Compounds having the formulaare hepatitis C (HCV) polymerase inhibitors. Also disclosed are a composition and method for inhibiting hepatitis C (HCV) polymerase, processes for making the compounds, and synthetic intermediates employed in the processes.

TECHNICAL FIELD

The present invention relates to novel anti-infective agents. Specifically, the present invention relates to compounds, a composition, a method for inhibiting hepatitis C virus (HCV) polymerase, a method for inhibiting HCV viral replication, and a method for treating or preventing HCV infection, and processes for making the compounds, and synthetic intermediates employed in the processes.

BACKGROUND OF THE INVENTION

Infection with hepatitis C virus (HCV) is a major cause of human liver disease throughout the world. More than 85% of all infected individuals become chronically infected. Chronic HCV infection accounts for 30% of all cirrhosis, end-stage liver disease, and liver cancer in the United States. The CDC estimates that the number of deaths due to HCV will increase to 38,000/year by the year 2010.

While initial therapy consisted of interferon alone, the combination of interferon alpha-2b with ribavirin for either 24 or 48 weeks is currently the most efficacious approved therapy for the treatment of chronic HCV infection. However, there are many adverse side effects associated with this therapy (flu-like symptoms, leukopenia, thrombocytopenia, and depression from interferon, as well as anemia induced by ribavirin). Furthermore, this therapy is less effective against infections caused by HCV genotype 1 which constitutes about 75% of all HCV infections.

Based on the foregoing, there exists a significant need to identify compounds with the ability to inhibit HCV. The present invention provides novel anti-infective agents which are HCV polymerase inhibitors.

SUMMARY OF THE INVENTION

In its principle embodiment, the present invention provides a compound of formula (I)

or a pharmaceutically acceptable salt form, stereoisomer or tautomer, or combination thereof, wherein:

A is a monocyclic or bicyclic ring selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocycle;

alternatively, R1and R2, together with the carbon atom to which they are attached, form a monocyclic ring selected from the group consisting of cycloalkyl and cycloalkenyl;

wherein each of the cycloalkyl and cycloalkenyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halo, —OH, —O(alkyl), —NH2, —N(H)(alkyl), —N(alkyl)2, alkyl and haloalkyl;

alternatively, R3and R4, together with the carbon atoms to which they are attached, form a ring selected from the group consisting of aryl, heteroaryl, cycloalkyl, cycloalkenyl and heterocycle,

wherein each of the of aryl, heteroaryl, cycloalkyl, cycloalkenyl and heterocycle is independently substituted with (R8)m;

Raat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and Rp;

Rbat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R106, haloalkyl, hydroxyalkyl, alkoxyalkyl, and -alkylR106;

alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl;

Rcat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R103;

Rdat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R106, haloalkyl, alkoxyalkyl, hydroxyalkyl, and -alkylR106;

alternatively, Rcand Rd, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl;

Reat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R106, haloalkyl, and -alkylR106;

Rfat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R103;

Rgat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R106, haloalkyl and -alkylR106;

alternatively, Rfand Rg, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl;

Rjat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R103, haloalkyl and -alkylR103;

Rkat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl;

p is 0, 1 or 2;

R102, R104, and R105, at each occurrence, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl and benzyl;

In another embodiment, the present invention provides a pharmaceutical composition comprising a compound or combination of compounds of formula (I) or a pharmaceutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, in combination with a pharmaceutically acceptable carrier. The invention is also directed to a prodrug of a compound of the present invention, or pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

In yet another embodiment, the present invention provides a method of inhibiting the replication of an RNA-containing virus comprising contacting said virus with a therapeutically effective amount of a compound or combination of compounds of the present invention or a pharmaceutically acceptable salt thereof. Particularly, this invention is directed to methods of inhibiting the replication of hepatitis C virus.

In still another embodiment, the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or combination of compounds of the present invention or a pharmaceutically acceptable salt form, stereoisomer, or tautomer, or combination thereof. Particularly, this invention is directed to methods of treating or preventing infection caused by hepatitis C virus.

Yet another embodiment of the present invention provides the use of a compound or combination of compounds of the present invention, or a therapeutically acceptable salt form, stereoisomer or tautomer, or combination thereof, as defined hereinafter, in the preparation of a medicament for the treatment or prevention of infection caused by RNA-containing virus, specifically hepatitis C virus (HCV).

DETAILED DESCRIPTION OF THE INVENTION

As used in the present specification the following terms have the meanings indicated:

The term “alkenyl,” as used herein, refers to a straight or branched chain group of 2, 3, 4, 5, 6, 7, or 8 carbon atoms containing at least one carbon-carbon double bond. Examples of alkenyl groups include allyl, propenyl, 3-methylbut-2-enyl, 4-ethylpenta-2,4-dienyl, and the like.

The term “alkoxy,” as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

The term “alkoxyalkyl” as used herein, refers to an alkoxy group, as defined herein, appendened to the parent molecular moiety through an alkyl group, as defined herein.

The term “alkyl,” as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Examples of alkyl groups include propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, and the like.

The term “alkynyl,” as used herein, refers to a straight or branched chain hydrocarbon of 2, 3, 4, 5, or 6 carbon atoms containing at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl, 2-methyl-3-butynyl, 3-pentynyl, and the like.

The term “aryl,” as used herein, refers to a phenyl group, or a bicyclic hydrocarbon fused ring systems wherein one or more of the rings is a phenyl group. Bicyclic fused ring systems have a phenyl group fused to a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group. Examples of aryl groups include anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl (naphthalenyl), phenyl, tetrahydronaphthyl, and the like. The aryl groups of the present invention can be substituted or unsubstituted, and can be connected to the parent molecular moiety through any substitutable carbon atom of the group.

The term “cyano,” as used herein, refers to —CN.

The term “cyanoalkyl” as used herein, refers to a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.

The term “cycloalkenyl,” as used herein, refers to a non-aromatic, partially unsaturated, monocyclic or bicyclic ring system, having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms and zero heteroatom. The three-, four- or five-membered ring have one double bond. The six-membered ring has one or two double bonds. The seven and eight-membered rings have one, two, or three double bonds. The bicyclic fused ring systems have a monocyclic cycloalkenyl group fused to a monocyclic cycloalkyl group, as defined herein, or a second monocyclic cycloalkenyl group, as defined herein. The monocyclic Examples of cycloalkenyl groups include cyclohexenyl, octahydronaphthalenyl, norbornylenyl, and the like. The cycloalkenyl groups of the present invention can be unsubstituted or substituted, and are attached to the parent molecular moiety through any substitutable carbon atom of the group.

The term “cycloalkyl,” as used herein, refers to a saturated monocyclic, or bicyclic fused ring system having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms and zero heteroatom. The bicyclic fused ring systems have a monocyclic cycloalkyl group fused to a second mocyclic cycloalkyl group, as defined herein. The cycloalkyl groups of the present invention can be unsubstituted or substituted, and are attached to the parent molecular moiety through any substitutable carbon atom of the group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[3.1.1]heptyl, 6,6-dimethylbcyclo[3.1.1]heptyl, adamantyl, and the like.

The term “formyl,” as used herein, refers to —CHO.

The terms “halo,” and “halogen,” as used herein, refer to F, Cl, Br, and I.

The term “haloalkyl,” as used herein, refers to an alkyl group substituted by one, two, three, or four halogen atoms.

The term “heteroaryl,” as used herein, refers to an aromatic five- or six-membered ring where at least one atom is selected from the group consisting of N, O, and S, and the remaining atoms are carbon. The term “heteroaryl” also includes bicyclic fused ring systems where a heteroaryl ring is fused to a phenyl group, a monocyclic cycloalkyl group, as defined herein, a heterocycle group, as defined herein, or an additional heteroaryl group. Examples of heteroaryl groups include benzimidazolyl, benzothienyl, benzoxadiazolyl, furanyl, imidazolyl, indazolyl, indolyl, isoindolyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, triazinyl, and the like. The heteroaryl groups of the present invention can be unsubstituted or substituted and are connected to the parent molecular moiety through any substitutable carbon or nitrogen atom of the groups. In addition, The nitrogen heteroatoms can be optionally quaternized or oxidized to the N-oxide. Also, the nitrogen containing rings can be optionally N-protected.

The term “heterocycle,” as used herein, refers to cyclic, non-aromatic, saturated or partially unsaturated, three, four, five-, six-, or seven-membered rings containing at least one atom selected from the group consisting of oxygen, nitrogen, and sulfur. The term “heterocycle” also includes bicyclic fused ring systems where a heterocycle ring is fused to a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or an additional monocyclic heterocycle group. The heterocycle groups of the invention can be unsubstituted or substituted and are connected to the parent molecular moiety through any substitutable carbon or nitrogen atom in the group. Examples of heterocycle groups include azetidinyl, 4,5-dihydro-1,3-oxazol-2-yl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, 1,1-dioxidoisothiazolidin-2-yl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, tetrahydropyranyl, and the like. In addition, The nitrogen heteroatoms can be optionally quaternized or oxidized to the N-oxide. Also, the nitrogen containing heterocyclic rings can be optionally N-protected.

The term “hydroxy” as used herein, refers to an —OH group.

The term “hydroxyalkyl,” as used herein, refers to a hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and 2-ethyl-4-hydroxyheptyl.

It is understood that each of the following terms as defined hereinabove: alkenyl, alkyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycle, may be unsubstituted or substituted.

The term “nitro,” as used herein, refers to —NO2.

The term “oxo,” as used herein, refers to ═O.

In a first embodiment the present invention provides a compound of formula (I)

or a pharmaceutically acceptable form, stereoisomer, or tautomer, or combination thereof, wherein:

A is a monocyclic or bicyclic ring selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocycle;

alternatively, R1and R2, together with the carbon atom to which they are attached, form a monocyclic ring selected from the group consisting of cycloalkyl and cycloalkenyl;

wherein each of the cycloalkyl and cycloalkenyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halo, —OH, —O(alkyl), —NH2, —N(H)(alkyl), —N(alkyl)2, alkyl and haloalkyl;

alternatively, R3and R4, together with the carbon atoms to which they are attached, form a ring selected from the group consisting of aryl, heteroaryl, cycloalkyl, cycloalkenyl and heterocycle,

wherein each of the of aryl, heteroaryl, cycloalkyl, cycloalkenyl and heterocycle is independently substituted with (R8)m;

Raat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and Rp;

Rbat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R106, haloalkyl, hydroxyalkyl, alkoxyalkyl, and -alkylR106;

alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl;

Rcat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R103;

Rdat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R106, haloalkyl, alkoxyalkyl, hydroxyalkyl, and -alkylR106;

alternatively, Rcand Rd, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl;

Reat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R106, haloalkyl, and -alkylR106;

Rfat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R103;

Rgat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R106, haloalkyl and -alkylR106;

alternatively, Rfand Rg, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl;

Rjat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R103, haloalkyl and -alkylR103;

Rkat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl;

p is 0, 1 or 2;

R102, R104, and R105, at each occurrence, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl and benzyl;

For example, the first embodiment of the present invention provides a compound of formula (I) wherein R5is —ORdwherein Rdis hydrogen.

For example, the first embodiment of the present invention provides a compound of formula (I) wherein R6is hydrogen or alkyl.

For example, the first embodiment of the present invention provides a compound of formula (I) wherein R1is —C(O)ORa, —C(O)NRaRb, R1p, alkyl or alkenyl; and R2is alkyl.

For example, the first embodiment of the present invention provides a compound of formula (I) wherein R1is —C(O)ORa, —C(O)NRaRb, R1p, alkyl or alkenyl, wherein the alkyl and alkenyl are independently substituted with 0, 1 or 2 substituents selected from the group consisting of halo, —ORa, —OC(O)Ra, —OC(O)NRaRb, —C(O)ORa, —C═CRjRk, and —R1q; and R2is alkyl.

For example, the first embodiment of the present invention provides a compound of formula (I) wherein R1isalkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting ofhalo,—ORa, wherein Rais hydrogen,—OC(O)Ra, wherein Rais alkyl,—OC(O)NRaRb, wherein Rais alkyl, Rbis hydrogen,—C(O)ORa, wherein Rais alkyl,—C═CRjRk, wherein Rjand Rktogether with the carbon atom to which they are attached form a cycloalkyl ring; and—R1q; wherein R1qis aryl or cycloalkyl;alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of—C(O)ORa, wherein Rais alkyl, and—R1q, wherein R1qis aryl,—C(O)ORa, wherein Rais alkyl, or alkyl substituted with one R1q, wherein R1qis a heterocyclic ring, unsubstituted or substituted with one —C(O)OR101and wherein R101is alkyl,—C(O)NRaRb, wherein Rais alkyl, or alkyl substituted with one substituent selected from the group consisting of —OC(O)Rc, and —ORcwherein Rcis hydrogen or alkyl, and Rbis alkyl, alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a heterocyclic ring substituted with one alkyl substitutent wherein the alkyl substituent is substituted with one substituent selected from the group consisting of —ORc, and —OC(O)Rc, and wherein Rcis hydrogen or alkyl, orR1p; wherein R1pis heterocycle; and

For example, the first embodiment of the present invention provides a compound of formula (I) wherein R1ispropyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, wherein each of the propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting ofhalo,—ORa, wherein Rais hydrogen,—OC(O)Ra, wherein Rais methyl, ethyl, or isopropyl,—OC(O)NRaRb, wherein Rais methyl, ethyl or isopropyl and Rbis hydrogen,—C(O)ORa, wherein Rais methyl, ethyl, or isopropyl,—C═CRjRk, wherein Rjand Rktogether with the carbon atom to which they are attached form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,—R1q; wherein R1qis phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;allyl, 3-methylbut-2-enyl, or 4-ethylpenta-2,4-dienyl, wherein each of the allyl, 3-methylbut-2-enyl or 4-ethylpenta-2,4-dienyl is unsubstituted or substituted with one substituent selected from the group consisting of—C(O)ORa, wherein Rais methyl, ethyl or isopropyl, and—R1qwherein R1qis aryl,—C(O)ORa, wherein Rais methyl, ethyl or isopropyl, wherein each of the methyl, ethyl or isopropyl is unsubstituted or substituted with one R1qwherein R1qis a pyrrolidine ring, unsubstituted or substituted with one —C(O)OR101, wherein R101is methyl, ethyl or isopropyl,—C(O)NRaRb, wherein Rais methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of —OC(O)Rc, and —ORcwherein Rcis hydrogen or methyl, and Rbis methyl, alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a pyrrolidine ring substituted with one methyl substitutent wherein the methyl is substituted with one substituent selected from the group consisting of —ORc, and —OC(O)Rc, and wherein Rcis hydrogen or methyl, orR1p; wherein R1pis 4,5-dihydro-1,3-oxazol-2-yl; and

For example, the first embodiment of the present invention provides a compound of formula (I) wherein R3and R4, together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, heterocycle or heteroaryl, wherein each of the ring is substituted with (R8)m.

For example, the first embodiment of the present invention provides a compound of formula (I) wherein R3and R4, together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.

For example, the first embodiment of the present invention provides a compound of formula (I) wherein R3and R4are indepentdently selected from the group consisting of hydrogen and alkyl.

For example, the first embodiment of the present invention provides a compound of formula (I) wherein A is a monocyclic ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl.

For example, the first embodiment of the present invention provides a compound of formula (I) wherein A is phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl.

For example, the first embodiment of the present invention provides a compound of formula (I) wherein A is a bicyclic ring selected from the group consisting of aryl and heteroaryl.

For example, the first embodiment of the present invention provides a compound of formula (I) wherein A is benzimidazolyl, benzthiazolyl or benzoxazolyl.

For example, the first embodiment of the present invention provides a compound of formula (I) wherein R5is —ORdwherein Rdis hydrogen, and R6is hydrogen or alkyl.

For example, the first embodiment of the present invention provides a compound of formula (I) wherein B is

For example, the first embodiment of the present invention provides a compound of formula (I) wherein B is

For example, the first embodiment of the present invention provides a compound of formula (I) R5is —ORdwherein Rdis hydrogen, R6is hydrogen or alkyl and R3and R4, together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl.

For example, the first embodiment of the present invention provides a compound of formula (I) wherein B is

R5is —ORdwherein Rdis hydrogen, R6is hydrogen or alkyl and R3and R4, together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl.

For example, the first embodiment of the present invention provides a compound of formula (I) R5is —ORdwherein Rdis hydrogen, R6is hydrogen or alkyl, and R3and R4, together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.

For example, the first embodiment of the present invention provides a compound of formula (I) wherein B is

For example, the first embodiment of the present invention provides a compound of formula (I) wherein R5is —ORdwherein Rdis hydrogen, R6is hydrogen or alkyl, and A is a monocyclic ring selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heterocycle or heteroaryl.

For example, the first embodiment of the present invention provides a compound of formula (I) wherein B is

R5is —ORdwherein Rdis hydrogen, R6is hydrogen or alkyl, and A is a monocyclic ring selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heterocycle or heteroaryl.

For example, the first embodiment of the present invention provides a compound of formula (I) wherein B is

R5is —ORdwherein Rdis hydrogen, R6is hydrogen or alkyl and A is a bicyclic heteroaryl ring.

For example, the first embodiment of the present invention provides a compound of formula (I) wherein R5is —ORdwherein Rdis hydrogen, R6is hydrogen or alkyl, R3and R4, together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl and A is a monocyclic ring selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heterocycle or heteroaryl.

For example, the first embodiment of the present invention provides a compound of formula (I) wherein B is

R5is —ORdwherein Rdis hydrogen, R6is hydrogen or alkyl, R3and R4, together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl and A is a monocyclic ring selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heterocycle or heteroaryl.

For example, the first embodiment of the present invention provides a compound of formula (I) wherein B is

For example, the first embodiment of the present invention provides a compound of formula (I) wherein B is

For example, the first embodiment of the present invention provides a compound of formula (I) wherein B is

For example, the first embodiment of the present invention provides a compound of formula (I) wherein B is

R5is —ORdwherein Rdis hydrogen, R6is hydrogen or alkyl, R3and R4, together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl; A is a monocyclic ring selected from the group consisting of phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl; R1isalkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting ofhalo,—ORa, wherein Rais hydrogen,—OC(O)Ra, wherein Rais alkyl,—OC(O)NRaRb, wherein Rais alkyl, Rbis hydrogen,—C(O)ORa, wherein Rais alkyl,—C═CRjRk, wherein Rjand Rktogether with the carbon atom to which they are attached form a cycloalkyl ring; and—R1q; wherein R1qis aryl or cycloalkyl;alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of—C(O)ORa, wherein Rais alkyl, and—R1q, wherein R1qis aryl,—C(O)ORa, wherein Rais alkyl, or alkyl substituted with one R1q, wherein R1qis a heterocyclic ring, unsubstituted or substituted with one —C(O)OR101and wherein R101is alkyl,—C(O)NRaRb, wherein Rais alkyl, or alkyl substituted with one substituent selected from the group consisting of —OC(O)Rc, and —ORcwherein Rcis hydrogen or alkyl, and Rbis alkyl, alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a heterocyclic ring substituted with one alkyl substitutent wherein the alkyl substituent is substituted with one substituent selected from the group consisting of —ORc, and —OC(O)Rc, and wherein Rcis hydrogen or alkyl, orR1p; wherein R1pis heterocycle; and

For example, the first embodiment of the present invention provides a compound of formula (I) wherein B is

R5is —ORdwherein Rdis hydrogen, R6is hydrogen or alkyl, R3and R4, together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl; A is a monocyclic ring selected from the group consisting of phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl; R1ispropyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, wherein each of the propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting ofhalo,—ORa, wherein Rais hydrogen,—OC(O)Ra, wherein Rais methyl, ethyl, or isopropyl,—OC(O)NRaRb, wherein Rais methyl, ethyl or isopropyl and Rbis hydrogen,—C(O)ORa, wherein Rais methyl, ethyl, or isopropyl,—C═CRjRk, wherein Rjand Rktogether with the carbon atom to which they are attached form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,—R1q; wherein R1qis phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;allyl, 3-methylbut-2-enyl, or 4-ethylpenta-2,4-dienyl, wherein each of the allyl, 3-methylbut-2-enyl or 4-ethylpenta-2,4-dienyl is unsubstituted or substituted with one substituent selected from the group consisting of—C(O)ORa, wherein Rais methyl, ethyl or isopropyl, and—R1q, wherein R1qis aryl,—C(O)ORa, wherein Rais methyl, ethyl or isopropyl, wherein each of the methyl, ethyl or isopropyl is unsubstituted or substituted with one R1q, wherein R1qis a pyrrolidine ring, unsubstituted or substituted with one —C(O)OR101, wherein R101is methyl, ethyl or isopropyl,—C(O)NRaRb, wherein Rais methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of —OC(O)Rc, and —ORcwherein Rcis hydrogen or methyl, and Rbis methyl, alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a pyrrolidine ring substituted with one methyl substitutent wherein the methyl is substituted with one substituent selected from the group consisting of —ORc, and —OC(O)Rc, and wherein Rcis hydrogen or methyl, orR1p; wherein R1pis 4,5-dihydro-1,3-oxazol-2-yl; and

Accordingly, a second embodiment fo this invention is directed to a compound of formula (II)

or a pharmaceutically acceptable form, stereoisomer, or tautomer, or combination thereof, wherein:

alternatively, R1and R2, together with the carbon atom to which they are attached, form a monocyclic ring selected from the group consisting of cycloalkyl and cycloalkenyl;

wherein each of the cycloalkyl and cycloalkenyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halo, —OH, —O(alkyl), —NH2, —N(H)(alkyl), —N(alkyl)2, alkyl and haloalkyl;

Raat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and Rp;

Rbat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R106, haloalkyl, hydroxyalkyl, alkoxyalkyl, and -alkylR106;

alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl;

Rcat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R103;

Rdat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R106, haloalkyl, alkoxyalkyl, hydroxyalkyl, and -alkylR106;

alternatively, Rcand Rd, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl;

Reat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R106, haloalkyl, and -alkylR106;

Rfat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R103;

Rgat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R106, haloalkyl and -alkylR106;

alternatively, Rfand Rg, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl;

Rjat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R103, haloalkyl and -alkylR103;

Rkat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl;

R102, R104, and R105, at each occurrence, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl and benzyl;

For example, the second embodiment of the present invention provides a compound of formula (II) wherein R5is —ORdwherein Rdis hydrogen.

For example, the second embodiment of the present invention provides a compound of formula (II) wherein R6is hydrogen or alkyl.

For example, the second embodiment of the present invention provides a compound of formula (II) wherein R1is —C(O)ORa, —C(O)NRaRb, R1p, alkyl or alkenyl; and R2is alkyl.

For example, the second embodiment of the present invention provides a compound of formula (II) wherein R1is —C(O)ORa, —C(O)NRaRb, R1p, alkyl or alkenyl, wherein the alkyl and alkenyl are independently substituted with 0, 1 or 2 substituents selected from the group consisting of halo, —ORa, —OC(O)Ra, —OC(O)NRaRb, —C(O)ORa, —C═CRjRk, and —R1q; and R2is alkyl.

For example, the second embodiment of the present invention provides a compound of formula (II) wherein R1isalkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting ofhalo,—ORa, wherein Rais hydrogen,—OC(O)Ra, wherein Rais alkyl,—OC(O)NRaRb, wherein Rais alkyl, Rbis hydrogen,—C(O)ORa, wherein Rais alkyl,—C═CRjRk, wherein Rjand Rktogether with the carbon atom to which they are attached form a cycloalkyl ring; and—R1q; wherein R1qis aryl or cycloalkyl;alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of—C(O)ORa, wherein Rais alkyl, andR1q, wherein R1qis aryl,—C(O)ORa, wherein Rais alkyl, or alkyl substituted with one R1q, wherein R1qis a heterocyclic ring, unsubstituted or substituted with one —C(O)OR101and wherein R101is alkyl,—C(O)NRaRb, wherein Rais alkyl, or alkyl substituted with one substituent selected from the group consisting of —OC(O)Rc, and —ORcwherein Rcis hydrogen or alkyl, and Rbis alkyl, alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a heterocyclic ring substituted with one alkyl substitutent wherein the alkyl substituent is substituted with one substituent selected from the group consisting of —ORc, and —OC(O)Rc, and wherein Rcis hydrogen or alkyl, orR1p; wherein R1pis heterocycle; and

For example, the second embodiment of the present invention provides a compound of formula (II) wherein R1ispropyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, wherein each of the propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting ofhalo,—ORa, wherein Rais hydrogen,—OC(O)Ra, wherein Rais methyl, ethyl, or isopropyl,—OC(O)NRaRb, wherein Rais methyl, ethyl or isopropyl and Rbis hydrogen,—C(O)ORa, wherein Rais methyl, ethyl, or isopropyl,—C═CRjRk, wherein Rjand Rktogether with the carbon atom to which they are attached form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,—R1q; wherein R1qis phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;allyl, 3-methylbut-2-enyl, or 4-ethylpenta-2,4-dienyl, wherein each of the allyl, 3-methylbut-2-enyl or 4-ethylpenta-2,4-dienyl is unsubstituted or substituted with one substituent selected from the group consisting of—C(O)ORa, wherein Rais methyl, ethyl or isopropyl, and—R1q, wherein R1qis aryl,—C(O)ORa, wherein Rais methyl, ethyl or isopropyl, wherein each of the methyl, ethyl or isopropyl is unsubstituted or substituted with one R1q, wherein R1qis a pyrrolidine ring, unsubstituted or substituted with one —C(O)OR101, wherein R101is methyl, ethyl or isopropyl,—C(O)NRaRb, wherein Rais methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of —OC(O)Rc, and —ORc, wherein Rcis hydrogen or methyl, and Rbis methyl, alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a pyrrolidine ring substituted with one methyl wherein the methyl is substituted with one substituent selected from the group consisting of —ORc, and —OC(O)Rc, and wherein Rcis hydrogen or methyl, orR1p; wherein R1pis 4,5-dihydro-1,3-oxazol-2-yl; and

For example, the second embodiment of the present invention provides a compound of formula (II) wherein R5is —ORdwherein Rdis hydrogen, and R6is hydrogen or alkyl.

For example, the second embodiment of the present invention provides a compound of formula (II) wherein R5is —ORdwherein Rdis hydrogen, R6is hydrogen or alkyl, R1is —C(O)ORa, —C(O)NRaRb, R1p, alkyl or alkenyl; and R2is alkyl.

For example, the second embodiment of the present invention provides a compound of formula (II) wherein R5is —ORdwherein Rdis hydrogen, R6is hydrogen or alkyl, R1is —C(O)ORa, —C(O)NRaRb, R1p, alkyl or alkenyl, wherein the alkyl and alkenyl are independently substituted with 0, 1 or 2 substituents selected from the group consisting of halo, —ORa, —OC(O)Ra, —OC(O)NRaRb, —C(O)ORa, —C═CRjRk, and —R1q; and R2is alkyl.

For example, the second embodiment of the present invention provides a compound of formula (II) wherein R5is —ORdwherein Rdis hydrogen, R6is hydrogen or alkyl, R1isalkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting ofhalo,—ORa, wherein Rais hydrogen,—OC(O)Ra, wherein Rais alkyl,—OC(O)NRaRb, wherein Rais alkyl, Rbis hydrogen,—C(O)ORa, wherein Rais alkyl,—C═CRjRk, wherein Rjand Rktogether with the carbon atom to which they are attached form a cycloalkyl ring; and—R1q; wherein R1qis aryl or cycloalkyl;alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of—C(O)ORa, wherein Rais alkyl, and—R1q, wherein R1qis aryl,—C(O)ORa, wherein Rais alkyl, or alkyl substituted with one R1q, wherein R1qis a heterocyclic ring, unsubstituted or substituted with one —C(O)OR101and wherein R101is alkyl,—C(O)NRaRb, wherein Rais alkyl, or alkyl substituted with one substituent selected from the group consisting of —OC(O)Rc, and —ORcwherein Rcis hydrogen or alkyl, and Rbis alkyl, alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a heterocyclic ring substituted with one alkyl substitutent wherein the alkyl substituent is substituted with one substituent selected from the group consisting of —ORc, and —OC(O)Rc, and wherein Rcis hydrogen or alkyl, orR1p; wherein R1pis heterocycle; and

For example, the second embodiment of the present invention provides a compound of formula (II) wherein R5is —ORdwherein Rdis hydrogen, R6is hydrogen or methyl, R1ispropyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, wherein each of the propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting ofhalo,—ORa, wherein Rais hydrogen,—OC(O)Ra, wherein Rais methyl, ethyl, or isopropyl,—OC(O)NRaRb, wherein Rais methyl, ethyl or isopropyl and Rbis hydrogen,—C(O)ORa, wherein Rais methyl, ethyl, or isopropyl,—C═CRjRk, wherein Rjand Rktogether with the carbon atom to which they are attached form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,—R1q; wherein R1qis phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;allyl, 3-methylbut-2-enyl, or 4-ethylpenta-2,4-dienyl, wherein each of the allyl, 3-methylbut-2-enyl or 4-ethylpenta-2,4-dienyl is unsubstituted or substituted with one substituent selected from the group consisting of—C(O)ORa, wherein Rais methyl, ethyl or isopropyl, and—R1q, wherein R1qis aryl,—C(O)ORa, wherein Rais methyl, ethyl or isopropyl, wherein each of the methyl, ethyl or isopropyl is unsubstituted or substituted with one R1q, wherein R1qis a pyrrolidine ring, unsubstituted or substituted with one —C(O)OR101, wherein R101is methyl, ethyl or isopropyl,—C(O)NRaRb, wherein Rais methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of —OC(O)Rc, and —ORcwherein Rcis hydrogen or methyl, and Rbis methyl, alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a pyrrolidine ring substituted with one methyl wherein the methyl is substituted with one substitutent selected from the group consisting of —ORc, and —OC(O)Rc, and wherein Rcis hydrogen or methyl, orR1p; wherein R1pis 4,5-dihydro-1,3-oxazol-2-yl; and

In a third embodiment the present invention is directed to a compound of formula (III)

or a pharmaceutically acceptable form, stereoisomer, or tautomer, or combination thereof, wherein:

alternatively, R1and R2, together with the carbon atom to which they are attached, form a monocyclic ring selected from the group consisting of cycloalkyl and cycloalkenyl;

wherein each of the cycloalkyl and cycloalkenyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halo, —OH, —O(alkyl), —NH2, —N(H)(alkyl), —N(alkyl)2, alkyl and haloalkyl;

Raat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and Rp;

Rbat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R106, haloalkyl, hydroxyalkyl, alkoxyalkyl, and -alkylR106;

alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl;

Rcat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R103;

Rdat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R106, haloalkyl, alkoxyalkyl, hydroxyalkyl, and -alkylR106;

alternatively, Rcand Rd, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl;

Reat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R106, haloalkyl, and -alkylR106;

Rfat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R103;

Rgat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R106, haloalkyl and -alkylR106;

alternatively, Rfand Rg, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl;

Rjat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R103, haloalkyl and -alkylR103;

Rkat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl;

R102, R104, and R105, at each occurrence, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl and benzyl;

For example, the third embodiment of the present invention provides a compound of formula (III) wherein R5is —ORdwherein Rdis hydrogen.

For example, the third embodiment of the present invention provides a compound of formula (III) wherein R6is hydrogen or alkyl.

For example, the third embodiment of the present invention provides a compound of formula (III) wherein R1is —C(O)ORa, —C(O)NRaRb, R1p, alkyl or alkenyl; and R2is alkyl.

For example, the third embodiment of the present invention provides a compound of formula (III) wherein R1is —C(O)ORa, —C(O)NRaRb, R1p, alkyl or alkenyl, wherein the alkyl and alkenyl are independently substituted with 0, 1 or 2 substituents selected from the group consisting of halo, —ORa, —OC(O)Ra, —OC(O)NRaRb, —C(O)ORa, —C═CRjRk, and —R1q; and R2is alkyl.

For example, the third embodiment of the present invention provides a compound of formula (III) wherein R1isalkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting ofhalo,—ORa, wherein Rais hydrogen,—OC(O)Ra, wherein Rais alkyl,—OC(O)NRaRb, wherein Rais alkyl, Rbis hydrogen,—C(O)ORa, wherein Rais alkyl,—C═CRjRk, wherein Rjand Rktogether with the carbon atom to which they are attached form a cycloalkyl ring; and—R1q; wherein R1qis aryl or cycloalkyl;alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of—C(O)ORa, wherein Rais alkyl, and—R1q, wherein R1qis aryl,—C(O)ORa, wherein Rais alkyl, or alkyl substituted with one R1q, wherein R1qis a heterocyclic ring, unsubstituted or substituted with one —C(O)OR101and wherein R101is alkyl,—C(O)NRaRb, wherein Rais alkyl, or alkyl substituted with one substituent selected from the group consisting of —OC(O)Rc, and —ORcwherein Rcis hydrogen or alkyl, and Rbis alkyl, alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a heterocyclic ring substituted with one alkyl substitutent wherein the alkyl substituent is substituted with one substituent selected from the group consisting of —ORc, and —OC(O)Rc, and wherein Rcis hydrogen or alkyl, orR1p; wherein R1pis heterocycle; and

For example, the third embodiment of the present invention provides a compound of formula (III) wherein R1ispropyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, wherein each of the propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting ofhalo,—ORa, wherein Rais hydrogen,—OC(O)Ra, wherein Rais methyl, ethyl, or isopropyl,—OC(O)NRaRb, wherein Rais methyl, ethyl or isopropyl and Rbis hydrogen,—C(O)ORa, wherein Rais methyl, ethyl, or isopropyl,—C═CRjRk, wherein Rjand Rktogether with the carbon atom to which they are attached form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,—R1q; wherein R1qis phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;allyl, 3-methylbut-2-enyl, or 4-ethylpenta-2,4-dienyl, wherein each of the allyl, 3-methylbut-2-enyl or 4-ethylpenta-2,4-dienyl is unsubstituted or substituted with one substituent selected from the group consisting of—C(O)ORa, wherein Rais methyl, ethyl or isopropyl, and—R1q, wherein R1qis aryl,—C(O)ORa, wherein Rais methyl, ethyl or isopropyl, wherein each of the methyl, ethyl or isopropyl is unsubstituted or substituted with one R1q, wherein R1qis a pyrrolidine ring, unsubstituted or substituted with one —C(O)OR101, wherein R101is methyl, ethyl or isopropyl,—C(O)NRaRb, wherein Rais methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of —OC(O)Rc, and —ORc, wherein Rcis hydrogen or methyl, and Rbis methyl, alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a pyrrolidine ring substituted with one methyl wherein the methyl is substituted with one substitutent selected from the group consisting of —ORc, and —OC(O)Rc, and wherein Rcis hydrogen or methyl, orR1p; wherein R1pis 4,5-dihydro-1,3-oxazol-2-yl; and

For example, the third embodiment of the present invention provides a compound of formula (III) wherein R5is —ORdwherein Rdis hydrogen, and R6is hydrogen or alkyl.

For example, the third embodiment of the present invention provides a compound of formula (III) wherein R5is —ORdwherein Rdis hydrogen, R6is hydrogen or alkyl, R1is —C(O)ORa, —C(O)NRaRb, R1p, alkyl or alkenyl; and R2is alkyl.

For example, the third embodiment of the present invention provides a compound of formula (III) wherein R5is —ORdwherein Rdis hydrogen, R6is hydrogen or alkyl, R1is —C(O)ORa, —C(O)NRaRb, R1p, alkyl or alkenyl, wherein the alkyl and alkenyl are independently substituted with 0, 1 or 2 substituents selected from the group consisting of halo, —ORa, —OC(O)Ra, —OC(O)NRaRb, —C(O)ORa, —C═CRjRk, and —R1q; and R2is alkyl.

For example, the third embodiment of the present invention provides a compound of formula (III) wherein R5is —ORdwherein Rdis hydrogen, R6is hydrogen or alkyl, R1isalkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting ofhalo,—ORa, wherein Rais hydrogen,—OC(O)Ra, wherein Rais alkyl,—OC(O)NRaRb, wherein Rais alkyl, Rbis hydrogen,—C(O)ORa, wherein Rais alkyl,—C═CRjRk, wherein Rjand Rktogether with the carbon atom to which they are attached form a cycloalkyl ring; and—R1q; wherein R1qis aryl or cycloalkyl;alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of—C(O)ORa, wherein Rais alkyl, and—R1q, wherein R1qis aryl,—C(O)ORa, wherein Rais alkyl, or alkyl substituted with one R1q, wherein R1qis a heterocyclic ring, unsubstituted or substituted with one —C(O)OR101and wherein R101is alkyl,—C(O)NRaRb, wherein Rais alkyl, or alkyl substituted with one substituent selected from the group consisting of —OC(O)Rc, and —ORc, wherein Rcis hydrogen or alkyl, and Rbis alkyl, alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a heterocyclic ring substituted with one alkyl substitutent wherein the alkyl substituent is substituted with one substituent selected from the group consisting of —ORc, and —OC(O)Rc, and wherein Rcis hydrogen or alkyl, orR1p; wherein R1pis heterocycle; and

For example, the third embodiment of the present invention provides a compound of formula (III) wherein R5is —ORdwherein Rdis hydrogen, R6is hydrogen or methyl, R1ispropyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, wherein each of the propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting ofhalo,—ORa, wherein Rais hydrogen,—OC(O)Ra, wherein Rais methyl, ethyl, or isopropyl,—OC(O)NRaRb, wherein Rais methyl, ethyl or isopropyl and Rbis hydrogen,—C(O)ORa, wherein Rais methyl, ethyl, or isopropyl,—C═CRjRk, wherein Rjand Rktogether with the carbon atom to which they are attached form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,—R1q; wherein R1qis phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;allyl, 3-methylbut-2-enyl, or 4-ethylpenta-2,4-dienyl, wherein each of the allyl, 3-methylbut-2-enyl or 4-ethylpenta-2,4-dienyl is unsubstituted or substituted with one substituent selected from the group consisting of—C(O)ORa, wherein Rais methyl, ethyl or isopropyl, and—R1q, wherein R1qis aryl,—C(O)ORa, wherein Rais methyl, ethyl or isopropyl, wherein each of the methyl, ethyl or isopropyl is unsubstituted or substituted with one R1q, wherein R1qis a pyrrolidine ring, unsubstituted or substituted with one —C(O)OR101wherein R101is methyl, ethyl or isopropyl,—C(O)NRaRb, wherein Rais methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of —OC(O)Rc, and —ORc, wherein Rcis hydrogen or methyl, and Rbis methyl, alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a pyrrolidine ring substituted with one methyl wherein the methyl is substituted with one substitutent selected from the group consisting of —ORc, and —OC(O)Rc, and wherein Rcis hydrogen or methyl, orR1p; wherein R1pis 4,5-dihydro-1,3-oxazol-2-yl; and
R2is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, or 3-methylpentyl.

Exemplary compounds of the third embodiment include, but are not limited to, the following:1,1-dibutyl-4-hydroxy-3-{7-[(methoxymethoxy)methyl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl}-2(1H)-naphthalenone;1,1-dibutyl-4-hydroxy-3-[7-(hydroxymethyl)-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-2(1H)-naphthalenone;(1R)-4-hydroxy-3-{7-[(methoxymethoxy)methyl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl}-1-methyl-1-(3-methylbutyl)naphthalen-2(1H)-one;(1R)-4-hydroxy-3-[7-(hydroxymethyl)-1,1-dioxido-4H-thieno [2,3-e][1,2,4]thiadiazin-3-yl]-1-methyl-1-(3-methylbutyl)naphthalen-2(1H)-one;(1R)-3-[7-(azidomethyl)-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-4-hydroxy-1-methyl-1-(3-methylbutyl)naphthalen-2(1H)-one;(1R)-3-[7-(aminomethyl)-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-4-hydroxy-1-methyl-1-(3-methylbutyl)naphthalen-2(1H)-one;N-({3-[(4R)-1-hydroxy-4-methyl-4-(3-methylbutyl)-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-thieno [2,3-e][1,2,4]thiadiazin-7-yl}methyl)methanesulfonamide;N-({3-[(4R)-1-hydroxy-4-methyl-4-(3-methylbutyl)-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl}methyl)-2-morpholin-4-ylethanesulfonamide;(1R)-1-(3,3-dimethylbutyl)-4-hydroxy-3-{7-[(methoxymethoxy)methyl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl}-1-methylnaphthalen-2(1H)-one;(1R)-1-(3,3-dimethylbutyl)-4-hydroxy-3-[7-(hydroxymethyl)-1,1-dioxido-4H-thieno [2,3-e][1,2,4]thiadiazin-3-yl]-1-methylnaphthalen-2(1H)-one;(1R)-3-[7-(aminomethyl)-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-1-(3,3-dimethylbutyl)-4-hydroxy-1-methylnaphthalen-2(1H)-one;N-({3-[(4R)-4-(3,3-dimethylbutyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-thieno [2,3-e][1,2,4]thiadiazin-7-yl}methyl)methanesulfonamide;N-({3-[(4R)-4-(3,3-dimethylbutyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-thieno [2,3-e][1,2,4]thiadiazin-7-yl}methyl)-N-methylmethanesulfonamide;N-({3-[(4R)-4-(3,3-dimethylbutyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-4-methyl-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl}methyl)-N-methylmethanesulfonamide;benzyl [({3-[(4R)-4-(3,3-dimethylbutyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl}methyl)amino]sulfonylcarbamate;N-({3-[(4R)-4-(3,3-dimethylbutyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl}methyl)sulfamide;3-chloro-N-({3-[(4R)-4-(3,3-dimethylbutyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl}methyl)propane-1-sulfonamide; and(1R)-1-(3,3-dimethylbutyl)-3-{7-[(1,1-dioxidoisothiazolidin-2-yl)methyl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl}-4-hydroxy-1-methylnaphthalen-2(1H)-one; or a pharmaceutically acceptable form, stereoisomer, or tautomer, or combination thereof.

In a fourth embodiment the present invention is directed to a pharmaceutical composition comprising a compound or combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, in combination with a pharmaceutically acceptable carrier.

For example, the fourth embodiment of the present invention provides a pharmaceutical composition comprising a compound or combination of compounds selected from the group consisting ofN-{3-[(4R)-4-(3,3-dimethylbutyl)-7-fluoro-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-1,2,4-benzothiadiazin-7-yl}methanesulfonamide;N-{3-[(4R)-1-hydroxy-4-methyl-4-(3-methylbutyl)-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-1,2,4-benzothiadiazin-7-yl}methanesulfonamide;N-{3-[(4R)-4-(3,3-dimethylbutyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-1,2,4-benzothiadiazin-7-yl}methanesulfonamide;N-(2-hydroxyethyl)-N′-{3-[1-hydroxy-4-methyl-4-(3-methylbutyl)-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-1,2,4-benzothiadiazin-7-yl}sulfamide;2-hydroxy-N-{3-[1-hydroxy-4-methyl-4-(3-methylbutyl)-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-1,2,4-benzothiadiazin-7-yl}ethanesulfonamide;N-{3-[(4R)-1-hydroxy-4-methyl-4-(3-methylbutyl)-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-1,2,4-benzothiadiazin-7-yl}sulfamide;N-{3-[(4R)-4-(2-cyclopropylethyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-1,2,4-benzothiadiazin-7-yl}methanesulfonamide;methyl 4-hydroxy-1-(3-methylbutyl)-3-{7-[(methylsulfonyl)amino]-1,1-dioxido-4H-1,2,4-benzothiadiazin-3-yl}-2-oxo-1,2-dihydronaphthalene-1-carboxylate;N-({3-[(4R)-4-(3,3-dimethylbutyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl}methyl)methanesulfonamide; andN-({3-[(4R)-4-(3,3-dimethylbutyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-thieno [2,3-e][1,2,4]thiadiazin-7-yl}methyl)sulfamide; or a pharmaceutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, in combination with a pharmaceutically acceptable carrier.

For example, the fourth embodiment of the present invention provides a pharmaceutical composition comprising a compound or combination of compounds selected from the group consisting ofN-{3-[(4R)-4-(3,3-dimethylbutyl)-7-fluoro-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-1,2,4-benzothiadiazin-7-yl}methanesulfonamide;N-{3-[(4R)-1-hydroxy-4-methyl-4-(3-methylbutyl)-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-1,2,4-benzothiadiazin-7-yl}methanesulfonamide;N-{3-[(4R)-4-(3,3-dimethylbutyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-1,2,4-benzothiadiazin-7-yl}methanesulfonamide;N-(2-hydroxyethyl)-N′-{3-[1-hydroxy-4-methyl-4-(3-methylbutyl)-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-1,2,4-benzothiadiazin-7-yl}sulfamide;2-hydroxy-N-{3-[1-hydroxy-4-methyl-4-(3-methylbutyl)-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-1,2,4-benzothiadiazin-7-yl}ethanesulfonamide;N-{3-[(4R)-1-hydroxy-4-methyl-4-(3-methylbutyl)-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-1,2,4-benzothiadiazin-7-yl}sulfamide;N-{3-[(4R)-4-(2-cyclopropylethyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-1,2,4-benzothiadiazin-7-yl}methanesulfonamide;methyl 4-hydroxy-1-(3-methylbutyl)-3-{7-[(methylsulfonyl)amino]-1,1-dioxido-4H-1,2,4-benzothiadiazin-3-yl}-2-oxo-1,2-dihydronaphthalene-1-carboxylate;N-({3-[(4R)-4-(3,3-dimethylbutyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-thieno [2,3-e][1,2,4]thiadiazin-7-yl}methyl)methanesulfonamide; andN-({3-[(4R)-4-(3,3-dimethylbutyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl}methyl)sulfamide; or a pharmaceutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, in combination with a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable salt form is potassium, sodium, calcium or magnesium.

Any one of the aforementioned pharmaceutical compositions can be used for the treatment or prevention of an infection caused by an RNA-containing virus, specifically when the RNA-containing virus is hepatitis C virus (HCV).

In a fifth embodiment the present invention is directed to a method of inhibiting the replication of an RNA-containing virus comprising contacting said virus with a therapeutically effective amount of a compound or combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer or combination thereof.

In a sixth embodiment the present invention is directed to a method of treating or preventing infection caused by an RNA-containing virus comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or combination thereof.

For example, the sixth embodiment of the present invention is directed to a method of treating or preventing infection caused by an RNA-containing virus comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or combination thereof, wherein the RNA-containing virus is hepatitis C virus.

For example, the sixth embodiment of the present invention is directed to a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, with a therapeutically effective amount of a compound or combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or combination thereof.

For example, the sixth embodiment of the present invention is directed to a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, with a therapeutically effective amount of a compound or combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or combination thereof, wherein the host immune modulator is selected from the group consisting of interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamma, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant.

For example, the sixth embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, with a therapeutically effective amount of a compound or combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or combination thereof, wherein said second antiviral agent inhibits replication of HCV by inhibiting host cellular functions associated with viral replication.

For example, the sixth embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, with a therapeutically effective amount of a compound or combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or combination thereof, wherein said second antiviral agent inhibits replication of HCV by targeting proteins of the viral genome.

For example, the sixth embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment an agent or combination of agents that treat or alleviate symptoms of HCV infection including cirrhosis and inflammation of the liver, with a therapeutically effective amount of a compound or combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or combination thereof.

For example, the sixth embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents that treat patients for disease caused by hepatitis B (HBV) infection, with a therapeutically effective amount of a compound or a combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or combination thereof. An agent that treats patients for disease caused by hepatitis B (HBV) infection may be for example, but not limited thereto, L-deoxythymidine, adefovir, lamivudine or tenfovir, or any combination thereof.

For example, the sixth embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents that treat patients for disease caused by human immunodeficiency virus (HIV) infection, with a therapeutically effective amount of a compound or a combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer or combination thereof. The agent that treats patients for disease caused by human immunodeficiency virus (HIV) infection may include, but is not limited thereto, ritonavir, lopinavir, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide (T-20) or T-1249, or any combination thereof.

In a seventh embodiment, the present invention provides the use of a compound or a combination of compounds having formula (I), (II) or (III), or a therapeutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, to prepare a medicament for the treatment of infection caused by RNA-containing virus in a patient.

For example, the seventh embodiment of the present invention provides the use of a compound or a combination of compounds having formula (I), (II) or (III), or a therapeutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, to prepare a medicament for the treatment of infection caused by hepetitus C virus in a patient.

For example, the seventh embodiment of the present invention provides the use of a compound or a combination of compounds having formula (I), (II) or (III), or a therapeutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, and one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, to prepare a medicament for the treatment of an infection caused by an RNA-containing virus in a patient.

For example, the seventh embodiment of the present invention provides the use of a compound or a combination of compounds having formula (I), (II) or (III), or a therapeutically acceptable salt form, stereoisomer, or tautomer, or a combination thereof, and one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, to prepare a medicament for the treatment of an infection caused by an RNA-containing virus in a patient, wherein the host immune modulator is selected from the group consisting of interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamma, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant.

For example, the seventh embodiment of the present invention provides the use of a compound or a combination of compounds having formula (I), (II) or (III), or a therapeutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, and one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, to prepare a medicament for the treatment of an infection caused by an RNA-containing virus in a patient, wherein said second antiviral agent inhibits replication of HCV by inhibiting host cellular functions associated with viral replication.

For example, the seventh embodiment of the present invention provides the use of a compound or a combination of compounds having formula (I), (II) or (III), or a therapeutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, and one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, to prepare a medicament for the treatment of an infection caused by an RNA-containing virus in a patient, wherein said second antiviral agent inhibits replication of HCV by targeting proteins of the viral genome.

For example, the seventh embodiment of the present invention provides the use of a compound or a combination of compouns having formula (I), (II) or (III), or a therapeutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, and an agent or combination of agents that treat or alleviate symptoms of HCV infection including cirrhosis and inflammation of the liver, to prepare a medicament for the treatment of an infection caused by an RNA-containing virus in a patient.

For example, the seventh embodiment of the present invention provides the use of a compound or a combination of compounds having formula (I), (II) or (III), or a therapeutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, and one or more agents that treat patients for disease caused by hepatitis B (HBV) infection, to prepare a medicament for the treatment of an infection caused by an RNA-containing virus in a patient. An agent that treats patients for disease caused by hepatitis B (HBV) infection may be for example, but is not limited thereto, L-deoxythymidine, adefovir, lamivudine or tenfovir, or any combination thereof.

For example, the seventh embodiment of the present invention provides the use of a compound or a combination of compounds having formula (I), (II) or (III), or a therapeutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, and one or more agents that treat patients for disease caused by human immunodeficiency virus (HIV) infection, to prepare a medicament for the treatment of an infection caused by an RNA-containing virus in a patient. The agent that treats patients for disease caused by human immunodeficiency virus (HIV) infection may include, but is not limited thereto, ritonavir, lopinavir, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide (T-20) or T-1249, or any combination thereof.

A “patient” is any individual treated with a compound of the present invention, or a therapeutically acceptable salt form, stereoisomer, or tautomer, as defined herein. Patients include humans, as well as other animals such as companion animals (e.g. dogs and cats) and livestock. Patients may be experiencing one or more symptoms of a condition responsive to inhibition of HCV, or may be free of such symptom(s) (i.e. treatment may be prophylactic).

In an eighth embodiment the present invention provides an intermediate of formula (IV) used in the preparation of a compound of formula (I), (II) or (III)

or a pharmaceutically acceptable salt form, tautomer or stereoisomer, or a combination thereof, wherein:

alternatively, R1and R2, together with the carbon atom to which they are attached, form a monocyclic ring selected from the group consisting of cycloalkyl and cycloalkenyl;

wherein each of the cycloalkyl and cycloalkenyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halo, —OH, —O(alkyl), —NH2, —N(H)(alkyl), —N(alkyl)2, alkyl and haloalkyl;

alternatively, R3and R4, together with the carbon atoms to which they are attached, form a ring selected from the group consisting of aryl, heteroaryl, cycloalkyl, cycloalkenyl and heterocycle,

wherein each of the of aryl, heteroaryl, cycloalkyl, cycloalkenyl and heterocycle is independently substituted with (R8)m;

Raat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and Rp;

Rbat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R106, haloalkyl, hydroxyalkyl, alkoxyalkyl, and -alkylR106;

alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl;

Rcat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R103;

Rdat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R106, haloalkyl, alkoxyalkyl, hydroxyalkyl, and -alkylR106;

alternatively, Rcand Rd, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl;

Reat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R106, haloalkyl, and -alkylR106;

Rfat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R103;

Rgat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R106, haloalkyl and -alkylR106;

alternatively, Rfand Rg, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl;

Rjat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R103, haloalkyl and -alkylR103;

Rkat each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl;

R102, R104, and R105, at each occurrence, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl and benzyl;

R12and R13are independently selected from the group consisting of alkyl, alkenyl and alkynyl.

For example, the eighth embodiment of the present invention provides an intermediate of formula (IV) wherein R3and R4together with the carbon atoms to which they are attached form an aryl ring.

For example, the eighth embodiment of the present invention provides an intermediate of formula (IV) R3and R4together with the carbon atoms to which they are attached form an aryl ring, R1is —C(O)ORa, —C(O)NRaRb, R1p, alkyl or alkenyl; and R2is alkyl.

For example, the eighth embodiment of the present invention provides an intermediate of formula (IV) R3and R4together with the carbon atoms to which they are attached form an aryl ring, R1is —C(O)ORa, —C(O)NRaRb, R1p, alkyl or alkenyl, wherein the alkyl and alkenyl are independently substituted with 0, 1 or 2 substituents selected from the group consisting of halo, —ORa, —OC(O)Ra, —OC(O)NRaRb, —C(O)ORa, —C═CRjRk, and —R1q; and R2is alkyl.

For example, the eighth embodiment of the present invention provides an intermediate of formula (IV) R3and R4together with the carbon atoms to which they are attached form an aryl ring; R1isalkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting ofhalo,—ORa, wherein Rais hydrogen,—OC(O)Ra, wherein Rais alkyl,—OC(O)NRaRb, wherein Rais alkyl, Rbis hydrogen,—C(O)ORa, wherein Rais alkyl,—C═CRjRk, wherein Rjand Rktogether with the carbon atom to which they are attached form a cycloalkyl ring; and—R1q; wherein R1qis aryl or cycloalkyl;alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of—C(O)ORa, wherein Rais alkyl, and—R1qwherein R1qis aryl,—C(O)ORa, wherein Rais alkyl, or alkyl substituted with one R1q, wherein R1qis a heterocyclic ring, unsubstituted or substituted with one —C(O)OR101, wherein R101is alkyl,—C(O)NRaRb, wherein Rais alkyl, or alkyl substituted with one substituent selected from the group consisting of —OC(O)Rc, and —ORc, wherein Rcis hydrogen or alkyl, and Rbis alkyl, alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a heterocyclic ring substituted with one alkyl substitutent wherein the alkyl is substituted with one substituent selected from the group consisting of —ORc, and —OC(O)Rc, and wherein Rcis hydrogen or alkyl, orR1p; wherein R1pis heterocycle; andR2is alkyl.

For example, the eighth embodiment of the present invention provides an intermediate of formula (IV) R3and R4together with the carbon atoms to which they are attached form an aryl ring; R1ispropyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, wherein each of the propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl is independently unsubstituted or substituted with 1 or 2 substituents selected from the group consisting ofhalo,—ORa, wherein Rais hydrogen,—OC(O)Ra, wherein Rais methyl, ethyl, or isopropyl,—OC(O)NRaRb, wherein Rais methyl, ethyl or isopropyl and Rbis hydrogen,—C(O)ORa, wherein Rais methyl, ethyl, or isopropyl,—C═CRjRk, wherein Rjand Rktogether with the carbon atom to which they are attached form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,—R1q; wherein R1qis phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;allyl, 3-methylbut-2-enyl, or 4-ethylpenta-2,4-dienyl, wherein each of the allyl, 3-methylbut-2-enyl or 4-ethylpenta-2,4-dienyl is unsubstituted or substituted with one substituent selected from the group consisting of—C(O)ORa, wherein Rais methyl, ethyl or isopropyl, and—R1q, wherein R1qis aryl,—C(O)ORa, wherein Rais methyl, ethyl or isopropyl, wherein each of the methyl, ethyl or isopropyl is unsubstituted or substituted with one R1q, wherein R1qis a pyrrolidine ring, unsubstituted or substituted with one —C(O)OR101wherein R101is methyl, ethyl or isopropyl,—C(O)NRaRb, wherein Rais methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of —OC(O)Rc, and —ORc, wherein Rcis hydrogen or methyl, and Rbis methyl, alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a pyrrolidine ring substituted with one methyl wherein the methyl is substituted with one substitutent selected from the group consisting of —ORc, and —OC(O)Rc, and wherein Rcis hydrogen or methyl, orR1p; wherein R1pis 4,5-dihydro-1,3-oxazol-2-yl; and
R2is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, or 3-methylpentyl.

For example, the eighth embodiment of the present invention provides an intermediate of formula (IV) R3and R4together with the carbon atoms to which they are attached form an aryl ring, R1is —C(O)ORa, —C(O)NRaRb, R1p, alkyl or alkenyl; R2is alkyl; R12is alkyl and R13is alkyl.

For example, the eighth embodiment of the present invention provides an intermediate, of formula (IV) R3and R4together with the carbon atoms to which they are attached form an aryl ring, R1is —C(O)ORa, —C(O)NRaRb, R1p, alkyl or alkenyl, wherein the alkyl and alkenyl are independently substituted with 0, 1 or 2 substituents selected from the group consisting of halo, —ORa, —OC(O)Ra, —OC(O)NRaRb, —C(O)ORa, —C═CRjRk, and —R1q; R2is alkyl; R12is alkyl; and R13is alkyl.

For example, the eighth embodiment of the present invention provides an intermediate of formula (IV) R3and R4together with the carbon atoms to which they are attached form an aryl ring; R1isalkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting ofhalo,—ORa, wherein Rais hydrogen,—OC(O)Ra, wherein Rais alkyl,—OC(O)NRaRb, wherein Rais alkyl, Rbis hydrogen,—C(O)ORa, wherein Rais alkyl,—C═CRjRk, wherein Rjand Rktogether with the carbon atom to which they are attached form a cycloalkyl ring; and—R1q; wherein R1qis aryl or cycloalkyl;alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of—C(O)ORa, wherein Rais alkyl, and—R1q, wherein R1qis aryl,—C(O)ORa, wherein Rais alkyl, or alkyl substituted with one R1q, wherein R1qis a heterocyclic ring, unsubstituted or substituted with one —C(O)OR101, wherein R101is alkyl,—C(O)NRaRb, wherein Rais alkyl, or alkyl substituted with one substituent selected from the group consisting of —OC(O)Rc, and —ORc, wherein Rcis hydrogen or alkyl, and Rbis alkyl, alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a heterocyclic ring substituted with one alkyl substitutent wherein the alkyl is substituted with one substituent selected from the group consisting of —ORc, and —OC(O)Rc, and wherein Rcis hydrogen or alkyl, orR1p; wherein R1pis heterocycle;R2is alkyl; R12is alkyl; and R13is alkyl.

For example, the eighth embodiment of the present invention provides an intermediate of formula (IV) R3and R4together with the carbon atoms to which they are attached form an aryl ring; R1ispropyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, wherein each of the propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl is independently unsubstituted or substituted with 1 or 2 substituents selected from the group consisting ofhalo,—ORa, wherein Rais hydrogen,—OC(O)Ra, wherein Rais methyl, ethyl, or isopropyl,—OC(O)NRaRb, wherein Rais methyl, ethyl or isopropyl and Rbis hydrogen,—C(O)ORa, wherein Rais methyl, ethyl, or isopropyl,—C═CRjRk, wherein Rjand Rktogether with the carbon atom to which they are attached form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,—R1q; wherein R1qis phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;allyl, 3-methylbut-2-enyl, or 4-ethylpenta-2,4-dienyl, wherein each of the allyl, 3-methylbut-2-enyl or 4-ethylpenta-2,4-dienyl is unsubstituted or substituted with one substituent selected from the group consisting of—C(O)ORa, wherein Rais methyl, ethyl or isopropyl, and—R1q, wherein R1qis aryl,—C(O)ORa, wherein Rais methyl, ethyl or isopropyl, wherein each of the methyl, ethyl or isopropyl is unsubstituted or substituted with one R1q, wherein R1qis a pyrrolidine ring, unsubstituted or substituted with one —C(O)OR101, wherein R101is methyl, ethyl or isopropyl,—C(O)NRaRb, wherein Rais methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of —OC(O)Rc, and —ORc, wherein Rcis hydrogen or methyl, and Rbis methyl, alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a pyrrolidine ring substituted with one methyl wherin the methyl is substituted with one substitutent selected from the group consisting of —ORc, and —OC(O)Rc, and wherein Rcis hydrogen or methyl, orR1p; wherein R1pis 4,5-dihydro-1,3-oxazol-2-yl;R2is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, or 3-methylpentyl;R12is methyl; andR13is methyl.

For example, the eighth embodiment of the present invention provides an intermediate of formula (IV) R3and R4together with the carbon atoms to which they are attached form an aryl ring, R1is —C(O)ORa, —C(O)NRaRb, R1p, alkyl or alkenyl; R2is alkyl; R12is alkyl, R13is alkyl, R8is halo or —ORawherein Rais hydrogen or alkyl, and m is 0 or 1.

For example, the eighth embodiment of the present invention provides an intermediate of formula (IV) R3and R4together with the carbon atoms to which they are attached form an aryl ring, R1is —C(O)ORa, —C(O)NRaRb, R1p, alkyl or alkenyl, wherein the alkyl and alkenyl are independently substituted with 0, 1 or 2 substituents selected from the group consisting of halo, —ORa, —OC(O)Ra, —OC(O)NRaRb, —C(O)ORa, —C═CRjRk, and —R1q; R2is alkyl; R12is alkyl; R13is alkyl, R8is halo or —ORawherein Rais hydrogen or alkyl; and m is 0 or 1.

For example, the eighth embodiment of the present invention provides an intermediate of formula (IV) R3and R4together with the carbon atoms to which they are attached form an aryl ring; R1isalkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting ofhalo,—ORa, wherein Rais hydrogen,—OC(O)Ra, wherein Rais alkyl,—OC(O)NRaRb, wherein Rais alkyl, Rbis hydrogen,—C(O)ORa, wherein Rais alkyl,—C═CRjRk, wherein Rjand Rktogether with the carbon atom to which they are attached form a cycloalkyl ring; and—R1q; wherein R1qis aryl or cycloalkyl;alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of—C(O)ORa, wherein Rais alkyl, andR1q, wherein R1qis aryl,—C(O)ORa, wherein Rais alkyl, or alkyl substituted with one R1q, wherein R1qis a heterocyclic ring, unsubstituted or substituted with one —C(O)OR101, wherein R101is alkyl,—C(O)NRaRb, wherein Rais alkyl, or alkyl substituted with one substituent selected from the group consisting of —OC(O)Rc, and —ORc, wherein Rcis hydrogen or alkyl, and Rbis alkyl, alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a heterocyclic ring substituted with one alkyl substitutent wherein the alkyl is substituted with one substituent selected from the group consisting of —ORc, and —OC(O)Rc, and wherein Rcis hydrogen or alkyl, orR1p; wherein R1pis heterocycle;R2is alkyl; R12is alkyl; R13is alkyl, R8is halo or —ORawherein Rais hydrogen or alkyl; andm is 0 or 1.

For example, the eighth embodiment of the present invention provides an intermediate of formula (IV) R3and R4together with the carbon atoms to which they are attached form an aryl ring; R1ispropyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, wherein each of the propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl is independently unsubstituted or substituted with 1 or 2 substituents selected from the group consisting ofhalo,—ORa, wherein Rais hydrogen,—OC(O)Ra, wherein Rais methyl, ethyl, or isopropyl,—OC(O)NRaRb, wherein Rais methyl, ethyl or isopropyl and Rbis hydrogen,—C(O)ORa, wherein Rais methyl, ethyl, or isopropyl,—C═CRjRk, wherein Rjand Rktogether with the carbon atom to which they are attached form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,—R1q; wherein R1qis phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;allyl, 3-methylbut-2-enyl, or 4-ethylpenta-2,4-dienyl, wherein each of the allyl, 3-methylbut-2-enyl or 4-ethylpenta-2,4-dienyl is unsubstituted or substituted with one substituent selected from the group consisting of—C(O)ORa, wherein Rais methyl, ethyl or isopropyl, and—R1q, wherein R1qis aryl,—C(O)ORa, wherein Rais methyl, ethyl or isopropyl, wherein each of the methyl, ethyl or isopropyl is unsubstituted or substituted with one R1q, wherein R1qis a pyrrolidine ring, unsubstituted or substituted with one —C(O)OR101, wherein R101is methyl, ethyl or isopropyl,—C(O)NRaRb, wherein Rais methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of —OC(O)Rc, and —ORc, wherein Rcis hydrogen or methyl, and Rbis methyl, alternatively, Raand Rb, together with the nitrogen atom to which they are attached, form a pyrrolidine ring substituted with one methyl wherin the methyl is substituted with one substitutent selected from the group consisting of —ORc, and —OC(O)Rc, and wherein Rcis hydrogen or methyl, orR1p; wherein R1pis 4,5-dihydro-1,3-oxazol-2-yl;R2is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, or 3-methylpentyl;R12is methyl;R13is methyl;R8is halo or —ORawherein Rais hydrogen or methyl; andm is 0 or 1.

In a ninth embodiment, the present invention provides a process for the preparation of a compound of formula (V)

a is 1 when M is Na+or K+;

a is 2 when M is Ca2+or Mg2+;

A is a monocyclic ring selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocycle;

m is 0 or 1;

wherein said process comprises the step of:

(a) contacting a compound of formula (33)

with a compound having formula R2X wherein X is Cl, Br or I and a base in a solvent to provide a compound of formula (34)

(b) contacting the compound of formula (34) with a chlorinating agent in a solvent to provide a compound of formula (35);

(c) contacting the compound of formula (35) with a reagent having formula CH2(C(O)ORt)2wherein Rtis alkyl, a base and MgCl2, in a solvent, to provide a compound of formula (36);

(d) contacting the compound of formula (36) with an acid to provide a compound of formula (37) whererin Rtis alkyl;

(e) contacting the compound of formula (37) with a compound of formula (38) wherein RAis a nitrogen protecting group, and a base, in a solvent, to provide a compound of formula (39);

(f) contacting the compound of formula (39) with a deprotecting agent in a solvent to provide an acid salt of a compound of formula (40);

(g) contacting the acid salt of the compound of formula (40) with a neutralizing agent in a solvent to provide the compound of formula (40);

(h) contacting the compound of formula (40) with a sulfonating agent having formula RaSO2Cl in a solvent to provide a compound of formula (41); and

(i) contacting the compound of formula (41) with a base in a solvent to provide a compound of formula (V).

For example, the present invention provides a process for the preparation of a compound of formula (V) wherein R1is alkyl or alkenyl, R2is alkyl or alkenyl, m is 0, and Rais alkyl.

For example, the ninth embodiment of the present invention provides a process for the preparation of a compound of formula (V) wherein R1is methyl or allyl, R2is 3-methyl butyl, 3,3-dimethyl butyl, allyl or 3-methylbut-2-enyl, m is 0, and Rais methyl.

For example, the eight embodiment of the present invention provides a process for the preparation of sodium (4R)-4-(3,3-dimethylbutyl)-4-methyl-2-{7-[(methylsulfonyl)amino]-1,1-dioxido-4H-1,2,4-benzothiadiazin-3-yl}-3-oxo-3,4-dihydronaphthalen-1-olate.

For example, the ninth embodiment of the present invention provides a process for the preparation of a compound of formula (V) wherein in step (a) R1is alkyl or alkenyl, Examples of R2X include, but are not limited to, 1-bromo-3-methyl but-2-ene (prenyl bromide), 3-methylbutyl bromide, and 3,3-dimethyl-1-iodobutane, examples of the bases in step (a) include, but are not limited to, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, lithium diisopropylamide, sodium hydroxide, and potassium hydroxide, preferably lithium diisopropylamide and lithium bis(trimethylsilyl)amide, and more preferably lithium bis(trimethylsilyl)amide. Examples of the solvent used in step (a) include, but are not limited to, tetrahydrofuran, N,N-dimethylformamide, dioxane, and dimethoxyethane; preferably tetrahydrofuran and dioxane; and more preferably tetrahydrofuran. The reaction in step (a) is generally performed at a temperature from about 25° C. to about 70° C.; preferably at a temperature from about 40° C. to about 65° C., and most preferable at a temperature from about 50° C. to about 60° C.

For example, the ninth embodiment of the present invention provides a process for the preparation of a compound of formula (V) wherein in step (b) the chlorinating agent include, but are not limited to, oxalyl chloride with a catalytic amount of N,N-dimethylformamide, thionyl chloride and phosphorus oxychloride; preferred chlorinating agent is thionyl chloride and oxalyl chloride with a catalytic amount of N,N-dimethylformamide; most preferred chlorinating agent is oxalyl chloride with about 1% in total volume of N,N-dimethyl formamide. Examples of the solvent that can be employed in step (b) include, but are not limited to, dichloromethane, hexanes, heptanes, and tetrahydrofuran; preferred solvent is hexanes or heptanes; more preferred solvent is heptanes. The reaction can be performed at a temperature from about 0° C. to about 30° C.; preferably at a temperature from about 10° C. to about 25° C., and most preferable at a temperature from about 20° C. to about 25° C.

For example, the ninth embodiment of the present invention provides a process for the preparation of a compound of formula (V) wherein in step (c) the examples of the reagent having formula CH2(C(O)ORt)2include, but are not limited to, CH2(C(O)OC2H5)2, CH2(C(O)O(t-butyl))2; preferably CH2(C(O)OC2H5)2. Examples of the base include, but are not limited to, triethylamine and diisopropyethyl amine, preferably triethylamine. Examples of the solvent include, but are not limited to, acetonitrile, N,N-dimethylformamide and tetrahydrofuran; preferably acetonitrile or tetrahydrofuran; and more preferably acetonitrile. The reaction of step (c) can be performed at a temperature from about 20° C. to about 60° C.; preferably at a temperature from about 40° C. to about 60° C., and more preferable at a temperature from about 50° C. to about 55° C.

For example, the ninth embodiment of the present invention provides a process for the preparation of a compound of formula (V) wherein in step (d) the acid is sulfuric acid or methanesulfonic acid, and preferably methanesulfonic acid. The reaction of step (d) can be performed at a temperature from about 0° C. to about 50° C.; preferably at a temperature from about 10° C. to about 40° C., and most preferable at a temperature from about 20° C. to about 25° C.

For example, the ninth embodiment of the present invention provides a process for the preparation of a compound of formula (V) wherein in step (e) RAis tert-butyloxycarbonyl or benzyloxycarbonyl, preferably tert-butyloxycarbonyl. Examples of the base include, but are not limited to, triethylamine, N,N-diisopropylethylamine, sodium hydroxide, cesium carbonate and DABCO™ (1,4-diazabicyclo[2.2.2]octane, Aldrich, catalog number 29,073-4), preferably DABCO™ or triethylamine, and more preferably triethylamine. Examples of the solvent that can be employed in step (e) include, but are not limited to toluene, water, xylene, acetonitrile, and s-butanol, preferably acetonitrile or toluene, and more preferably, toluene. The reaction can be performed at a temperature from about 60° C. to about 140° C.; preferably at a temperature from about 80° C. to about 105° C., and more preferably at a temperature from about 90° C. to about 100° C.

For example, the ninth embodiment of the present invention provides a process for the preparation of a compound of formula (V) wherein in step (f) the deprotecting agent include, but are not limited to, anhydrous hydrogen chloride in dioxane or trifluoroacetic acid; and more preferably anhydrous hydrogen chloride in dioxane. Examples of the solvent include, but are not limited to, ethyl acetate, toluene, dichloromethane and dioxane; preferably dichloromethane or dioxane; more preferably dichloromethane. The reaction can be performed at a temperature from about 0° C. to about 40° C.; preferably at a temperature from about 10° C. to about 30° C., and most preferable at a temperature from about 20° C. to about 25° C.

For example, the ninth embodiment of the present invention provides a process for the preparation of a compound of formula (V) wherein in step (g) examples of the neutralizing agent include, but are not limited to, Na2CO3, NaHCO3, and pH 7 phosphate buffer; preferably NaHCO3or a pH 7 phosphate buffer; and more preferably a pH 7 phosphate buffer. Examples of the solvent include, but are not limited to, dichloromethane, toluene, ethyl acetate, and isopropyl acetate, preferably toluene or ethyl acetate; and more preferably ethyl acetate. The reaction can be performed at a temperature from about 0° C. to about 40° C.; preferably at a temperature from about 110° C. to about 30° C., and more preferably at a temperature from about 20° C. to about 25° C.

For example, the ninth embodiment of the present invention provides a process for the preparation of a compound of formula (V) wherein examples of the solvent that can be employed in step (h) include, but are not limited to, isopropyl acetate, dichloromethane, tetrahydrofuran, ethyl acetate and acetone, preferably acetone or dichloromethane, and more preferably dichloromethane. The reaction can be performed at a temperature from about 0° C. to about 40° C.; preferably at a temperature from about 10° C. to about 30° C., and more preferably at a temperature from about 20° C. to about 25° C.

For example, the ninth embodiment of the present invention provides a process for the preparation of a compound of formula (V) wherein in step (i) examples of the base include, but are not limited to, alkali metal ethoxide, alkali metal hydroxide, and alkali metal carbonate, preferably alkali metal hydroxide or alkali metal ethoxide; more preferably alkali metal ethoxide and most preferably sodium ethoxide. Examples of the solvent include, but are not limited to, water, acetone, ethanol, acetonitrile, and mixture of water and ethanol; preferably acetone or ethanol; more preferably ethanol. The reaction can be performed at a temperature from about 10° C. to about 80° C.; preferably at a temperature from about 30° C. to about 75° C., and most preferable at a temperature from about 50° C. to about 75° C.

The process of the ninth embodiment of the present invention further comprises the process of resolving the chiral amine salt by contacting the compound of formula (34) with a chiral amine, isolating the chiral acid-amine salt and contacting the chiral acid-amine salt with an acid in a solvent. Examples of the chiral amine include, but are not limited to, (R) 2-amino-1-butanol, (S) phenethylamine, (+) pseudoephedrine, (−) and cinchonidine; preferred chiral amine is (+) pseudoephedrine or (S) phenethylamine; more preferred chiral amine is (S) phenethylamine. Examples of the solvent include, but are not limited to, acetone, methyl tert-butyl ether, ethanol and ethyl acetate, preferably methyl tert-butyl ether or ethyl acetate; and more preferably ethyl acetate. The reaction can be performed at a temperature from about 0° C. to about 60° C., preferably at a temperature from about 10° C. to about 40° C., and more preferably at a temperature from about 20° C. to about 30° C. The steps of isolating the chiral acid-amine salt comprises of filtering precipitate, dissolving the precipitate in a solvent to a solution, cooling the solution to room temperature and filtering the precipitate, wherein the solvent is ethyl acetate. Examples of the acid used to contact the chiral acid-amine salt include aqueous hydrochloric acid, sulfuric acid, and phosphoric acid; preferably sulfuric acid or aqueous hydrochloric acid; more preferably aqueous hydrochloric acid. Examples of the solvent employed include, but are not limited to, ethyl acetate, heptanes or isopropyl acetate; preferably heptanes or ethyl acetate; and more preferably ethyl acetate. The reaction can be performed at a temperature from about 0° C. to about 40° C.; preferably at a temperature from about 10° C. to about 30° C., and more preferably at a temperature from about 20° C. to about 25° C.

For example, the ninth embodiment of the present invention provides a process for the preparation of sodium (4R)-4-(3,3-dimethylbutyl)-4-methyl-2-{7-[(methylsulfonyl)amino]-1,1-dioxido-4H-1,2,4-benzothiadiazin-3-yl}-3-oxo-3,4-dihydronaphthalen-1-olate or sodium (4R)-4-methyl-4-(3-methylbutyl)-2-{7-[(methylsulfonyl)amino]-1,1-dioxido-4H-1,2,4-benzothiadiazin-3-yl}-3-oxo-3,4-dihydronaphthalen-1-olate, whereinin step (a) R1is methyl, R2is 3,3-dimethylbutyl, X is iodo, the base is lithium bis(trimethylsilyl)amide, and the solvent is tetrahydrofuran;in step (b) the chlorinating agent is oxalyl chloride and 1% in volume of N,N-dimethylformamide, the base is triethylamine and the solvent is heptane;in step (c) the reagent is CH2(C(O)OC2H5)2and the solvent is acetonitrile;in step (d) the acid is methanesulfonic acid;in step (e) A is phenyl, RAis tert-butyloxycarbonyl, the base is triethylamine and the solvent is toluene;in step (f) the deprotecting agent is anhydrous hydrogen chloride in dioxane, and the solvent is dichloromethane;in step (g) the neutralizing agent is pH 7 phosphate buffer and the solvent is ethyl acetate;in step (h) the sulfonating reagent is RaSO2Cl wherein Rais methyl, and the solvent is dichloromethane; andin step (i) the base is sodium ethoxide and the solvent is ethanol. The process further comprises contacting the compound of formula (34) from step (a) with (S)-α-methyl benzylamine in ethyl acetate, isolating the chiral-amine salt by filtration of the precipitate, dissolution of the precipitate in ethyl acetate to a solution, cooling the solution to room temperature and filtering the precipitate, and contacting the chiral acid-amine salt with hydrochloric acid in ethyl acetate.

It will be apprecitated by those skilled in the art that the compounds of this invention, exemplified by formula (I) wherein B is a six membered ring, exist in tautomeric forms. All tautomeric forms of the compounds described herein are intended to be encompassed within the scope of the present invention. Examples of some of the possible tautomer forms of the compounds of this invention include, but are not limited to:

As a convention, the compounds exemplified herein have been assigned names based on the structure of the tautomer of formula 1-A. It is to be understood that any reference to such named compounds is intended to encompass all tautomers of the named compounds and any mixture of tautomers of the named compounds.

Compounds of this invention may contain at least one chiral center and may exist as single stereoisomers (e.g. single enantiomer), mixtures of stereoisomers (e.g. any mixture of enantiomers or diastereomers) or racemic mixtures thereof. As a result, all stereoisomers of the compounds of the invention are meant to be included in the invention, including racemic mixtures, mixtures of diastereomers, mixtures of enantiomers, as well as individual optical isomers, including, enantiomers and single diastereomers of the compounds of the invention substantially free from their enantiomers or other diastereomers. By “substantially free” is meant greater than about 80% free of other enantiomers or diastereomers of the compound, more preferably greater than about 90% free of other enantiomers or diastereomers of the compound, even more preferably greater than about 95% free of other enantiomers or diastereomers of the compound, even more highly preferably greater than about 98% free of other enantiomers or diastereomers of the compound and most preferably greater than about 99% free of other enantiomers or diastereomers of the compound. Where the stereochemistry of the chiral centers present in the chemical structures illustrated herein is not specified, the chemical structure is intended to encompass compounds containing either stereoisomer of each chiral center present in the compound.

In addition, compounds comprising the possible geometric isomers of carbon-carbon double bonds and carbon-nitrogen double are also meant to be included in this invention.

Individual stereoisomers of the compounds of this invention can be prepared by any one of a number of methods which are within the knowledge of one of ordinary skill in the art. These methods include stereospecific synthesis from commercially available optically pure (enantiomerically pure) or substantially optically pure starting materials. Alternatively, these compounds may be obtained by resolution/separation of a mixture of stereoisomers, including racemic mixtures, using conventional procedures. Exemplary procedures that may be useful for the resolution/separation of mixtures of stereoisomers include enzymatic resolution, chromatographic separation, crystallization/re-crystallization, and conversion of enantiomers in an enantiomeric mixture to diastereomers followed by separation/resolution of the diastereomers using techniques known in the art, such as recrystallization and or chromatographic resolution, and regeneration of the individual enantiomers. Other useful methods may be found in “Enantiomers, Racemates, and Resolutions,” J. Jacques et al., 1981, John Wiley and Sons, New York, N.Y., the disclosure of which is incorporated herein by reference.

Stereospecific synthesis involves the use of appropriate chiral starting materials and synthetic reactions which do not cause racemization or inversion of stereochemistry at the chiral centers. Starting materials of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.

Diastereomeric mixtures of compounds resulting from a synthetic reaction can often be separated by chromatographic techniques which are well-known to those of ordinary skill in the art.

Chromatographic resolution of enantiomers can be accomplished on chiral chromatography resins. Chromatography columns containing chiral resins are commercially available. In practice, the racemate is placed in solution and loaded onto the column containing the chiral stationary phase. The enantiomers are then separated by HPLC.

Resolution of enantiomers can also be accomplished by converting the enantiomers in the mixture to diastereomers by reaction with chiral auxiliaries. The resulting diastereomers can then be separated by column chromatography. This technique is especially useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group that will form a salt or covalent bond with the chiral auxiliary. Chirally pure amino acids, organic carboxylic acids or organosulfonic acids are especially useful as chiral auxiliaries. Once the diastereomers have been separated by chromatography, the individual enantiomers can be regenerated. Frequently, the chiral auxiliary can be recovered and used again. Alternatively, the diastereomers can also be separated by crystallization/re-crystallization and the individual enantiomers regenerated therefrom.

Enzymes, such as esterases, phosphatases and lipases, can be useful for resolution of derivatives of the enantiomers in an enantiomeric mixture. For example, an ester derivative of a carboxyl group in the compounds to be separated can be prepared. Certain enzymes will selectively hydrolyze only one of the enantiomers in the mixture. Then the resulting enantiomerically pure acid can be separated from the unhydrolyzed ester.

The present compounds may exhibit the phenomena of tautomerism or structural isomerism. As the drawings within this specification can only represent one possible tautomeric or structural isomeric form, it should be understood that the invention encompasses any tautomeric or structural isomeric form, or mixtures thereof, which possess the ability to inhibit hepatitis C, and is not limited to any one tautomeric or structural isomeric form utilized within the drawings.

In addition, solvates and hydrates of the compounds of the invention are meant to be included in this invention.

When any variable (for example R7, R8, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rj, Rk, Rp, Rq, R1p, R1q, R2p, R2q, R3p, R3q, R4p, R4q, R7p, R7q, R8p, R8q, R9p, R9q, R101, R102, R103, R104, R105, R106, m, n, etc.) occurs more than one time in any substituent or in the compound of the invention or any other formula herein, its definition on each occurrence is independent of its definition at every other occurrence. In addition, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds which can be isolated in a useful degree of purity from a reaction mixture.

The compounds of the present invention can exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt,” as used herein, represents acid or base salts or zwitterionic forms of the compounds of the present invention which are water or oil-soluble or dispersible, which are suitable for treatment of diseases without undue toxicity, irritation, and allergic response; which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting a basic group (for example, a nitrogen containing group) with a suitable acid. Representative acid addition salts include acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, bisulfates, bisulfites, butyrates, camphorates, camphorsulfonates, caproates, caprylates, citrates, chlorobenzoates, digluconates, dinitrobenzoates, formates, fumarates, glutamates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochloride, hydrobromide, hydroiodides, 2-hydroxyethansulfonates, lactates, maleates, mandelates, methoxybenzoates, methylbenzoates, malonates, mesitylenesulfonate, methanesulfonates, naphthylenesulfonates, nicotinates, nitrates, nitrites, 2-naphthalenesulfonates, oxalates, pamoates, pectinates, persulfates, phenylbutyrates, phenylproprionates, phosphates, phthalates, picrates, pivalates, propanesulfonates, propionates, pyrosulfates, salicylates, succinates, sulfonates, tartrate, trichloroacetate, trifluoroacetate, para-toluenesulfonates, and undecanoates. Also, amino groups in the compounds of the present invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, nitric acid, sulfuric, and phosphoric, and the like, and organic acids such as acetic, fumaric, trifluoroacetic, mandelic, methanesulfonic, pyruvic, oxalic, glycolic, salicylic, oxalic, maleic, succinic, tartaric, aspartic, glutamic, cinnamic and citric.

Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting an acidic group (for example, a carboxy group or an enol) with a suitable base such as the alkoxide, (for example, ethoxide or methoxide and the like) hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of pharmaceutically acceptable salts include lithium, sodium, potassium, calcium, copper, manganese, iron, zinc, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N′-dibenzylethylenediamine. Other representative organic amines useful for the formation of basic addition salts include amino acids such as glycine and arginine, primary, secondary and tertiary amines such as ethylenediamine, ethanolamine, and diethanolamine, and cyclic amines such as dicyclohexylamine, morpholine, piperidine, and piperazine.

Representative pharmaceutically acceptable salts of the compounds of the present invention include sodium, potassium, calcium, magnesium, triethylamine, trifluoroacetate, methanesulfonate, hydrobromide and hydrochloride.

The present compounds can also exist as pharmaceutically acceptable prodrugs. The term “pharmaceutically acceptable prodrug,” refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. “Prodrugs” are considered to be any covalently bonded carriers which release the active parent drug of formula (I), (II) or (III) in vivo metabolically or by solvolysis when such prodrugs is administered to a mammalian subject. Prodrugs of the compounds of formula (I), (II) or (III) can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds respectively. Examples of such modification include, but not limited to, treatment of a compound of formula (I), (II) or (III), containing an amino, amido or hydroxyl moiety with a suitable derivatising agent, for example, a carboxylic acid halide or acid anhydride, treatment of a compound of formula (I), (II) or (III), containing a carboxyl moiety, to an ester or amide and treatment of a compound of formula (I), (II) or (III), containing a carboxylic acid ester moiety to an enol-ester. Prodrugs include compounds wherein hydroxy, amine, carboxy, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves under physiological conditions to form a free hydroxyl, amino, carboxy, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of the hydroxy, carboxy and amine functional groups in the compounds of formula (I), (II) or (III).

The pharmaceutical compositions of this invention can be formulated in a conventional manner using one or more of the aforementioned pharmaceutically acceptable carriers.

In accordance with methods of treatment and pharmaceutical compositions of the invention, the compounds of formula (I), (II) or (III), or a tautomer, stereoismer, or a pharmaceutically acceptable salt thereof, can be administered alone or in combination with other antiviral agents. When using the compounds of formula (I), (II) or (III), the specific pharmaceutically effective dose level for any particular patient will depend upon factors such as the disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the compound employed; the duration of treatment; and drugs used in combination with or coincidently with the compound used. The compounds of formula (I), (II) or (III), or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof can be administered orally, parenterally, osmotically (nasal sprays), rectally, vaginally, or topically in unit dosage formulations containing carriers, adjuvants, diluents, vehicles, or combinations thereof. The term “parenteral” includes infusion as well as subcutaneous, intravenous, intramuscular, and intrasternal injection.

Parenterally administered aqueous or oleaginous suspensions of the compounds can be formulated with dispersing, wetting, or suspending agents. The injectable preparation can also be an injectable solution or suspension in a diluent or solvent. Among the acceptable diluents or solvents employed are water, saline, Ringer's solution, buffers, monoglycerides, diglycerides, fatty acids such as oleic acid, and fixed oils such as monoglycerides or diglycerides.

The antiviral effect of parenterally administered compounds can be prolonged by slowing their absorption. One way to slow the absorption of a particular compound is administering injectable depot forms comprising suspensions of crystalline, amorphous, or otherwise water-insoluble forms of the compound. The rate of absorption of the compound is dependent on its rate of dissolution which is, in turn, dependent on its physical state. Another way to slow absorption of a particular compound is administering injectable depot forms comprising the compound as an oleaginous solution or suspension. Yet another way to slow absorption of a particular compound is administering injectable depot forms comprising microcapsule matrices of the compound trapped within liposomes, microemulsions, or biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides. Depending on the ratio of drug to polymer and the composition of the polymer, the rate of drug release can be controlled.

Transdermal patches can also provide controlled delivery of the compounds. The rate of absorption can be slowed by using rate controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound can optionally comprise diluents such as sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, tableting lubricants, and tableting aids such as magnesium stearate or microcrystalline cellulose. Capsules, tablets and pills can also comprise buffering agents, and tablets and pills can be prepared with enteric coatings or other release-controlling coatings. Powders and sprays can also contain excipients such as talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures thereof. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons or substitutes thereof.

Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs comprising inert diluents such as water. These compositions can also comprise adjuvants such as wetting, emulsifying, suspending, sweetening, flavoring, and perfuming agents.

Topical dosage forms include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and transdermal patches. The compound is mixed under sterile conditions with a carrier and any needed preservatives or buffers. These dosage forms can also include excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Suppositories for rectal or vaginal administration can be prepared by mixing the compounds with a suitable non-irritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina. Ophthalmic formulations comprising eye drops, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.

The compounds of formula (I), (II) or (III), or their pharmaceutically acceptable salts, stereoisomers or tautomers thereof, inhibit HCV RNA dependent RNA polymerase, an enzyme essential for HCV viral replication. They can be administered as the sole active pharmaceutical agent, or used in combination with one or more agents to treat hepatitis C infections or the symptoms associated with HCV infection. Other agents to be administered in combination with a compound of the present invention include therapies for disease caused by HCV infection that suppresses HCV viral replication by direct or indirect mechanisms. These include agents such as host immune modulators, for example, interferon-alpha, pegylated interferon-alpha, interferon-beta, interferon-gamma, CpG oligonucleotides and the like, or antiviral compounds that inhibit host cellular functions such as inosine monophosphate dehydrogenase, for example, ribavirin and the like. Also included are cytokines that modulate immune function. Also included are vaccines comprising HCV antigens or antigen adjuvant combinations directed against HCV. Also included are agents that interact with host cellular components to block viral protein synthesis by inhibiting the internal ribosome entry site (IRES) initiated translation step of HCV viral replication or to block viral particle maturation and release with agents targeted toward the viroporin family of membrane proteins such as, for example, HCV P7 and the like. Other agents to be administered in combination with a compound of the present invention include any agent or combination of agents that inhibit the replication of HCV by targeting proteins of the viral genome involved in the viral replication. These agents include but are not limited to other inhibitors of HCV RNA dependent RNA polymerase such as, for example, nucleoside type polymerase inhibitors described in WO0190121(A2), or U.S. Pat. No. 6,348,587 or WO0160315 or WO0132153 or non-nucleoside inhibitors such as, for example, benzimidazole polymerase inhibitors described in EP1162196A1 or WO0204425 or inhibitors of HCV protease such as, for example, peptidomimetic type inhibitors such as BILN2061 and the like or inhibitors of HCV helicase.

Other agents to be administered in combination with a compound of the present invention include any agent or combination of agents that inhibit the replication of other viruses for co-infected individuals. These agent include but are not limited to therapies for disease caused by hepatitis B (HBV) infection such as, for example, adefovir, lamivudine, and tenofovir or therapies for disease caused by human immunodeficiency virus (HIV) infection such as, for example, protease inhibitors: ritonavir, lopinavir, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir; reverse transcriptase inhibitors: zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125; integrase inhibitors: L-870812, S-1360, or entry inhibitors: enfuvirtide (T-20), T-1249.

Other agents to be administered in combination with a compound of the present invention include any agent or combination of agents that treat or alleviate symptoms of HCV infection including cirrhosis and inflammation of the liver.

When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or within a predetermined period of time, or the therapeutic agents can be given as a single unit dosage form.

The phrase “therapeutically effective amount” of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated; the treatment desired; the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of formula (I), (II) or (III), or pharmaceutically acceptable salts, stereoisomers of tautomers thereof, administered to a host in single or divided doses can be in amounts from about 0.1 to about 200 mg/kg body weight or preferably from about 0.25 to about 100 mg/kg body weight. Single dose compositions can contain these amounts or submultiples thereof to make up the daily dose.

Determination of Biological Activity

Either two-fold serial dilutions (fractional inhibition assay) or a narrower range of dilutions spanning the IC50 of the inhibitor (tight binding assay) of the inhibitors were incubated with 20 mM Tris-Cl pH 7.5, 5 mM MgCl2, 50 mM NaCl, 1 mM dithiothreitol, 1 mM ethylene diamine tetraacetic acid (EDTA), 300 μM GTP and 150 to 300 nM NS5B (HCV Strain 1B (J4, Genbank accession number AF054247, or H77, Genbank accession number AF011751)) for 15 minutes at room temperature. The reaction was initiated by the addition of 20 μM CTP, 20 μM ATP, 1 μM 3H-UTP (10 mCi/umol), 150 nM template RNA and 0.4 U/μl RNase inhibitor (RNasin, Promega), and allowed to proceed for 2 to 4 hours at room temperature. Reaction volume was 50 μl. The reaction was terminated by the addition of 1 volume of 4 mM spermine in 10 mM Tris-Cl pH 8.0, 1 mM EDTA. After incubation for at least 15 minutes at room temperature, the precipitated RNA was captured by filtering through a GF/B filter (Millipore) in a 96 well format. The filter plate was washed three times with 200 μl each of 2 mM spermine, 10 mM Tris-Cl pH 8.0, 1 mM EDTA, and 2 times with ethanol. After air drying, 30 μl of Microscint 20 scintillation cocktail (Packard) was added to each well, and the retained cpm were determined by scintillation counting. IC50 values were calculated by a two-variable nonlinear regression equation using an uninhibited control and a fully inhibited control sample to determine the minimum and maximum for the curve. Tight-binding assays were performed on those compounds exhibiting IC50 values less than 0.15 μM in the fractional inhibition assay in order to more precisely measure the IC50 values. Retained cpm were plotted vs. inhibitor concentration and fit to equation 1 using non-linear regression (ref. 1) to obtain the IC50 values.
Retainedcpm=A[sqrt{(IC50+It−Et)2+4IC50Et}−(IC50+It−Et)]  eqn 1.
where A=Vmax[S]/2(Km+[S]); It=total inhibitor concentration and Et=total active concentration of enzyme.
Ref. 1: Morrison, J. F. and S. R. Stone. 1985. Approaches to the study and analysis of the inhibition of enzymes by slow- and tight-binding inhibitors. Comments Mol. Cell. Biophys. 2: 347-368.

The sequence of hte template RNA used was:

When tested by the above method, the compounds of the present invention inhibit HCV polymerase 1B with IC50's in the range of 0.002 μM to 500 μM.

Evaluation of the HCV Inhibitors in HCV Replicon: Cell Culture EC50

The cell lines and assays were conducted according to the methods described by Ikeda M, Yi M, Li K, Lemon S M., J Virol 2002 March;76(6):2997-3006, and Blight K. J, Kolykhalov A., Rice C. M., Science 2000 December, 290:1972-1974) with the following modifications:

RNA Assay

Replicon cells were plated at 3×103cells per well in 96-well plate in DMEM medium containing 5% fetal calf serum. At day 1, culture medium was removed and replaced with fresh medium containing eight serial 2-fold dilutions of compound. The final concentration of DMSO in medium was 0.5%. The untreated control culture was treated in an identical manner except no inhibitor was added to the medium. Plates were incubated in a CO2incubator at 37° C. On Day 4, 100 μL lysis buffer (RTL) (Qiagen) was added to each well after removal of culture medium. RNA was purified according to manufacturer's recommendations (Qiagen RNAeasy) and eluted in 200 μl of water. The HCV RNA level was quantified from a portion (5 μL out of 200 μL) of the purified RNA by real-time RT-PCR method. The primers and probe are derived from specific sequence in the 5′UTR region. RT-PCR reaction was performed at 48° C. for 30 min, followed by 40 cycles set to 95° C., 15 s; 54° C., 30 s; and 72° C., 40 s. The percentage reduction of HCV RNA in the presence of compound was calculated and the 50% inhibitory concentration (IC50) was calculated by non-linear regression analysis using the Prism program.

When tested by the above method, the compounds of the present invention inhibit replicon production with EC50's in the range of 0.005 μM to >100 μM.

Cytotoxicity assays were performed in replicon cells. Briefly, HCV replicon cells were plated at 3×103cells per well in 96-well plate in DMEM medium containing 5% FCS. At day 1, culture medium was removed and replaced with fresh medium containing eight serial 2-fold dilutions of compound. The final concentration of DMSO in medium was 0.5%. All experiments were performed in duplicate. The untreated control culture was treated in an identical manner except no inhibitor was added to the medium. Plates were incubated in a CO2incubator at 37° C. On day 4, stock solution of the tetrazolium salt, MTT (4 mg/ml in PBS, Sigma cat.# M 2128) was added to each well at 25 μL per well. Plates were further incubated for 4 hours, treated with 20% SDS plus 0.02 N HCl at 50 μL per well to lyse the cells. After an overnight incubation, optical density was measured by reading the plates at 570/650 nm wavelengths. The percent reduction of formazan blue color formed relative to control was calculated and the cytopathic effect was described as a 50% toxicity concentration (TC50) was calculated by non-linear regression analysis using the Prism program.

When tested by the above method, the compounds of the present invention exhibited CPE reduction with TC50's in the range of 6.6 μM to >100 μM.

Cell culture assays for agents targeted toward hepatitis C are not yet available because of the inability to produce infectious virus in a sustained cell line. The hepatitis C virus genome encodes a large polyprotein, which after processing produces the necessary functional components to synthesize progeny RNA. Selectable cell lines that produce high and sustained levels of subgenomic HCV RNA (replicons) have been derived from human hepatoma cells (Huh7) as described in the references above. The mechanism of RNA replication in these cell lines is considered to be identical to the replication of full length HCV RNA in infected hepatocytes. The compounds and methods of this invention are inhibitors of HCV RNA replication in the replicon assay systems described above. This forms the basis of the claim for their potential as therapies in treating disease resulting from hepatitis C viral infection.

Synthetic Methods

Abbreviations which have been used in the descriptions of the schemes and the examples that follow are: THF is tetrahydrofuran and DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene.

The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention may be prepared. Starting materials can be obtained from commercial sources or prepared by well-established literature methods known to those of ordinary skill in the art. The groups R1, R2, R3, R4, R7, R8, R10, R11, m and n are as defined above unless otherwise noted below.

This invention is intended to encompass compounds having formula (I), (II) or (III) when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.

Compounds of formula (8) wherein R1is alkyl, alkenyl or alkynyl, R2is alkyl, alkenyl or alkynyl, and R8is as defined in formula (I), ring D represents the ring formed by R3, R4(as defined in formula (I)), and the carbon atoms to which they are attached, and is selected from the group consisting of aryl, heteroaryl, cycloalkenyl, cycloalkyl and heterocycle, can be prepared as shown in Scheme 1. Examples of D include, but are not limited to, phenyl, furanyl and thienyl.

Compounds of formula (1) wherein Rpis hydrogen, alkyl, alkenyl, alkynyl or benzyl, wherein the alkyl, alkenyl and benzyl are unsubstituted or substituted, can be monoalkylated with one equivalent of an alkylating agent having formula R1X, wherein X is Cl, Br or I, in the presence of appropriate amount of a base (for example, if Rpis hydrogen, about two equivalents of the base can be used, if Rpis other than hydrogen, than about one equivalent of the base can be used) in a solvent such as, but not limited to, tetrahydrofuran, diethyl ether, N, N-dimethylformamide, or mixtures thereof, at a temperatures from about −78° C. to about 70° C. to afford compounds of formula (2).

Compounds of formula (2), either purchased or prepared as shown above, can be alkylated again by treatment with the same or a second alkylating agent by reaction with a base and an alkylating agent having formula R2X, wherein X is Cl, Br or I. The reaction can be carried out in a solvent such as, but not limted to, tetrahydrofuran, diethyl ether, N,N-dimethylformamide, or mixtures thereof, at a temperatures from about −78° C. to about 70° C. The reaction can be performed with or without an additive such as lithium or sodium iodide or hexamethylphosphoric triamide (HMPA) and the like. Most conveniently, in the case where R1is the same as R2, compounds of formula (1) can be transformed in a one step operation to compounds of formula (3) by using an excess of an alkylating agent, in the presence of about two equivalents of the base (if Rpis not hydrogen) or about three equivalents of the base (if Rpis hydrogen), in a solvent such as tetrahydrofuran, diethyl ether, N,N-dimethylformamide, or mixtures thereof, at a temperature from about 0° C. to about 100° C., with or without the presence of an additive such as lithium, sodium or potassium iodide, tetrabutylammonium iodide, 18-crown-6, or hexamethylphosphoric triamide (HMPA), and the like.

Examples of Rpinclude, but not limited to hydrogen, methyl, ethyl, tert-butyl and benzyl.

Examples of the bases include, but not limited to, sodium hydride, potassium hydride, lithium bis(trimethylsilyl)amide, lithium diisopropyl amide, lithium tetramethyl piperidide, and potassium tert-butoxide,

Compounds of formula (3) wherein Rpis methyl can be converted into carboxylic acid of formula (4) by treatment with potassium trimethylsilanoate in a solvent such as tetrahydrofuran, dioxane, dichloromethane, acetonitrile, toluene, and the like, or mixtures thereof, at a temperature from about 60° C. to about 100° C. Compounds of formula (3) wherein Rpis benzyl can be converted to compounds of formula (4) by hydrogenation with hydrogen over a metal catalyst such as 5-10% palladium on carbon or platinum oxide (Adam's catalyst) and the like, in a solvent such as ethyl acetate, ethanol, methanol, or mixtures thereof, at a pressure of about 1-20 atmospheres and at a temperature from about 25° C. to about 80° C.

Compounds of formula (3) wherein R1and R2are allyl, crotyl, or 3-methylbut-2-ene, and Rpis benzyl can be converted to compounds of formula (4) wherein R1and R2are n-propyl, n-butyl, or 3-methylbutyl by either one step or stepwise hydrogenation using the conditions as specified above.

Compounds of formula (5) can be prepared from compounds of formula (4) by refluxing for several days with excess thionyl chloride. A preferred method of transformation can be accomplished by treatment of a hexane or heptane solution of acid (4) and one equivalent of N,N-dimethylformamide with an excess of oxalyl chloride. The acid chloride (5) is reacted with the magnesium salt of either diethyl or dimethyl malonate (generated in acetonitrile according as described by Rathke (Rathke, M. W.; Cowan, P. J.J. Org Chem.1985, 50, 2622) at a temperatures of about 40° C. to about 60° C. The ketodiester (6), wherein R is methyl or ethyl, is then subjected to Friedel-Crafts-type cyclization by treatment with an acid such as, but not limited to, concentrated sulfuric acid, methanesulfonic acid, or polyphosphoric acid, and the like, at a temperature from about 25° C. to about 100° C., to afford the diketo ester (7). Transformation of the diketo ester (7) to the compounds of formula (8) can be achieved by treatment with a dilute aqueous acid such as, but not limited to, hydrochloric acid or sulfuric acid, methanesulfonic acid or p-toluenesulfonic acid, admixed with a solvent such as tetrahydrofuran, dioxane, and the like, at preferably reflux temperature.

Compounds of formula (11) wherein R1, R2, R7, R8, m and n are as defined in formula (I), and ring D is formed by R3, R4(as defined in formula (I)) and the carbon atomes to which they are attached, can be prepared as shown in Scheme 2 from compounds of formula (7) by (a) reacting with an aminobenzenesulfonamide derivatives of formula (9) in a solvent such as toluene, xylene, dioxane and the like, at a temperature from about 80° C. to about 140° C., and (b) reacting the product of step (a) with a base at a temperature from about 80° C. to about 150° C. in a solvent such as, but not limited to, water, pyridine, picoline or collidine, and the like, to facilitate the cyclization of compounds of formula (10) to compounds of formula (11).

Examples of the base are, but not limited to, 5-20% of aqueous solution of sodium or potassium hydroxide, anhydrous cesium carbonate, potassium carbonate and 1,8 diazabicyclo[5.4.0]undec-7-ene.

A preferred method of step (b) is to treat compounds of formula (10) with one equivalent of anhydrous potassium or cesium carbonate in a solvent such as pyridine, picoline or collidine at a temperature from about 80° C. to about 150° C.

A more preferred method for the transformation is to treat compounds of formula (10) with 1,8 diazabicyclo[5.4.0]undec-7-ene in a solvent such as pyridine, picoline or collidine, and the like, at a temperature from about 80° C. to about 150° C.

Another route for the preparation of compounds of formula (11) is illustrated above in Scheme 3. Compounds of formula (8) can be treated with 1-10 equivalents of a tris(alkylthio)methyl salt of formula (12) (prepared according to the procedure of Degani,Synthesis1988, 22), in the presence of an excess of a base, in a dipolar aprotic solvent such as, but not limited to, tetrahydrofuran, acetonitrile, toluene, xylene or dioxane, or mixtures thereof, at a temperature of about 25° C. to about 130° C. to afford compounds of formula (13). A preferred tris(alkylthio)methyl salt is tris(methylthio)methyl methyl sulfate or tris(methylthio)methyl tetrafluoroborate.

Examples of the base are, but not limited to, pyridine, picoline and collidine.

Compounds of formula (13) can be converted to compounds of formula (11) by treating with an amino benzenesulfonamide of formula (9) in a solvent such as toluene, xylene or dioxane, and the like, or mixtures thereof, at a temperatures from about 70° C. to about 150° C.

Compounds of this invention having formula (I) wherein B is a five, six or seven membered ring, and wherein R3and R4together do not form a ring, or wherein R3and R4together form a cycloalkyl or cycloalkenyl ring, can be prepared as shown in schemes 4 and 5.

Using methodology developed by Stork (Stork, G.; Danheiser, R. L.J. Org. Chem.1973, 38, 1775), alkoxydihydroresorcinol derivative (14) wherein R is methyl, ethyl, n-propyl, or isobutyl can be converted to compounds of formula (15) by (a) reacting with a base in a solvent such as, but not limited to, tetrahydrofuran or 2-methyltetrahydrofuran, or mixtures thereof, at a temperature from about −78° C. to about 0° C., and with or without the presence of an additive, and (b) treating the product from step (a) with an alkylating agent of formula R11X, wherein X is Cl, Br, or I, at a temperature from about −78° C. to about 25° C. Compounds of formula (15) can be further alkylated with the same or a second alkylating agent of formula R4X, wherein X is Cl, Br, or I, by the conditions as described in steps (a) and (b) to afford compounds of formula (16).

Examples of the base include, but are not limited to, lithium bis(trimethylsilyl)amide (LiHMDS), Lithium tetramethyl piperidide and lithium diisopropyl amide (LDA).

Compounds of formula (16) can be directly hydrolyzed to the diketone derivatives of formula (17) by treatment with an acid such as dilute aqueous hydrochloric acid, dilute aqueous sulfuric acid, aqueous sodium bisulfate or aqueous trifluoroacetic acid in a solvent, such as tetrahydrofuran, acetone, dioxane, and the like, or mixtures thereof, at a temperatures from about 0° C. to about 25° C. Compounds of formula (18) can be prepared from diketones of formula (17), using the conditions for the transformation of compounds of formula (8) to compounds of formula (13).

Alternatively, using methodology developed independently by Nicolaou and Suzuki (Nicolaou, K. C.; et al.Chem. Commun.2002, 2478;Angew. Chem. Int. Ed. Eng.2002, 41, 3276; Bode, J. W.; Suzuki, K.Tetrahedron Lett.2003, 44, 3559), compounds of formula (16) wherein R10and R11are hydrogen, can be treated with a base such as, but not limited to, lithium diisopropyl amide (LDA) in a solvent such as tetrahydrofuran, 2-methyltetrahydrofuran or diethyl ether, and the like, or mixtures thereof, in the presence of an additive such as hexamethylphosphoric triamide (HMPA) or 1,3-dimethyl-2-imidazolidinone (DMI) at a temperature from about −78° C. to about 0° C., followed by the addition of phenyl selenyl chloride and warming the reaction to ambient temperature. The resulting selenium derivative (19) can be treated with an oxidizing agent such as, but not limited to, aqueous hydrogen peroxide, m-chloroperbenzoic acid, sodium periodate, peracetic acid or monoperphthalic acid, at a temperatures from about 30° C. to about 50° C. The resulting dienone (20) can be hydrolyzed using a base such as, but not limited to, lithium hyroxide hydrate in a solvent mixture such as methanol or ethanol in water, at a temperatures of about 50° C. to about 100° C. to afford the diketone (21). The diketone (21) can be transformed to compounds of formula (22) using the conditions for the transformation of compounds of formula (8) to compounds of formula (13).

Compounds of formulae (18) and (22) can be converted to compounds of formulae (23) and (24), respectively, using the conditions for the transformation of compounds of formula (13) to compounds of formula (11).

Compounds of the formula (25) wherein X is I, Br, Cl or F can be treated with alkyl thiols such as benzene methylthiol in the presence of a base such as sodium carbonate in solvents such as ethanol and the like under heated conditions to give compounds of the formula (26). Treatment of (26) with chlorine gas in hydrochloric acid or acetic acid provides compounds of the formula (27). Compounds of the formula (27) in solvents such as but not limited to dichloromethane, tetrahydrofuran or dioxane can be treated with ammonia or ammonium hydroxide to give compounds of the formula (28). Reduction of compounds of the formula (32) with iron powder and ammonium chloride in aqueous alcoholic solvents such as methanol or ethanol under heated conditions optionally with iron powder in acetic acid under heated conditions to provide compounds of the formula (9).

Alternatively, compounds of formula (20) whererin R1, R2, R3and R4are as defined in formula (I) and R is methyl, ethyl, isopropyl or butyl, can be prepared as shown in Scheme 7.

Compounds of formula (29), either purchased or prepared by methodologies known to one skilled in the art, can be transformed to compounds of formula (30), wherein R2is allyl, by reaction with a base, a palladium reagent, a ligand and allyl acetate. The reaction is typically performed in a solvent such as, but not limited to, tetrahydrofuran, dichloromethane, diethyl ether, N,N-dimethylformamide, dimethoxyethane or tert-butyl methyl ether, at a temperature from about room temperature to about 100° C. Examples of the base include, but are not limited to cesium carbonate. Examples of the palladium reagent include, but are not limited to, tris(dibenzylideneacetone)dipalladium(0) and allylpalladium chloride dimmer. Examples of the ligand include, but are not limited to, 1,2-diaminocyclohexane-N,N′-bis(2′-diphenylphosphinobenzoyl) and (+)-11(S), 12(S)-Bis[2′-(diphenylphosphino)benzamido]-9,10-dihydro-9,10ethanoanthracene. Compounds of formula (29) wherein R2is an alkyl or substituted alkyl, as defined in formula (I), can be converted to compounds of formula (30) by reaction with a base and an alkylating agent having formula R2X, wherein X is Cl, Br or I, optionally in the presence of hexamethylphosphoric triamide (HMPA) or 1,3-Dimethyl-2-imidazolidinone (DMI). The reaction can be performed at a temperature from about −78° C. to about room temperature for about 1 to 48 hours. The reaction is generally carried out in an aprotic solvent such as, but are not limited to, tetrahydrofuran, dimethoxyethane or tert-butyl methyl ether. Examples of the base include, but are not limited to, lithium diisopropylamide, and lithium hexamethyldisilazide.

Compounds of formula (30) can be converted to compounds of formula (32) by reaction with a trialkylorthoformated of formula CH(OR3)3, and p-toluenesulfonic acid in an alcoholic solvent such as, but not limited to, methanol. The reaction is generally carried out at a temperature from about room temperature to about 70° C.

Alternatively, compounds of formula (32) can be obtained from compounds of formula (31) wherein R1is an electron withdrawing group such as —C(O)Raor —C(O)ORa, by reaction with an alkylating agent having formula R2X, wherein X is Cl, Br, or I, with a metal, ammonia and a proton source. The reaction can be carried out at about −78° C. and optionally in the presence of a co-solvent such as, but are not limited to, tetrahydrofuran and diethyl ether. Examples of the metal include potassium or sodium. Examples of the proton sounce include, but are not limited to, tert-butanol and a weak acid such as, but not limited to, water.

Conversion of compounds of formula (32) to compounds of formula (20) can be achieved by reaction with pyridinium dichromate and tert-butyl hydroperoxide. The reaction can be performed in a solvent such as, but not limited to, benzene, chloroform or dichloromethane, at a temperature from about room temperature to about 60° C., for about 1 hour to about 24 hours.

The present invention will now be described in connection with certain preferred embodiments which are not intended to limit its scope. On the contrary, the present invention covers all alternatives, modifications, and equivalents as can be included within the scope of the claims. Routine experimentation, including appropriate manipulation and protection of any chemical functionality, synthesis of the compounds of formula (I), (II) or (III) may be aaccomplished by methods analogous to those described above and in the following examples. Thus, the following examples, which include preferred embodiments, will illustrate the preferred practice of the present invention, it being understood that the examples are for the purpose of illustration of certain preferred embodiments and are presented to provide what is believed to be the most useful and readily understood description of its procedures and conceptual aspects.

Compounds of the invention were named by ACD/ChemSketch version 5.06 (developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada) or were given names consistent with ACD nomenclature.

A solution of methyl 2-phenylacetate (12.0 g, 80 mmol), allyl bromide (17.3 mL, 200 mmol) and sodium iodide (1 g) in tetrahydrofuran (160 mL) at 0° C. was treated portionwise with sodium hydride (7.36 g, 60% in oil, 184 mmol) over 10 minutes. The solution was allowed to warm to 25° C. and heated at reflux for 18 hours. The mixture was cooled to 0° C., treated with glacial acetic acid (2 mL) and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was filtered through a plug of 70-230 mesh silica gel eluting first with hexane and then with 10% ethyl acetate in hexane to give the title compound (17.89 g, 97%).1H NMR (300 MHz, CDCl3): δ 7.29 (m, 5 H), 5.52 (m, 2 H), 5.06 (m, 4 H), 3.65 (s, 3 H), 2.78 (m, 4 H).

A solution of the product of Example 1B (7.63 g, 32.61 mmol) and potassium trimethylsilanoate (23.2 g of 90% material, 163 mmol) in tetrahydrofuran (163 mL) was warmed at reflux for 18 hours. The solution was cooled to 25° C. and concentrated in vacuo to remove the tetrahydrofuran. A solution of the residue in water (250 mL) was cooled to 0° C., and adjusted to pH 1 by addition of 4 N HCl solution. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound (6.78 g, 95%).1H NMR (300 MHz, CDCl3): δ 7.25 (m, 5 H), 1.99 (m, 4 H), 1.12 (m, 4 H), 0.90 (t, J=7.17 Hz, 6 H).

A suspension of the product of Example 1C (4.13 g, 18.77 mmol) and N,N-dimethylformamide (1.45 mL, 18.77 mmol) in hexanes (700 mL) was treated with oxalyl chloride (4.91 mL, 56.31 mmol) and stirred at 25° C. for 2 hours. The mixture was treated with celite®, and then filtered through a pad of celite®. The filtrate was concentrated in vacuo to afford the title compound which was used directly in the next procedure.

A solution of diethyl malonate (3.03 g, 18.77 mmol) and anhydrous magnesium chloride in acetonitrile (36 mL) at 0° C. was treated with triethylamine (5.2 mL, 37.55 mmol), stirred at 0° C. for 30 min, stirred at 25° C. for 3 hours, cooled to 0° C. and treated dropwise with a solution of the product of Example 1D (18.77 mmol) in acetonitrile (15 mL) over 10 min and stirred at 50° C. for 18 hours. The solution was cooled to 25° C. and concentrated in vacuo. The solids were suspended in ethyl acetate and cooled to 0° C., treated with 4N HCl solution until all solids had dissolved. The organic layer was extracted with water (2×) and with saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (4.51 g, 66%).1H NMR (300 MHz, CDCl3): δ 7.32 (m, 5 H), 4.50 (s, 1 H), 4.04 (q, J=7.35 Hz, 4 H), 1.97 (m, 4 H), 1.28 (m, 3 H), 0.98 (m, 10 H).

A suspension of the product of Example 2B (10.71 g, 30.51 mmol) in glacial acetic acid (100 mL) and water (11 mL) at 0° C. was treated with chlorine gas for 10 min, stirred at 0° C. for 45 min, poured into a mixture of ice and water (500 mL), stirred for 30 min at 0° C. and then extracted with dichloromethane (2×). The combined organic layers were cooled to 0° C. and treated portionwise with 28% ammonium hydroxide solution (80 mL), stirred for 30 min, treated with water (120 mL) and the layers were separated. The organic layer was washed with 1M citric acid solution, water, and saturated sodium chloride solution, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was triturated with ether, collected by filtration and dried to give the title compound (7.26 g, 77%).1H NMR (300 MHz, DMSO-d6) : δ 8.01 (d, J=8.82 Hz, 1 H), 7.79 (s, 1 H), 7.63 (d, J=2.57 Hz, 1 H), 7.43 (m, 5 H), 5.28 (s, 2 H).

The title compound (4.3 g) was prepared following the procedure of Example 1D, substituting the product of Example 4C for the product of Example 1C.

Dimethyl trithiocarbonate (2.76 g, 20 mmol) was treated with dimethyl sulfate (2.5 g, 20 mmol) and stirred at 90° C. for 1 h, and cooled to 25° C. The solid was broken up under ether, collected by filtration, and washed with ether to give the title compound (5.1 g, 91%).

The title compound was prepared according to the procedure of Example 1D, substituting the product of Example 6C for the product of Example 1C.

A solution of methyl 2-phenylacetate (10.0 g, 66.7 mmol) and methyl iodide (10.4 mL, 167 mmol) in tetrahydrofuran (67 mL) at 0° C. was treated portionwise with sodium hydride (5.9 g of 60% in oil, 147 mmol), warmed to 25° C., stirred at 25° C. for 18 hours, cooled to 0° C. and quenched by addition of glatial acetic acid (2 mL). The mixture was concentrated in vacuo. A solution of the residue in ethyl acetate was washed with water, saturated sodium bicarbonate solution (2×) and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo to afforded an oil which was distilled (70-75° C./0.3 mm Hg) to afford the title compound (10 g, 85%).1H NMR (300 MHz, CDCl3): δ 7.27 (m, 5 H), 3.65 (s, 3 H), 1.60 (m, 6 H).

The title compound was prepared according to the procedure of Example 1C, substituting the product of Example 9A for the product of Example 1B.1H NMR (300 MHz, CDCl3): δ 7.33 (m, 5 H), 1.60 (s, 6 H).

The title compound was prepared according to the procedure of Example 1D, substituting the product of Example 9B for the product of Example 1C.

The title compound was prepared according to the procedure as described in Stanetty, P. et al.,J. Heterocyclic Chem.1999, 36, 761-765.

A solution of the product of Example 10C (4 g, 12.3 mmol) in dichloromethane (70 mL) and 1 N hydrochloric acid (35 mL) at 0° C. was treated with chlorine gas over a period of 0.5 hour, stirred at 0° C. for 1 h. The mixture was purged with nitrogen gas to remove excess chlorine and treated slowly with solid sodium bisulfite (11 g) over 5 minutes and diluted with dichloromethane and water. The organic layer was separated and eluted through 40 g of a 1:1 mixture of MgSO4/Na2SO4. The filtrate was concentrated in vacuo. A solution of the residue in dichloromethane (100 mL) at −40° C. was treated with ammonia gas over a period of 10 min, stirred for an additional 15 min, purged with nitrogen gas to expel the excess ammonia and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with methanol in dichloromethane to give the title compound (2.3 g, 66%).1H NMR (300 MHz, CDCl3): δ 7.88 (s, 1 H), 7.85 (m, 2 H), 4.73 (s, 2 H), 4.70 (s, 2 H), 3.31 (m, 3 H).

The title compound was prepared according to the procedure of Example 1D, substituting the compound of Example 14D for the compound of Example 1C. The compound was used directly in the next procedure.

The compound of Example 14F (6.0 g, 15.75 mmol) was dissolved in methanesulfonic acid (35 mL) and warmed at 50° C. for 5 h. The mixture was cooled and added to a mixture of ice and dichloromethane, followed by stirring until all ice had melted. The layers were separated and the aqueous phase was extracted again with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford an amber oil, which was dissolved in tetrahydrofuran (60 mL) and warmed at reflux with 1 N HCl solution (50 mL) for 18 h. The mixture was cooled and diluted with water and extracted with ethyl acetate. The organic layer was extracted with water and saturated NaCl solution. Drying (Na2SO4) and concentration in vacuo afforded a brown solid, which was triturated with ether-hexane and collected by filtration. These procedures afforded the title compound (2.89 g, 70%) as an off-white solid.1H NMR (300 MHz, DMSO-d6): δ 0.51 (m, 2 H) 0.64 (m, 6 H) 0.84 (m, 2 H) 1.84 (m, 2 H) 1.99 (m, 2 H) 5.80 (s, 1 H) 7.43 (m, 1 H) 7.57 (dd, J=9.56, 2.57 Hz, 1 H) 7.67 (d, J=5.52 Hz, 1 H) 11.75 (s, 1 H).

To a solution of thionyl chloride (240 mL) and 2-chloro-5-nitro-benzenesulfonic acid (104 g, 437.6 mmol) was added N,N-dimethylformamide (2 mL) and the reaction mixture was heated up to reflux for 4 hours. The reaction mixture was then carefully quenched into water and the product was isolated by filtration. The sulfonyl chloride 2 was then dissolved in toluene and added to a mixture of NH4OH (520 mL) and tetrahydrofuran (520 mL) at −10° C. After mixing for 1 h, the reaction was quenched by addition of 6 M HCl to a final pH of 4. The layers were separated and the organic layer was concentrated to a slush. Pentane was added and the product was isolated by filtration and dried to give the title compound (82.6 g, 80%).

A mixture of the product of Example 17A-1 (95 g, 401.5 mmol), ammonium carbonate (95 g, MW=96.07, 988.9 mmol), and CuSO4(18.91 g, MW=159.60, 118.5 mmol) in conc. aq. NH4OH solution (475 mL) was heated for four hours at 120° C. in a pressure reaction vessel. The mixture was then cooled to room temperature and the resulting solid was collected by filtration, washed with water and dried to give the title compound (66.3 g, 76% yield).

A mixture of the product of Example 17A-2 (50 g, 230 mmol), Ra—Ni (50 g), in THF (800 mL) and methanol (800 mL) was stirred at rt for 2 hours under H2pressure (40 psi). The mixture was then filtered and concentrated under reduced pressure to a smaller volume (about 80 mL). The solid was collected and washed with methyl tert-butyl ether (200 mL) and then dried under a vacuum to give the title compound (38.8 g, 90% yield).

To a suspension of Example 17A-3 158.9 g, 0.85 mol) in methanol (1120 mL) at 16° C. was added a solution of Boc anhydride (196.48 g, 0.90 mol) in methanol (470 mL). The solution was warmed to RT and mixed for 2 h then the reaction was quenched by addition of N,N-dimethylethylenediamine (14 mL). The solution was concentrated, chased with ethyl acetate then the product was isolated from ethyl acetate/heptane (1/1, 4 volumes) to give the title compound (201.7 g, 82.7%).

A solution of the product of Example 17D (28 mg, 0.042 mmol) in 2:1 methanol-ethyl acetate (15 mL) was treated with 10% Pd/C (20 mg) and hydrogenated at one atmosphere for 18 h. The mixture was filtered through celite® and the filtrate concentrated in vacuo to afford the title compound (13 mg).

The title compound was prepared according to the procedure of Example 1D, substituting the compound of Example 18C for the compound of Example 1C. The title compound was used directly in the next procedure.

A solution of the compound of Example 20B (65 mg, 0.11 mmol), acrylamide (9 mg, 0.12 mmol), triethylamine (45 μL, 0.33 mmol), and palladium (II) acetate (1.2 mg, 0.005 mmol) in N,N-dimethylformamide (1.5 mL) in a resealable pressure tube was degassed by evacuation and purging with nitrogen. The pressure tube was sealed and warmed at 100° C. for 1 h. The solution was cooled and diluted with ethyl acetate and water. The mixture was acidified by addition of citric acid solution (1 M, 2 mL). The organic layer was extracted with water (2×) and with saturated NaCl solution. Drying (Na2SO4) and concentration in vacuo afforded a solid, which was purified by flash chromatography eluting with methanol in dichloromethane. These procedures afforded the title compound (33 mg, 56%) as a light amber solid.

A solution of the compound of Example 14A (23.2 g, 0.138 mol) in dry tetrahydrofuran (30 mL) was added dropwise over 30 min to a −78° C. solution of lithium hexamethyldisilazide (prepared from hexamethyldisilazane (35 mL, 0.165 mol) and n-butyllithium in hexane (2.5 M, 58 mL, 0.145 mol)) in dry tetrahydrofuran (100 mL). The solution was stirred at −78° C. for 1 h, and then a large excess of methyl iodide was added. The solution was stirred at −78° C. for 30 min and was then warmed to ambient temperature for 18 h. The solution was quenched by addition of saturated ammonium chloride solution and diluted with water. The mixture was concentrated in vacuo to remove tetrahydrofuran and then extracted with ethyl acetate. The organic layer was extracted with water (2×) and saturated NaCl solution, followed by drying (Na2SO4) and concentration in vacuo. The residue was distilled under reduced pressure (70-75° C./0.5 mm Hg) to afford the title compound (21.9 g, 87%) as a colorless oil.1H NMR (300 MHz, CDCl3): δ 1.49 (d, J=7.35 Hz, 3 H) 3.70 (m, 4 H) 7.01 (m, 2 H) 7.27 (m, 2 H).

A solution of the compound of Example 22A (10.0 g, 55 mmol) in tetrahydrofuran (30 mL) was added dropwise over 30 min to a −78° C. solution of lithium hexamethyldisilazide (prepared from hexamethyldisilazane (14.5 mL, 68.7 mmol) and n-butyllithium in hexane (2.5 M, 26.4 mL, 65.9 mmol)). The solution was stirred at −78° C. for 1 h. The solution was then treated with neat isoamyl bromide (9.9 mL, 82.4 mmol) followed by stirring at −78° C. for 30 min, and then warming to ambient temperature for 48 h. The solution was quenched by addition of saturated ammonium chloride solution (6 mL) and diluted with water. The mixture was concentrated in vacuo to remove tetrahydrofuran, and then extracted with ethyl acetate. The organic layer was extracted with water (2×) and saturated NaCl solution. Drying (Na2SO4) and concentration in vacuo afforded a brown oil, which was distilled under reduced pressure (90-93° C./0.3 mm Hg) to afford the title compound (11.8 g, 85%) as a colorless oil.1H NMR (300 MHz, CDCl3): δ 0.87 (m, 6 H) 1.03 (m, 2 H) 1.51 (m, 4 H) 1.95 (m, 2 H) 3.65 (s, 3 H) 7.01 (m, 2 H) 7.28 (m, 2 H).

The title compound was prepared according to the procedure of Example 1D, substituting the compound of Example 22E for the compound of Example 1C.

The title compound was prepared according to the procedure of Example 1D, substituting the compound of Example 23B for the compound of Example 1C.

A solution of the compound of Example 22A (11.75 g, 64.6 mmol) in tetrahydrofuran (30 mL) was added dropwise over 20 min to a −78° C. solution of lithium hexamethyldisilazide (previously prepared from hexamethyldisilazane (17.0 mL, 80.7 mmol) and n-butyllithium in hexane (2.5 M, 31.0 mL, 77.5 mmol)) in tetrahydrofuran (40 mL) and allowed to stir at that temperature for 1 h. The solution was then treated with 1-bromo-3,3-dimethylbutane (12.0 mL, 83.9 mmol), followed by stirring at −78° C. for 30 min, and then warming to 25° C. for 18 h. The solution was quenched by addition of saturated ammonium chloride solution (4 mL) and then concentrated in vacuo. The residue was diluted with ethyl acetate and water. The organic layer was extracted with water (2×), saturated NaCl solution and dried (Na2SO4). Concentration in vacuo afforded an oil, which was distilled under reduced pressure (90-93° C./0.3 mm Hg) to afford the product (4.85 g, 28%) as a colorless oil.1H NMR (300 MHz, CDCl3): δ 0.86 (s, 9 H) 1.03 (m, 2 H) 1.51 (m, 3 H) 1.86 (m, 1 H) 2.00 (m, 1 H) 3.65 (m, 3 H) 7.03 (m, 2 H) 7.27(m, 2 H).

The title compound was prepared according to the procedure of Example 1D, substituting the compound of Example 24D for the compound of Example 1C.

The title compound was prepared according to the procedure of Example 1D, substituting the compound of Example 25B for the compound of Example 1C.

The title compound was prepared according to the procedure of Example 13C, substituting the compound of Example 25F for the compound of Example 13B.

The title compound was prepared according to the procedure of Example 1I, substituting the compound of Example 25G for the compound of Example 1H.

A solution of 2-phenyl-propionic acid benzyl ester (2.0 g, 8.32 mmol), allyl bromide (0.865 mL, 9.99 mmol), and lithium iodide (1 g) in tetrahydrofuran (15 mL) at 0° C. was treated dropwise with the lithium hexamethyldisilazide (9.99 mL, 1M in tetrahydrofuran, 9.99 mmol). The reaction was allowed to warm to 25° C. and stirred for 18 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the ethyl acetate layers were combined, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 10% ethyl acetate in hexane, and 20% ethyl acetate in hexane to give the title compound (2.31 g, 99%).1H NMR (300 MHz, CDCl3): δ ppm 1.56 (m, 3 H) 2.68 (m, 1 H) 2.85 (m, 1 H) 5.05 (m, 4 H) 5.59 (m, 1 H) 7.26 (m, 10 H).

A solution of diethyl malonate (1.27 mL, 8.36 mmol) in acetonitrile (15 mL) was cooled to 0° C. and treated with magnesium chloride (0.796 g, 8.36 mmol) followed by dropwise addition of triethylamine (2.45 mL, 17.6 mmol). The solution was stirred at 0° C. for 15 minutes and then stirred at 25° C. for 2 hours. A solution of 2-methyl-2-phenyl-pentanoic acid (1.61 g, 8.36 mmol) and dimethylformamide (0.712 mL, 9.20 mmol) in hexane (350 mL) was treated with oxalyl chloride (2.19 mL, 25.1 mmol) and stirred at 25° C. for 2 hours. The hexane supernatant was decanted from the residue, filtered through celite, and concentrated in vacuo to give the acid chloride. The resulting acid chloride was dissolved in acetonitrile (10 mL) and added dropwise to the magnesium malonate solution stirring at 0° C. The reaction was stirred at 50° C. for 18 hours, cooled, and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1N hydrochloric acid solution. The aqueous phase was extracted three times with ethyl acetate, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 10% ethyl acetate in hexane, and 20% ethyl acetate in hexane to give the title compound (2.45 g, 87%).1H NMR (300 MHz, CDCl3): δ ppm 0.89 (m, 3 H) 1.02 (m, 2 H) 1.18 (m, 6 H) 1.53 (m, 3 H) 1.94 (m, 2 H) 4.08 (m, 4 H) 4.51 (m, 1 H) 7.34 (m, 5 H). MS (ESI+) m/z 352 (M+NH4)+.

A solution of 2-phenyl-propionic acid benzyl ester (2.0 g, 8.32 mmol), crotyl chloride (1.02 mL, 9.99 mmol), and lithium iodide (1 g) in tetrahydrofuran (15 mL) at 0° C. was treated dropwise with the lithium hexamethyldisilazide (9.99 mL, 1M in tetrahydrofuran, 9.99 mmol). The reaction was allowed to warm to 25° C. and stirred for 18 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the ethyl acetate layers were combined, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 10% ethyl acetate in hexane, and 20% ethyl acetate in hexane to give the title compound (2.43 g, 99%).1H NMR (300 MHz, CDCl3): δ ppm 1.55 (m, 6 H) 2.68 (m, 2 H) 5.10 (m, 2 H) 5.21 (m, 1 H) 5.45 (m, 1 H) 7.26 (m, 10 H). MS (ESI+) m/z 312 (M+NH4)+.

A solution of diethyl malonate (1.27 mL, 8.34 mmol) in acetonitrile (15 mL) was cooled to 0° C. and treated with magnesium chloride (0.794 g, 8.34 mmol) followed by dropwise addition of triethylamine (2.44 mL, 17.6 mmol). The solution was stirred at 0° C. for 15 minutes and then stirred at 25° C. for 2 hours. A solution of Example 27B (1.72 g, 8.34 mmol) and dimethylformamide (0.710 mL, 9.17 mmol) in hexane (350 mL) was treated with oxalyl chloride (2.18 mL, 25.0 mmol) and stirred at 25° C. for 2 hours. The hexane supernatant was decanted from the residue, filtered through celite, and concentrated in vacuo to give the acid chloride. The resulting acid chloride was dissolved in acetonitrile (10 mL) and added dropwise to the magnesium malonate solution stirring at 0° C. The reaction was stirred at 50° C. for 18 hours, cooled, and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1N hydrochloric acid solution. The aqueous phase was extracted three times with ethyl acetate, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 10% ethyl acetate in hexane, and 20% ethyl acetate in hexane to give the title compound (2.59 g, 89%).1H NMR (300 MHz, CDCl3): δ ppm 0.85 (m, 3 H) 1.23 (m, 10 H) 1.53 (m, 3 H) 1.96 (m, 2 H) 4.08 (m, 4 H) 4.51 (m, 1 H) 7.32 (m, 5 H). MS (ESI−) m/z 347 (M−H)−.

A solution of diethyl malonate (1.16 mL, 7.66 mmol) in acetonitrile (15 mL) was cooled to 0° C. and treated with magnesium chloride (0.730 g, 7.66 mmol) followed by dropwise addition of triethylamine (2.24 mL, 16.1 mmol). The solution was stirred at 0° C. for 15 minutes and then stirred at 25° C. for 2 hours. A solution of Example 28B (1.69 g, 7.66 mmol) and dimethylformamide (0.653 mL, 8.43 mmol) in hexane (350 mL) was treated with oxalyl chloride (2.01 mL, 23.0 mmol) and stirred at 25° C. for 2 hours. The hexane supernatant was decanted from the residue, filtered through celite, and concentrated in vacuo to give the acid chloride. The resulting acid chloride was dissolved in acetonitrile (10 mL) and added dropwise to the magnesium malonate solution stirring at 0° C. The reaction was stirred at 50° C. for 18 hours, cooled, and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1N hydrochloric acid solution. The aqueous phase was extracted three times with ethyl acetate, dried with sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a crude product (2.78 g).1H NMR (300 MHz, CDCl3): δ ppm 0.84 (m, 6 H) 1.13 (m, 8 H) 1.50 (m, 4 H) 1.97 (m, 2 H) 4.08 (m, 4 H) 4.51 (m, 1 H) 7.32 (m, 5 H).

A solution of Example 32B (0.050 g, 0.112 mmol), mesyl chloride (0.035 mL, 0.447 mmol), and pyridine (0.073 mL, 0.893 mmol) in acetone (1.5 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.049 g, 89%).

A solution of Example 33B (0.052 g, 0.112 mmol), mesyl chloride (0.035 mL, 0.447 mmol), and pyridine (0.073 mL, 0.893 mmol) in acetone (1.5 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.054 g, 96%).

A solution of 3,3-dimethylbutyraldehyde (5.0 mL, 39.8 mmol) in tetrahydrofuran (30 mL) was added dropwise to a solution of vinylmagnesium bromide (47.8 mL, 1M in tetrahydrofuran, 47.8 mmol) stirring at −20° C. The solution was stirred for 30 minutes at −20° C. at which time saturated ammonium chloride solution (75 mL) was added and the reaction was allowed to warm to 25° C. The solution was diluted with water and extracted three times with ethyl acetate. The ethyl acetate layers were combined and washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, followed by 5% and 10% ethyl acetate in hexane to give the title compound (0.780 g, 15%).1H NMR (300 MHz, CDCl3): δ ppm 0.98 (m, 9 H) 1.45 (m, 2 H) 4.26 (m, 1 H) 5.06 (m, 1 H) 5.21 (m, 1 H) 5.90 (m, 1 H).

A solution of 2-phenyl-propionic acid benzyl ester (3.15 g, 13.1 mmol) in tetrahydrofuran (25 mL) at −78° C. was treated dropwise with a lithium hexamethyldisilazide solution (14.4 mL, 1M in tetrahydrofuran, 14.4 mmol) and stirred for 30 minutes at −78° C. Example 35B (3.26 g, 17.0 mmol) was added to the solution and the reaction was allowed to warm to 25° C. and stirred for an additional 4 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the ethyl acetate layers were combined, washed with a saturated sodium bicarbonate solution, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 5% ethyl acetate in hexane, and 10% ethyl acetate in hexane to give the title compound (3.32 g, 72%).1H NMR (300 MHz, CDCl3): δ ppm 0.80 (m, 9 H) 1.53 (m, 3 H) 1.79 (m, 2H) 2.63 (m, 1 H) 2.82 (m, 1 H) 5.10 (m, 2 H) 5.18 (m, 1 H) 5.47 (m, 1 H) 7.27 (m, 10 H). MS (ESI+) m/z 368 (M+NH4)+.

A solution of Example 35C (3.32 g, 9.47 mmol) in ethyl acetate (50 mL) was treated with 10% palladium on carbon (0.332 g, 10 weight percent) and stirred under a hydrogen balloon for 72 hours. The vessel was purged with nitrogen gas and the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give the title compound (2.48 g, 99%).1H NMR (300 MHz, CDCl3): δ ppm 0.84 (m, 9 H) 1.19 (m, 6 H) 1.57 (m, 3 H) 1.98 (m, 2 H) 7.34 (m, 5 H).

A solution of diethyl malonate (1.53 mL, 9.95 mmol) in acetonitrile (20 mL) was cooled to 0° C. and treated with magnesium chloride (0.966 g, 9.95 mmol) followed by dropwise addition of triethylamine (2.91 mL, 20.9 mmol). The solution was stirred at 0° C. for 15 minutes and then stirred at 25° C. for 2 hours.

A solution of Example 35D (2.61 g, 9.95 mmol) and dimethylformamide (0.85 mL, 10.9 mmol) in hexane (475 mL) was treated with oxalyl chloride (2.65 mL, 29.8 mmol) and stirred at 25° C. for 2 hours. The hexane supernatant was decanted from the residue, filtered through celite, and concentrated in vacuo to give the acid chloride.

The resulting acid chloride was dissolved in acetonitrile (10 mL) and added dropwise to the magnesium malonate solution stirring at 0° C. The reaction was stirred at 50° C. for 18 hours, cooled, and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1N hydrochloric acid solution. The aqueous phase was extracted three times with ethyl acetate, dried with sodium sulfate, filtered, and concentrated in vacuo to give the desired product which was taken onto the next reaction without further purification (4.01 g, 99%).

A solution of cyclohexanecarbaldehyde (4.79 mL, 39.8 mmol) in tetrahydrofuran (30 mL) was added dropwise to a solution of vinylmagnesium bromide (47.8 mL, 1M in tetrahydrofuran, 47.8 mmol) stirring at −20° C. The solution was stirred for 30 minutes at −20° C. at which time saturated ammonium chloride solution (75 mL) was added and the reaction was allowed to warm to 25° C. The solution was diluted with water and extracted three times with ethyl acetate. The ethyl acetate layers were combined and washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, followed by 5% and 10% ethyl acetate in hexane to give the title compound (2.11 g, 38%).1H NMR (300 MHz, CDCl3): δ ppm 1.40 m, 11 H) 3.85 (m, 1 H) 5.17 m, 2 H) 5.86 m, 1 H).

A solution of Example 36B (3.15 g, 13.1 mmol) in tetrahydrofuran (25 mL) at −78° C. was treated dropwise with a lithium hexamethyldisilazide solution (14.4 mL, 1M in tetrahydrofuran, 14.4 mmol) and stirred for 30 minutes at −78° C. (3-bromo-propenyl)-cyclohexane (3.46 g, 17.0 mmol) was added to the solution and the reaction was allowed to warm to 25° C. and stirred for an additional 4 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the ethyl acetate layers were combined, washed with a saturated sodium bicarbonate solution, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 5% ethyl acetate in hexane, and 10% ethyl acetate in hexane to give the title compound (3.52 g, 74%).1H NMR (300 MHz, CDCl3): δ ppm 1.09 m, 6 H) 1.50 (m, 3 H) 1.64 (m, 5H) 2.56 m, 1 H) 2.78 m, 1 H) 5.14 m, 3 H) 5.38 m, 1 H) 7.27 (m, 10 H). MS (ESI+) m/z 380 (M+NH4)+.

A solution of Example 36C (3.52 g, 9.71 mmol) in ethyl acetate (50 mL) was treated with 10% palladium on carbon (0.352 g, 10 weight percent) and stirred under a hydrogen balloon for 72 hours. The vessel was purged with nitrogen gas and the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give the title compound (2.79 g, 99%).

A solution of diethyl malonate (1.54 mL, 10.2 mmol) in acetonitrile (20 mL) was cooled to 0° C. and treated with magnesium chloride (0.968 g, 10.2 mmol) followed by dropwise addition of triethylamine (2.98 mL, 21.4 mmol). The solution was stirred at 0° C. for 15 minutes and then stirred at 25° C. for 2 hours.

A solution of Example 36D (2.79 g, 10.2 mmol) and dimethylformamide (0.87 mL, 11.2 mmol) in hexane (475 mL) was treated with oxalyl chloride (2.66 mL, 30.5 mmol) and stirred at 25° C. for 2 hours. The hexane supernatant was decanted from the residue, filtered through celite, and concentrated in vacuo to give the acid chloride.

The resulting acid chloride was dissolved in acetonitrile (10 mL) and added dropwise to the magnesium malonate solution stirring at 0° C. The reaction was stirred at 50° C. for 18 hours, cooled, and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1N hydrochloric acid solution. The aqueous phase was extracted three times with ethyl acetate, dried with sodium sulfate, filtered, and concentrated in vacuo to give the desired product which was taken onto the next reaction without further purification (4.01 g, 95%).

A solution of Example 36F (2.14 g, 5.78 mmol) in 1,4-dioxane (20 mL) was treated with aqueous 1N hydrochloric acid solution (20 mL) and refluxed for 3 hours. The mixture was cooled to 25° C. and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated in hot hexane and filtered. The precipitate was dried to give the title compound (0.513 g, 30%).

A solution of Example 37A (0.775 g, 1.33 mmol) in 4M hydrochloric acid in 1,4-dioxane (10 mL) was stirred at 25° C. for 1 hour. The solution was concentrated in vacuo and the residue was triturated in diethyl ether to give the title compound (0.374 g, 54%).

A solution of Example 37B (0.374 g, 0.722 mmol), mesyl chloride (0.224 mL, 2.89 mmol), and pyridine (0.467 mL, 5.78 mmol) in acetone (15 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.302 g, 75%).

A solution of Example 38A (0.570 g, 0.960 mmol) in 4M hydrochloric acid in 1,4-dioxane (10 mL) was stirred at 25° C. for 1 hour. The solution was concentrated in vacuo and the residue was triturated in diethyl ether to give the title compound (0.357 g, 70%).

A solution of Example 38B (0.357 g, 0.674 mmol), mesyl chloride (0.209 mL, 2.69 mmol), and pyridine (0.436 mL, 5.39 mmol) in acetone (15 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.339 g, 88%).

To a solution of Example 39A (4.26 g, 12.55 mmol) in 1,4-dioxane (15 mL) was added 4M sulfuric acid (15 mL) and the reaction was stirred at reflux for 48 hours. The solution was concentrated in vacuo and partitioned between water and methylene chloride. The methylene chloride layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, 10% ethyl acetate in hexane, and 20% ethyl acetate in hexane to give the title compound (2.70 g, 97%).1H NMR (300 MHz, CDCl3): δ ppm 0.88 m, 6 H) 1.09 m, 2 H) 1.52 m, 4 H) 1.99 m, 2 H) 7.35 m, 5 H).

A solution of diethyl malonate (1.77 mL, 11.7 mmol) in acetonitrile (20 mL) was cooled to 0° C. and treated with magnesium chloride (1.11 g, 11.7 mmol) followed by dropwise addition of triethylamine (3.41 mL, 24.5 mmol). The solution was stirred at 0° C. for 15 minutes and then stirred at 25° C. for 2 hours. A solution of Example 39B (2.57 g, 11.7 mmol) and dimethylformamide (0.993 mL, 12.8 mmol) in hexane (400 mL) was treated with oxalyl chloride (3.06 mL, 35.0 mmol) and stirred at 25° C. for 2 hours. The hexane supernatant was decanted from the residue, filtered through celite, and concentrated in vacuo to give the acid chloride. The resulting acid chloride was dissolved in acetonitrile (10 mL) and added dropwise to the magnesium malonate solution stirring at 0° C. The reaction was stirred at 50° C. for 18 hours, cooled, and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1N hydrochloric acid solution. The aqueous phase was extracted three times with ethyl acetate, dried with sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a crude product (4.23 g, 99%).1H NMR (300 MHz, CDCl3): δ ppm 0.84 m, 6 H) 1.13 m, 8 H) 1.50 m, 4 H) 1.97 m, 2 H) 4.08 m, 4 H) 4.51 m, 1 H) 7.32 m, 5 H).

To a solution of lithium bis(trimethylsilyl)amide (278.57 g, 1.66 mol) in tetrahydrofuran (700 mL) was added 2-phenyl propionic acid (100.0 g, 0.666 mol) over 40 minutes maintaining the temperature below 15° C. The solution was warmed 40-45° C. for 20 minutes, then cooled below 25° C. and 1-bromo-3-methylbutane (156.0 g, 1.03 mol) was added. The reaction mixture was heated to 50° C. for 10 h, then was cooled to RT, and concentrated to a thick sludge. Methyl tert-butyl ether (900 mL) and water (1100 mL) were added, and the layers were separated. The organic phase was extracted with H2O (200 mL). The combined aqueous phases were treated with 3 M HCl (520 mL) to adjust the pH to approximately 2. The product was extracted with ethyl acetate (1000 mL) and the organic layer was concentrated to a thick oil to give the title compound. The crude oil (assayed for 136.99 g of Example 39-1, 95.3% assay yield) was used directly.

The product of Example 39-1 (136.99 g, 0.622 mol) was dissolved in ethyl acetate (2055 mL). To this solution was added (S)-α-methyl benzylamine (44.47 g, 0.375 mol). A white solid precipitated and the slurry was mixed for 19 h at RT. The product was isolated by filtration and the wet cake was dried under vacuum at ambient temperature to give 74.32 g of white solid. This solid was heated with ethyl acetate (1115 mL) to 73° C. to give a clear solution, which was cooled slowly to room temperature and a white solid precipitated. After mixing for 18 h at RT, the product was isolated by filtration and the product was dried to give the title compound (65.11 g, 30.7% 97.3% ee measured using the following conditions: Column: ChiralPak, AD-RH; mobile phase: acetonitrile (60%)/H2O (40%), trifluoroacetic acid (0.06%); column temp: ambient; flow rate: 0.8 mL/min; and λ: 220 nm).

A suspension of acid-amine salt of Example 39-2 (532.0 g, 1.56 mol) in ethyl acetate (3350 mL) was treated with water (1500 mL) then enough 3 M HCl to bring the pH to <2. The solution was mixed and the layers were separated. The organic phase was concentrated to thick oil. The oil was dissolved in heptane (500 mL) and concentrated then redissolved in heptane (1700 mL). To this solution was added N,N-dimethylformamide (10.3 g, 0.141 mol) and oxalyl chloride (312.2 g, 2.46 mol). The solution was mixed at RT overnight, filtered through celite and concentrated to a residue. The crude acid chloride was dissolved in acetonitrile (300 mL) and concentrated to a residue then dissolved in acetonitrile (240 mL). To a separate vessel containing a 0° C. solution of diethyl malonate (254.0 g, 1.59 mol), and MgCl2(151.0 g, 1.59 mol) in acetonitrile (2.2 L) was added triethylamine (320.8 g, 3.17 mol). The solution was warmed to RT and mixed for 1 h, then cooled back to 0-10° C. The acid chloride/CH3CN solution was added over 30 minutes and the reaction mixture was heated to 50° C. for 3 h. The reaction mixture was cooled and concentrated to a thick sludge. Ethyl acetate (2400 mL) and water (2400 mL) were added and the pH was adjusted to 6 with concentrated HCl. The layers were separated and the organic solution was washed with 10% NaCl. The organic layer was concentrated to a thick oil then chased with heptane (400 mL). The crude oil was used directly (assayed for 565.7 g, 100%).

To the crude diester of Example 39-4 (565.7 g, 1.56 mol) at 10-15° C. was added methanesulfonic acid (1715 mL). The solution was warmed to 30° C. and mixed for 24 h. The reaction mixture was slowly quenched into a mixture of H2O (2240 mL) and ethyl acetate (3.24 mL) at 5° C. The layers were separated and the organic layer was washed with 10% NaCl. The solution was concentrated and the resulting oil was dissolved in toluene (1330 mL). The crude product of Example 39-4/toluene solution (assayed for 454.14 g of Example 39-4, 92%) was used directly.

To a solution of the product of Example 39-4 (320 g, 1.01 mol) in toluene (1100 mL) was added product of Example 17A-4 (291 g, 1.01 mol). The solution was heated to 100° C. for 4 h then cooled to RT. The solution was transferred to a pressure bottle and triethylamine (472, 4.66 mol) was added and the solution was heated to 100° C. for 26 h. The solution was concentrated to ⅓ of the original volume and ethyl acetate (2000 mL) was added. The organic layer was washed with 10% KH2PO4and 10% NaCl then concentrated to a thick oil then chased with CH2Cl2. The crude product of Example 39-5 (assay for 406.5 g, 74.5%) was used directly.

To a solution of the product of Example 39-5 (407 g, 0.754 mol) in dichloromethane (550 mL) was added 4 M HCl in dioxane (760 mL, 3.04 mol) and the solution was mixed at RT for 3.5 h. The reaction was quenched by addition of ethyl acetate (1.5 L) and pH 7 phosphate buffer (1.7 L) and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (400 mL) and the combined organic layers were concentrated and chased with ethanol to a final volume of approximately 2500 mL. The product precipitated and was isolated by filtration and dried to give the title compound (309.7 g, 93.4%).

To a solution of the product of Example 39-6 (310 g, 0.705 mol) and pyridine (167.6 g, 2.12 mol) in dichloromethane (1645 mL) at 18-20° C. was added methanesulfonyl chloride (121.1 g, 1.06 mol) over 45 minutes. The solution was mixed at RT for 16 h then quenched with 1 M HCl (2000 mL). The layers were separated and the organic layer was concentrated under vacuum. The product was crystallized from ethyl acetate/heptane (1/1, 8 volumes) to give the title compound (236.0 g, 65%).

A solution of 7.54 M NaOH (20.2 mL, 0.152 mol) was added over 5 minutes to a solution of the product of Example 39-7 (71.72 g, 0.139 mol) in ethanol (1450 mL) at 30-35° C. The product precipitated and the slurry was cooled slowly to RT and the product was isolated by filtration and dried to give the title compound (62.24 g, 83%).

To a solution of Example 40A (4.26 g, 12.55 mmol) in 1,4-dioxane (15 mL) was added 4M sulfuric acid (15 mL) and the reaction was stirred at reflux for 48 hours. The solution was concentrated in vacuo and partitioned between water and methylene chloride. The methylene chloride layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, 10% ethyl acetate in hexane, and 20% ethyl acetate in hexane to give the title compound (2.02 g, 73%).1H NMR (300 MHz, CDCl3): δ ppm 0.88 m, 6 H) 1.09 m, 2 H) 1.52 m, 4 H) 1.99 m, 2 H) 7.35 m, 5 H).

A solution of diethyl malonate (1.41 mL, 9.17 mmol) in acetonitrile (20 mL) was cooled to 0° C. and treated with magnesium chloride (0.891 g, 9.17 mmol) followed by dropwise addition of triethylamine (2.68 mL, 19.3 mmol). The solution was stirred at 0° C. for 15 minutes and then stirred at 250C for 2 hours. A solution of Example 40B (2.02 g, 9.17 mmol) and dimethylformamide (0.781 mL, 10.1 mmol) in hexane (400 mL) was treated with oxalyl chloride (2.45 mL, 27.5 mmol) and stirred at 25° C. for 2 hours. The hexane supernatant was decanted from the residue, filtered through celite, and concentrated in vacuo to give the acid chloride. The resulting acid chloride was dissolved in acetonitrile (10 mL) and added dropwise to the magnesium malonate solution stirring at 0° C. The reaction was stirred at 50° C. for 18 hours, cooled, and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1N hydrochloric acid solution. The aqueous phase was extracted three times with ethyl acetate, dried with sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a crude product (3.31 g, 99%).1H NMR (300 MHz, CDCl3): δ ppm 0.84 m, 6 H) 1.13 m, 8 H) 1.50 m, 4 H) 1.97 m, 2 H) 4.08 m, 4 H) 4.51 m, 1 H) 7.32 m, 5 H).

A solution of 2-phenyl-propionic acid methyl ester (3.0 g, 18.27 mmol) in tetrahydrofuran (25 mL) at −78° C. was treated dropwise with the lithium hexamethyldisilazide (21.9 mL, 1M in tetrahydrofuran, 21.9 mmol) and stirred for 1 hour. Bromomethyl-cyclohexane (3.09 mL, 21.92 mmol) was added to the reaction and the reaction was allowed to warm to 25° C. and stirred for 18 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the ethyl acetate layers were combined, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 2.5% ethyl acetate in hexane, and 5% ethyl acetate in hexane to give the title compound (4.02 g, 84%).1H NMR (300 MHz, CDCl3): δ ppm 1.11 m, 10 H) 1.55 m, 4 H) 1.80 m, 1 H) 2.04 m, 1 H) 3.64 m, 3 H) 7.29 (m, 5 H).

A solution of Example 41A (4.02 g, 15.4 mmol) and potassium trimethyl silanolate (11.0 g, 77.2 mmol) in tetrahydrofuran (80 mL) was heated to reflux for 18 hours. The mixture was cooled to 25° C., treated with water (10 mL), and concentrated in vacuo to remove the tetrahydrofuran. The residue was dissolved in water and washed with hexane. The aqueous layer was acidified to pH 1 with 1N hydrochloric acid and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to give the title compound (3.80 g, 99%).1H NMR (300 MHz, CDCl3): δ ppm 1.10 m, 6 H) 1.57 m, 8 H) 1.82 m, 1 H) 2.04 m, 1 H) 7.32 m, 5 H).

A solution of diethyl malonate (2.37 mL, 15.4 mmol) in acetonitrile (25 mL) was cooled to 0° C. and treated with magnesium chloride (1.50 g, 15.4 mmol) followed by dropwise addition of triethylamine (4.51 mL, 32.4 mmol). The solution was stirred at 0° C. for 15 minutes and then stirred at 25° C. for 2 hours. A solution of Example 41B (3.80 g, 15.4 mmol) and dimethylformamide (1.31 mL, 17.0 mmol) in hexane (600 mL) was treated with oxalyl chloride (4.12 mL, 46.3 mmol) and stirred at 25° C. for 2 hours. The hexane supernatant was decanted from the residue, filtered through celite, and concentrated in vacuo to give the acid chloride. The resulting acid chloride was dissolved in acetonitrile (10 mL) and added dropwise to the magnesium malonate solution stirring at 0° C. The reaction was stirred at 50° C. for 18 hours, cooled, and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1N hydrochloric acid solution. The aqueous phase was extracted three times with ethyl acetate, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 10% ethyl acetate in hexane, and 20% ethyl acetate in hexane to give the title compound (5.94 g, 99%).1H NMR (300 MHz, CDCl3): δ ppm 0.74 m, 1 H) 1.12 m, 11 H) 1.57 m, 8 H) 1.88 (m, 2 H) 4.10 (m, 4 H) 4.49 m, 1 H) 7.31 m, 5 H).

Lithium bis(trimethylsilyl)amide (32.3 g, 193 mmol) was added to 80 mL of tetrahydrofuran and the resulting solution was cooled in an ice bath. Addition of a solution of 2-phenyl-propionic acid (11.6 g, 77.3 mmol) in 10 mL of tetrahydrofuran to the reaction solution was followed by addition of 1-bromo-3,3-dimethyl-butane (20.4 g, 124 mmol). The reaction vessel was removed from the cooling bath, placed in a 50° C. oil bath, and the reaction solution was stirred for 17 hours. After concentration, the resulting residue was dissolved in 250 mL of 1 N NaOH, washed with 250 mL of 2:1 hexane/iso-propyl acetate, acidified to pH 1 with 6 N HCl, and extracted with ethyl acetate (3×300 mL). The combined organic layers were dried over Na2SO4and concentrated to give 17.3 g (96%) of clear oil.1H NMR (300 MHz, CDCl3): δ ppm 0.86 (s, 9 H) 1.09 m, 2 H) 1.56 (s, 3 H) 1.99 m, 2 H) 7.33 m, 5 H).

A solution of diethyl malonate (1.53 mL, 10.1 mmol) in acetonitrile (25 mL) was cooled to 0° C. and treated with magnesium chloride (0.961 g, 10.1 mmol) followed by dropwise addition of triethylamine (2.95 mL, 21.2 mmol). The solution was stirred at 0° C. for 15 minutes and then stirred at 25° C. for 2 hours. A solution of Example 42A (2.37 g, 10.1 mmol) and dimethylformamide (0.783 mL, 10.1 mmol) in hexane (350 mL) was treated with oxalyl chloride (2.65 mL, 30.3 mmol) and stirred at 25° C. for 2 hours. The hexane supernatant was decanted from the residue, filtered through celite, and concentrated in vacuo to give the acid chloride. The resulting acid chloride was dissolved in acetonitrile (10 mL) and added dropwise to the magnesium malonate solution stirring at 0° C. The reaction was stirred at 50° C. for 18 hours, cooled, and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1 N hydrochloric acid solution. The aqueous phase was extracted three times with ethyl acetate, dried with sodium sulfate, filtered, and concentrated in vacuo to give a clear oil.

A solution of Example 42F (0.250 g, 0.510 mmol), mesyl chloride (0.158 mL, 2.04 mmol), and pyridine (0.330 mL, 4.08 mmol) in acetone (3 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give a yellow solid.

Lithium bis(trimethylsilyl)amide (3.23 g, 19.3 mmol) was added to 8 mL of tetrahydrofuran and the resulting solution was cooled in an ice bath. Addition of a solution of 2-phenyl-propionic acid (1.16 g, 7.73 mmol) in 1 mL of tetrahydrofuran to the reaction solution was followed by addition of (S)-1-bromo-3-methyl-pentane (2.05 g, 12.4 mmol). The reaction vessel was removed from the cooling bath, placed in a 50° C. oil bath, and the reaction solution was stirred for 17 hours. After concentration, the resulting residue was dissolved in 25 mL of 1 N NaOH, washed with 25 mL of 2:1 hexane/iso-propyl acetate, acidified to pH 1 with 6 N HCl, and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over Na2SO4and concentrated to give 1.63 g (90%) of a clear oil.1H NMR (300 MHz, CDCl3): δ ppm 0.83 m, 6 H) 1.20 m, 5 H) 1.57 (s, 3 H) 1.98 m, 2 H) 7.35 m, 5 H).

A solution of diethyl malonate (0.525 mL, 3.46 mmol) in acetonitrile (10 mL) was cooled to 0° C. and treated with magnesium chloride (0.329 g, 3.46 mmol) followed by dropwise addition of triethylamine (1.01 mL, 7.26 mmol). The solution was stirred at 0° C. for 15 minutes and then stirred at 25° C. for 2 hours. A solution of Example 43A (0.810 g, 3.46 mmol) and dimethylformamide (0.268 mL, 3.46 mmol) in hexane (30 mL) was treated with oxalyl chloride (0.905 mL, 10.4 mmol) and stirred at 25° C. for 2 hours. The hexane supernatant was decanted from the residue, filtered through celite, and concentrated in vacuo to give the acid chloride. The resulting acid chloride was dissolved in acetonitrile (5 mL) and added dropwise to the magnesium malonate solution stirring at 0° C. The reaction was stirred at 50° C. for 18 hours, cooled, and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1 N hydrochloric acid solution. The aqueous phase was extracted three times with ethyl acetate, dried with sodium sulfate, filtered, and concentrated in vacuo to give a clear oil.

A solution of Example 43F (0.119 g, 0.240 mmol), mesyl chloride (0.075 mL, 0.970 mmol), and pyridine (0.157 mL, 1.94 mmol) in acetone (3 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give a yellow solid.

A solution of Example 42A (8.42 g, 35.9 mmol) and dimethylformamide (2.78 mL, 35.9 mmol) in hexane (500 mL) was treated with oxalyl chloride (9.40 mL, 108 mmol) and stirred at 25° C. for 2 hours. The mixture was filtered through celite and the filtrate was concentrated in vacuo to give the acid chloride residue.

To a solution of Example 48A (4.48 g, 12.7 mmol) in 1,4-dioxane (60 mL) was added 4 M sulfuric acid (60 mL) and the reaction was stirred at reflux for 48 hours. The solution was concentrated in vacuo, dissolved in 1 N NaOH (250 mL), and washed with hexane (200 mL). The aqueous layer was acidified to pH 1 with 6 N HCl and extracted with ethyl acetate (3×200 mL). The combined ethyl acetate layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give a clear oil (2.66 g, 90%).1H NMR (300 MHz, CDCl3): δ ppm 0.86 (s, 9 H) 1.09 m, 2 H) 1.56 (s, 3 H) 1.99 m, 2 H) 7.33 m, 5 H).

A solution of diethyl malonate (1.53 mL, 10.1 mmol) in acetonitrile (25 mL) was cooled to 0° C. and treated with magnesium chloride (0.961 g, 10.1 mmol) followed by dropwise addition of triethylamine (2.95 mL, 21.2 mmol). The solution was stirred at 0° C. for 15 minutes and then stirred at 25° C. for 2 hours. A solution of Example 48B (2.37 g, 10.1 mmol) and dimethylformamide (0.783 mL, 10.1 mmol) in hexane (350 mL) was treated with oxalyl chloride (2.65 mL, 30.3 mmol) and stirred at 25° C. for 2 hours. The hexane supernatant was decanted from the residue, filtered through celite, and concentrated in vacuo to give the acid chloride. The resulting acid chloride was dissolved in acetonitrile (10 mL) and added dropwise to the magnesium malonate solution stirring at 0° C. The reaction was stirred at 50° C. for 18 hours, cooled, and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1 N hydrochloric acid solution. The aqueous phase was extracted three times with ethyl acetate, dried with sodium sulfate, filtered, and concentrated in vacuo to give a clear oil.

A solution of Example 48G (0.250 g, 0.510 mmol), mesyl chloride (0.158 mL, 2.04 mmol), and pyridine (0.330 mL, 4.08 mmol) in acetone (3 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give a yellow solid.

To a solution of Example 49A (3.78 g, 10.7 mmol) in 1,4-dioxane (60 mL) was added 4 M sulfuric acid (60 mL) and the reaction was stirred at reflux for 48 hours. The solution was concentrated in vacuo, dissolved in 1 N NaOH (250 mL), and washed with hexane (200 mL). The aqueous layer was acidified to pH 1 with 6 N HCl and extracted with ethyl acetate (3×200 mL). The combined ethyl acetate layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give a clear oil (2.47 g, 98%).1H NMR (300 MHz, CDCl3): δ ppm 0.86 (s, 9 H) 1.09 m, 2 H) 1.56 (s, 3 H) 1.99 m, 2 H) 7.33 m, 5 H).

A solution of Example 49G (0.250 g, 0.510 mmol), mesyl chloride (0.158 mL, 2.04 mmol), and pyridine (0.330 mL, 4.08 mmol) in acetone (3 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give a yellow solid.

To a solution of lithium bis(trimethylsilyl)amide in (154.48 g, 0.923 mol) in tetrahydrofuran (350 mL) was added 2-phenyl propionic acid (50.0 g, 0.333 mol) over 27 minutes maintaining the temperature below 25° C. Following a THF rinse (35 mL), the solution was heated to 50° C. for 23 minutes. The solution was then cooled below 25° C. and 3,3-dimethyl-1-iodobutane (110.3 g, 0.416 mol) was added. The reaction mixture was heated to 60° C. for 31 h, then was cooled to RT, and concentrated to a thick oil. Water (500 mL) was added and the solution was cooled to 10-15° C. and the pH was adjusted to <2 by the addition of 6 N HCl (75.59 g). The product was extracted with ethyl acetate (440 mL) and the organic layer was washed with 10% NaCl. The crude ethyl acetate solution (assayed for 66.8 g of 49-1, 85.6%) was concentrated to a thick oil and used in the resolution.

The crude racemic acid of Example 49-1 in ethyl acetate (401.5 g of 49-1, 1.71 mol) was dissolved in ethyl acetate (9 L). To this solution was added (S)-α-methyl benzylamine (145.3 g, 1.20 mol). A white solid precipitated and the slurry was mixed for 18 h at room temperature. The product was isolated by filtration and dried to give the first crop salt (231.27 g). The first crop salt was dissolved in ethyl acetate (4 L) at 73° C. The solution was cooled slowly to room temperature and a white solid precipitated. After mixing for 18 h at room temperature, the product was isolated by filtration and the product was dried to give the title compound (194.30 g, 32% 97.6% ee measured using the following conditions: Column: ChiralPak, AD-RH; mobile phase: acetonitrile (60%)/H2O (40%), trifluoroacetic acid (0.06%); column temp: ambient; flow rate: 0.8 mL/min; and λ: 220 nm.).

A suspension of Example 49-2 (63.5 g, 0.179 mol) in ethyl acetate (400 mL) was treated with water (200 mL) then enough 3 M HCl to bring the pH to <2. The solution was mixed and the layers were separated. The organic phase was concentrated to thick oil. The oil was dissolved in heptane (500 mL) and concentrated then redissolved in heptane (210 mL). To this solution was added N,N-dimethylformamide (1.2 g, 17.1 mmol) and oxalyl chloride (34.0 g, 0.268 mol). The solution was mixed at room temperature overnight, filtered through celite and concentrated to a residue. The crude acid chloride was dissolved in CH3CN (50 mL). To a separate vessel containing a 0° C. solution of diethyl malonate (30.0 g, 0.187 mol), and MgCl2(17.8 g, 0.187 mol) in acetonitrile (240 mL) was added triethylamine (38.0 g, 0.376 mol). The solution was warmed to room temperature and mixed for 1 h, then cooled back to 0-10° C. The acid chloride/CH3CN solution was added over 30 minutes and the reaction mixture was heated to 50° C. for 3 h. The reaction mixture was cooled and concentrated to a thick sludge. Ethyl acetate (400 mL) and water (400 mL) were added and the pH was adjusted to 6 with concentrated HCl. The layers were separated and the organic solution was washed with 10% NaCl. The organic layer was concentrated to a thick oil then chased with heptane (300 mL) to give the title compound (assayed for 62.6 g, 93%).

To the product of Example 49-4 (260.86 g, 0.693 mol) at 10-15° C. was added methanesulfonic acid (780 mL). The solution was warmed to room temperature and mixed for 24 h. The reaction mixture was slowly quenched into a mixture of H2O (1150 mL) and ethyl acetate (1800 mL) at 5° C. The layers were separated and the organic layer was washed with 10% NaCl. The solution was concentrated and the resulting oil was dissolved in toluene (1100 mL). The crude title compound/toluene solution (assayed for 224 g of the title compound, 98%) was used directly in the next step.

To a solution of the product of Example 49-4 (330.1 g, 0.999 mol) in toluene (1500 mL) was added the product of Example 17A-4 (287.1 g, 0.999 mol). The solution was heated to 100° C. for 4 h then cooled to RT. The solution was transferred to a pressure bottle and triethylamine (505.4, 4.99 mol) was added and the solution was heated to 100° C. for 26 h. The solution was concentrated to ⅓ of the original volume and ethyl acetate (1500 mL) was added. The organic layer was washed with 10% KH2PO4and 10% NaCl then concentrated to a thick oil then chased with dichloromethane. The crude title compound (assay for 375.8 g, 68%) was used directly in the next step.

To a solution of the product of Example 49-5 (185.0 g, 0.334 mol) in dichloromethane (220 mL) was added 4 M HCl in dioxane (430 mL, 1.72 mol) and the solution was mixed at room temperature for 3.5 h. The reaction was quenched by addition of ethyl acetate (1 L) and pH 7 phosphate buffer (1.5 L) and the layers were separated. The organic layer was concentrated and chased with ethanol to a final volume of approximately 1100 mL. The product precipitated and was isolated by filtration and dried to give the title compound (105.79 g, 70%).

To a solution of the product of Example 49-6 (235.0 g, 0.518 mol) and pyridine (123.0 g, 1.55 mol) in dichloromethane (1645 mL) at 18-200C was added methane sulfonyl chloride (89.0 g, 0.777 mol) over 45 minutes. The solution was mixed at RT for 3.5 h then quenched with 1 M HCl (1500 mL). The layers were separated and the organic layer was concentrated under vacuum. The product was crystallized from ethyl acetate/heptane (1/1, 8 volumes) to give the title compound (240.01 g, 87%).

A solution of sodium ethoxide (31.4 g, 0.462 mol) in ethanol (450 mL) was added over 50 minutes to a solution of the product of Example 49-7 (223.16 g, 0.420 mol) in ethanol (1700 mL) at 73° C. The product precipitated and the slurry was cooled slowly to room temperature and the product was isolated by filtration and dried to give the title compound (216.9 g, 93%).

2-Phenylbutyric acid (10 g, 61 mmole) was dissolved in methanol (30 ml) treated with concentrated HCl (1 ml) and heated at reflux for 20 hours. The heating was stopped and the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the oily residue was treated with ethyl acetate (100 ml). The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a clear oil. Yield 10.61 g (97%).1H NMR (300 MHz, DMSO-d6): δ ppm 0.81 (t, J=7.35 Hz, 3 H) 1.69 m, 1 H) 1.98 (m, 1 H) 3.53 (d, J=7.35 Hz, 1 H) 3.58 (s, 3 H) 7.30 m, 5 H).

A solution of diethyl malonate (0.33 ml, 2.18 mmole) in acetonitrile (4 ml) was cooled in an ice bath to 0° C. and treated with magnesium chloride (0.21 g, 2.18 mmole), followed by dropwise addition of triethylamine (0.64 ml, 4.58 mmole). The resulting slurry was stirred at 0° C. 15 minutes, then stirred for another 2 hr at room temperature. Example 50C (0.51 g, 2.18 mmole) was treated with hexane (40 ml), oxalyl chloride (0.6 ml, 6.54 mmole) and dimethylformamide (0.18 ml, 2.4 mmole) and stirred at room temperature for 2 hr. The resulting solution was treated with 1 g Celite, filtered and concentrated in vacuo to give 2-Ethyl-5-methyl-2-phenyl-hexanoyl chloride as a yellow oil. The oil was dissolved in acetonitrile (5 ml) and added dropwise to the slurry prepared from diethyl malonate and magnesium chloride recooled to 0° C. When addition was complete, the reaction mixture is heated and stirred at 50° C. 18 hr. The mixture was cooled to room temperature and concentrated in vacuo. The residue was suspended in Ethyl acetate/1N HCl (3:1) and stirred approximately 30 minutes until all solid had dissolved. The layers were separated and the aqueous layer was extracted with additional ethyl acetate (2×25 ml). The combined organic extracts were washed with saturated sodium chloride, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified on silica gel eluting first with hexane, then hexane/ethyl acetate (95:5) to give the title compound as a yellow oil (0.59 g, 72%).1H NMR (300 MHz, DMSO-d6): δ ppm 0.65 m, 3 H) 0.84 (dd, J=8.82, 6.62 Hz, 6 H) 1.06 (t, J=7.17 Hz, 3 H) 1.20 m, 3 H) 1.48 m, 2 H) 1.98 m, 4 H) 3.47 (s, 1 H) 3.92 (m, 2 H) 4.11 (q, J=7.11 Hz, 2 H) 7.31 m, 5 H).

Example 51B (400 mg, 1.722 mmol, 1 equiv) was dissolved in dry dichloromethane (16 mL) under a N2atmosphere and treated with oxalyl chloride (2M in dichloromethane, 1.29 mL, 2.58 mmol, 1.5 equiv) and dry N,N-dimethyl formamide (2 drops from 250 μL syringe). After stirring at room temperature for 3 hr, the solvent was removed by rotary evaporation and the residue azeotroped with dry toluene (10 mL). The residue was further dried on hi-vacuum for 30 min before using in Example 1D.

To a stirring solution of freshly prepared lithium diisopropylamine (76.5 mmol) in 500 mL of tetrahydrofuran at 0° C. was added methyl phenylacetate (10.44 g, 69.50 mmol) in 125 mL tetrahydrofuran dropwise over 30 minutes. After stirring at 0° C. for 1 hour the reaction mixture was cooled to −78° C. and treated with 50 mL of hexamethylphosphoric triamide followed by the dropwise addition of bromomethyl cyclobutane (9.37 mL, 83.4 mmol) and LiI (200 mg). The reaction mixture was stirred for 18 hours warming to 25° C. The reaction was quenched over 1 L of water containing 250 mL of sat. NH4Cl and extracted 3× with ethyl acetate. The combined organic layers were washed sequentially with saturated sodium bicarbonate, brine, and dried over MgSO4yielding the crude product as an oil that was used without further purification.1H NMR (300 MHz, CDCl3): δ ppm 1.59 m, 2 H) 1.89 m, 5 H) 2.17 m, 2 H) 3.47 (t, J=7.54 Hz, 1 H) 3.64 (s, 3 H) 7.31 (m, 5 H). MS (ESI+) m/z=236 (M+NH4)+.

To a freshly prepared solution of lithium diisopropylamine (0.0182 mmol) in 20 mL of tetrahydrofuran at 0° C. was added Example 55A (3.60 g, 0.0165 mmol) in 10 mL of tetrahydrofuran dropwise over 10 minutes. The solution was then cooled to −78° C. and treated with hexamethylphosphoric triamide (5 mL) followed by the addition of methyl iodide (1.54 mL, 24.8 mmol). The reaction mixture was allowed to warm to 25° C. while stirring overnight. An additional portion of MeI (5.15 mL, 82.7 mmol) was added and the reaction was continued for 2 days). The reaction was quenched over 250 mL of water containing 25 mL of sat. NH4Cl and extracted 3× with ethyl acetate. The combined organic layers were washed sequentially with saturated sodium bicarbonate, brine, and dried over MgSO4yielding the crude product after solvent was removed in. vacuo. as a reddish oil that was used without further purification.1H NMR (300 MHz, CDCl3): δ ppm 1.50 (s, 3 H) 1.64 m, 3 H) 1.82 m, 2 H) 2.01 m, 2 H) 2.21 m, 2 H) 3.63 (s, 3 H) 7.29 (m, 5 H).). MS (ESI+) m/z=250 (M+NH4)+.

To a round bottom flask was added Example 55C (0.230 g, 1.05 mmol), oxalyl chloride (0.276 mL, 3.20 mmol), dichloromethane (10 mL), and 1 drop of N,N-dimethyl formamide. After the bubbling ceased, the reaction mixture was filtered through a pad of celite and concentrated in vacuo and used in the next step without further manipulation. To a second round bottom flask was added diethylmalonate (0.167 mL, 1.05 mmol) and CH3CN and the resulting mixture was cooled in an ice bath. Then, MgCl2(0.104 g, 1.05 mmol) was added portionwise over 5 minutes followed by the addition of Et3N (0.320 mL, 2.30 mmol). This slurry was warmed to 25° C. and stirred for 2 hours. The acid chloride was dissolved in 10 mL of CH3CN and added dropwise to the stirring slurry containing the diethylmalonate. After the complete addition, the reaction mixture was stirred at 25° C. for 12 hours and then heated at 60° C. for 24 hours. The reaction mixture was cooled and quenched with In HCl. The aqueous layer was extracted with 3× ethyl acetate and then the combined organic layers dried over MgSO4. Ethyl acetate was removed in vacuo producing an oil that was used without further purification.

To a round bottom flask was added Example 55D (0.150 g, 0.1462 mmol) and 4 mL of methanesulfonic acid. The reaction mixture was stirred at room temperature for 16 hours and then was partitioned between ethyl acetate and water. The aqueous layer was extracted 2× with ethyl acetate and the combined organic layers were dried over MgSO4. The product was purified by flash chromatography on SiO2eluting with a 5% acetone/hexane yielding the title compound (0.055 g, 42% yield) as an off white solid.

Combine Example 55F (0.150 g, 0.619 mmol), pyridine (0.396 mL, 4.952 mmol), and Example 5A (0.657 g, 2.476 mmol) in 4 mL of dioxane and place directly in a preheated oil bath at 100° C. for 1.5 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed sequentially with bicarb, brine, and dried over MgSO4. The product was purified by flash chromatography on SiO2eluting with a 0-20% ethyl acetate/hexane gradient yielding the title compound (0.175 g, 84% yield) as a yellow solid that solidifies upon standing.

Example 55G (0.087 g, 0.2511 mmol) was combined with Example 17A (0.075 g, 0.263 mmol) and toluene (10 mL). The reaction mixture was stirred at 100° C. overnight. After cooling to room temperature, the reaction mixture was concentrated in. vacuo and purified by flash chromatography on SiO2eluting with a 0-35% ethyl acetate/hexane gradient yielding the title compound (0.083 g, 62% yield) as a light yellow solid.

Example 90A (30 mg, 0.05 mmol) in acetonitrile (2 ml) was added pyrrolidin-3-yl-carbamic acid tert-butyl ester (18 mg, 0.1 mmol). The mixture was microwaved at 80° C. for 2 hours. The solvent was evaporated and the residue was purified by reverse phase eluting with 0.1% trifluoroacetic acid aqueous/methanol (50:50) to (5:95) to give product (7 mg, 20%).

Example 90A (59 mg, 0.1 mmol) in acetonitrile (2 ml) was added Example 17A (32 mg, 0.2 mmol). The mixture was microwaved at 80° C. for 2 hours. The solvent was evaporated and the residue was purified by reverse phase eluting with 0.1% trifluoroacetic acid aqueous/methanol (90:10) to (5:95) to give product (37 mg, 56%).

Acetic acid (0.60 g, 10 mmol) was added slowly dropwise to chlorosulfonyl isocyanate (1.42 g, 10 mmol), with ice/water bath cooling as required to maintain gentle gas evolution. After the addition was complete, the residue was recrystallized from refluxing benzene (10 mL), to provide the title compound (1.5 g, 95%) as a crystalline, hygroscopic solid.

n-Pentanoic acid (1.02 g, 10 mmol) was added slowly dropwise to chlorosulfonyl isocyanate (1.42 g, 10 mmol), with ice/water bath cooling as required to maintain gentle gas evolution. After the addition was complete, the residue was taken up in benzene (10 mL) and the mixture concentrated in vacuo to provide the title compound (2.0 g, quantitative) as a crystalline, hygroscopic solid.

n-Butanoic acid (0.881 g, 10 mmol) was added slowly dropwise to chlorosulfonyl isocyanate (1.42 g, 10 mmol), with ice/water bath cooling as required to maintain gentle gas evolution. After the addition was complete, the residue was taken up in benzene (10 mL) and the mixture concentrated in vacuo to provide the title compound (1.85 g, quantitative) as a crystalline, hygroscopic solid.

n-Propionic acid (0.741 g, 10 mmol) was added slowly dropwise to chlorosulfonyl isocyanate (1.42 g, 10 mmol), with ice/water bath cooling as required to maintain gentle gas evolution. After the addition was complete, the residue was taken up in benzene (10 mL) and the mixture concentrated in vacuo to provide the title compound (1.71 g, quantitative) as a crystalline, hygroscopic solid.

A mixture of Example 39H (23.8 mg, 0.050 mmol), pyridine (31.6 mg, 0.80 mmol), and 1-naphthalenesulfonyl chloride (45.3 mg, 0.20 mmol) in acetone (1.5 mL) was stirred at rt for 72 h. The reaction mixture was evaporated in vacuo and partitioned between ethyl acetate and 1 N HCl. The organic phase was separated, dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with 99:1 dichloromethane/methanol to provide the title compound (32.0 mg, quant. yield).

Chlorine gas was bubbled through a solution of Example 107A (0.253 g, 1.30 mmol) in water (24 mL) and acetic acid (6 mL) with stirring at 0° C. for 30 min. The solid that resulted was isolated by vacuum filtration and rinsed quickly with water and air-dried to provide the title compound (0.170 g, 50%).

Chlorine gas was bubbled through a solution of 5-nitro-1H-benzoimidazole-2-thiol (0.150 g, 0.768 mmol) in water (8 mL) and acetic acid (2 mL) with stirring at 0° C. for 30 min. The solid that resulted was isolated by vacuum filtration and rinsed quickly with water and air-dried to provide the title compound (0.150 g, 75%).

Example 88 (110 mg) was chromatographed on a Chiralcel AS (4.6×250 cm) column using a mobile phase of Hexane/EtOH/methanol/trifluoroacetic acid (70/15/15/1) to yield the desired enantiomer (51 mg, 97% pure). [α]D21.6=−50.3°.

Example 88 (110 mg) was chromatographed on a Chiralcel AS (4.6×250 cm) column using a mobile phase of Hex/EtOH/methanol/trifluoroacetic acid (70/15/15/1) to yield the desired enantiomer (59 mg, 95% pure). [α]D21.9=+41.5°.

Example 139 (90 mg) was chromatographed on a Chiralcel OD (4.6×250 cm) column using a mobile phase of Hexanes/ethanol/methanol/trifluoroacetic acid (70/15/15/0.1) to yield the desired enantiomer (39 mg, 92% ee).

Example 139 (90 mg) was chromatographed on a Chiralcel OD (4.6×250 cm) column using a mobile phase of Hex/EtOH/methanol/trifluoroacetic acid (70/15/15/0.1) to yield the desired enantiomer (38 mg, >99% ee).

To a cooled solution of Example 155C (8.52 g, 0.034 mol) in 200 mL anhydrous dichloromethane was added 2 N oxalyl chloride in dichloromethane (26 mL, 0.052 mol) and drops of dimethylforamide. The solution was stirred for 30 minutes at 0° C. and then room temperature for 2 hours. The solvent was removed under vacuum and the crude product used directly.

A solution of Example 155G (2.0 g, 7.3 mmol) and Example 5A (8 g, 30 mmol) in 50 mL anhydrous dioxane was treated with 5 mL pyridine (62 mmol) and immediately heated to 90° C. for two hours. The cooled solution was partitioned between ethyl acetate and water. The organic layer was extracted with water and brine and then concentrated. The residue was chromatographed on silica using 25% ethyl acetate and hexanes as elutent to give 2.7 grams of the product as a yellow solid (98%).

A mixture of p-toluenesulfonic acid (cat., 5 mg), methanol (50 mL), trimethyl orthoformate (6.47 mL, 59.1 mmol), and Example 157A (1.35 g, 5.9 mmol) was heated at reflux for 2 hours. After cooling the reaction mixture to room temperature, the solution was concentrated in vacuo to oil and used without further purification.

A solution of Example 164D (0.100 g, 0.1912 mmol) in dichloromethane (4 mL) was treated with trifluoroacetic acid (4 mL) at room temperature for 1 hour. After concentrating in. vacuo, the resulting oil was partitioned between ethyl acetate and aqueous NaHCO3, the organic layer was removed and the bicarb layer extracted 3× with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in. vacuo to yield a solid that was used without further purification.

To a solution of 2-methoxynaphthoic acid (458 mg, 2.3 mmol) in dry dichloromethane (9 mL) at 0° C. under a N2atmosphere was added oxalyl chloride (1.4 mL of a 2M solution in dichloromethane, 2.8 mmol) and 4 drops of N,N-dimethyl formamide. The mixture was stirred at 0° C. for 20 minutes then allowed to warm to room temperature and stirred for one hour. The mixture was concentrated in vacuo. To this dry powder was added isopropanol (9 mL) and pyridine (367 μL, 4.5 mmol), with stirring. After stirring for 2 hours at room temperature, the mixture was concentrated and partitioned between H2O (10 mL) and ethyl acetate (3×10 mL) and the combined organic layers was washed with saturated NaCl (10 mL). The organic layer was dried over Na2SO4, and the crude product was purified by column chromatography on silica gel using 10% ethyl acetate in hexane. The title compound was obtained as a colorless solid (260 mg, 47%).

Example 168A (254 mg, 1.0 mmol) and tert-butanol (99 μL, 1.0 mmol) were dissolved in anhydrous tetrahydrofuran (2 mL) and cooled to −78° C. under a N2atmosphere. Ammonia (about 12 mL) was condensed into the mixture and potassium metal was added in small portions until the resulting blue solution persisted for 20 min. To this mixture was added methyl iodide (220 μL, 3.4 mmol) and the resulting solution was allowed to slowly warm to room temperature (NH3was evaporated using a dry N2stream). The resulting mixture was partitioned between saturated NaHCO3(10 mL) and ethyl acetate (3×10 mL) and the combined organic layers were dried over Na2SO4. The crude product was purified by column chromatography on silica gel using 5% ethyl acetate in hexane. The title compound was obtained as a colorless solid (175 mg, 65%).

Example 169A (296 mg, 1.3 mmol) and tert-butanol (148 uL, 1.6 mmol) were dissolved in anhydrous tetrahydrofuran (3 mL) and cooled to −78° C. under a N2atmosphere. Ammonia (about 18 mL) was condensed into the mixture and potassium metal was added in small portions until the resulting blue solution persisted for 20 min. To this mixture was added isoamyl iodide (581 μL, 4.4 mmol) and the resulting solution was allowed to slowly warm to room temperature (NH3was evaporated using a dry N2stream). The resulting mixture was partitioned between saturated NaHCO3(10 mL) and ethyl acetate (3×10 mL), and the combined organic layers were dried over Na2SO4. The crude product was purified by column chromatography on silica gel using 5% ethyl acetate in hexane. The title compound was used immediately in the next step.

Example 169C (56 mg, 0.18 mmol) and trimethylsilyl iodide (38 uL, 0.27 mmol) were dissolved in acetonitrile (1 mL) and stirred for one hour at room temperature under a N2atmosphere. Another 38 μL of trimethylsilyl iodide was added and the mixture was stirred for one hour, concentrated in vacuo and the crude product was partitioned between H2O (5 mL) and ethyl acetate (3×5 mL). The combined organic extracts were washed one time with saturated NaCl (1×5 mL), dried over Na2SO4and purified by column chromatography on silica gel using 5% methanol in chloroform. The title compound was obtained as colorless oil (32 mg, 60%).

The title compound was prepared using the procedure described for Example 170D, substituting the product of Example 171D for the product of Example 170C. The title compound was purified by column chromatography on silica gel using a solvent gradient of 65-100% ethyl acetate in hexane, and it was obtained as a colorless solid.

The title compound was prepared using the procedure described for Example 170E, substituting the product of Example 171E for the product of Example 170D. The title compound was purified by column chromatography on silica gel using a solvent gradient of 50-65% ethyl acetate in hexane, and was obtained as a yellow solid.

A solution of 2-methoxy-naphthalene-1-carboxylic acid (0.50 g, 2.5 mmol) in anhydrous dichloromethane at 0° C. was treated dropwise with a 2.0 M solution of oxalyl chloride in dichloromethane (1.9 mL, 3.8 mmol). The resulting solution was stirred under a N2atmosphere at 0° C. for 20 min, then allowed to warm to r.t. and stirred 1 hr. The solution was cooled to 0° C., and ethanolamine (0.3 mL, 5.0 mmol) and triethylamine (1.0 mL, 7.2 mmol) were added. The resulting mixture was stirred at 0° C. for 15 min, then allowed to warm to r.t. and stirred 90 min. The mixture was poured into 1N HCl (20 mL) and extracted with dichloromethane (2×20 mL), and the combined organic layers were washed with saturated NaHCO3(20 mL) and dried over Na2SO4. The drying agent was filtered off, and the solvent was removed in vacuo to give the title compound as colorless syrup.

The title compound was prepared using the procedure described for Example 170E, substituting the product from Example 175E for the product from Example 170D. The title compound was purified by column chromatography on silica gel using a solvent gradient of 50-65% ethyl acetate in hexane, and was obtained as a yellow solid.

The title compound was prepared using the procedure described for Example 170B, substituting the product from Example 176A for the product from Example 170A. The title compound was purified by column chromatography on silica gel using a solvent gradient of 35-65% ethyl acetate in hexane, and was obtained as a colorless solid.

The title compound was prepared using the procedure described for Example 171C, substituting the product from Example 176B for the product from Example 171B. The title compound was purified by column chromatography on silica gel using a solvent gradient of 35-65% ethyl acetate in hexane, and was obtained as a colorless solid.

The title compound was prepared using the procedure described for Example 170C, substituting the product from Example 176C for the product from Example 170B. The title compound was purified by column chromatography on silica gel using 1:3 ethyl acetate:hexane, and was obtained as a colorless solid.

The title compound was prepared using the procedure described for Example 170D, substituting the product from Example 176D for the product from Example 170C. The title compound was purified by column chromatography on silica gel using a solvent gradient of 65-100% ethyl acetate in hexane, and was obtained as a colorless solid.

The title compound was prepared using the procedure described for Example 170E, substituting the product from Example 176E for the product from Example 170D. The title compound was purified by column chromatography on silica gel using a solvent gradient of 50-65% ethyl acetate in hexane, and was obtained as a yellow solid.

To a solution of Example 180B (32 mg, 0.09 mmol) in acetonitrile (1 mL) was added iodotrimethylsilane (TMSI) (19 μL, 0.13 mmol). The reaction solution was stirred at room temperature for 3 h. After which, additional 1.5 equivalents of TMSI (19 μL) were added and stirring was continued for 2 h. The solution was quenched with water (2 mL) and extracted with ethyl acetate (2×1 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica (70% ethyl acetate/hexane) afforded product as a white foam (24 mg, 77%). MS m/z 346.0 (M+H)+.

To a solution of Example 180C (23 mg, 0.07 mmol) in dioxane (0.7 mL) was added Example 5A (82 mg, 0.3 mmol) followed by pyridine (27 μL, 0.3 mmol). The heterogeneous solution was heated at 55° C. for 3 h. The solution was cooled to room temperature and concentrated in vacuo. Column chromatography on silica afforded product as a yellow oil (14 mg, 47%).

To a solution of Example 181C (42 mg, 0.16 mmol) in methanol (1 mL) was added a solution of 1 N NaOH (0.5 mL, 0.5 mmol). The reaction solution was stirred at 60° C. for 96 h. The solution was cooled to room temperature, acidified with 0.1 N HCl, and extracted with ethyl acetate (3×1 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica (20%-40% ethyl acetate/hexane) afforded product as an off-white solid (24 mg, 60%).

To a solution of Example 181D (18 mg, 0.07 mmol) in dioxane (1 mL) was added Example 5A (86 mg, 0.35 mmol) followed by pyridine (28 μL, 0.35 mmol). The heterogeneous solution was heated at 55° C. for 3 h. The solution was cooled to room temperature and concentrated in vacuo. Column chromatography on silica (0-5% ethyl acetate/hexane) afforded product as a yellow solid (20 mg, 80%).

Placed 245.12 mg of the product of Example 49-7 into a 10 mL receiver flask. Added 6 mL of 50/50 ethanol/water. Warmed to in an oil bath on a hot-plate set to 90° C. and added 29.02 mg of potassium hydroxide. Solution clarified. Cooled in 10° C. increments to 55° C. Solid precipitated. Cooled to 40° C. and held for ˜1 hour. Cooled to ambient temperature and stirred overnight. Collected solid via vacuum filtration the next morning and dried the solid at 50° C./vacuum for 3 days.

Placed 52.71 mg of the product of Example 49-7 into a 3 mL reactivial. Added 300 μL of isopropyl alcohol and warmed on a hot-plate. Added 7.34 mg of calcium hydroxide. Solution clarified. Allowed to cool to ambient temperature. Apparent precipitate formed upon cool down. Warmed vial at 40° C. for approximately 20 minutes. No apparent change in precipitate. Allowed to stir at ambient for 6 days. Collected solid by vacuum filtration.

Placed 42.59 mg of the product of Example 49-7 into a 3 mL reactivial. Added 600 μL of 50/50 ethanol/water. Added 2.51 mg of calcium hydroxide. Warmed to boiling, solution clarified. Allowed to cool to ambient. Stirred overnight at ambient. No apparent change the next morning. Loosened the caps on the vials and continued stirring at ambient. 3 days later, there was an apparent gel/faint white precipitate in the vial. Warmed to 50° C., whereby suspension clarified. Capped vials and allowed to cool to ambient. Precipitate formed. Added 100 μL of water and broke up the precipitate. Added an additional 100 μL of water. Stirred at 40° C. overnight. Cooled to ambient and collected solid by vacuum filtration.

The following additional compounds of the present invention, can be prepared by one skilled in the art using known synthetic methodology or by using analogous synthetic methodology described in the Schemes and Examples contained herein, with appropriate manipulation and protection of chemical functionality. If a substituent described herein is not compatible with the synthetic methods of this invention, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions used in these methods. The protecting group may be removed at a suitable point in the reaction sequence of the method to provide a desired target molecule. Suitable protecting groups and the methods for protection and deprotection are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts,Protecting Groups in Chemical Synthesis(3rded.), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety. The additional compounds encompassed by the following tables can be described by taking one core from Table 1 (wherein—represents a single bond or is absent), R1and R2substituents from Table 2 (wherein X1represents the core ring structures), R3and R4substituents from Table 3 when necessary, and Y from Table 4.

TABLE 1Examples of Core Ring Structures12345678910111213

alternatively, R1and R2, together with the carbon atom to which they are attached, form a monocyclic ring selected from the group consisting of cycloalkyl and cycloalkenyl;

wherein each of the cycloalkyl and cycloalkenyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halo, —OH, —O(alkyl), —NH2, —N(H)(alkyl), —N(alkyl)2, alkyl and haloalkyl;