AS ANTI-HIV AGENTS

Kuo-Hsiung Lee, Keduo Qian, Donglei Yu, Chin-Ho Chen, Li Huang, and Ibrahim D. Bori

Government Funding

This invention was made with United States Government support under grant number AI 077417 from the National Institute of Allergy and Infectious Diseases. The United States government has certain rights to this invention.

Field of the Invention

The present invention concerns compounds, compositions and methods useful for the treatment of retroviral infections in human or animal subjects in need thereof.

Background of the Invention

As the world enters the third decade of the AIDS epidemic, this pandemic has rapidly grown into the fourth leading cause of mortality globally. ¹ Introduction of highly active antiretroviral therapy (HAART), which employs a combination of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and/or protease inhibitors (Pis), has significantly improved the treatment of

2 5 6 8

HIV/AIDS. However, the virus is suppressed rather than eradicated by HAART. ^" On HAART regimens, multiple drug therapies can lead to increased adverse effects and toxicities due to long-term use and drug-drug interactions. ⁹ ' ¹⁰ Moreover, it inevitably leads to the emergence of multi-drug-resistant viral strains. ¹¹ In fact, a significant proportion of newly

• 12 13 infected individuals harbor HIV-1 isolates that are resistant to at least one ART. ' Therefore, novel potent antiretroviral agents are needed, with different targets than currently approved drugs and preferably with simplified treatment regimens (fewer pills and less- frequent administration).

Triterpenes, such as betulinic acid (BA, 1), represent a promising class of anti-HIV agents with novel mechanisms. Two types of BA derivatives have exhibited potent anti-HIV profiles. C-3 esterification of BA led to the discovery of bevirimat (DSB, PA-457, 2), which is a HIV-1 maturation inhibitor (MI) that blocks cleavage of p25 (CA-SP1) to functional p24 (CA), resulting in the production of noninfectious HIV-1 particles. ^14"16 Bevirimat (2) has suceeded Phase Ila and lib clinical trials launched by Panacos Pharmaceuticals, Inc in 2009- 2010. ^17,18 On the other hand, the C-28 side chain was proven to be a necessary pharmacophore for anti-HIV entry activity, as seen with the equipotent diastereomers RPR103611 (3a) and IC9564 (3b). ^19"22 Mechanism of action studies have revealed that C-28 modified BA derivatives function at a post-binding, envelope-dependent step involved in fusion of the virus to the cell membrane. ²³ Recent studies further suggested that 3b may also function by targeting the V3 loop of gpl20, a domain involved in chemokine receptor binding. ²⁴ Although 3a showed potent antiviral activity in vitro, the clinical development of 3a by Rhone-Poulenc (now Sanofi-Aventis) was stopped due to poor "pharmacodynamic properties".

Summary of the Invention

first aspect of the invention is a compound according to Formula (I):

wherein:

a is 1 or 2;

Z is O, S, NH, or N-alkyl;

Ri is a hydrogen, acyl carboxylic acid, C ₂ to C ₂₀ substituted or unsubstituted c

R _a , R _b , R _c and R _d are the same or different and are each independently selected from the group consisting of hydrogen and lower alkyl, i is an integer from 0 to 3, and m is an integer from 1 to 4;

R _2c is C2 to CIO saturated or unsaturated alkyl ene, R _2d is present or absent and when present is CI to C5 saturated or unsaturated alkylene,

Rio is CONH or NHCO;

Rii and R ₁₂ are each independently CI to C4 alkylene or -NH-;

Ri ₃ is loweralkyl;

Ri4 and R15 are each independently H or loweralkyl;

R ₃ and R4 are either H or lower alkyl {e.g., methyl);

R ₅ is H, lower alkyl, or -CRiRuRiu, where:

Ri is a methyl radical or forms with ¾ a methylene radical or an oxo radical;

Rii is a hydrogen atom or forms with Rj or Rm a methylene radical or an oxo radical; and

Rijj is a hydroxyl, methyl, hydroxymethyl, -CEbOR'in, -CHiSR'jjj, or - CH ₂ NHR'iii, which R'iu is alkyl, hydroxyalkyl, dihydroxyalkyl, acetamidoalkyl, acetyl, heteroalkylene, or polyalkylene oxide; or Rm is an amino radical substituted with hydroxyalkyl, carboxyhydroxyalkyl, or dialkylamino, the alkyl parts of which can form, with the nitrogen atom to which they are joined, a 5- or 6-membered heterocycle optionally containing 1 or 2 additional hetero atoms selected from the group consisting of O, S, NH, and N-alkyl;

or R ₅ is a bond to an immediately adjacent carbon atom (thus forming a double bond in the ring between immediately adjacent carbon atoms);

R ₆ and R ₇ are either H or form a bond with one another (thus forming a double bond between their immediately adjacent carbon atoms);

Rg and R9 are either hydrogen or together form an oxo radical;

R ₁₀ is either H or a bond with an immediately adjacent carbon atom (thus forming a double bond in the ring between immediately adjacent carbon atoms); and

the dashed line in Formula (I) is an optional double bond;

or a stereoisomer, enantiomer, tautomer thereof or mixtures thereof;

or a pharmaceutically acceptable salt or prodrug thereof.

A further aspect of the present invention is a compound according to Formula (II):

wherein:

a is 1 or 2;

Z is O, S, NH, or N-alkyl;

R\ is a hydrogen, acyl carboxylic acid, C ₂ to C ₂ o substituted or unsubstituted carboxyacyl, or a substituent of the formula:

wherein R _a , R _b , R _c and are the same or different and are each independently selected from the group consisting of hydrogen and lower alkyl, i is an integer from 0 to 3, and m is an integer from 1 to 4;

R _2a is C3 to C12 alkyl, C3 to C12 heteroloweralkyl containing one, two or three heteroatoms independently selected from N, O, and S, C3 to C12 cycloalkyl, or C3 to CI 2 heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O, and S, each of which may be unsubstituted or substituted one, two, or three times with substituents independently selected from hydroxyl, halo, and alkoxy;

R ₃ and R are either H or lower alkyl (e.g., methyl);

R5 is H, lower alkyl, or — CRjRiiRin, where:

Ri is a methyl radical or forms with ¾ a methylene radical or an oxo radical;

Rii is a hydrogen atom or forms with Ri or Rm a methylene radical or an oxo radical; and Riii is a hydroxyl, methyl, hydroxymethyl, -CH ₂ OR'ni, -CH ₂ SR'iii, or - CH ₂ NHR'iii, which R'ju is alkyl, hydroxyalkyl, dihydroxyalkyl, acetamidoalkyl, acetyl, heteroalkylene, or polyalkylene oxide; or Rni is an amino radical substituted with hydroxyalkyl, carboxyhydroxyalkyl, or dialkylamino, the alkyl parts of which can form, with the nitrogen atom to which they are joined, a 5- or 6-membered heterocycle optionally containing 1 or 2 additional hetero atoms selected from the group consisting of 0, S, NH, and N-alkyl;

or R ₅ is a bond to an immediately adjacent carbon atom (thus forming a double bond in the ring between immediately adjacent carbon atoms);

R ₆ and R ₇ are either H or form a bond with one another (thus forming a double bond between their immediately adjacent carbon atoms);

Rg and R9 are either hydrogen or together form an oxo radical;

Rio is either H or a bond with an immediately adjacent carbon atom (thus forming a double bond in the ring between immediately adjacent carbon atoms); and

the dashed line in Formula (II) is an optional double bond;

or a stereoisomer, enantiomer, tautomer thereof or mixtures thereof;

or a pharmaceutically acceptable salt or prodrug thereof.

A further aspect of the present invention is a composition comprising a compound of Formula (I) or (II) (an active compound) in a pharmaceutically acceptable carrier (such as an aqueous carrier).

A further aspect of the present invention is a composition comprising a compound of Formula (I) or (II) (an active compound) in a pharmaceutically acceptable carrier (such as an aqueous carrier) and one or more additional antiviral agent such as an HIV entry inhibitor.

A further aspect of the present invention is directed to methods for treating a viral infection, particularly a retroviral infection (e.g., HIV-1 infection) in cells or tissue of an animal, in an animal subject or human, comprising administering an effective retroviral inhibiting amount of a compound of Formula (I) or (II). The examples of HIV infection includes, but not limit to, DSB-resistant HIV-1 infection and RPR103611-resistant HIV-1 infection, etc.

In some embodiments, the HIV-1 infection is a bevirimat-resistant HIV-1 infection. The disclosure of our prior US Patent Application No. 13/320,642, filed December 16, 2011 (previously published November 18, 2010 as PCT WO 2010/132334; republished April 26, 2012 as US Patent Application Pub. No. US 2012/0101098; Attorney Docket No. 5470-508), is incorporated herein by reference in its entirety.

The present invention is explained in greater detail in the specification set forth below.

Detailed Description of the Preferred Embodiments

The present invention will now be described more fully hereinafter. This invention may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the description of the invention and the appended claims, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.

"Moiety" and "group" are used interchangeably herein to refer to a portion of a molecule, typically having a particular functional or structural feature, e.g. a linking group (a portion of a molecule connecting two other portions of the molecule).

"Substituted" as used herein to describe chemical structures, groups, or moieties, refers to the structure, group, or moiety comprising one or more substituents. As used herein, in cases in which a first group is "substituted with" a second group, the second group is attached to the first group whereby a moiety of the first group (typically a hydrogen) is replaced by the second group. The substituted group may contain one or more substituents that may be the same or different.

"Substituent" as used herein references a group that replaces another group in a chemical structure. Typical substituents include nonhydrogen atoms (e.g. halogens), functional groups (such as, but not limited to amino, sulfhydryl, carbonyl, hydroxyl, alkoxy, carboxyl, silyl, silyloxy, phosphate and the like), hydrocarbyl groups, and hydrocarbyl groups substituted with one or more heteroatoms. Exemplary substituents include, but are not limited to, alkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl, aryl, aralkyl, lower alkoxy, thioalkyl, hydroxyl, thio, mercapto, amino, imino, halo, cyano, nitro, nitroso, azido, carboxy, sulfide, sulfone, sulfoxy, phosphoryl, silyl, silyloxy, boronyl, and modified lower alkyl.

"Alkyl" as used herein alone or as part of another group, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. "Lower alkyl" as used herein, is a subset of alkyl, in some embodiments preferred, and refers to a straight or branched chain hydrocarbon group containing from 1 to 4 carbon atoms. Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, and the like. The term "alkyl" or "loweralkyl" is intended to include both substituted and unsubstituted alkyl or loweralkyl unless otherwise indicated and these groups may be substituted with groups selected from polyalkylene oxides (such as PEG), halo (e.g., haloalkyl), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy (thereby creating a polyalkoxy such as polyethylene glycol), alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, alkyl-S(0) _m , haloalkyl-S(0) _m , alkenyl-S(0) _m , alkynyl- S(0) _m , cycloalkyl-S(0) _m , cycloalkylalkyl-S(0) _m , aryl-S(0) _m , arylalkyl-S(0) _m , heterocyclo- S(0) _m , heterocycloalkyl-S(0) _m , amino, carboxy, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano where m= 0, 1 , 2 or 3.

"Alkenyl" as used herein alone or as part of another group, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms (or in loweralkenyl 1 to 4 carbon atoms) which include 1 to 4 double bonds in the normal chain. Representative examples of alkenyl include, but are not limited to, methylene (=CH ₂ ), vinyl, 2-propenyl, 3- butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2,4-heptadiene, and the like. The term "alkenyl" or "loweralkenyl" is intended to include both substituted and unsubstituted alkenyl or loweralkenyl unless otherwise indicated and these groups may be substituted with groups such as those described in connection with alkyl and loweralkyl above.

"Alkynyl" as used herein alone or as part of another group, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms (or in loweralkynyl 1 to 4 carbon atoms) which include 1 triple bond in the normal chain. Representative examples of alkynyl include, but are not limited to, 2-propynyl, 3-butynyl, 2- butynyl, 4-pentynyl, 3- pentynyl, and the like. The term "alkynyl" or "loweralkynyl" is intended to include both substituted and unsubstituted alkynyl or loweralkynyl unless otherwise indicated and these groups may be substituted with the same groups as set forth in connection with alkyl and loweralkyl above.

"Cycloalkyl" as used herein alone or as part of another group, refers to a saturated or partially unsaturated cyclic hydrocarbon group containing from 3, 4 or 5 to 6, 7 or 8 carbons (which carbons may be replaced in a heterocyclic group as discussed below). Representative examples of cycloalkyl include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. These rings may be optionally substituted with additional substituents as described herein such as halo or loweralkyl. The term "cycloalkyl" is generic and intended to include heterocyclic groups as discussed below unless specified otherwise.

"Cycloalkylalkyl" as used herein refers to a cycloalkyl group, as defined herein, that is substituted with an alkyl group, as defined herein. Either the alkyl group or the cycloalkyl group may be attached to the parent molecular moiety and either group may be further substituted as defined herein.

"Cycloalkylalkenyl" as used herein refers to a cycloalkyl group, as defined herein, that is substituted with an alkenyl group, as defined herein. Either the alkenyl group or the cycloalkyl group may be attached to the parent molecular moiety and either group may be further substituted, as defined herein.

"Cycloalkylalkynyl" as used herein refers to a cycloalkyl group, as defined herein, that is substituted with an alkynyl group, as defined herein. Either the alkynyl group or the cycloalkyl group may be attached to the parent molecular moiety and either group may be further substituted, as defined herein.

"Heterocyclic group" or "heterocyclo" as used herein alone or as part of another group, refers to an aliphatic (e.g., fully or partially saturated heterocyclo) or aromatic (e.g., heteroaryl) monocyclic- or a bicyclic-ring system. Monocyclic ring systems are exemplified by any 5 or 6 membered ring containing 1 , 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur. The 5 membered ring has from 0-2 double bonds and the 6 membered ring has from 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone, thiopyran, triazine, triazole, trithiane, and the like. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein. Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3- benzodioxole, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, purine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, thiopyranopyridine, and the like. These rings include quaternized derivatives thereof and may be optionally substituted with groups selected from halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, alkyl-S(0) _m , haloalkyl-S(0) _m , alkenyl- S(0) _m , alkynyl-S(0) _m , cycloalkyl-S(0) _m , cycloalkylalkyl-S(0) _m , aryl-S(0) _m , arylalkyl- S(0) _m , heterocyclo-S(0) _m , heterocycloalkyl-S(0) _m , amino, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano where m = 0, 1, 2 or 3.

"Aryl" as used herein alone or as part of another group, refers to a monocyclic carbocyclic ring system or a bicyclic carbocyclic fused ring system having one or more aromatic rings. Representative examples of aryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like. The term "aryl" is intended to include both substituted and unsubstituted aryl unless otherwise indicated and these groups may be substituted with the same groups as set forth in connection with alkyl and loweralkyl above.

"Arylalkyl" as used herein alone or as part of another group, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2- phenyl ethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.

"Arylalkenyl" as used herein alone or as part of another group, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkenyl group, as defined herein.

"Arylalkynyl" as used herein alone or as part of another group, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkynyl group, as defined herein.

"Heteroaryl" as used herein is as described in connection with heterocyclo and aryl above.

"Heteroalkyl" as used herein by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical (e.g., "heterocycloalkyl" or "heteroarylalkyl"), or combinations thereof, comprising an alkyl group, as defined herein, and at least one heteroatom selected from the group consisting of O, N, and S, and wherein the nitrogen, carbon and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N and S may be placed at any interior position of the alkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH ₂ - CH ₂ -0-CH ₃ , -CH ₂ -CH ₂ -0-CH ₂ -CH ₃ , -CH ₂ -0-CH ₂ -CH ₂ -0-CH ₃ , -0-CH ₂ -CH ₂ -0-CH ₂ -CH ₃ , - 0-CH ₂ -0-CH ₃ , -0-CH ₂ -0-CH ₂ -CH ₂ -0-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ , - C¾-S-CH ₂ -CH ₃ , -CH ₂ -CH ₂ , -S(0)-CH ₃ , and -CH ₂ -CH ₂ -S(0) ₂ -CH ₃ . Up to two heteroatoms may be consecutive, such as, for example, -CH ₂ -NH-OCH ₃ . Examples of heterocycloalkyl include, but are not limited to, l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3- piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

"Heteroalkylene" as used herein by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical (e.g., "heterocycloalkenyl" or "heteroarylalkenyl"), or combinations thereof, comprising an alkenyl group, as defined herein, and at least one heteroatom selected from the group consisting of O, N, and S, and wherein the nitrogen, carbon and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N and S may be placed at any interior position of the alkenyl group or at the position at which the alkenyl group is attached to the remainder of the molecule. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Exemplary heteroalkylenes include, but not limited to, -CH=CH-0-CH ₃ , -CH ₂ -CH=N-OCH ₃ , and -CH=CH-N(CH ₃ )-CH ₃ . The terms "heteroalkyl" and "heteroalkylene" encompass poly(ethylene glycol) and its derivatives (see, for example, Shearwater Polymers Catalog, 2001). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula - C(0) ₂ R' represents both -C(0) ₂ R' and -R'C(0) ₂ .

"Heteroalkynyl" as used herein by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical (e.g., "heterocycloalkynyl" or "heteroarylalkynyl"), or combinations thereof, comprising an alkynyl group, as defined herein, and at least one heteroatom selected from the group consisting of O, N, and S, and wherein the nitrogen, carbon and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N and S may be placed at any interior position of the alkynyl group or at the position at which the alkenyl group is attached to the remainder of the molecule.

"Alkoxy" as used herein alone or as part of another group, refers to an alkyl or loweralkyl group, as defined herein (and thus including substituted versions such as polyalkoxy), appended to the parent molecular moiety through an oxy group, -0-. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.

"Aryloxy" as used herein alone or as part of another group refers to an aryl group, as defined herein (and thus including substituted versions), appended to the parent molecular moiety through an oxy group, -0-.

"Hydroxyalkyl" as used herein alone or as part of another group refers to a hydroxyl group, as defined herein, appended to the parent molecular moiety through an alkyl group as defined herein (and thus including substituted versions). Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl and the like. "DiHydroxyalkyl" as used herein refers to two hydroxyl groups, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein (and thus including substituted versions). The hydroxyl groups may be attached to the same carbon atom or different carbon atoms of the alkyl group.

"Halo" as used herein refers to any suitable halogen, including F, CI, Br and I.

"Mercapto" as used herein refers to an -SH group.

"Azido" as used herein refers to an -N ₃ group.

"Cyano" as used herein refers to a -CN group.

"Formyl" as used herein refers to a -C(0)H group.

"Carboxylic acid" or "carboxy" as used herein alone or as part of another group, refers to a -C(0)OH group.

"Hydroxyl" as used herein alone or as part of another group, refers to an -OH group. "Nitro" as used herein refers to an -N0 ₂ group.

"Oxo" as used herein, refers to a =0 moiety.

"Acyl" as used herein alone or as part of another group refers to a -C(0)R radical, where R is any suitable substituent such as aryl, alkyl, alkenyl, alkynyl, cycloalkyl or other suitable substituent as described herein.

"Carboxyacyl" as used herein refers to a carboxylic acid, as defined herein, appended to the parent molecular moiety through an acyl group, as defined herein. Representative examples of carboxyacyl include, but are not limited to, the following:

"Carboxyhydroxyalkyl" as used herein refers to a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein, that is substituted with one or more hydroxy groups, as defined herein. The one or more hydroxy groups may be attached to the same carbon atom or different carbon atoms of the alkyl group and the alkyl group may be further substituted, as defined herein.

"Alkylthio" as used herein alone or as part of another group, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of alkylthio include, but are not limited, methylthio, ethylthio, tert-butylthio, hexylthio, and the like.

"Amino" as used herein means the radical -N¾.

"Alkylamino" as used herein alone or as part of another group means the radical - NHR, where R is an alkyl group.

"Dialkylamino" as used herein refers to the radical -NRR', where R and R' are alkyl groups, as defined herein.

"Disubstituted amino" as used herein refers to the radical -NRR', where R and R' are substituents, as defined herein and may be the same or different.

"Acetyl" as used herein refers to the radical -C(=0)CH ₃ .

"Acetamidoalkyl" as used herein refers to a group of the structure

C

H

H,C C N R where R is appended to the parent molecular moiety and is an alkyl group, as defined herein.

"Arylalkylamino" as used herein alone or as part of another group means the radical - NHR, where R is an arylalkyl group.

"Disubstituted-amino" as used herein alone or as part of another group means the radical -NR _a R _b , where R _a and R _b are independently selected from the groups alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl.

"Acylamino" as used herein alone or as part of another group means the radical - NR _a R _b , where R _a is an acyl group as defined herein and R _b is selected from the groups hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl.

"Acyloxy" as used herein alone or as part of another group means the radical -OR, where R is an acyl group as defined herein.

"Ester" as used herein alone or as part of another group refers to a -C(0)OR radical, where R is any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

"Amide" as used herein alone or as part of another group refers to a -C(0)NR _a Rb radical, where R _a and R _b are any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

"Sulfoxyl" as used herein refers to a compound of the formula -S(0)R, where R is any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

"Sulfonyl" as used herein refers to a compound of the formula -S(0)(0)R, where R is any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

"Sulfonate" as used herein refers to a compound of the formula -S(0)(0)OR, where R is any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

"Sulfonic acid" as used herein refers to a compound of the formula -S(0)(0)OH. "Sulfonamide" as used herein alone or as part of another group refers to a -

S(0) ₂ NR _a R _b radical, where R _a and R _b are any suitable substituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

"Urea" as used herein alone or as part of another group refers to an -N(R _c )C(0)NR _a Rb radical, where R _a , R _b and R _c are any suitable substituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

"Alkoxyacylamino" as used herein alone or as part of another group refers to an - N(R _a )C(0)OR _b radical, where R _a , R _b are any suitable substituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl. "Aminoacyloxy" as used herein alone or as part of another group refers to an - OC(0)NR _a Rb radical, where R _a and Rb are any suitable substituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

"Peptide" as used herein refers to a polymer of 2, 3 or 4 or more, up to 5 or 10, aminocarboxylic acid (or amino acid) monomers linked to one another by peptide bonds. When a substituent or radical, the polypeptide may be coupled to the parent molecule by its caroboxy terminus or its amino terminus. The individual amino acids may be natural or synthetic, standard or rare, and in the D or L configuration. Examples of individual amino acids include but are not limited to alanine, valine, leucine, isoleucine, glycine, serine, threonine, methionine, cysteine, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamic acid, lysine, arginine, histidine and proline.

"Polyalkylene oxide" as used herein are known (see, e.g., US Patent No. 7,462,687) and include poly(ethylene glycol) or "PEG". Additional examples may contain hetero atoms such as S or N, and are typically linear polyalkylene oxides such as: 0-(CH ₂ CH 0) _x -, -O- C(0)CH ₂ -0-(CH ₂ CH ₂ 0) _x — CH ₂ C(0)-O, -NRCH ₂ CH ₂ 2-0-(CH ₂ CH ₂ 0) _x -CH ₂ CH ₂ NR-, and - SHCH ₂ CH ₂ -0-(CH ₂ CH ₂ 0) _x -CH ₂ CH ₂ SH-, wherein R is H or loweralkyl (preferably methyl), and x is an integer of from about 1 to 6 or 10. Thus the polyalkylene oxide typically has a total number average molecular weight of from about 50 to 300 Daltons.

"Pharmaceutically acceptable" as used herein means that the compound or composition is suitable for administration to a subject to achieve the treatments described herein, without unduly deleterious side effects in light of the severity of the disease and necessity of the treatment.

A "prodrug" as used herein means a compound that is converted under physiological conditions or by solvolysis or metabolically to a specified compound that is pharmaceutically active.

The compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

"Stereoisomer" as used herein refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.

"Tautomer" as used herein refers to a proton shift from one atom of a molecule to another atom of the same molecule. As one skilled in the art would recognize tautomers often exist in equilibrium with each other and can interconvert under environmental and physiological conditions providing the same useful biological effects. Thus, the present invention includes mixtures of such tautomers. Additionally, a single compound may exhibit more than one type of isomerism. The present invention includes tautomers of any said active compounds of the present invention.

"Treat" as used herein refers to any type of treatment that imparts a benefit to a patient afflicted with a disease, including improvement in the condition of the patient (e.g., in one or more symptoms), delay in the progression of the disease, etc.

"Concurrently administer " as used herein means that the two compounds or agents are administered closely enough in time to produce a combined effect (that is, concurrently may be simultaneously, or it may be two or more events occurring within a short time period before or after each other, e.g., sequentially). Simultaneous administration may be carried out by mixing the compounds prior to administration, or by administering the compounds at the same point in time but at different anatomic sites and/or by using different routes of administration.

All publications, U.S. patent applications, U.S. patents and other references cited herein are incorporated by reference in their entireties.

1. Active compounds The methods of the present invention include the administration of active compounds as described herein (e.g., compounds of Formula (I) or (II)), while pharmaceutical compositions of the present invention comprise active compounds in a pharmaceutically acceptable carrier or diluent.

Active compounds of the present invention are made in accordance with known techniques, includinb but not limited to those described in US Patent Application No. 13/320,642, filed December 16, 2011 (previously published Novermber 18, 2010 as PCT WO 2010/132334) (Attorney Docket No. 5470-580), the disclosure of which is incorporated herein by reference in its entirety, or variations thereof that will be apparent to those skilled in the art based upon the present disclosure.

As noted above the present invention provides compounds according to Formula (I):

wherein:

a is 1 or 2;

Z is O, S, NH, or N-alkyl;

Ri is a hydrogen, acyl carboxylic acid, C ₂ to C ₂₀ substituted or unsubstituted c

R _a , R _b , R _c and R _d are the same or different and are each independently selected from the group consisting of hydrogen and lower alkyl, i is an integer from 0 to 3, and m is an integer from 1 to 4;

R _2c is C2 to CIO saturated or unsaturated alkylene, R ₂ d is present or absent and when present is CI to C5 saturated or unsaturated alkylene,

Rio is CONH or NHCO;

Ri i and Rj ₂ are each independently CI to C4 alkylene or -NH-;

R ₁₃ is loweralkyl;

Ri4 and R15 are each independently H or loweralkyl;

R ₃ and R4 are either H or lower alkyl (e.g., methyl);

R ₅ is H, lower alkyl, or -CRiRi,Riii, where:

Rj is a methyl radical or forms with ¾ a methylene radical or an oxo radical;

Rii is a hydrogen atom or forms with Rj or Rjjj a methylene radical or an oxo radical; and

Riii is a hydroxyl, methyl, hydroxymethyl, -CH ₂ OR'uj, -CH ₂ SR'jii, or - CH ₂ NHR'iji, which R'jjj is alkyl, hydroxyalkyl, dihydroxyalkyl, acetamidoalkyl, acetyl, heteroalkylene, or polyalkylene oxide; or ¾ι is an amino radical substituted with hydroxyalkyl, carboxyhydroxyalkyl, or dialkylamino, the alkyl parts of which can form, with the nitrogen atom to which they are joined, a 5- or 6-membered heterocycle optionally containing 1 or 2 additional hetero atoms selected from the group consisting of O, S, NH, and N-alkyl;

or R ₅ is a bond to an immediately adjacent carbon atom (thus forming a double bond in the ring between immediately adjacent carbon atoms);

R ₆ and R ₇ are either H or form a bond with one another (thus forming a double bond between their immediately adjacent carbon atoms);

R ₈ and R9 are either hydrogen or together form an oxo radical;

Rio is either H or a bond with an immediately adjacent carbon atom (thus forming a double bond in the ring between immediately adjacent carbon atoms); and

the dashed line in Formula (I) is an optional double bond;

or a stereoisomer, enantiomer, tautomer thereof or mixtures thereof;

or a pharmaceutically acceptable salt or prodrug thereof.

As also noted above, the present invention further provides compounds according to Formula (II):

wherein:

a is 1 or 2;

Z is O, S, NH, or N-alkyl;

Ri is a hydrogen, acyl carboxylic acid, C ₂ to C ₂₀ substituted or unsubstituted carboxyacyl, or a substituent of the formula:

wherein R _a , Rb, R _c and Rd are the same or different and are each independently selected from the group consisting of hydrogen and lower alkyl, i is an integer from 0 to 3, and m is an integer from 1 to 4;

R _2a is C3 to C12 alkyl, C3 to C12 heteroloweralkyl containing one, two or three heteroatoms independently selected from N, O, and S, C3 to C12 cycloalkyl, or C3 to C12 heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O, and S, each of which may be unsubstituted or substituted one, two, or three times with substituents independently selected from hydroxyl, halo, and alkoxy;

R ₃ and R are either H or lower alkyl (e.g., methyl);

R ₅ is H, lower alkyl, or -CRjRjjRjjj, where:

Ri is a methyl radical or forms with Ru a methylene radical or an oxo radical;

Rii is a hydrogen atom or forms with Rj or a methylene radical or an oxo radical; and Riii is a hydroxyl, methyl, hydroxymethyl, -CH ₂ OR'j,i, -CH ₂ SR'iii, or - CH ₂ NHR'iii, which R'uj is alkyl, hydroxyalkyl, dihydroxyalkyl, acetamidoalkyl, acetyl, heteroalkylene, or polyalkylene oxide; or Km is an amino radical substituted with hydroxyalkyl, carboxyhydroxyalkyl, or dialkylamino, the alkyl parts of which can form, with the nitrogen atom to which they are joined, a 5- or 6-membered heterocycle optionally containing 1 or 2 additional hetero atoms selected from the group consisting of O, S, NH, and N-alkyl;

or R ₅ is a bond to an immediately adjacent carbon atom (thus forming a double bond in the ring between immediately adjacent carbon atoms);

R ₆ and R are either H or form a bond with one another (thus forming a double bond between their immediately adjacent carbon atoms);

R ₈ and R9 are either hydrogen or together form an oxo radical;

R ₁₀ is either H or a bond with an immediately adjacent carbon atom (thus forming a double bond in the ring between immediately adjacent carbon atoms); and

the dashed line in Formula (II) is an optional double bond;

or a stereoisomer, enantiomer, tautomer thereof or mixtures thereof;

or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments of both of the foregoing, Z is O.

In some embodiments of both of the foregoing, K is a hydrogen, or a substituent of the formula:

wherein R _a , Rb, R _c and Rd are the same or different and are each independently selected from the group consisting of hydrogen or lower alkyl, i is an integer from 0 to 3, and m is an integer from 1 to 4.

In some embodiments of both of the foregoing, Ri contains at least one asymmetric center with a (S) configuration.

Examples of compounds of Formula I include, but are not limited to:

pharmaceutically acceptable salts thereof.

Examples of d to:

harmaceutically acceptable salts thereof. The active compounds disclosed herein or described above can, as noted above, be prepared in the form of their pharmaceutically acceptable salts. Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects. Examples of such salts are (a) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; and salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p- toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; (b) salts formed from elemental anions such as chlorine, bromine, and iodine, and (c) salts derived from bases, such as ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium, and salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine.

Active compounds may be provided as pharmaceutically acceptable prodrugs, which are those prodrugs of the active compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable risk/benefit ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Prodrugs as Novel delivery Systems, Vol. 14 of the A.C.S. Symposium Series and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated by reference herein. See also US Patent No. 6,680,299. Examples include a prodrug that is metabolized in vivo by a subject to an active drug having an activity of active compounds as described herein, wherein the prodrug is an ester of an alcohol or carboxylic acid group, if such a group is present in the compound; an acetal or ketal of an alcohol group, if such a group is present in the compound; an N-Mannich base or an imine of an amine group, if such a group is present in the compound; or a Schiff base, oxime, acetal, enol ester, oxazolidine, or thiazolidine of a carbonyl group, if such a group is present in the compound, such as described in US Patent No. 6,680,324 and US Patent No. 6,680,322. 2. Pharmaceutical formulations

The active compounds described above may be formulated for administration in a pharmaceutical carrier in accordance with known techniques. See, e.g., Remington, The Science And Practice of Pharmacy (9 ^th Ed. 1995). In the manufacture of a pharmaceutical formulation according to the invention, the active compound (including the physiologically acceptable salts thereof) is typically admixed with, inter alia, an acceptable carrier. The carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the patient. The carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose formulation, for example, a tablet, which may contain from 0.01 or 0.5% to 95% or 99% by weight of the active compound. One or more active compounds may be incorporated in the formulations of the invention, which may be prepared by any of the well known techniques of pharmacy consisting essentially of admixing the components, optionally including one or more accessory ingredients.

The formulations of the invention include those suitable for oral, rectal, topical, buccal (e.g., sub-lingual), vaginal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), topical {i.e., both skin and mucosal surfaces, including airway surfaces) and transdermal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular active compound which is being used.

Formulations of the present invention suitable for parenteral administration comprise sterile aqueous and non-aqueous injection solutions of the active compound, which preparations are preferably isotonic with the blood of the intended recipient. These preparations may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient. Aqueous and non-aqueous sterile suspensions may include suspending agents and thickening agents. The formulations may be presented in unit\dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or water-for-injection immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. For example, in one aspect of the present invention, there is provided an injectable, stable, sterile composition comprising a compound of Formula (I-II), or a salt thereof, in a unit dosage form in a sealed container. The compound or salt is provided in the form of a lyophilizate which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid composition suitable for injection thereof into a subject. The unit dosage form typically comprises from about 1 or 10 mg to about 100 milligrams, 1 gram or 10 grams of the compound or salt. When the compound or salt is substantially water-insoluble, a sufficient amount of emulsifying agent which is physiologically acceptable may be employed in sufficient quantity to emulsify the compound or salt in an aqueous earner. One such useful emulsifying agent is phosphatidyl choline.

Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable carrier (which may contain one or more accessory ingredients as noted above). In general, the formulations of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture. For example, a tablet may be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s). Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.

Formulations suitable for buccal (sub-lingual) administration include lozenges comprising the active compound in a flavoured base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.

Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof. Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis {see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound. Suitable formulations comprise citrate or bis\tris buffer (pH 6) or ethanol/water and contain from 0.1 to 0.2M active ingredient.

In addition to compounds of Formula (I-II) or their salts, the pharmaceutical compositions may contain other additives, such as pH-adjusting additives. In particular, useful pH-adjusting agents include acids, such as hydrochloric acid, bases or buffers, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate. Further, the compositions may contain microbial preservatives. Useful microbial preservatives include methylparaben, propylparaben, and benzyl alcohol. The microbial preservative is typically employed when the formulation is placed in a vial designed for multidose use. Of course, as indicated, the pharmaceutical compositions of the present invention may be lyophilized using techniques well known in the art.

3. Methods of treatment

The present invention is primarily concerned with the treatment of human subjects, but the invention may also be carried out on animal subjects, particularly mammalian subjects such as mice, rats, dogs, cats, non-human primates, livestock and horses for veterinary purposes, and for drug screening and drug development purposes.

Examples of retroviral infections that may be treated by the methods of the present invention include but are not limited to feline leukemia virus (FeLV), human immunodeficiency virus (HIV; including both HIV-1 and HIV-2) simian immunodeficiency virus (SIV) and other lentiviral infections such as equine infectious anemia virus (EAIV) and feline immunodeficiency virus (FIV). A particularly preferred embodiment is use of the methods, compounds and compositions of the present invention for the treatment of HIV-1 infection in human subjects.

4. Dosage and routes of administration

As noted above, the present invention provides pharmaceutical formulations comprising the active compounds (including the pharmaceutically acceptable salts thereof), in pharmaceutically acceptable carriers for oral, rectal, topical, buccal, parenteral, intramuscular, intradermal, or intravenous, and transdermal administration.

The therapeutically effective dosage of any one active agent, the use of which is in the scope of present invention, will vary somewhat from compound to compound, and patient to patient, and will depend upon factors such as the age and condition of the patient and the route of delivery. Such dosages can be determined in accordance with routine pharmacological procedures known to those skilled in the art.

Typical dosages comprise at about 0.1 to about 100 mg/kg body weight. One preferred dosages comprise about 1 to about 100 mg/kg body weight of the active ingredient. One still more preferred dosages comprise about 10 to about 100 mg/kg body weight.

5. Combination methods and compositions

Methods of treatment as described herein can include concurrently administering one or more additional antiviral agent (including HIV entry inhibitors as discussed below), and compositions as described herein can optionally include one or more such additional antiviral agents. Examples of such additional antiviral agents include, but are not limited to, AZT (Glaxo Wellcome), 3TC (Glaxo Wellcome), ddl (Bristol-Myers Squibb), ddC (Hoffmann-La Roche), D4T (Bristol-Myers Squibb), abacavir (Glaxo Wellcome), nevirapine (Boehringher Ingelheim), delavirdine (Pharmacia and Upjohn), efavirenz (DuPont Pharmaceuticals), saquinavir (Hoffmann-La Roche), ritonavir (Abbott Laboratories), indinavir (Merck and Company), nelfinavir (Agouron Pharmaceuticals), amprenavir (Glaxo Wellcome), adefovir (Gilead Sciences), hydroxyurea (Bristol-Meyers Squibb), AL-721 (lipid mixture) manufactured by Ethigen Corporation and Matrix Research Laboratories; Amphotericin B methyl ester; Ampligen (mismatched RNA) developed by DuPont/HEM Research; anti-AIDS antibody (Nisshon Food); 1 AS-101 (heavy metal based immunostimulant); Betaseron (.beta.- interferon) manufactured by Triton Biosciences (Shell Oil); butylated hydroxytoluene; Carrosyn (polymannoacetate); Castanospermine; Contracan (stearic acid derivative); Creme Pharmatex (containing benzalkonium chloride) manufactured by Pharmalec; CS-87 (5- unsubstituted derivative of Zidovudine), Cytovene (ganciclovir) manufactured by Syntex Corporation; dextran sulfate; D-penicillamine (3 -mercapto-D- valine) manufactured by Carter- Wallace and Degussa Pharmaceutical; Foscarnet (trisodium phosphonoformate) manufactured by Astra AB; fusidic acid manufactured by Leo Lovens; glycyrrhizin (a constituent of licorice root); HPA-23 (ammonium-21-tungsto-9-antimonate) manufactured by Rhone-Poulenc Sante; human immune virus antiviral developed by Porton Products International; Ornidyl (eflornithine) manufactured by Merrell-Dow; nonoxinol; pentamidine isethionate (PENTAM-300) manufactured by Lypho Med; Peptide T (octapeptide sequence) manufactured by Peninsula Laboratories; Phenytoin (Warner-Lambert); Ribavirin; Rifabutin (ansamycin) manufactured by Adria Laboratories; CD4-IgG2 (Progenies Pharmaceuticals) or other CD4-containing or CD4-based molecules; T-20 (Trimeris); Trimetrexate manufactured by Warner-Lambert Company; SK-818 (germanium-derived antiviral) manufactured by Sanwa Kagaku; suramin and analogues thereof manufactured by Miles Pharmaceuticals; UAOOl manufactured by Ueno Fine Chemicals Industry; and alpha-interferon, manufactured by Glaxo Wellcome.

HIV entry inhibitors are a class of anti HIV drugs that work by preventing HIV from entering susceptible cells in the body. In generally, it is preferred that the HIV entry inhibitor (1) block virus entry into susceptible cells by preventing HIV-1 binding to the cellular receptor CD4, the coreceptors CXCR4/CCR5 and to receptors on dendritic/migratory cells (capturing and transmitting virus to cells which are directly involved in virus replication), respectively. (See The entry of entry inhibitors: a fusion of science and medicine, Moore, J. P, etc, Proc. Natl. Acad. Sci, USA, 100, 10598-10602, (2003); HIV-1 entry inhibitors: new targets, novel therapies, Pierson, T. C, etc., Immunol. Lett., 85,113-118, (2003); HIV Transmission: Closing all the Doors, Davis, C. W., etc, J. Exp. Med., 199, 1037-1040, (2004); Blockade of attachment and fusion receptors inhibits HIV-1 infection of human cervical tissue, Hu, Q., Frank, etc, J. Exp. Med., 199,1065-1075, (2004)), and/or (2) are virucidal. )

Examples of HIV inhibitors include but not limited to: CCR5 inhibitors TAK-779, Fusion inhibitors T20, CXCR4 inhibitor AMD 3100, and other inhibitors BMS 378806, etc. The structures of representative HIV entry inhibitors are illustrated below.

TAK-779 is also known as N,N-dimethyl-N-(4[[[2-(4-methylphenyl)-6,7-dihydro-5H- benzocyclohepten-8-yl]carbon-yl]benzyl]-tetrahydro-2H-pyran (See Structure Modeling of the Chemkine Receptor CCR5: Implications for Ligand Binding and Selectivity, M. Germana Paterlini, Biophysical Journal, 83, 3012-3031 (2002).)

T20 is also known as enfuviritide and is commercially available as FUZEON (TM). It is a linear 36-amino acid synthetic peptide with an acetylated N-terminus and a carboxamide C-terminus. It is composed of naturally occurring L-amino acid residues. The empirical formula of enfuvirtide is C ₂₀₄ H ₃₀ iN5 ₁ O64. It has the following primary amino acid sequence: CH ₃ CO-Tyr-Thr-Ser-Leu-Ile-His-Ser-Leu-Ile-Glu-Glu-Ser-Gln -Asn-Gln-Gln-Glu- Lys-Asn-Glu-Gln-Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-Ser-Leu- Trp-Asn-Trp-Phe-NH2.

BMS-378806 is also known as (2R)- 4-benzoyl-l-[2-(4-methoxy-lH-pyrrolo[2,3- b]pyridin-3-yl)-l,2-dioxoethyl]-2-methyl-Piperazine (See A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding, Pin-Fang Lin, et al., PNAS, 100, 19, 1103-1 1018 (2003, September)).

AMD 3100, is also known as l,r-[l,4-phenylenebis(methylene)]-bis-l,4,8,l l- tetraazacyclotetradecane is shown below. (See AMD 3100, a Potent and Specific Antagonist of the Stromal Cell -Derived Factor- 1 Chemokine Receptor CXCR4, Inhibits Autoimmune Joint Inflammation in IFN-γ Receptor-Deficient Mice, Patrick Matthys, etc, The Journal of Immunology, 167, 4686-4692. (2001).)

The compounds of the present invention may be concurrently administered in combination with one or more HIV entry inhibitors for the treatment of a mammal, such as a human, that is suffering from an infection with the HIV virus, AIDS, AIDS-related complex, or any disease or condition which is related to infection with the HIV virus.

Pharmaceutical compositions of the present invention can also further comprise immunomodulators, and methods of treatment of the present invention can include the coadministration of an immunomodulator. Suitable immunomodulators for optional use with the active compounds of the present invention in accordance with the present invention can include, but are not limited to: ABPP (Bropririmine); Ampligen (mismatched RNA) DuPont/HEM Research; anti-human interferon-. alpha. -antibody (Advance Biotherapy and Concepts); anti-AIDS antibody (Nisshon Food); AS-101 (heavy metal based immunostimulant; ascorbic acid and derivatives thereof; interferon-.beta.; Carrosyn (polymannoacetate); Ciamexon (Boehringer-Mannheim); cyclosporin; cimetidine; CL- 246,738 (American Cyanamid); colony stimulating factors, including GM-CSF (Sandoz, Genetics Institute); dinitrochlorobenzene; HE2000 (Hollis-Eden Pharmaceuticals); interferon- . alpha.; inteferon-gamma; glucan; hyperimmune gamma-globulin (Bayer); IMREG-1 (leukocyte dialyzate) and IMREG-2 (IMREG Corp.); immuthiol (sodium diethylthiocarbamate) (Institut Merieux); interleukin-1 (Cetus Corporation; Hoffmann- LaRoche; Immunex); interleukin-2 (IL-2) (Chiron Corporation); isoprinosine (inosine pranobex); Krestin (Sankyo); LC-9018 (Yakult); lentinan (Ajinomoto/Yamanouchi); LF- 1695 (Fournier); methionine-enkephalin (TNI Pharmaceuticals; Sigma Chemicals); Minophagen C; muramyl tripeptide, MTP-PE (Ciba-Geigy); naltrexone ("Trexan" DuPont); Neutropin, RNA immunomodulator (Nippon Shingaku); Remune (Immune Response Corporation); Reticulose (Advanced Viral Research Corporation); shosaikoto and ginseng; thymic humoral factor; TP-05 (Thymopentin, Ortho Pharmaceuticals); Thymosin factor 5 and Thymosin 1 ; Thymostimulin; TNF (Tumor necrosis factor) manufactured by Genentech; and vitamin B preparations.

Further embodiments of the present invention will now be described with reference to the following examples. It should be appreciated that these examples are for the purposes of illustrating embodiments of the present invention, and do not limit the scope of the invention.

EXAMPLES

Compounds of the present invention include those set forth in Scheme 1 below:

SCHEME 1

The compounds shown in Scheme 1 above are made in accordance with Scheme 2 below:

When made in accordance with the schemes, the following results are achieved: DB124-2 (Methyl N-[N'-[3p-0-(3',3'-dimethylsuccinyl)-betulinic acid-28-oyl]-9- aminononanoyl]-L-glutaminate (5)): Yield 15 mg (40%). IH NMR (CDC13, 300 MHz) δ 7.03 (d, J - 7.5 Hz, IH, -CONH-), 6.86 (bs, IH, IH in -CONH2), 5.85-5.89 (m, 2H, -CONH- and IH in -CONH2), 4.66 (s, IH, =CH), 4.48-4.55 (m, 2H, -COCH-, =CH), 4.42 (dd, J = 4.5 Hz, J = 11.1 Hz, IH, -CH- in 3), 3.64 (s, 3H, -OCH3), 3.05-3.24 (m, 3H, -CONH-CH2-, -CH- in 19), 2.65 and 2.53 (2d, J - 15.1 Hz, IH each, -C(CH3)2-CH2-), 1.61 (s, 3H, -CH3 in 30), 1.26 and 1.21 (2s, 3H each, -CO-C(CH3)2), 0.88 (s, 3H, -CH3), 0.85 (s, 3H, -CH3), 0.76 (s, 3H, -CH3), 0.71 (s, 6H, 2 x -CH3). Calc'd for C51H84N309 (M+H)+: 882.6202. Found: 882.6203.

DCIOO (N-[N'-[3p-0-(3',3 '-dimethylsuccinyl)-betulinic acid-28-oyl]-9- aminononactyl]-Na-boc-L-asparaginamide (32)): Yield 8 mg (41%). IH NMR (CDC13, 300 MHz) δ 6.72, 6.21, 6.13 and 5.69 (4bs, IH each, 3 x -CONH-, IH in -CO-NH2), 4.73 and 4.59 (2s, IH each, =CH2), 4.42-4.50 (m, 2H, -COCH-, -CH- in 3), 3.64-3.24 and 2.84-3.20 (m, 7H, 2 x -CONH-CH2-,-COCH2-, -CH- in 19), 2.78 and 2.47 (2d, J = 15.0 Hz, IH each, - C(CH3)2-CH2-), 1.68 (s, 3H, -CH3 in 30), 1.46 (s, 9H, -C(CH3)3), 1.25 (m, 6H, -CO- C(CH3)2), 0.96 (s, 3H, -CH3), 0.92 (s, 3H, -CH3), 0.82 (s, 3H, -CH3), 0.81 (s, 3H, -CH3), 0.75 (s, 3H, -CH3). Calc'd for C54H89N409 (M-Hf : 937.6630. Found: 937.6595.

DD27: Yield 8 mg (25%). IH NMR (CDC13, 300 MHz) δ 6.15 (m, IH, -CONH-),

4.73 and 4.59 (2s, IH each, =CH2), 4.47 (m, IH, -CH- in 3), 3.38-3.20 (m, 2H, -CONH- CH2), 3.07 (m, IH, CH- in 19), 2.68 and 2.56 (2d, J = 15.8 Hz, IH each, -C(CH3)2-CH2-), 1.68 (s, 3H, -CH3 in 30), 1.30 and 1.28 (s, 3H each, -CO-C(CH3)2), 1.24 (s, 6H, HO- C(CH3)2), 0.96 (s, 3H, -CH3), 0.92 (s, 3H, -CH3), 0.82 (s, 6H, 3 x -CH3), 0.79 (s, 3H, - CH3). Calc'd for C40H65NO6_. Found: _.

DD57: Yield 8 mg (24%). IH NMR (CDC13, 300 MHz) δ 5.47 (m, IH, -CONH-),

4.72 and 4.59 (2s, IH each, =CH2), 4.47 (m, IH, -CH- in 3), 3.95 (m, 3H, -CONH-CH and - 0-CH2-), 3.51 (m, 2H, -0-CH2-), 3.09 (m, IH, CH- in 19), 2.66 and 2.55 (2d, J = 15.3 Hz, IH each, -C(CH3)2-CH2-), 1.67 (s, 3H, -CH3 in 30), 1.29 (s, 6H, -CO-C(CH3)2), 0.95 (s, 3H, -CH3), 0.91 (s, 3H, -CH3), 0.82 (s, 6H, 2 x -CH3), 0.79 (s, 3H, -CH3). Calc'd for C41H65N06_. Found: _.

DD63: Yield 12 mg (36%). IH NMR (CDC13, 300 MHz) δ 5.54 (m, IH, -CONH-),

4.73 and 4.58 (2s, IH each, =CH2), 4.48 (m, IH, -CH- in 3), 3.35-3.10 (m, 3H, -CONH-CH2 and -CH- in 19), 2.66 and 2.55 (2d, J = 16.2 Hz, IH each, -C(CH3)2-CH2-), 1.68 (s, 3H, - CH3 in 30), 1.30 and 1.28 (s, 3H each, -CO-C(CH3)2), 0.95 (s, 3H, -CH3), 0.94 (s, 3H, - CH3), 0.94 (s, 9H, -C(CH3)3), 0.93 (s, 3H, -CH3), 0.82 (s, 3H, -CH3), 0.79 (s, 3H, -CH3). Calc'd for C42H69N05_. Found: _.

The activity of compounds DD63 and DDI 24 in inhibiting bevirimat-resistant HIV-1 viruses in vitro is given in Table 1 below:

Table 1. Betulinic acid derivatives that inhibited bevirimat resistant viruses.

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The foregoing is illustrative of the present invention, and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein.