US20150218142A1 - Derivatives of Betulin - Google Patents

Derivatives of Betulin Download PDF

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Publication number
US20150218142A1
US20150218142A1 US14/365,802 US201214365802A US2015218142A1 US 20150218142 A1 US20150218142 A1 US 20150218142A1 US 201214365802 A US201214365802 A US 201214365802A US 2015218142 A1 US2015218142 A1 US 2015218142A1
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Prior art keywords
circumflex over
oxo
pentamethyl
dimethyl
oxy
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US14/365,802
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Inventor
Mark Andrew Hatcher
Brian Alvin Johns
Michael Tolar Martin
Elie Amine Tabet
Jun Tang
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GlaxoSmithKline LLC
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GlaxoSmithKline LLC
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Priority to US14/365,802 priority Critical patent/US20150218142A1/en
Assigned to GLAXOSMITHKLINE LLC reassignment GLAXOSMITHKLINE LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HATCHER, Mark Andrew, JOHNS, BRIAN ALVIN, MARTIN, MICHAEL TOLAR, TABET, Elie Amine, TANG, JUN
Assigned to GLAXOSMITHKLINE LLC reassignment GLAXOSMITHKLINE LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HATCHER, Mark Andrew, JOHNS, BRIAN ALVIN, MARTIN, MICHAEL TOLAR, TABET, Elie Amine, TANG, JUN
Assigned to GLAXOSMITHKLINE LLC reassignment GLAXOSMITHKLINE LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HATCHER, Mark Andrew, JOHNS, BRIAN ALVIN, MARTIN, MICHAEL TOLAR, TABET, Elie Amine, TANG, JUN
Publication of US20150218142A1 publication Critical patent/US20150218142A1/en
Abandoned legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
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    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
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    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
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    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
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    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/002—Carbocyclic rings fused
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/52—Ortho- or ortho- and peri-condensed systems containing five condensed rings

Definitions

  • the present invention relates to compounds, pharmaceutical compositions, and methods of use thereof for (i) inhibiting HIV replication in a subject infected with HIV, or (ii) treating a subject infected with HIV, by administering such compounds.
  • HIV-1 Human immunodeficiency virus type 1
  • AIDS acquired immune deficiency disease
  • AIDS acquired immune deficiency disease
  • the number of cases of HIV continues to rise, and currently over twenty-five million individuals worldwide suffer from the virus.
  • long-term suppression of viral replication with antiretroviral drugs is the only option for treating HIV-1 infection.
  • the U.S. Food and Drug Administration has approved twenty-five drugs over six different inhibitor classes, which have been shown to greatly increase patient survival and quality of life.
  • additional therapies are still required because of undesirable drug-drug interactions; drug-food interactions; non-adherence to therapy; and drug resistance due to mutation of the enzyme target.
  • HAART highly active antiretroviral therapy
  • salvage therapy includes at least two, and preferably three, fully active drugs.
  • first-line therapies combine three to four drugs targeting the viral enzymes reverse transcriptase and protease.
  • One option for salvage therapy is to administer different combinations of drugs from the same mechanistic class that remain active against the resistant isolates.
  • the options for this approach are often limited, as resistant mutations frequently confer broad cross-resistance to different drugs in the same class.
  • Alternative therapeutic strategies have recently become available with the development of fusion, entry, and integrase inhibitors.
  • resistance to all three new drug classes has already been reported both in the lab and in patients. Sustained successful treatment of HIV-1-infected patients with antiretroviral drugs will therefore require the continued development of new and improved drugs with new targets and mechanisms of action.
  • HAART highly active antiretroviral therapy
  • the HIV Gag polyprotein precursor (Pr55Gag), which is composed of four protein domains matrix (MA), capsid (CA), nucleocapsid (NC) and p6 and two spacer peptides, SP1 and SP2, represents a new therapeutic target.
  • Pr55Gag The HIV Gag polyprotein precursor (Pr55Gag), which is composed of four protein domains matrix (MA), capsid (CA), nucleocapsid (NC) and p6 and two spacer peptides, SP1 and SP2
  • MA protein domains matrix
  • CA capsid
  • NC nucleocapsid
  • SP1 and SP2 two spacer peptides
  • Gag-Pol is also cleaved by PR, liberating the viral enzymes PR, RT and IN.
  • Gag proteolytic processing induces a morphological rearrangement within the particle, known as maturation.
  • Maturation converts the immature, donut-shaped particle to the mature virion, which contains a condensed conical core composed of a CA shell surrounding the viral RNA genome in a complex with NC and the viral enzymes RT and IN. Maturation prepares the virus for infection of a new cell and is absolutely essential for particle infectivity.
  • Bevirimat (PA-457) is a maturation inhibitor that inhibits the final step in the processing of Gag, the conversion of capsid-SP1 (p25) to capsid, which is required for the formation of infectious viral particles.
  • Bevirimat has activity against ART-resistant and wild-type HIV, and has shown synergy with antiretrovirals from all classes.
  • Bevirimat users with Gag polymorphisms at Q369, V370 or T371 demonstrated significantly lower load reductions than patients without Gag polymorphisms at these sites.
  • PCT Patent Application No. WO2011/100308 “Derivatives of Betulin”
  • PCT Patent Application No. PCT/US2012/024288 “Novel Anti-HIV Compounds and Methods of Use Thereof”
  • Chinese PCT Application No. PCT/CN2011/001302 “Carbonyl Derivatives of Betulin”
  • Chinese PCT Application No. PCT/CN2011/001303 “Methylene Derivatives of Betulin”
  • Chinese PCT Application Nos. PCT/CN2011/002105 and PCT/CN2011/002159 “Propenoate Derivatives of Betulin”.
  • Maturation inhibitors in the prior art leave open gaps in the areas of polymorphism coverage whereby potency against a broad range of clinically relevant gag sequences is extremely important, along with overall potency including the clinically relevant protein adjusted antiviral activity that will be required for robust efficacy in long term durability trials. To date, no maturation inhibitor has achieved an optimal balance of these properties.
  • L 1 and L 2 are independently selected from a bond or [C(R 6 R 6′ )] q ;
  • each instance of Q is independently selected from —CH 2 — or —C( ⁇ O)—;
  • W is selected from a bond or O
  • R 1 is selected from the group consisting of hydrogen, (C 1 -C 12 )alkyl, —C(O)R 5 , —CH 2 —O—(C 1 -C 6 )alkyl, 2-tetrahydro-2H-pyran, and
  • R 2 is selected from the group consisting of —H, (C 1 -C 12 )alkyl, —(C 1 -C 6 )alkyl-OR 4 , —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, —C(O)R 5 , —(CH 2 ) r NR 7 R 8 , and —(CH 2 ) r N + (R 4 ) 3 , wherein when W is O, R 1 and R 2 can optionally be taken together with the O and N to which they are respectively joined to form a 4 to 8 membered heterocyclyl ring, wherein the heterocyclyl ring may be optionally substituted by one to two R 11 groups;
  • R 3 is selected from the group consisting of hydrogen, (C 1 -C 12 )alkyl, —NR 1 R 2 , —OR 5 ,
  • R 2 and R 3 can optionally be taken together with the nitrogen and L 2 to which they are respectively joined to form a 4 to 8 membered heterocyclyl ring, wherein the heterocyclyl ring may be optionally substituted by one to two R 11 groups;
  • R 4 is selected from the group consisting of —H and (C 1 -C 6 )alkyl
  • R 5 is selected from the group consisting of —H, (C 1 -C 6 )alkyl, —R 3 , —(CH 2 ) r NR 7 R 8 , and —(CH 2 ) r OR 7 .
  • R 6 and R 6′ are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, haloalkyl, —Y, —(CH 2 ) r NR 7 R 8 , —C(O)OH, and —C(O)NH 2 , wherein the R 6 and R 6′ groups can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring, and wherein the cycloalkyl ring may be optionally substituted by one to three R 11 groups;
  • R 7 and R 8 are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, -Q-aryl-(R 4 ) n , —NR 14 R 15 , —C(O)CH 3 , wherein R 7 and R 8 can optionally be taken together with the nitrogen to which they are joined to form a 4 to 8 membered heterocyclyl or heteroaryl ring containing one to three heteroatoms selected from —NR 5 —, —O—, —S—, —S(O)—, or —SO 2 —, wherein the heterocyclyl or heteroaryl ring may be optionally substituted by one to three R 11 groups;
  • R 9 is halo
  • R 10 is —N(R 16 ) 2 ;
  • R 11 , R 12 , and R 13 are independently selected from the group consisting of oxo, hydroxyl, halo, (C 1 -C 6 )alkoxy, —R 6 (R 9 ) q , —OR 6 (R 9 ) q , nitro, —SO 2 R 6 , (C 1 -C 6 )alkyl, —C(O)R 10 , —R 4 YR 6 , —CO(O)R 4 , and —CO(O)R 5 , wherein any two R 11 , R 12 or R 13 groups can optionally join to form a 3 to 8 membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring, wherein the heterocyclyl or heteroaryl ring may contain one to three heteroatoms selected from —NR 5 —, —O—, —S—, —S(O)—, or —SO 2 —, and wherein the cycloalkyl,
  • R 14 and R 15 are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, —[C(R 6 ) 2 ] r —, —O[C(R 6 ) 2 ] r —, oxo, hydroxyl, halo, —C(O)R 7 , —R 10 , and —CO(O)R 2 , wherein R 14 and R 15 can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring or 4 to 8 membered heterocyclyl ring containing one to three heteroatoms selected from —NR 5 —, —O—, —S—, —S(O)—, or —SO 2 —, wherein the cycloalkyl ring or heterocyclyl ring may be optionally substituted by
  • R 16 is independently selected from the group consisting of —H, halo, oxo, hydroxyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl, —R 6 (R 9 ) q , —OR 6 (R 9 ) q , —N(R 4 ) 2 , —(CH 2 ) r -heterocyclyl, —C(O)OH, —C(O)NH 2 , —R 5 (R 9 ) q , —OR 5 (R 9 ) q , nitro, —SO 2 R 6 , —C(O)R 10 and —CO(O)R 4 ;
  • n and n in each instance are independently 0, 1, 2, 3, or 4;
  • p is independently 0, 1, 2, 3, or 4;
  • r and q in each instance are independently 0, 1, 2, 3, or 4.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a) the compound of Formula I or Formula II or a pharmaceutically acceptable salt the thereof; and b) a pharmaceutically acceptable excipient.
  • the present invention is a method of treating an HIV infection comprising administering to a subject suffering therefrom a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof.
  • Compounds of the present invention are useful for the treatment of subjects with an HIV infection or for the treatment of subjects at risk of acquiring an HIV infection.
  • FIG. 1 shows a bar graph representing a comparison between Bevirimat and compound 51 of their relative ability to inhibit HIV reverse transcriptase activity across a broad panel of HIV-1 isolates.
  • FIG. 2 shows a bar graph representing a comparison between compound 51 and compound C of their relative ability to inhibit HIV reverse transcriptase activity across a broad panel of HIV-1 isolates.
  • FIG. 3 shows a line graph representing an extrapolation of Bevirimat normalized IC 50 values to 100% human serum.
  • FIG. 4 shows a line graph representing an extrapolation of compound B normalized IC 50 values to 100% human serum.
  • FIG. 5 shows a line graph representing an extrapolation of compound 51 normalized IC 50 values to 100% human serum.
  • alkyl refers to a monovalent saturated aliphatic hydrocarbyl group having from 1 to 14 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms.
  • (C x -C y )alkyl refers to alkyl groups having from x to y carbon atoms.
  • alkyl includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 —), ethyl (CH 3 CH 2 —), n-propyl (CH 3 CH 2 CH 2 —), isopropyl ((CH 3 ) 2 CH—), n-butyl (CH 3 CH 2 CH 2 CH 2 —), isobutyl ((CH 3 ) 2 CHCH 2 —), sec-butyl ((CH 3 )(CH 3 CH 2 )CH—), t-butyl ((CH 3 ) 3 C—), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 —), and neopentyl ((CH 3 ) 3 CCH 2 —).
  • Alkylene or “alkylene” refers to divalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms.
  • (C u -C v )alkylene refers to alkylene groups having from u to v carbon atoms.
  • the alkylene groups include branched and straight chain hydrocarbyl groups.
  • (C 1 -C 6 )alkylene is meant to include methylene, ethylene, propylene, 2-methypropylene, dimethylethylene, pentylene, and so forth.
  • the term “propylene” could be exemplified by the following structure:
  • dimethylbutylene could be exemplified by any of the following three structures or more:
  • (C 1 -C 6 )alkylene is meant to include such branched chain hydrocarbyl groups as cyclopropylmethylene, which could be exemplified by the following structure:
  • Alkenyl refers to a linear or branched hydrocarbyl group having from 2 to 10 carbon atoms and in some embodiments from 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least 1 site of vinyl unsaturation (>C ⁇ C ⁇ ).
  • (C x -C y )alkenyl refers to alkenyl groups having from x to y carbon atoms and is meant to include for example, ethenyl, propenyl, isopropylene, 1,3-butadienyl, and the like.
  • Alkynyl refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond.
  • alkynyl is also meant to include those hydrocarbyl groups having one triple bond and one double bond.
  • (C 2 -C 6 )alkynyl is meant to include ethynyl, propynyl, and the like.
  • Alkoxy refers to the group —O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.
  • Acyl refers to the groups H—C(O)—, alkyl-C(O)—, alkenyl-C(O)—, alkynyl-C(O)—, cycloalkyl-C(O)—, aryl-C(O)—, heteroaryl-C(O)—, and heterocyclic-C(O)—.
  • Acyl includes the “acetyl” group CH 3 C(O)—.
  • “Acylamino” refers to the groups —NR 20 C(O)alkyl, —NR 20 C(O)cycloalkyl, —NR 20 C(O)alkenyl, —NR 20 C(O)alkynyl, —NR 20 C(O)aryl, —NR 20 C(O)heteroaryl, and —NR 20 C(O)heterocyclic, wherein R 20 is hydrogen or alkyl.
  • Alkyloxy refers to the groups alkyl-C(O)O—, alkenyl-C(O)O—, alkynyl-C(O)O—, aryl-C(O)O—, cycloalkyl-C(O)O—, heteroaryl-C(O)O—, and heterocyclic-C(O)O—.
  • Amino refers to the group —NR 21 R 22 where R 21 and R 22 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclic, —SO 2 -alkyl, —SO 2 -alkenyl, —SO 2 -cycloalkyl, —SO 2 -aryl, —SO 2 -heteroaryl, and —SO 2 -heterocyclic, and wherein R 21 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic group.
  • R 21 is hydrogen and R 22 is alkyl
  • the amino group is sometimes referred to herein as alkylamino.
  • R 21 and R 22 are alkyl, the amino group is sometimes referred to herein as dialkylamino.
  • dialkylamino When referring to a monosubstituted amino, it is meant that either R 21 or R 22 is hydrogen but not both.
  • R 21 or R 22 When referring to a disubstituted amino, it is meant that neither R 21 nor R 22 are hydrogen.
  • Haldroxyamino refers to the group —NHOH.
  • Alkoxyamino refers to the group —NHO-alkyl wherein alkyl is defined herein.
  • Aminocarbonyl refers to the group —C(O)NR 26 R 27 where R 26 and R 27 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclic, hydroxy, alkoxy, amino, and acylamino, and where R 26 and R 27 are optionally joined together with the nitrogen bound thereto to form a heterocyclic group.
  • Aryl refers to an aromatic group of from 6 to 14 carbon atoms and no ring heteroatoms and having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl).
  • a single ring e.g., phenyl
  • multiple condensed (fused) rings e.g., naphthyl or anthryl.
  • the term “Aryl” or “Ar” applies when the point of attachment is at an aromatic carbon atom (e.g., 5,6,7,8 tetrahydronaphthalene-2-yl is an aryl group as its point of attachment is at the 2-position of the aromatic phenyl ring).
  • AUC refers to the area under the plot of plasma concentration of drug (not logarithm of the concentration) against time after drug administration.
  • EC 50 refers to the concentration of a drug that gives half-maximal response.
  • IC 50 refers to the half-maximal inhibitory concentration of a drug. Sometimes, it is also converted to the pIC 50 scale ( ⁇ log IC 50 ), in which higher values indicate exponentially greater potency.
  • Clades refers to a hypothetical construct based on experimental data. Clades are found using multiple (sometimes hundreds) of traits from a number of species (or specimens) and analyzing them statistically to find the most likely phylogenetic tree for the group.
  • Cycloalkyl refers to a saturated or partially saturated cyclic group of from 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and spiro ring systems.
  • cycloalkyl applies when the point of attachment is at a non-aromatic carbon atom (e.g. 5,6,7,8,-tetrahydronaphthalene-5-yl).
  • Cycloalkyl includes cycloalkenyl groups, such as cyclohexenyl.
  • cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl.
  • cycloalkyl groups that include multiple bicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like. Two such bicycloalkyl multiple ring structures are exemplified and named below:
  • (C u -C v )cycloalkyl refers to cycloalkyl groups having u to v carbon atoms.
  • “Spiro cycloalkyl” refers to a 3 to 10 member cyclic substituent formed by replacement of two hydrogen atoms at a common carbon atom in a cyclic ring structure or in an alkylene group having 2 to 9 carbon atoms, as exemplified by the following structure wherein the group shown here attached to bonds marked with wavy lines is substituted with a spiro cycloalkyl group:
  • “Fused cycloalkyl” refers to a 3 to 10 member cyclic substituent formed by the replacement of two hydrogen atoms at different carbon atoms in a cycloalkyl ring structure, as exemplified by the following structure wherein the cycloalkyl group shown here contains bonds marked with wavy lines which are bonded to carbon atoms that are substituted with a fused cycloalkyl group:
  • Halo or “halogen” refers to fluoro, chloro, bromo, and iodo.
  • Haloalkyl refers to substitution of an alkyl group with 1 to 3 halo groups (e.g., bifluoromethyl or trifluoromethyl).
  • Haloalkoxy refers to substitution of alkoxy groups with 1 to 5 (e.g. when the alkoxy group has at least 2 carbon atoms) or in some embodiments 1 to 3 halo groups (e.g. trifluoromethoxy).
  • “Human Serum Protein Shift Assay” refers to an HIV assay using a Luciferase Reporter to determine percent inhibition—pIC 50 .
  • the HIV assay makes use of a two-cell co-culture system. In this assay, an infected cell line J4H ⁇ B2 and an indicator cell line HOS (delta LTR+luciferase) are co-cultured in the presence and absence of compound.
  • the assay is designed to find inhibitors that prevent the infection of HOS cells by the J4H ⁇ B2 cell line.
  • the assay can detect inhibitors of any stage of the HIV infection cycle.
  • “Hydroxy” or “hydroxyl” refers to the group —OH.
  • Heteroaryl refers to an aromatic group of from 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from oxygen, nitrogen, and sulfur and includes single ring (e.g. imidazolyl) and multiple ring systems (e.g. benzimidazol-2-yl and benzimidazol-6-yl).
  • single ring e.g. imidazolyl
  • multiple ring systems e.g. benzimidazol-2-yl and benzimidazol-6-yl.
  • the term “heteroaryl” applies if there is at least one ring heteroatom and the point of attachment is at an atom of an aromatic ring (e.g.
  • the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ O), sulfinyl, or sulfonyl moieties.
  • heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, imidazolinyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, purinyl, phthalazyl, naphthylpryidyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, indolizinyl, dihydroindolyl, indazolyl, indolinyl, benzoxazolyl, quinolyl, isoquinolyl, quinolizyl, quianazolyl, quinoxalyl, tetrahydro
  • Heterocyclic or “heterocycle” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially saturated cyclic group having from 1 to 14 carbon atoms and from 1 to 6 heteroatoms selected from nitrogen, sulfur, phosphorus or oxygen and includes single ring and multiple ring systems including fused, bridged, and spiro ring systems.
  • heterocyclic or “heterocycle” or “heterocycloalkyl” or “heterocyclyl” apply when there is at least one ring heteroatom and the point of attachment is at an atom of a non-aromatic ring (e.g.
  • the nitrogen, phosphorus and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, phosphinane oxide, sulfinyl, sulfonyl moieties.
  • the heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidinyl, piperazinyl, 3-pyrrolidinyl, 2-pyrrolidon-1-yl, morpholinyl, and pyrrolidinyl.
  • a prefix indicating the number of carbon atoms (e.g., C 3 -C 10 ) refers to the total number of carbon atoms in the portion of the heterocyclyl group exclusive of the number of heteroatoms.
  • heterocycle and heteroaryl groups include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyridone, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline
  • “Fused heterocyclic” or “fused heterocycle” refer to a 3 to 10 member cyclic substituent formed by the replacement of two hydrogen atoms at different carbon atoms in a cycloalkyl ring structure, as exemplified by the following structure wherein the cycloalkyl group shown here contains bonds marked with wavy lines which are bonded to carbon atoms that are substituted with a fused heterocyclic group:
  • Compound refers to a compound encompassed by the generic formulae disclosed herein, any subgenus of those generic formulae, and any forms of the compounds within the generic and subgeneric formulae, including the racemates, stereoisomers, and tautomers of the compound or compounds.
  • heteroatom means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen, such as N(O) ⁇ N + —O ⁇ ⁇ and sulfur such as S(O) and S(O) 2 , and the quaternized form of any basic nitrogen.
  • Oxazolidinone refers to a 5-membered heterocyclic ring containing one nitrogen and one oxygen as heteroatoms and also contains two carbons and is substituted at one of the two carbons by a carbonyl group as exemplified by any of the following structures, wherein the oxazolidinone groups shown here are bonded to a parent molecule, which is indicated by a wavy line in the bond to the parent molecule:
  • Oxo refers to a ( ⁇ O) group.
  • Polymorphism refers to when two or more clearly different phenotypes exist in the same population of a species where the occurrence of more than one form or morph. In order to be classified as such, morphs must occupy the same habitat at the same time and belong to a panmictic population (one with random mating).
  • Protein binding refers to the binding of a drug to proteins in blood plasma, tissue membranes, red blood cells and other components of blood.
  • Protein shift refers to determining a binding shift by comparing the EC 50 values determined in the absence and presence of human serum.
  • QVT refers to the amino acids at positions 369, 370, and 371, respectively in the Sp1 fragment of HIV-1 Gag.
  • Racemates refers to a mixture of enantiomers.
  • the compounds of Formula I, or pharmaceutically acceptable salts thereof are enantiomerically enriched with one enantiomer wherein all of the chiral carbons referred to are in one configuration.
  • reference to an enantiomerically enriched compound or salt is meant to indicate that the specified enantiomer will comprise more than 50% by weight of the total weight of all enantiomers of the compound or salt.
  • Solvate or “solvates” of a compound refer to those compounds, as defined above, which are bound to a stoichiometric or non-stoichiometric amount of a solvent.
  • Solvates of a compound includes solvates of all forms of the compound.
  • solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts. Suitable solvates include water.
  • Stereoisomer or “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • Tautomer refer to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring —NH— moiety and a ring ⁇ N— moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.
  • atropisomer refers to a stereoisomer resulting from an axis of asymmetry. This can result from restricted rotation about a single bond where the rotational barrier is high enough to allow differentiation of the isomeric species up to and including complete isolation of stable non-interconverting diastereomer or enantiomeric species.
  • R x a nonsymmetrical R x to core
  • the formation of atropisomers is possible.
  • the two chiral elements taken together can create diastereomeric and enantiomeric stereochemical species.
  • interconversion between the atropisomers may or may not be possible and may depend on temperature.
  • the atropisomers may interconvert rapidly at room temperature and not resolve under ambient conditions.
  • Other situations may allow for resolution and isolation but interconversion can occur over a period of seconds to hours or even days or months such that optical purity is degraded measurably over time.
  • Yet other species may be completely restricted from interconversion under ambient and/or elevated temperatures such that resolution and isolation is possible and yields stable species.
  • the resolved atropisomers were named using the helical nomenclature. For this designation, only the two ligands of highest priority in front and behind the axis are considered. When the turn priority from the front ligand 1 to the rear ligand 1 is clockwise, the configuration is P, if counterclockwise it is M.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium, and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002.
  • Patient or “subject” refers to mammals and includes humans and non-human mammals.
  • Treating” or “treatment” of a disease in a patient refers to 1) preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating or causing regression of the disease.
  • dashed line represents an optional double bond at that position.
  • dashed circles appear within ring structures denoted by solid lines or solid circles, then the dashed circles represent one to three optional double bonds arranged according to their proper valence taking into account whether the ring has any optional substitutions around the ring as will be known by one of skill in the art.
  • the dashed line in the structure below could either indicate a double bond at that position or a single bond at that position:
  • ring A below could be a cyclohexyl ring without any double bonds or it could also be a phenyl ring having three double bonds arranged in any position that still depicts the proper valence for a phenyl ring.
  • any of X 1 -X 5 could be selected from: C, CH, or CH 2 , N, or NH, and the dashed circle means that ring B could be a cyclohexyl or phenyl ring or a N-containing heterocycle with no double bonds or a N-containing heteroaryl ring with one to three double bonds arranged in any position that still depicts the proper valence:
  • the present invention includes compounds as well as their pharmaceutically acceptable salts. Accordingly, the word “or” in the context of “a compound or a pharmaceutically acceptable salt thereof” is understood to refer to either: 1) a compound alone or a compound and a pharmaceutically acceptable salt thereof (alternative), or 2) a compound and a pharmaceutically acceptable salt thereof (in combination).
  • substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
  • substituent “arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-O—C(O)—.
  • —C(R x ) 2 it should be understood that the two R x groups can be the same, or they can be different if R x is defined as having more than one possible identity.
  • certain substituents are drawn as —R x R y , where the “—” indicates a bond adjacent to the parent molecule and R y being the terminal portion of the functionality.
  • impermissible substitution patterns e.g., methyl substituted with 5 fluoro groups. Such impermissible substitution patterns are well known to the skilled artisan.
  • Bevirimat is a yet unapproved anti-HIV drug derived from a betulinic acid-like compound, first isolated from Syzygium claviflorum , a Chinese herb. It is believed to inhibit HIV by a novel mechanism, so-called maturation inhibition. Like protease inhibitors, Bevirimat and other maturation inhibitors interfere with protease processing of newly translated HIV polyprotein precursor, called gag. Gag is an essential structural protein of the HIV virus. Gag undergoes a chain of interactions both with itself and with other cellular and viral factors to accomplish the assembly of infectious virus particles.
  • this structural difference has now been discovered to unexpectedly improve many of the properties that are involved with creating an efficacious drug for the prevention and/or treatment of viral diseases, such as HIV.
  • viral diseases such as HIV.
  • One or more of such properties of certain compounds described within the present application include, but are not limited to, improving the HIV virus polymorphism coverage, improving the in vitro potency (EC 50 ), reducing the projected clinical human AUC target, potentially reducing any toxicity window by lowering the required dosage to be efficacious, and reducing the impact of protein binding and/or serum shift upon the projected clinical AUC target.
  • L 1 and L 2 are independently selected from a bond or [C(R 6 R 6′ )] q ;
  • each instance of Q is independently selected from —CH 2 — or —C( ⁇ O)—;
  • W is selected from a bond or O
  • R 1 is selected from the group consisting of —H, (C 1 -C 12 )alkyl, —C(O)R 5 , —CH 2 —O—(C 1 -C 6 )alkyl, 2-tetrahydro-2H-pyran, and
  • R 2 is selected from the group consisting of —H, (C 1 -C 12 )alkyl, —(C 1 -C 6 )alkyl-OR 4 , —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, —C(O)R 5 , —(CH 2 ) r NR 7 R 8 , and —(CH 2 ) r N + (R 4 ) 3 , wherein when W is O, R 1 and R 2 can optionally be taken together with the O and N to which they are respectively joined to form a 4 to 8 membered heterocyclyl ring, wherein the heterocyclyl ring may be optionally substituted by one to two R 11 groups;
  • R 3 is selected from the group consisting of —H, (C 1 -C 12 )alkyl, —NR 1 R 2 , —OR 5 ,
  • R 2 and R 3 can optionally be taken together with the nitrogen and L 2 to which they are respectively joined to form a 4 to 8 membered heterocyclyl ring, wherein the heterocyclyl ring may be optionally substituted by one to two R 11 groups;
  • R 4 is selected from the group consisting of —H and (C 1 -C 6 )alkyl
  • R 5 is selected from the group consisting of —H, (C 1 -C 6 )alkyl, —R 3 , —(CH 2 ) r NR 7 R 8 , and —(CH 2 ) r OR 7 .
  • R 6 and R 6′ are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, haloalkyl, —Y, —(CH 2 ) r NR 7 R 8 , —C(O)OH, and —C(O)NH 2 , wherein the R 6 and R 6′ groups can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring, and wherein the cycloalkyl ring may be optionally substituted by one to three R 11 groups;
  • R 7 and R 8 are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, -Q-aryl-(R 4 ) n , —NR 14 R 15 , —C(O)CH 3 , wherein R 7 and R 8 can optionally be taken together with the nitrogen to which they are joined to form a 4 to 8 membered heterocyclyl or heteroaryl ring containing one to three heteroatoms selected from —NR 5 —, —O—, —S—, —S(O)—, or —SO 2 —, wherein the heterocyclyl or heteroaryl ring may be optionally substituted by one to three R 11 groups;
  • R 9 is halo
  • R 10 is —N(R 16 ) 2 ;
  • R 11 , R 12 , and R 13 are independently selected from the group consisting of oxo, hydroxyl, halo, (C 1 -C 6 )alkoxy, —R 6 (R 9 ) q , —OR 6 (R 9 ) q , nitro, —SO 2 R 6 , (C 1 -C 6 )alkyl, —C(O)R 10 , —R 4 YR 6 , —CO(O)R 4 , and —CO(O)R 5 , wherein any two R 11 , R 12 or R 13 groups can optionally join to form a 3 to 8 membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring, wherein the heterocyclyl or heteroaryl ring may contain one to three heteroatoms selected from —NR 5 —, —O—, —S—, —S(O)—, or —SO 2 —, and wherein the cycloalkyl,
  • R 14 and R 15 are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, —[C(R 6 ) 2 ] r —, —O[C(R 6 ) 2 ] r —, oxo, hydroxyl, halo, —C(O)R 7 , —R 10 , and —CO(O)R 2 , wherein R 14 and R 15 can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring or 4 to 8 membered heterocyclyl ring containing one to three heteroatoms selected from —NR 5 —, —O—, —S—, —S(O)—, or —SO 2 —, wherein the cycloalkyl ring or heterocyclyl ring may be optionally substituted by
  • R 16 is independently selected from the group consisting of —H, halo, oxo, hydroxyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl, —R 6 (R 9 ) q , —OR 6 (R 9 ) q , —N(R 4 ) 2 , —(CH 2 ) r -heterocycle, —C(O)OH, —C(O)NH 2 , —R 5 (R 9 ) q , —OR 5 (R 9 ) q , nitro, —SO 2 R 6 , —C(O)R 10 , and —CO(O)R 4 ;
  • n and n in each instance are independently 0, 1, 2, 3, or 4;
  • p is independently 0, 1, 2, 3, or 4;
  • r and q in each instance are independently 0, 1, 2, 3, or 4.
  • L 1 and L 2 are [C(R 6 R 6′ )] q ;
  • each Q is independently selected from —CH 2 — or —C( ⁇ O)—;
  • W is selected from a bond or O
  • R 1 is selected from the group consisting of —H, (C 1 -C 6 )alkyl, —C(O)R 4 , and
  • R 2 is selected from the group consisting of —H, (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-OR 4 , —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, —C(O)R 5 , —(CH 2 ) r NR 7 R 8 , and —(CH 2 ) r N + (R 4 ) 3 ;
  • R 3 is selected from the group consisting of hydrogen, (C 1 -C 12 )alkyl, —NR 1 R 2 , —OR 5 ,
  • R 4 is selected from the group consisting of —H and (C 1 -C 6 )alkyl
  • R 5 is selected from the group consisting of (C 1 -C 6 )alkyl, —(CH 2 ) r NR 7 R 8 , and —(CH 2 ) r OR 7 ;
  • R 6 and R 6′ are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, haloalkyl, —(CH 2 ) r NR 7 R 8 , —C(O)OH, and —C(O)NH 2 , wherein the R 6 and R 6′ groups can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring, and wherein the cycloalkyl ring may be optionally substituted by one to three R 11 groups;
  • R 7 and R 8 are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —NR 14 R 15 , and —C(O)CH 3 ;
  • R 9 is halo
  • R 10 is —N(R 16 ) 2 ;
  • R 11 , R 12 , and R 13 are independently selected from the group consisting of oxo, hydroxyl, halo, (C 1 -C 6 )alkoxy, —R 6 (R 9 ) q , —OR 6 (R 9 ) q , nitro, —SO 2 R 6 , (C 1 -C 6 )alkyl, —C(O)R 10 , —R 4 YR 6 , —CO(O)R 4 , and —CO(O)R 5 ;
  • R 14 and R 15 are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, —[C(R 6 ) 2 ] r —, —O[C(R 6 ) 2 ] r —, oxo, hydroxyl, halo, —C(O)R 7 , —R 10 , and —CO(O)R 2 ;
  • R 16 is independently selected from the group consisting of —H, oxo, halo, hydroxyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl, —R 6 (R 9 ) q , —OR 6 (R 9 ) q , —N(R 4 ) 2 , —(CH 2 ) r -heterocycle, —C(O)OH, —C(O)NH 2 , —R 5 (R 9 ) q , —OR 5 (R 9 ) q , nitro, —SO 2 R 6 , —C(O)R 10 , and —CO(O)R 4 ;
  • n and n in each instance are independently 0, 1, 2, 3, or 4;
  • p is independently 0, 1, 2, 3, or 4;
  • r and q in each instance are independently 0, 1, 2, 3, or 4.
  • L 1 and L 2 are both (—CH 2 —);
  • W is O
  • R 1 is —H
  • R 2 is selected from the group consisting of —H, (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-OR 4 , —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, —C(O)R 5 , and —(CH 2 ) r NR 7 R 8 ;
  • R 3 is selected from the group consisting of —H, (C 1 -C 12 )alkyl, —NR 1 R 2 , —OR 5 ,
  • R 4 is selected from the group consisting of —H and (C 1 -C 6 )alkyl
  • R 5 is selected from the group consisting of (C 1 -C 6 )alkyl, —(CH 2 ) r NR 7 R 8 , and —(CH 2 ) r OR 7 ;
  • R 6 and R 6′ are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, haloalkyl, —(CH 2 ) r NR 7 R 8 , —C(O)OH, and —C(O)NH 2 ;
  • R 7 and R 8 are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —NR 14 R 15 , and —C(O)CH 3 ;
  • R 9 is halo
  • R 10 is —N(R 16 ) 2 ;
  • R 11 , R 12 , and R 13 are independently selected from the group consisting of oxo, hydroxyl, halo, (C 1 -C 6 )alkoxy, —R 6 (R 9 ) q , —OR 6 (R 9 ) q , nitro, —SO 2 R 6 , (C 1 -C 6 )alkyl, —C(O)R 10 , —R 4 YR 6 , —CO(O)R 4 , and —CO(O)R 5 ;
  • R 14 and R 15 are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, —[C(R 6 ) 2 ] r —, —O[C(R 6 ) 2 ] r —, oxo, hydroxyl, halo, —C(O)R 7 , —R 10 , and —CO(O)R 2 ;
  • R 16 is independently selected from the group consisting of —H, oxo, halo, hydroxyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl, —R 6 (R 9 ) q , —OR 6 (R 9 ) q , —N(R 4 ) 2 , —(CH 2 ) r -heterocyclyl, —C(O)OH, —C(O)NH 2 , —R 5 (R 9 ) q , —OR 5 (R 9 ) q , nitro, —SO 2 R 6 , —C(O)R 10 , and —CO(O)R 4 ;
  • n and n in each instance are independently 0, 1, or 2;
  • p is independently 0, 1, or 2;
  • r and q in each instance are independently 0, 1, 2, or 3.
  • L 1 and L 2 are both (—CH 2 —);
  • W is O
  • R 1 is —H
  • R 2 is selected from the group consisting of —H, (C 1 -C 6 )alkyl, —C(O)R 5 , and —(CH 2 ) r NR 7 R 8 ;
  • X is a monocyclic or bicyclic (C 5 -C 14 )aryl
  • R 4 is selected from the group consisting of —H and (C 1 -C 6 )alkyl
  • R 5 is selected from the group consisting of (C 1 -C 6 )alkyl, —(CH 2 ) r NR 7 R 8 , and —(CH 2 ) r OR 7 ;
  • R 6 is selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, haloalkyl, —(CH 2 ) r NR 7 R 8 , —C(O)OH, and —C(O)NH 2 ;
  • R 7 and R 8 are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —NR 14 R 15 , and —C(O)CH 3 ;
  • R 9 is halo
  • R 10 is —N(R 16 ) 2 ;
  • R 11 , R 12 , and R 13 are independently selected from the group consisting of oxo, hydroxyl, halo, (C 1 -C 6 )alkoxy, —R 6 (R 9 ) q , —OR 6 (R 9 ) q , nitro, —SO 2 R 6 , (C 1 -C 6 )alkyl, —C(O)R 10 , —CO(O)R 4 , and —CO(O)R 5 ;
  • R 14 and R 15 are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, —[C(R 6 ) 2 ] r —, —O[C(R 6 ) 2 ] r —, oxo, hydroxyl, halo, —C(O)R 7 , —R 10 , and —CO(O)R 2 ;
  • R 16 is independently selected from the group consisting of —H, oxo, halo, hydroxyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl, —R 6 (R 9 ) q , —OR 6 (R 9 ) q , —N(R 4 ) 2 , —(CH 2 ) r -heterocyclyl, —C(O)OH, —C(O)NH 2 , —R 5 (R 9 ) q , —OR 5 (R 9 ) q , nitro, —SO 2 R 6 , —C(O)R 10 , and —CO(O)R 4 ;
  • n and n in each instance are independently 0, 1, or 2;
  • p is independently 0, 1, or 2;
  • r and q in each instance are independently 0, 1, 2, or 3.
  • L 1 and L 2 are both (—CH 2 —);
  • W is O
  • R 1 is —H
  • R 2 is —(CH 2 ) r NR 7 R 8 ;
  • R 7 and R 8 are independently selected from the group consisting of —H and methyl
  • R 9 is selected from the group consisting of chloro, bromo, and fluoro
  • R 11 is selected from the group consisting of chloro, bromo, and fluoro
  • n 0, 1, or 2;
  • r is 1, 2, or 3.
  • L 1 and L 2 are independently selected from a bond or [C(R 6 R 6′ )] q ;
  • each instance of Q is independently selected from —CH 2 — or —C( ⁇ O)—;
  • W is selected from a bond or O
  • R 1 is selected from the group consisting of —H, (C 1 -C 12 )alkyl, —C(O)R 5 , —CH 2 —O—(C 1 -C 6 )alkyl, 2-tetrahydro-2H-pyran, and
  • R 2 is selected from the group consisting of —H, (C 1 -C 12 )alkyl, —(C 1 -C 6 )alkyl-OR 4 , —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, —C(O)R 5 , —(CH 2 ) r NR 7 R 8 , and —(CH 2 ) r N + (R 4 ) 3 , wherein when W is O, R 1 and R 2 can optionally be taken together with the O and N to which they are respectively joined to form a 4 to 8 membered heterocyclyl ring, wherein the heterocyclyl ring may be optionally substituted by one to two R 11 groups;
  • R 3 is selected from the group consisting of hydrogen, (C 1 -C 12 )alkyl, —NR 1 R 2 , —OR 5 ,
  • R 2 and R 3 can optionally be taken together with the nitrogen and L 2 to which they are respectively joined to form a 4 to 8 membered heterocyclyl ring, wherein the heterocyclyl ring may be optionally substituted by one to two R 11 groups;
  • R 4 is selected from the group consisting of —H and (C 1 -C 6 )alkyl
  • R 5 is selected from the group consisting of —H, (C 1 -C 6 )alkyl, —R 3 , —(CH 2 ) r NR 7 R 8 , and —(CH 2 ) r OR 7 .
  • R 6 and R 6′ are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, haloalkyl, —Y, —(CH 2 ) r NR 7 R 8 , —C(O)OH, and —C(O)NH 2 , wherein the R 6 and R 6′ groups can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring, and wherein the cycloalkyl ring may be optionally substituted by one to three R 11 groups;
  • R 7 and R 8 are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, -Q-aryl-(R 4 ) n , —NR 14 R 15 , —C(O)CH 3 , wherein R 7 and R 8 can optionally be taken together with the nitrogen to which they are joined to form a 4 to 8 membered heterocyclyl or heteroaryl ring containing one to three heteroatoms selected from —NR 5 —, —O—, —S—, —S(O)—, or —SO 2 —, wherein the heterocyclyl or heteroaryl ring may be optionally substituted by one to three R 11 groups;
  • R 9 is halo
  • R 10 is —N(R 16 ) 2 ;
  • R 11 , R 12 , and R 13 are independently selected from the group consisting of oxo, hydroxyl, halo, (C 1 -C 6 )alkoxy, —R 6 (R 9 ) q , —OR 6 (R 9 ) q , nitro, —SO 2 R 6 , (C 1 -C 6 )alkyl, —C(O)R 10 , —R 4 YR 6 , —CO(O)R 4 , and —CO(O)R 5 , wherein any two R 11 , R 12 or R 13 groups can optionally join to form a 3 to 8 membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring, wherein the heterocyclyl or heteroaryl ring may contain one to three heteroatoms selected from —NR 5 —, —O—, —S—, —S(O)—, or —SO 2 —, and wherein the cycloalkyl,
  • R 14 and R 15 are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, —[C(R 6 ) 2 ] r —, —O[C(R 6 ) 2 ] r —, oxo, hydroxyl, halo, —C(O)R 7 , —R 10 , and —CO(O)R 2 , wherein R 14 and R 15 can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring or 4 to 8 membered heterocyclyl ring containing one to three heteroatoms selected from —NR 5 —, —O—, —S—, —S(O)—, or —SO 2 —, wherein the cycloalkyl ring or heterocyclyl ring may be optionally substituted by
  • R 16 is independently selected from the group consisting of —H, halo, oxo, hydroxyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl, —R 6 (R 9 ) q , —OR 6 (R 9 ) q , —N(R 4 ) 2 , —(CH 2 ) r -heterocycle, —C(O)OH, —C(O)NH 2 , —R 5 (R 9 ) q , —OR 5 (R 9 ) q , nitro, —SO 2 R 6 , —C(O)R 10 , and —CO(O)R 4 ;
  • n and n in each instance are independently 0, 1, 2, 3, or 4;
  • p is independently 0, 1, 2, 3, or 4;
  • r and q in each instance are independently 0, 1, 2, 3, or 4.
  • L 1 and L 2 are [C(R 6 R 6′ )] q ;
  • each Q is independently selected from —CH 2 — or —C( ⁇ O)—;
  • W is selected from a bond or O
  • R 1 is selected from the group consisting of —H, (C 1 -C 6 )alkyl, —C(O)R 4 , and
  • R 2 is selected from the group consisting of —H, (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-OR 4 , —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, —C(O)R 5 , —(CH 2 ) r NR 7 R 8 , and —(CH 2 ) r N + (R 4 ) 3 ;
  • R 3 is selected from the group consisting of —H, (C 1 -C 12 )alkyl, —NR 1 R 2 , —OR 5 ,
  • R 4 is selected from the group consisting of —H and (C 1 -C 6 )alkyl
  • R 5 is selected from the group consisting of (C 1 -C 6 )alkyl, —(CH 2 ) r NR 7 R 8 , and —(CH 2 ) r OR 7 ;
  • R 6 and R 6′ are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, haloalkyl, —(CH 2 ) r NR 7 R 8 , —C(O)OH, and —C(O)NH 2 , wherein the R 6 and R 6′ groups can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring, and wherein the cycloalkyl ring may be optionally substituted by one to three R 11 groups;
  • R 7 and R 8 are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —NR 14 R 15 , and —C(O)CH 3 ;
  • R 9 is halo
  • R 10 is —N(R 16 ) 2 ;
  • R 11 , R 12 , and R 13 are independently selected from the group consisting of oxo, hydroxyl, halo, (C 1 -C 6 )alkoxy, —R 6 (R 9 ) q , —OR 6 (R 9 ) q , nitro, —SO 2 R 6 , (C 1 -C 6 )alkyl, —C(O)R 10 , —R 4 YR 6 , —CO(O)R 4 , and —CO(O)R 5 ;
  • R 14 and R 15 are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, —[C(R 6 ) 2 ] r —, —O[C(R 6 ) 2 ] r —, oxo, hydroxyl, halo, —C(O)R 7 , —R 10 , and —CO(O)R 2 ;
  • R 16 is independently selected from the group consisting of —H, oxo, halo, hydroxyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl, —R 6 (R 9 ) q , —OR 6 (R 9 ) q , —N(R 4 ) 2 , —(CH 2 ) r -heterocycle, —C(O)OH, —C(O)NH 2 , —R 5 (R 9 ) q , —OR 5 (R 9 ) q , nitro, —SO 2 R 6 , —C(O)R 10 , and —CO(O)R 4 ;
  • n and n in each instance are independently 0, 1, 2, 3, or 4;
  • p is independently 0, 1, 2, 3, or 4;
  • r and q in each instance are independently 0, 1, 2, 3, or 4.
  • L 1 and L 2 are both (—CH 2 —);
  • W is O
  • R 1 is —H
  • R 2 is selected from the group consisting of —H, (C 1 -C 6 )alkyl, —C(O)R 5 , and —(CH 2 ) r NR 7 R 8 ;
  • X is a monocyclic or bicyclic (C 5 -C 14 )aryl
  • R 4 is selected from the group consisting of —H and (C 1 -C 6 )alkyl
  • R 5 is selected from the group consisting of (C 1 -C 6 )alkyl, —(CH 2 ) r NR 7 R 8 , and —(CH 2 ) r OR 7 ;
  • R 6 is selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, haloalkyl, —(CH 2 ) r NR 7 R 8 , —C(O)OH, and —C(O)NH 2 ;
  • R 7 and R 8 are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —NR 14 R 15 , and —C(O)CH 3 ;
  • R 9 is halo
  • R 10 is —N(R 16 ) 2 ;
  • R 11 , R 12 , and R 13 are independently selected from the group consisting of oxo, hydroxyl, halo, (C 1 -C 6 )alkoxy, —R 6 (R 9 ) q , —OR 6 (R 9 ) q , nitro, —SO 2 R 6 , (C 1 -C 6 )alkyl, —C(O)R 10 , —CO(O)R 4 , and —CO(O)R 5 ;
  • R 14 and R 15 are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, —[C(R 6 ) 2 ] r —, —O[C(R 6 ) 2 ] r —, oxo, hydroxyl, halo, —C(O)R 7 , —R 10 , and —CO(O)R 2 ;
  • R 16 is independently selected from the group consisting of —H, oxo, halo, hydroxyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl, —R 6 (R 9 ) q , —OR 6 (R 9 ) q , —N(R 4 ) 2 , —(CH 2 ) r -heterocycle, —C(O)OH, —C(O)NH 2 , —R 5 (R 9 ) q , —OR 5 (R 9 ) q , nitro, —SO 2 R 6 , —C(O)R 10 , and —CO(O)R 4 ;
  • n and n in each instance are independently 0, 1, or 2;
  • p is independently 0, 1, or 2;
  • r and q in each instance are independently 0, 1, 2, or 3.
  • L 1 and L 2 are both (—CH 2 —);
  • W is O
  • R 1 is —H
  • R 7 and R 8 are independently selected from the group consisting of —H and methyl
  • R 9 is selected from the group consisting of chloro, bromo, and fluoro
  • R 11 is selected from the group consisting of chloro, bromo, and fluoro
  • n 0, 1, or 2;
  • r is 1, 2, or 3.
  • L 1 and L 2 are independently selected from a bond or [C(R 6 R 6 )] q ;
  • Q is selected from —CH 2 — or —C( ⁇ O)—;
  • W is selected from a bond or oxygen
  • R 1 is selected from the group consisting of —H, (C 1 -C 12 )alkyl, —C(O)R 5 , —CH 2 —O—(C 1 -C 6 )alkyl, 2-tetrahydro-2H-pyran and
  • R 2 is selected from the group consisting of —H, (C 1 -C 12 )alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-O—C 1-6 alkyl, —C(O)R 5 , and —(CH 2 ) r NR 7 R 8 , —C(O)R 5 , wherein when W is oxygen, R 1 and R 2 can optionally be taken together with the oxygen and nitrogen to which they are respectively joined to form a 4 to 8 membered heterocyclyl ring. wherein the heterocyclyl ring may be optionally substituted by one to two R 11 groups;
  • R 3 is selected from the group consisting of hydrogen, (C 1 -C 12 )alkyl, —NR 1 R 2 , —OR 5 ,
  • R 2 and R 3 can optionally be taken together with the nitrogen and L 2 to which they are respectively joined to form a 4 to 8 membered heterocyclyl ring, wherein the heterocyclyl ring may be optionally substituted by one to two R 11 groups;
  • R 4 is selected from —H and (C 1 -C 6 )alkyl
  • R 5 is selected from (C 1 -C 6 )alkyl, —R 3 , —(CH 2 ) r NR 7 R 8 , or —(CH 2 ) r OR 7 ;
  • R 6 and R 6′ are independently —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, haloalkyl, —Y, —(CH 2 ) r NR 7 R 8 , —C(O)OH, —C(O)NH 2 , wherein the R 6 and R 6′ groups can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring, wherein the cycloalkyl ring may be optionally substituted by one to three R 11 groups;
  • R 7 and R 8 are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, -Q-aryl-(R 4 ) n , —NR 14 R 15 , —C(O)CH 3 , wherein R 7 and R 8 can optionally be taken together with the nitrogen to which they are joined to form a 4 to 8 membered heterocyclyl or heteroaryl ring containing one to three heteroatoms selected from —NR 5 —, —O—, —S—, —S(O)—, or —SO 2 —, wherein the heterocyclyl or heteroaryl ring may be optionally substituted by one to three R 11 groups;
  • R 9 is halo
  • R 10 is —N(R 16 ) 2 ;
  • R 11 , R 12 , and R 13 are independently selected from the group consisting of oxo, hydroxyl, halo, (C 1 -C 6 )alkoxy, —R 6 (R 9 ) q , —OR 6 (R 9 ) q , nitro, —SO 2 R 6 , (C 1 -C 6 )alkyl, —C(O)R 10 , —R 4 YR 6 , and —CO(O)R 5 , wherein any two R 9 , R 10 or R 11 groups can optionally join to form a 3 to 8 membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring, wherein the heterocyclyl or heteroaryl ring may contain one to three heteroatoms selected from —NR 5 —, —O—, —S—, —S(O)—, or —SO 2 —, and wherein the cycloalkyl, aryl, heterocyclyl or hetero
  • R 14 and R 15 are independently selected from the group consisting of —H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, —[C(R 6 ) 2 ] r —, —O[C(R 6 ) 2 ] r —, oxo, hydroxyl, halo, —C(O)R 7 , —R 10 , and —CO(O)R 2 , wherein R 14 and R 15 can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring or 4 to 8 membered heterocyclyl ring containing one to three heteroatoms selected from —NR 5 —, —O—, —S—, —S(O)—, or —SO 2 —, wherein the cycloalkyl ring or heterocyclyl ring may be optionally substituted by
  • R 16 is independently selected from the group consisting of halo, oxo, hydroxyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl, —R 6 (R 9 ) q , —OR 6 (R 9 ) q , —N(R 4 ) 2 , —(CH 2 ) r -heterocyclyl, —C(O)OH, —C(O)NH 2 , —R 5 (R 9 ) q , —OR 5 (R 9 ) q , nitro, —SO 2 R 6 , —C(O)R 10 , and —CO(O)R 4 ;
  • n and n in each instance are independently 0, 1, 2, 3, or 4;
  • p is independently 0, 1, 2, 3, or 4;
  • r and q in each instance are independently 0, 1, 2, 3, or 4.
  • a compound having the structure of Formula I or Formula II above wherein Q m in the A group is absent and Q n in the A group is —CH 2 — and the Q in the Formula I structure is —C( ⁇ O)—.
  • a pharmaceutical composition comprising a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.
  • a method of treating HIV comprising administering to a patient suffering therefrom an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the compound is present in an amorphous form.
  • a pharmaceutical composition comprising a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the composition is in a tablet form.
  • a pharmaceutical composition comprising a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the compound is present as a spray dried dispersion.
  • a method of treating an HIV infection in a subject comprising administering to the subject a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof.
  • the subject is a mammal, and in other embodiments, the subject is a human.
  • a method of treating an HIV infection in a subject comprising administering to the subject a pharmaceutical composition comprising a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a method of preventing an HIV infection in a subject at risk for developing an HIV infection comprising administering to the subject a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof.
  • a method of preventing an HIV infection in a subject at risk for developing an HIV infection comprising administering to the subject a pharmaceutical composition comprising a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present invention also provides the use of a compound or salt as defined in any of Formula I or Formula II in the manufacture of a medicament for use in the treatment of an HIV infection in a human.
  • the compounds of the invention can exist in particular geometric or stereoisomeric forms.
  • the invention contemplates all such compounds, including cis- and trans-isomers, ( ⁇ )- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms can be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • Optically active (R)- and (S)-isomers and d and l isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If, for instance, a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.
  • separation of enantiomers and diastereomers is frequently accomplished using chromatography employing chiral, stationary phases, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).
  • a compound of Formula I or Formula II wherein the compound or salt of the compound is used in the manufacture of a medicament for use in the treatment of a viral infection in a human.
  • a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in Formula I.
  • the pharmaceutical formulation containing a compound of Formula I or Formula II or a salt thereof is a formulation adapted for parenteral administration.
  • the formulation is a long-acting parenteral formulation.
  • the formulation is a nano-particle formulation.
  • the methods of treating and/or preventing an HIV infection in a subject may in addition to administration of a compound of Formula I or Formula II further comprise administration of one or more additional pharmaceutical agents active against HIV.
  • the one or more additional agents active against HIV is selected from the group consisting of zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, lersivirine, GSK2248761, TMC-278, TMC-125, etravirine, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir, tipranavir, palinavir, lasinavir, enf
  • the compounds of the present invention and any other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order.
  • the amounts of the compounds of the present invention and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the administration in combination of a compound of the present invention and salts, solvates, or other pharmaceutically acceptable derivatives thereof with other treatment agents may be in combination by administration concomitantly in: (1) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • the amounts of the compound(s) of Formula I or Formula II or salts thereof and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the compounds of the present invention may be used in combination with one or more other agents useful in the prevention or treatment of HIV.
  • Nucleotide reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, and similar agents;
  • Non-nucleotide reverse transcriptase inhibitors include an agent having anti-oxidation activity such as immunocal, oltipraz, etc.
  • an agent having anti-oxidation activity such as immunocal, oltipraz, etc.
  • nevirapine delavirdine, efavirenz, loviride
  • immunocal immunocal
  • oltipraz immunocal
  • capravirine capravirine
  • lersivirine GSK2248761
  • TMC-278 TMC-125
  • etravirine and similar agents
  • Protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir, tipranavir, palinavir, lasinavir, and similar agents;
  • Entry, attachment and fusion inhibitors such as enfuvirtide (T-20), T-1249, PRO-542, PRO-140, TNX-355, BMS-806, BMS-663068 and BMS-626529, 5-Helix and similar agents;
  • Integrase inhibitors such as raltegravir, elvitegravir, GSK1349572, GSK1265744 and similar agents;
  • Maturation inhibitors such as PA-344 and PA-457, and similar agents.
  • CXCR4 and/or CCR5 inhibitors such as vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK 427,857), TAK449, as well as those disclosed in WO 02/74769, PCT/US03/39644, PCT/US03/39975, PCT/US03/39619, PCT/US03/39618, PCT/US03/39740, and PCT/US03/39732, and similar agents.
  • combinations of compounds of this invention with HIV agents is not limited to those mentioned above, but includes in principle any combination with any pharmaceutical composition useful for the treatment of HIV.
  • the compounds of the present invention and other HIV agents may be administered separately or in conjunction.
  • one agent may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the present invention may be used in combination with one or more agents useful as pharmacological enhancers as well as with or without additional compounds for the prevention or treatment of HIV.
  • agents useful as pharmacological enhancers include, but are not limited to, ritonavir, GS-9350, and SPI-452.
  • Ritonavir is 10-hydroxy-2-methyl-5-(1-methyethyl)-1-1[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5S*,8R*,10R*,11R*)] and is available from Abbott Laboratories of Abbott park, Illinois, as Norvir.
  • Ritonavir is an HIV protease inhibitor indicated with other antiretroviral agents for the treatment of HIV infection.
  • Ritonavir also inhibits P450 mediated drug metabolism as well as the P-gycoprotein (Pgp) cell transport system, thereby resulting in increased concentrations of active compound within the organism.
  • Pgp P-gycoprotein
  • GS-9350 is a compound being developed by Gilead Sciences of Foster City Calif. as a pharmacological enhancer.
  • SPI-452 is a compound being developed by Sequoia Pharmaceuticals of Gaithersburg, Md., as a pharmacological enhancer.
  • a compound of Formula I or Formula II is used in combination with ritonavir.
  • the combination is an oral fixed dose combination.
  • the compound of Formula I or Formula II is formulated as a long acting parenteral injection and ritonavir is formulated as an oral composition.
  • the compound of Formula I or Formula II is formulated as a long acting parenteral injection and ritonavir is formulated as an injectable composition.
  • a compound of Formula I or Formula II is used in combination with GS-9350.
  • the combination is an oral fixed dose combination.
  • the compound of Formula I or Formula II is formulated as a long acting parenteral injection and GS-9350 is formulated as an oral composition.
  • the compound of Formula I or Formula II is formulated as a long acting parenteral injection and GS-9350 is formulated as an injectable composition.
  • is a kit containing the compound of Formula I or Formula II is formulated as a long acting parenteral injection and GS-9350 formulated as an injectable composition.
  • a compound of Formula I or Formula II is used in combination with SPI-452.
  • the combination is an oral fixed dose combination.
  • the compound of Formula I or Formula II is formulated as a long acting parenteral injection and SPI-452 is formulated as an oral composition.
  • the compound of Formula I or Formula II is formulated as a long acting parenteral injection and SPI-452 is formulated as an injectable composition.
  • a compound of Formula I or Formula II is used in combination with compounds which are found in previously filed PCT/CN2011/0013021, which is herein incorporated by reference.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula I or Formula II.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula I or Formula II, wherein said virus is an HIV virus.
  • the HIV virus is the HIV-1 virus.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula I or Formula II, further comprising administration of a therapeutically effective amount of one or more agents active against an HIV virus.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of viruses comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula I or Formula II, further comprising administration of a therapeutically effective amount of one or more agents active against the HIV virus, wherein said agent active against HIV virus is selected from Nucleotide reverse transcriptase inhibitors; Non-nucleotide reverse transcriptase inhibitors; Protease inhibitors; Entry, attachment and fusion inhibitors; Integrase inhibitors; Maturation inhibitors; CXCR4 inhibitors; and CCR5 inhibitors.
  • the compound of the present invention is chosen from the compounds set forth in Table 2.
  • the compound(s) of the present invention is chosen from the compounds set forth in Table 2.
  • the methods of this invention may employ protecting groups which prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • the provided chemical entities may contain one or more chiral centers and such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this specification, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Ernka-Chemce or Sigma (St. Louis, Mo., USA).
  • reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about ⁇ 78° C. to about 110° C. over a period of about 1 to about 24 hours; reactions left to run overnight average a period of about 16 hours.
  • solvent each mean a solvent inert under the conditions of the reaction being described in conjunction therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuranyl (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N-methylpyrrolidone (“NMP”), pyridine and the like.
  • solvent inert under the conditions of the reaction being described in conjunction therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuranyl (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N-methylpyrrolidone (“NMP”), pyridine and the like.
  • THF tetrahydrofuranyl
  • DMF dimethylformamide
  • NMP
  • Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures.
  • suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can also be used.
  • the (R)- and (S)-isomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric
  • MS analytical low-resolution mass spectra
  • Solvent A 0.01% trifluoroacetic acid (TFA) in water
  • Solvent B 0.01% TFA in acetonitrile
  • the stereochemistry of the C28 secondary alcohol when present was not definitively confirmed as to its absolute configuration.
  • the compounds exemplified in the present application were isolated as optically pure stereoisomers and initially assigned to a configuration as drawn. There is the possibility that some of these may be listed as the opposite stereochemistry at that single C28 position as shown. This in no way is meant to limit the scope of the invention or utility of the compounds of Formula I. Additional examples contained within were determined to have the shown configuration by spectroscopic methods well known to those skilled in the art including, but not limited to, 1D and 2D NMR methods, vibrational circular dichroism and X-ray crystallography.
  • HBr in acetic acid (40 mL, 33%) was added to a suspension of the intermediate 2 (20 g, 38 mmol) in toluene (40 mL), Ac 2 O (40 mL), and acetic acid (AcOH, 40 mL) previously heated at 105° C.
  • the reaction mixture was stirred and heated at this temperature for 1.5 h. After cooling down, sodium acetate (24 g) was added and the resulting reaction mixture was evaporated to dryness.
  • the organic phase was washed successively with: water (100 mL), a saturated solution of sodium carbonate (100 mL ⁇ 2) and brine (100 mL ⁇ 2), then dried over sodium sulfate, and concentrated under reduced pressure to afford a sticky oil.
  • the sticky oil was triturated with MeOH (250 mL) and the precipitates were collected to give the intermediate 4 (6 g, 11.1 mmol, 83%) as a white solid.
  • reaction mixture was stirred at 20° C. for 2 h.
  • the reaction mixture was then cooled to 0° C. and NaBH 4 (1.541 g, 40.7 mmol) was added in portions within 30 min, after which the solution was allowed to stirred for 1 h.
  • the mixture was purified by preparative-TLC eluting with DCM/MeOH (20:1) to give 39 (108 mg, 0.147 mmol, 29%).
  • reaction mixture was stirred at rt for 2 h.
  • TFA (6 mL) was added to the reaction mixture.
  • the reaction solution was stirred at rt for another 1.5 h, and the product was extracted with DCM (60 mL*3), and the combined organic phase was washed with brine (100 ml), dried over Na 2 SO 4 , concentrated and the residue was purified by recrystallization from DCM and hexane (1:6) resulting in 800 mg of the TFA salt of 41 as white solid.
  • the reaction mixture was stirred at 40° C. for 2 h.
  • the reaction was cooled to rt and sodium cyanoborohydride (24.84 mg, 0.395 mmol) was added and the resultant solution was stirred overnight.
  • the reaction was diluted with ammonium chloride (40 ml), and extracted with DCM (60 ml ⁇ 3). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative-HPLC to afford 42 as a trifluoroacetic acid salt (200 mg, 49% yield) as a white solid.
  • the pH was adjusted to 7 with Et 3 N.
  • the reaction mixture was stirred at rt for 1 h and sodium cyanoborohydride (50.9 mg, 0.810 mmol) was added and the resultant mixture was stirred overnight.
  • the reaction was diluted with water (40 ml) and extracted with DCM (60 ml ⁇ 3).
  • Step D Compounds 62 and 63
  • reaction mixture was stirred at rt for 2 h. Then it was added NaCNBH 3 (85 mg, 1.345 mmol) portionwise and stirred for overnight. The solvent was evaporated and the residue diluted with DCM and washed with water and brine.
  • reaction mixture was stirred at 40° C. for 2 h.
  • the reaction was cooled to rt and sodium cyanoborohydride (7.75 g, 123 mmol) was added and the resultant mixture was stirred overnight.
  • the reaction was diluted with ammonium chloride solution (40 ml), and extracted with DCM (60 ml ⁇ 3).
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