sodium sulfate. Biotage purification using EtOAc/Hexane (8:2) as the elute afforded the titled compound as a white solid.

To a mixture of the titled compound from Step H (0.50 g, 1.15 mmol) and aqueous NaHCO₃ (0.5 M, 50 mL) in EtOAc (50 mL) at 0°C, N-iodosuccinimide (NTS) (0.57 g, 2.53 mmol) was added slowly. The mixture was stined at room temperature for 24 h. LC/MS indicated that there was significant starting material left. Another 2 eq of NTS was added and the reaction was allowed to stined for one more day. After 48 h, LC/MS showed no more starting material left. The mixture was extracted with EtOAc (3x50 mL), washed with brine (50 mL), and dried over sodium sulfate. The solvent was removed via vacuum and the residue was dissolved in EtOAc (20 mL). NaOMe (3.37 mL, 1.68 mmol, 0.5 M in MeOH) was added dropwise to the solution. The brown solution was stined at room temperature for lh. TLC (EtOAc) showed no more starting material. The reaction was quenched with saturated NaHCO₃ solution and extracted with EtOAc (3x50 mL). The organic layers were washed with brine (50 mL), and dried over sodium sulfate. Biotage purification using EtOAc as the elute gave the titled compound as a yellow solid.

Step J

A mixture of the titled compound from Step I (0.060 g, 0.133 mmol) and the titled compound from Example 3, Step O (0.069 g, 0.16 mmol) in 2-propanol (1 mL) was heated to reflux overnight. The solvent was removed. The titled compound was obtained as a white solid after flash chromatography using EtO Ac/acetone (7:3) as the elute.

Step K

(αS,γ_lS,2S)-4-[l-[5-(4-chlorophenyl)-2-oxazolyl]-l-methylethyl]-N-[(3»S,4S)-2,3- dihydro-3-hydroxy-3H-l-benzopyran-4-yl]-γ-hydroxy-α-(thieno[3,2-c]pyridin-2- ylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-l-piperazinepentananιide

The titled compound from Step J (0.04 g, 0.045 mmol) was mixed with 1 mL of MeOΗ and 2 mL of IM ΗC1 in ether. The solution was stined at room temperature for 2 h. The solvent was removed. The residue was mixed with saturated ΝaΗCO₃ (2 mL) and extracted with EtOAc (3x20 mL). The combined EtOAc layers were washed with brine, and dried over sodium sulfate. The titled compound was obtained as a white solid after flash chromatography using EtO Ac/acetone (1:1) as the elute. 1H NMR (δ, CDC1₃, 500 MHz): 9.32 (m, IH), 9.08 (s, IH), 8.40 (m, IH), 7.90 (m, IH), 7.59 (d, 7= 8.5 Hz, 2H), 7.42 (d, 7= 8.5 Hz, 2H), 7.40 (m, IH), 7.18 (m IH), 7.10 (m, IH), 6.80 (m, 2H), 5.28 (m, IH), 4.10 (m, 4H), 3.95 (m, IH), 3.90 (m, IH), 3.77 (m, IH), 3.43 (m, ZH), 3.15 (m, 3H), 3.08 (m, IH), 2.98 (IH), 2.65-2.90 (m, 3H), 2.58 (m, 3H), 1.85 (m, IH), 1.60 (s, 6H).LC-MS (M+l) (El): 842.

EXAMPLE 10

(α/?,γ5,25)-4-[l-[5-(4-chlorophenyl)-2-oxazolyl]-l-methylethyl]-N-[(35,4S)-3,4- dihydro-3-hydroxy-2H-l-benzopyran-4-yl]-α-(furo[2,3-c]pyrimidin-2-ylmethyl)-γ- hydroxy-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-l-piperazinepentanamide

Step A:

To the title lactone from Example 5 Step C ( 0.67 mmol, 192 mg) in isopropanol (2.2 mL) containing DTEA (1 mmol, 175 μL) was added the title piperidine from Example 3 Step O (0.74 mmol, 318 mg). After 16 h the reaction was concentrated and the product was purified by flash chromatography eluting with 3% MeOH DCM, affording a light yellow foamy solid. MS (ESI): m/z 567 (M + H).

Step B:

A solution of 5-hydroxypyrimidine (7.3 mmol, 700 mg) and N- iodosuccinimide (23.4 mmol, 5.28 g) in saturated NaHCO₃ (5 mL) and EtOAc (5 mL) was stined for 72 h. LC-MS analysis revealed the presence of the mono- and bis- iodinated products in approximately a 4:6 ratio. The aqueous layer containing the product was washed with hexanes and concentrated. The residue was triturated in EtOH and filtered. The filtrate was reduced and purified by flash chromatography eluting with a gradient of 2 - 4% MeOH/DCM (0.5% NH₄OH), affording a mixture of mono- and bis-iodinated products. The monoiodide was isolated by reverse-phase chromatography eluting with a gradient of 10% - 90% MeCN/H₂O (0.1 % TFA), affording the desired product as a reddish oil. MS (ESI): m/z 223 (M + H).

The iodopyrimidine from previous Step B (0.25 mmol, 113 mg), the acetylene from previous Step A (0.25 mmol, 142 mg), Pd(Ph₃P)₂Cl₂ (0.0075 mol, 5.3 mg), Cul (0.013 mmol, 2.3 mg) and triethylamine (1.5 mmol, 150 mg) were stined in dry DMF (3 mL) at 60° under N₂. After 1.5 h the acetylene was still present, and the reaction was replenished with 0.25 mmol of the iodopyrimidine, 0.0075 mmol of Pd(Ph₃P)₂Cl and 0.013 mol of Cul. After 2 h the reaction was concentrated. The product was purified by flash chromatography on silica eluting with 3% MeOH/DCM, followed by reverse-phase chromatography eluting with a gradient of 10% - 90%

MeCN/H₂O (0.1%o TFA). The product was partitioned between NaHCO₃ and EtOAc, and the organic phase was concentrated affording the desired product as a yellow solid. MS (ESI): m/z 661 (M + H).

Step D:

To the title compound from the previous Step C (0.07 mmol, 46 mg) in dioxane (1 mL) was added a solution of LiOH (0.2 mmol, 9 mg) in H O (200 μL). After 1.5 h the solvent was removed and the residue was concentrated twice from toluene. The compound was dissolved in dry DMF(1 mL) and brought to 0°. tert- Butyldimethylsilyl chloride (0.7 mmol, 105 mg) and imidazole (1.4 mmol, 95 mg) were added and the reaction was stined at 0° for 3 h. The reaction mixture was partitioned between EtOAc and pH 7 buffer. The organic phase was concentrated and the product was lyophilized from benzene and used without further purification. MS (ESI): m/z 793 (M + H).

Step E:

To a solution of the title compound from previous Step D (0.07 mmol), the title compound in Example 1 Step D (0.1 mmol, 13 mg), DIEA ( 0.21 mmol, 40 μL) and HOBt (0.14 mmol, 21 mg) in DMF (1 mL) was added EDC (0.1 mmol, 13 mg). After 3 h the reaction mixture was partitioned between EtOAc and H₂O. The organic layer was concentrated and the product was lyophilized from benzene affording a solid which was used without further purification.

Step F:

(αR,γ5,2S)-4-[l-[5-(4-chlorophenyl)-2-oxazolyl]-l-methylethyl]-N-[(35,4,S)-3,4- dihydro-3-hydroxy-2H-l-benzopyran-4-yl]-α-(furo[2,3-c]pyrimidin-2-ylmethyl)-γ- hydroxy-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-l-piperazinepentanamide

The title compound from the previous Step E (0.07 mmol) was stined in a 2 mL solution of TΗF containing ΗF-pyridine (0.08 mmol) for 24 h. The reaction mixture was taken up in EtOAc (10 mL) and washed twice with saturated ΝaΗCO₃. The product was purified by reverse-phase chromatography eluting with a linear gradient of 30% - 50% MeCN/ H₂O (0.1 % TFA). The combined product fractions were partitioned between saturated NaHCO₃ and EtOAc. The organic layer was concentrated, and the residue was lyophilized from MeCN/H₂O affording the title product as an off-white powder. MS (ESI): m/z 826 (M + H).

EXAMPLE 11 (αS,γ>S,2S)-4-[l-[5-(4-chlorophenyl)-2-oxazolyl]-l-methylethyl]-N-[(35_J4_>S)-2,3- dihydro-3 -hydroxy-3H- 1 -benzopyran-4-yl] -γ-hydroxy-α- [(5 -pyridin-3-yl- 1 ,4-oxazol- 2-yl)methyl]-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-l-piperazinepentanamide, tris- trifluoroacetic acid salt

Step A

To a solution of 3-bromopyridine (57 g, 160 mmol) in 150 mL anhydrous THF at 0 °C was added 178 mL 2.13 M i-propylmagnesium bromide in THF dropwise slowly. The cooling bath was removed after finishing addition. The reaction mixture was stined for 1.5 hours. A solution of 40 g BOC-Gly-N(OMe)Me in 150 mL THF was added over 10 minutes. The reaction mixture was stined for 5 hours and quenched by adding saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting product was purified by flash chromatography using 2:1 hexanes and ethyl acetate to give the titled compound. lH NMR (CDCI3, 500 MHz): 9.23 (d, 7= 1.9 Hz, IH), 8.88 (dd, 7= 1.4 and 4.8 Hz, IH),

8.34-8.37 (m, IH), 7.57 (dd, 7 = 5.1 and 8.1 Hz, IH), 5.48 (br s, IH), 4.69 (d, 7= 4.4 Hz, IH), 1.49 (s, 9H). LC-MS: 1.04 min. (237.1 m/Z, El).

Step B

To a solution of 29.3 g of the product from Step A above in methanol (25 mL) at 0 °C was added 200 mL 4.36 M HCI in methanol. The reaction was stined overnight and allowed to warm to room temperature. The solid was collected by filtration, washed with cold methanol and dried to give the title product. lH NMR (CD3OD, 500 MHz): 9.46 (d, 7 = 1.8 Hz, IH), 9.10 (dd, 7= 1.2 and 5.6 Hz, IH),

9.05-9.07 (m, IH), 8.205 (dd, 7 = 5.6 and 8.1 Hz, IH), 4.77 (s, 2H).

To a solution of 8.0 g of the product from Step B above in methylene chloride (200 mL) was added methyl 4-chloro-4-oxobutyrate (7.1 mL, 57.5 mmol). The reaction mixture was cooled at 0 °C. Diisopropylethylamine (20 mL, 114.9 mmol) was added to the reaction mixture dropwise. After 4 hours, the reaction mixture was concentrated under vacuum without heating, mixed with 25 g silica gel, and dry-loaded onto a silica gel column. It was eluted with 3-6% methanol in ethyl acetate to give the title product as a yellowish solid. lH NMR (CD3OD, 500 MHz):

9.12 (d, 7= 1.6 Hz, IH), 8.76 (dd, 7= 1.6 and 4.8 Hz, IH), 8.38-8.40 (m, IH), 7.59 (dd, 7 = 5.1 and 8.0 Hz, IH), 4.70 (s, 2H), 3.67 (s, 3H), 2.63 (s, 4H). LC-MS: 0.43 min. (251.2 m/Z, El).

A solution of 3.08 g of the product from Step C above in 100 mL phosphorus oxychloride was refluxed under nitrogen for 2 hours. The reaction mixture was cooled, concentrated under vacuum to dryness, mixed with some silica gel, dry-loaded onto a silica gel column, and purified by flash chromatography to give pure title compound as a solid. lH NMR (CDCI3, 500 MHz): 8.86 (d, 7= 1.4 Hz, IH), 8.49 (dd, 7= 1.2 and 4.9 Hz, IH), 8.08-8.11 (m, IH), 7.54 (s, IH), 7.50 (dd, 7 = 4.8 and 8.0 Hz, IH), 3.69 (s, 3H), 3.17 (t, 7 = 7.1 Hz, 2H) 2.89 (t, 7 = 7.1 Hz, 2H). LC-MS: 0.77 min. (233 m/Z, El).

To a solution of 0.9 g product from Step D above in 10 mL methanol was added a solution of 186 mg sodium hydroxide in 6 mL water. The reaction mixture was stined at room temperature for 3 hours. The solvents were removed under vacuum. The residue was re-dissolve in 10 mL water and the pH was adjusted to 6.5 with 1 N HCI. The resulting precipitated was collected by filtration and dried to give title compound as a solid. lH NMR (CD3OD, 500 MHz): 8.88 (d, 7= 1.8 Hz,

IH), 8.49 (dd, 7= 1.5 and 4.9 Hz, IH), 8.10-8.13 (m, IH), 7.56 (s, IH), 7.51 (dd, 7 = 5.1 and 8.1 Hz, IH), 3.15 (t, 7 = 7.2 Hz, 2H) 2.86 (t, 7= 7.2 Hz, 2H). LC-MS: 0.43 min. (219.2 m/Z, El).

To a suspension of the intermediate from Step E (0.92 g, 4.22 mmol) in NN-Dimethyl formamide (50 mL) was added diisopropylethylamine (1.83 mL, 10.55 mmol). To this clear solution was added (35,45)-4-amino-3,4-dihydro-2H- chromen-3-ol from Step D of Example 1 (0.73 g, 4.43 mmol), 1-hydroxybenzotriazole hydrate (0.86 g, 6.33 mmol), and l-ethyl-3-(3-dimethylaminopyropyl)carbodiimide hydrochloride (1.21 g 6.33 mmol) in that order. Additional portion of (3S,4S)-4- amino-3,4-dihydro-2H-chromen-3-ol (0.17 g) was added after 5 hours. The reaction mixture was stined for 60 hours and purified by flash chromatography using 5-10% methanol in ethyl acetate with 1% triethylamine to give title compound as an off- white solid.lΗ ΝMR (CD3OD, 500 MHz): 8.895 (d, 7 = 2.0 Hz, IH), 8.50 (dd, 7 = 1.5 and 4.9 Hz, IH), 8.12-8.14 (m, IH), 7.59 (s, lh), 5.505 (dd, 7 = 4.9 and 8.1 Hz, IH), 7.08-7.11 (m, 2H), 6.75-6.79 (m, 2H), 5.26 (d, 7 = 4.1 Hz, IH), 4.16 (d, 7= 3.7 Hz, 2H), 4.07-4.10 (m, IH), 3.20-3.32 (m, 2H), 2.82-2.94 (m, 2H). LC-MS (M+l, El) 366.1.

Step G

To a solution of the intermediate from Step F above (0.47 g, 1.29 mmol) in 50 mL 1:1 dimethyl formamide and methylene chloride was added 2- methoxypropene (0.465 g, 6.45 mmol) followed by camphor sulfonic acid (0.36 g, 1.55 mmol). The reaction mixture was stined overnight, diluted with ethyl acetate, washed with water (4x), saturated brine, and dried over anhydrous sodium sulfate. Solvents were removed in vacuo. The resulting crude product was purified by flash chromatography (2.5 and 3% MeOH in ethyl acetate) to give the title compound. lH NMR (CD3OD, 500 MHz) showed about 1 :3 ratio of amide rotomers. LC-MS (El)

406.1 (M+l) and 428.1 (M+Na).

Step H

To a solution of the intermediate obtained from Step G (0.368 g, 0.908 mmol) and allyl bromide (94.3 μL, 1.09 mmol) in THF (13 mL) cooled to -78 °C was added drop- wise a solution of LHMDS (1.1 mL, 1.0 M in THF). The reaction mixture was stined at -78 °C, warmed to -20 °C over 45 minutes, and quenched with saturated NaHCO₃ solution. The resulting bi-phasic mixture was extracted with ethyl acetate (2X), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography with 0 and 1% methanol-ethyl acetate to give the desired compound. lH NMR (CDCI3, 500 MHz) showed about 1:3 ratio of amide rotomers. LC-MS (El) 913.3 (2M+Na).

To a solution of the intermediate obtained from Step H (0.84 g, 1.89 mmol) in ethyl acetate (15 mL) was added NaHCO₃ solution (15 mL, 0.5 M) and the reaction cooled to 0 °C. N-iodo-succinimide (1.06 g, 4.73 mmol) was added and the reaction stined at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with a saturated solution of sodium thiosulfate (2x), water (3x), brine (lx) and dried over anhydrous sodium sulfate. The reaction mixture was filtered and concentrated in vacuo to give the desired compound as light brown foam. . lH ΝMR (CDCI3, 500 MHz) showed about 1 :3 ratio of amide rotomers. LC-MS (El) 590.0 (M+l).

To a solution of the intermediate from Step I (0.899 , 1.52 mmol) in ethyl acetate (13 mL) was added a solution of 0.5 M sodium methoxide in methanol (4.6 mL). After 20 minutes the reaction mixture was quenched with saturated ΝaHCO₃ solution and extracted with ethyl acetate(3x). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography with 1% methanol in ethyl acetate to give the desired compound as a yellowish solid. lH NMR (CDCI3, 500 MHz) showed about 1:4 ratio of amide rotomers. LC-MS (ET) 462.1 (M+l).

Step K

To a solution of the intermediate obtained from Step J (67.4 mg, 0.146 mmol) in 2-propanol (1.5 mL) was added the intermediate from Example 3 Step O (52.5 mg, 0.122 mmol) and the resulting mixture refluxed overnight. The reaction mixture was purified on RP HPLC using 25-55% MeCN gradient over 15 minutes at 6.0 mL per minute with 0.1% TFA on a 9.4x250 mm Zorbax SB-C18 column. Pure product fractions were pooled and evaporated in vacuo to give the title compound. lH NMR (CD3OD, 500 MHz) showed about 1:5 ratio of amide rotomers. LC-MS (El)

892.3 (M+l) and 914.3 (M+Na).

Step L

(αS,γ5,2,S)-4-[l-[5-(4-chlorophenyl)-2-oxazolyl]-l-methylethyl]-N-[(3₁S,45)-2,3- dihydro-3 -hydroxy-3H- 1 -benzopyran-4-yl] -γ-hydroxy-α- [(5 -pyridin-3-yl- 1 ,4-oxazol- 2-yl)methyl]-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-l-piperazinepentanamide, tris- trifluoroacetic acid salt

To a solution of the intermediate from Step K (49.7 mg mg, 0.04 mmol) in anhydrous methanol (2 mL) was added a solution of ΗC1 in ether (0.80 mL, 1.0 M solution). After 20 hours, the reaction mixture was concentrated in vacuo. The residue was purified on RP ΗPLC using 30-60% MeCΝ gradient over 15 minutes at 6.0 mL per minute with 0.1%) TFA on a 9.4x250 mm Zorbax SB-C18 column. Pure product fractions were pooled, evaporated in vacuo, and lyophilized to give the title compound as a white solid. lH NMR (CD3OD, 500 MHz): 8.88 (d, 7= 1.8 Hz, IH), 8.50 (d, 7 = 4.8 Hz, IH), 8.255 (d, 8.7 Hz, IH), 8.11-8.13 (m, IH), 7.67-7.70 (m, 2H), 7.45-7.55 (m, 4H), 7.20 (d, 7= 6.9 Hz, IH), 7.10-7.13 (m, IH), 6.84-6.87 (m, IH), 6.77 (d, 8.3 Hz, IH), 5.23-5.25 (m, IH), 4.12-4.15 (m, 2H), 4.03-4.05 (m, IH), 3.96-4.01 (m, IH), 3.76-3.9 (m), 3.22-3.27 (m), 3.04-3.08 (m), 2.45-2.65 (m), 2.05-2.15 (m), 1.61 (s, 6H), 1.46- 1.53 (m), 1.28-1.34 (m). LC-MS (El) 852.3 (M+l).

EXAMPLE 12 (α5,γS,25)-4-[[5-(4-chloroρhenyl)-2-furanyl]methyl]-N-[(35,45)-2,3-dihydro- 3-hydroxy-3H-l-benzopyran-4-yl]-γ-hydroxy-α-[(5-pyridin-3-yl-l,4-oxazol-2- yl)methyl]-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-l-piperazinepentanamide, tris- trifluoroacetic acid salt

To a solution of the intermediate obtained from Example 11, Step J (51.6 mg, 0.12 mmol) in 2-propanol (1.5 mL) was added the intermediate from

Example 1 Step N (55.5 mg, 0.12 mmol) and the resulting mixture refluxed overnight. The reaction mixture was purified on RP HPLC using 30-60% MeCN gradient over 15 minutes at 6.0 mL per minute with 0.1%) TFA on a 9.4x250 mm Zorbax SB-C18 column. Pure product fractions were pooled and evaporated in vacuo to give the title compound. LC-MS (El) 863.3 (M+l) and 885.3 (M+Na).

Step B

(α5,γS,2S)-4-[[5-(4-chlorophenyl)-2-furanyl]methyl]-N-[(3S,45)-2,3-dihydro- 3 -hydroxy-3H- 1 -benzopyran-4-yl] -γ-hydroxy-α- [(5 -pyridin-3-yl- 1 ,4-oxazol-2- yl)methyl] -2- [ [(2,2,2-trifluoroethyl)amino] carbonyl] - 1 -piperazinepentanamide, tris- trifluoroacetic acid salt

To a solution of the intermediate from Step A above (61.4 mg, 0.051 mmol) in anhydrous methanol (2 mL) was added a solution of ΗC1 in ether (1.02 mL, l.O M solution). After 20 hours, the reaction mixture was concentrated in vacuo. The residue was purified on RP ΗPLC using 30-60% MeCΝ gradient over 15 minutes at 6.0 mL per minute with 0.1% TFA on a 9.4x250 mm Zorbax SB-C18 column. Pure product fractions were pooled, evaporated in vacuo, and lyophilized to give the title compound as a white solid. lΗ ΝMR (CD3OD, 500 MHz): 9.05-9.07 (m, IH), 8.64-8.68 (m, lh), 8.48-8.57

(m, IH), 8.25 (d, 8.7 Hz, 1ΝH), 7.80-7.88 (m, IH), 7.70-7.72 (m, 3H), 7.41 (d, 7 = 8.5 Hz, 2H), 7.20 (d, 7 = 7.8 Hz, IH), 7.10-7.13 (m, IH), 6.88 (d, 7= 3.4 Hz, IH), 6.83-6.86 (m, IH), 6.74-6.78 (m, 2H), 5.24-5.26 (m, IH), 4.28-4.40 (m, 2H), 4.08-4.14 (m, 2H), 4.01-4.03 (m, IH), 3.84-3.97 (m, 3H), 3.79-3.81 (m, IH), 3.37-3.42 (m, IH), 3.25-3.30 (m, IH), 3.09-3.15 (m, IH), 2.97-3.03 (m, IH), 2.70-2.79 (m, 2H), 2.00-2.06 (m, IH), 1.56- 1.52 (m. IH). LC-MS (El) 823.2 (M+l).

EXAMPLE 13 Preparation of Enzymes

Synthetic oligonucleotide cassettes of 444 base pairs were designed according to the wild-type sequence of pET-3b-HTVPR. Point mutations were incorporated into the DNA with a bias toward optimal codon usage in E. Coli to yield amino acid mutations listed in Table 2 below. The oligonucleotides were annealed and ligated into pUC-18 or pUC-19 by Midland Certified Reagent Company. The primary sequence was verified before subcloning into a pET-3b expression vector via Nde I and Bpull021 sites and reconfirmed by automated double-stranded DNA sequencing. Clones carrying the mutant DNA were transformed and expressed as previously described in Schock et al., 7. Biol. Chem. 1996, 271: 31957-31963 and Chen et al., J. Biol. Chem. 1995, 270: 21433-21436. The cells were lysed in 50 mM Tris-HCl pH 8.0, 1 mM EDTA, 0.1% NP40, 10 mM MgCl₂ , and lOOμg / mL DNase I using a microfluidizer processor ( Microfluidics International Corp., Newton, MA). The mutant protease was extracted, refolded, and purified over affinity columns as previously described in Schock et al., 7. Biol. Chem. 1991, 271: 31957-31963. Protein concentrations were determined by amino acid analysis and purity was confirmed by SDS gel electrophoresis.

EXAMPLE 14 Assay for Inhibition of Microbial Expressed HTV Protease

Inhibition studies of the reaction of the protease (which was expressed in Eschericia coli) with a peptide substrate [Val-Ser-Gln-Asn-(betanapthyl)Ala-Pro- De-Val, 0.5 mg/mL at the time the reaction is initiated] were in 50 mM Na acetate, pH 5.5, 0.1% bovine serum albumin, 3.75% DMSO at 30°C for 1 hour. Various concentrations of inhibitor in 2 mL DMSO were added to 50 μL of the peptide solution in buffer. The reaction is initiated by the addition of 28 μL of 14.3 picomolar (wild type, K-60, Q-60) and 28.6 pM (V-18) protease in a solution of 50mM Na acetate pH 5.5 and 0.1% bovine serum albumin. The reaction was quenched with 120 μL of 10% phosphoric acid. Products of the reaction were separated by HPLC (VYDAC wide pore 5 cm C-18 reverse phase, acetonitrile gradient, 0.1% phosphoric acid). The extent of inhibition of the reaction was determined from the peak heights of the products. HPLC of the products, independently synthesized, proved quantitation standards and confirmation of the product composition. The compounds of the invention prepared in Examples 1-12 exhibited IC50 values ranging from about 0.05 to about 1 nM against the wild-type enzyme. The indinavir IC50 value against the wild type enzyme is 0.6 nM (average). The compounds of the invention prepared in Examples 1-12 exhibited IC50 values in the range of about 0.02 to about 5 nM against the mutant enzymes Q-60, K-60, and V-18. These IC50 values range from about 4-fold to greater than about 100-fold more potent than the values of of 20 to 50 nM obtained for indinavir against these same mutant enzymes.

EXAMPLE 15

Preparation of Viral Constructs Mutant viruses were constructed using gapped-duplex oligonucleotide mutagenesis of a subclone of plasmid pWT-6 as described in Colonno et al., Proc. Natl Acad. Sci. 1988, 85: 5449-5453. Infectious mutant proviral clones were constructed by subcloning the 833-b.p. Apal-Sse83871 fragment containing the mutagenized protease gene into the conesponding sites of plasmid pNL4-3 (see J. Virol. 1986, 59: 284-291). After transfection of the mutant proviral clone into HeLa cells and growth of viral stocks in cocultivated H9 human T-lymphoid cells, the complete sequence of the viral protease gene from the mutant viral population was verified as described in Nature 1995, 374: 569-571. The amino acid changes from wild type sequence for three of these viral constructs are shown in Table 2. Table 2 - Wild-type and Mutant HTV-1 Protease Sequences

See Condra et al., 7. Virol. 1996, 70: 8270-8276 and Olsen et al., 7. Biol. Chem. 1999, 274: 23699-23701 for further details.

EXAMPLE 16

Cell Spread Assay Inhibition of the spread of HTV in cell culture was measured according to Nunberg et al., J. Virol. 1991, 65: 4887. In this assay, MT-4 T-lymphoid cells were infected with HTV-1 (wild-type, unless otherwise indicated) by using a predetermined inoculum, and cultures were incubated for 24 h. At this time, <1% of the cells were positive by indirect immunofluorescence. Cells were then extensively washed and distributed into 96-well culture dishes. Serial twofold dilutions of inhibitor were added to the wells, and cultures were continued for 3 additional days. At 4 days postinfection, 100% of the cells in control cultures were infected. HTV-1 p24 accumulation was directly conelated with virus spread. The cell culture inhibitory concentration was defined as the inhibitor concentration in nanomoles/liter which reduced the spread of infection by at least 95%, or CIC95. The compounds of the invention prepared in Examples 1-12 exhibited CIC95 values in the range of from less than about 8 to about 50 nM against the wild-type viral construct. The CIC95 of indinavir against the wild-type viral construct is from 50 to 100 nM. The compounds of the invention prepared in Examples 1-12 exhibited CIC95 values in the range of about 8 to about 125 nM against the viral constructs Q60, K-60, and V-18. These CIC95 values range from about 4-fold to more than about 100-fold more potent than the values of greater than 1000 nM obtained for indinavir against these same viral constructs.

EXAMPLE 17 Inhibition of Virus Spread

A. Preparation of HTV-infected MT-4 cell Suspension MT cells are infected at Day 0 at a concentration of 250,000 per ml with a 1:1000 dilution of HTV-1 strain Tub stock (final 125 pg p24/ml; sufficient to yield <1% infected cells on day 1 and 25-100% on day 4). Cells are infected and grown in the following medium: RPMI 1640 (Whittaker BioProducts), 10% inactivated fetal bovine serum, 4 mM glutamine (Gibco Labs) and 1:100 Penicillin- Streptomycin (Gibco Labs). The mixture is incubated overnight at 37°C in 5% CO2 atmosphere.

B. Treatment with Inhibitors

A matrix of nanomolar range concentrations of the pairwise combinations is prepared. At Day 1, aliquots of 125 ml of inhibitors are added to equal volumes of HTV-infected MT-4 cells (50,000 per well) in a 96-well microtiter cell culture plate. Incubation is continued for 3 days at 37°C in 5% CO2 atmosphere.

C. Measurement of Virus Spread Using a multichannel pipettor, the settled cells are resuspended and

125 ml harvested into a separate microtiter plate. The supernatant is assayed for HTV p24 antigen.

The concentration of HTV p24 antigen is measured by an enzyme immunoassay, described as follows. Aliquots of p24 antigen to be measured are added to microwells coated with a monoclonal antibody specific for HTV core antigen. The microwells are washed at this point, and at other appropriate Steps that follow. Biotinylated HTV-specific antibody is then added, followed by conjugated streptavidin-horseradish peroxidase. A color reaction occurs from the added hydrogen peroxide and tetramethylbenzidine substrate. Color intensity is proportional to the concentration of HTV p24 antigen.

Calculation of Degree of Synergy

When there is synergy, pairwise combinations of inhibitors are found to exhibit markedly enhanced inhibition of virus spread, in comparison to each inhibitor alone, or in comparison to merely additive inhibition of each inhibitor.

The data is processed as follows: fractional inhibitory concentration ratios (F C) are calculated according to Elion, et al., J. Biol. Chem. 1954, 208: 477. The minimum sum of FICs, which is the maximum synergy, is determined for various pairwise combinations. The smaller the number, the greater the synergy.

EXAMPLE 18 Preparation of 4-(tert-butyloxycarbonyl)-2(5)-((2,2,2-trifluoroethyl)aminocarbonyl) piperazine Step One: Preparation of the pyrazine amide

Pyrazine 2-carboxylic acid (1204 g) was suspended in DMF (4.8 L, 4 mL/g acid). 2,2,2-trifluoroethylarnine»HCl (TFEA»HC1) (1200 g), 1- hydroxybenzotriazole (HOBT) (60 g) and triethylamine (TEA) (1410 mL) were then added sequentially (exotherm upon addition of TEA, flask cooled with ice bath and temperature kept below 35 °C). The reaction was cooled to 15 °C and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide«HCl (EDC»HC1) (1940 g) was added portionwise over 15-30 min. The reaction temperature was kept below 35 °C. When the reaction appeared complete (approx. two hours, <5% pyrazine 2-carboxylic acid byLC assay), the reaction mixture (yellow/white slurry) was diluted with 10% K₂CO₃ in water (24 L, 20 mL/g acid) and the reaction slurry was kept below 35 °C. The slurry was cooled to 10 °C, aged for two hours and filtered (mother liquor assay=3- 4mg/mL). The wet cake was washed with deionized water (12 L, 10 mL/g acid) and dried under vacuum (22" Hg) at 40 °C with a nitrogen purge. Theoretical yield of 1816 g . Actual yield 1533 g (84%). 1H NMR: (CD₃CN, 400 MHz): δ 9.29(d, J=1.5 Hz, IH), 8.82 (d, J= 2.5 Hz, IH), 8.63 (dd, J= 2.6,1.4 Hz, IH), 8.40 (bs, IH), 4.14 (dq, J=9.4, 6.8 Hz, 2H).

HPLC Assay conditions: Waters Xtena RP8 column, elution with acetonitrile and 5 mM K phosphate adjusted to pH= 8, detection at 220 nm.

Step Two: Preparation of the piperazine amide

Pyrazine amide (60.2 g 0.268 mol, not conected for water content) was suspended in absolute ethanol (550 mL) in a 1.0 L autoclave hydrogenation vessel and cooled to 15 °C. Wet 20% Pd(OH)₂/C 11.0 g (20wt%, 50wt%wet) was added and reaction was purged with N₂ three times. H₂ (5 psig) was introduced with stirring and the temperature maintained at 15 °C for 60 minutes. The temperature was then increased to 60 °C and the hydrogen pressure increased to 40 psig and the reaction mixture stined for 18 additional hours. The reaction was considered complete when conversion is >99% by LC assay. The reaction mixture was filtered through Solka- Floe and the catalyst solids were washed with ethanol 2 X 110 mL. Assay of the combined filtrate and washes gave 53.5 g of racemic piperazine amide (Yield = 86%) IH NMR (CD3CN, 400 MHz): δ 7.58 (bs, IH), 3.90 (dq, J=9.5,6.7 Hz, 2H), 3.24(dd, J=7.9, 5.5 Hz, IH), 2.96 (dd, J= 12.1, 3.6 Hz, IH), 2.84-2.78 (m, IH), 2.77-2.67 (m, 3H), 2.66-2.56 (m, IH), 1.90 (s, 2 H). HPLC Assay conditions: YMC Basic column, elution with acetonitrile and 0.1% aqueous H₃PO₄, detection at 210 nm.

Step Three: Resolution of the piperazine amide

The pip amide ethanol filtrate (116.37 g containing 10.3 g of racemic pip amide by LC assay) was concentrated in vacuo to a final volume of 40.2 mL (3.9 mL per gram of pip amide) and the slurry is diluted with 82.4 mL (8 mL per gram pip amide) of acetonitrile (ACN) and stined until homogenous. Separately (S)- camphorsulfonic acid ( (S)-CSA) (19.26 g, MW= 232.30, 1.7 eq) was dissolved in 185 mL of ACN (18 mL per gram of pip amide). The water content of the two solutions was then determined by Karl Fisher titration. The CSA solution was added to the pip amide solution giving a small exotherm to approx. 31-32 °C. Water (11.02 mL, 1.118 mL per gram of pip amide minus the total water content of the two solutions) was then added, such that the acetonitrile:ethanol:water ratio was 26:2.9:1.1 (v/v/v). Solids began to form after 15-30 min. The solution/slurry was heated to 72 °C to completely dissolve all solids. The yellow solution was recooled to 62 °C and seeded with a slurry of 10.3 mg of pip amide salt in 1 mL of acetonitrile. After a two hour age at 62 °C the slurry was allowed to cool to room temperature overnight

(crystallization was complete when loss to mother liquors was < 21 mg pip amide/mL by LC assay. The slurry was filtered then washed with 2 x 30 mL of ACN:EtOH:H₂O [(26:2.9:1.1), (v:v:v)] solution. The wet cake (-13 g, white solid) was dried at 40 °C in a vacuum oven (24 in Hg, nitrogen sweep) to give 11.16 g of product (yield = 33%). Assay method (Pip Amide) as above. Chiral assay gives an enantiomeric excess (ee) of 98.0%.

IH NMR (CD₃OD, 400 MHz): d4.84(bs, 5H), 4.64 (dd, J=12.0, 3.6 Hz, IH), 4.13- 3.94 (m, 3H), 3.77 (m, 2H), 3.66 (m, IH), 3.54-3.43 (m, 2H), 3.28(d, J= 14.7 Hz, 2H), 2.82 (d, 14.7 Hz, 2H), 2.55 (m, 2H), 2.36 (m, 2H), 2.12-1.998 (m, 4H), 1.92 (d, J=18.4 Hz, 2H), 1.72 (m, 2H), 1.45 (m, 2H), 1.09 (s, 6H), 0.87 (s, 6H).

Enantiomeric excess determined by chiral HPLC of the mono BOC piperazine amide. HPLC assay conditions: Chiral AGP column, elution with acetonitrile and 10 mM Kphospate, pH=6.5, detection at 210 nm.

Step Four: Upgrade of ee of (SVpiperazine amide bis (S)-CS A salt

S)-CSA- H₂0

To a 12 L flask was charged (S)-pip amide salt (412.87 g) having an ee of less than 98%), 7.43 L of ACN and 825 mL of 190 proof EtOH. The slurry was heated to 75 °C, aged for 1 hr at 75 °C (during heating the slurry thickened considerably), then allowed to cool to 25 °C overnight. The slurry was filtered and washed with EtOH (190 proof):ACN (10:90) (2 x 800 mL, 2 mL g). The white solid was dried in a vacuum oven at 24 in Hg, 40 °C with a nitrogen sweep to give 400 g of product with an ee of 99%. Assays (normal and chiral) were performed as described above in the prior steps.

Step Five: Procedure for (S)-Mono BOC piperazine amide: BOC Protection

Bis (S)-CS A piperazine amide salt (20 g) was suspended in a mixture of 113 mL of isopropyl acetate (TPAc) and 57 mL of acetonitrile. Triethylamine (8.26 mL, 2 eq) was added and the mixture stined until homogenous. A solution of di t- butyl dicarbonate (TBDC) (6.46 g, 1.0 eq) in a mixture of 20 mL isopropyl acetate and 10 mL of acetonitrile (ACN) was then added over 10 minutes. After aging for two hours the solution was assayed as necessary by LC (Pip Amide Assay, see above) until the reaction was complete (i.e., less than 5% starting material). When the reaction was complete, 100 mL of water and 135 mL of isopropyl acetate were added, the resulting layers were separated and the organic layer was concentrated to 28 mL. The residue was then diluted with 28 mL of isopropyl alcohol and reconcentrated to 28 mL. This was repeated two additional times. The yield of BOC pip amide was 87% with a mono:bis BOC ratio of 95:5, as determined by HPLC. 1H NMR (CDC1₃, 400MHz): δ=7.39 (app t, 7=6.3Hz, IH), 3.96 (dd, 7=3.5, 13.4Hz, IH), 3.88 (m, 2H), 3.67 (d, 7=11.5Hz, IH), 3.39 (dd, 7=3.8, 8.6Hz, IH), 3.13 (dd, 7=8.6, 13.3Hz, IH), 3.02 (br, IH), 2.91 (m, IH), 2.77 (m, IH), 1.43 (s, 9H).

¹³C NMR (CDC1₃, ) δ= 171.43, 154.41, 123.89 (q, J=78.5Hz), 80.16, 57.65, 43.63, 45.6 (br), 44.0 (br), 40.20 (q, J=34.7Hz), 28.19. HPLC Assay conditions: YMC Basic column, elution with acetonitrile and 0.1% aqueous H₃PO , detection at 210 nm. While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, the practice of the invention encompasses all of the usual variations, adaptations and/or modifications that come within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula:

wherein

A is CH or N;

Rl is -F or -Cl;

R2 and R3 are each independently -H or methyl; and

R4 is

X is O or S;

Y is pyridyl which is optionally substituted with from 1 to 3 substituents each of which is independently halogen, cyano, Cχ-C6 alkyl, or Cχ-C6 alkoxy; each Z is independently hydrogen, halogen, cyano, Cχ-C6 alkyl, or Cχ-C6 alkoxy; and

q is an integer from zero to 2;

and with the proviso that when A is N and R4 is:

o- , then R2 and R3 are both -H;

or a pharmaceutically acceptable salt thereof.

The compound according to claim 1, wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof.

The compound according to claim 1, wherein

R2 and R3 are either both -H or both methyl; R4 IS

Y is pyridyl which is optionally substituted with from 1 to 3 substituents each of which is independently halogen, cyano, C1-C4 alkyl, or C1-C4 alkoxy;

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3, wherein

R i is

Q is -H, -F, -Cl, -Br, C1-C4 alkyl, or C1-C4 alkoxy;

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein

R2 and R3 are either both -H or both methyl;

X is S or O;

each Z is independently -H, -F, -Cl, -Br, C1-C4 alkyl, or C1-C4 alkoxy; and

q is an integer from zero to 2;

or a pharmaceutically acceptable salt thereof.

The compound according to claim 5, wherein

R4 IS

Z is -H, C1-C4 alkyl, or C1-C4 alkoxy;

or a pharmaceutically acceptable salt thereof.

The compound according to claim 1, wherein

R and R3 are either both -H or both methyl;

R4 i is

each Z is independently -H, -F, -Cl, -Br, C1-C4 alkyl, or C1-C4 alkoxy; and

q is an integer from zero to 2;

and with the proviso that when A is N and R is:

then R2 and R3 are both -H;

or a pharmaceutically acceptable salt thereof.

The compound according to claim 7, wherein

R2 and R3 are either both -H or both methyl; and

R4 is

and with the proviso that when A is N and R4 is:

or , then R2 and R3 are both -H;

or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, wherein

R2 and R3 are either both -H or both methyl;

R4 IS

each Z is independently -H, -F, -Cl, -Br, C1-C4 alkyl, or C1-C4 alkoxy; and

q is an integer from zero to 2; or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9, wherein

R4 i is

Z is -H, C1-C4 alkyl, or C1-C4 alkoxy;

or a pharmaceutically acceptable salt thereof.

11. A compound selected from the group consisting of

and pharmaceutically acceptable salts thereof.

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition which comprises the product made by combining a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. A combination useful for inhibiting HTV protease, for treating or preventing infection by HTV, or for preventing, treating or delaying the onset of ADDS, which comprises a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an HTV infection/ ADDS treatment agent selected from the group consisting of HTV/ATDS antiviral agents, immunomodulators, and anti-infective agents.

15. The combination according to claim 14, wherein the HTV infection/ ADDS treatment agent is an antiviral selected from the group consisting of non-nucleoside HTV reverse transcriptase inhibitors, nucleoside HTV reverse transcriptase inhibitors, HTV integrase inhibitors, and CCR5 receptor antagonists.

16. A method of inhibiting HTV protease in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

17. A method for preventing or treating infection by HTV or for preventing, treating or delaying the onset of ADDS in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

18. The method according to claim 17, wherein the compound is administered in combination with a therapeutically effective amount of at least one

HTV infection/ ADDS treatment agent selected from the group consisting of HTV/ ADDS antiviral agents, immunomodulators, and anti-infective agents.

19. The method according to claim 17, wherein the compound is administered in combination with a therapeutically effective amount of at least one antiviral selected from the group consisting of non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HTV reverse transcriptase inhibitors, HTV integrase inhibitors, and CCR5 receptor antagonists.

20. A method of inhibiting HTV protease in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the composition according to claim 12.

21. A method for preventing or treating infection by HTV or for preventing, treating, or delaying the onset of ADDS in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the composition according to claim 12.