WO2015130966A1 - Agents antiviraux - Google Patents

Agents antiviraux Download PDF

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Publication number
WO2015130966A1
WO2015130966A1 PCT/US2015/017822 US2015017822W WO2015130966A1 WO 2015130966 A1 WO2015130966 A1 WO 2015130966A1 US 2015017822 W US2015017822 W US 2015017822W WO 2015130966 A1 WO2015130966 A1 WO 2015130966A1
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WO
WIPO (PCT)
Prior art keywords
inhibitor
hiv
compound
pharmaceutically acceptable
acceptable salt
Prior art date
Application number
PCT/US2015/017822
Other languages
English (en)
Inventor
Steven S. Bondy
Chien-Hung Chou
John O. Link
Winston C. Tse
Original Assignee
Gilead Sciences, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Gilead Sciences, Inc. filed Critical Gilead Sciences, Inc.
Publication of WO2015130966A1 publication Critical patent/WO2015130966A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • Positive-single stranded RNA viruses comprising the Retroviridae family include those of the subfamily Orikoreirovirin e and genera Aipharetrovirus, Betareirovirus, Gamaretrovirm, Deliaretrovir s, Epsilonreirovirus, Lentivirus, and Spumavirm which cause many human and animal diseases.
  • Lenttvims ' HIV- 1 kfection in humans leads to depletion of T helper cells and immune dysfunction, producing immunodeficiency and vulnerability to opportunistic infections.
  • Treating HFV-i infections with highly active antiretrovirai therapies has proven to be effective at reducing viral load and significantly delaying disease progression (Hammer, S.M., et al; JAMA 2008, 300: 555-570). However, these treatments could lead, to the emergence of H!V strains that are resistant to current therapies (Taiwo, B. s International Journal of Infectious Diseases 2009, 13:552-559: Smith, R. J,, et al, Science 2010, 327:697-701 ). Therefore, there is a need to discover new antiretrovira! agents.
  • the present disclosure provides a compound of Formula (I):
  • One embodiment provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • One embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof; and an additional therapeutic agent, wherein the additional therapeutic agent is an HJY protease inhibiting compound, an HTV non-
  • HIV integrase inhibitor an HIV integrase inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp!20 inhibitor, a CCR5 inhibitor, a capsid polymerisation inhibitor, or a non-catalytic site HIV integrase inhibitor or combinations thereof.
  • Retroviridae viral infection e.g., an HIV virus
  • HIV viral infection in a patient in need thereof (e.g., a human), comprising administering a compound of formula I, or a pharmaceutically acceptable salt thereof, to the patient.
  • One embodiment provides a method for treating an HIV infection in a patient in need thereof (e.g., a human), comprising administering a compound of formula ⁇ , or a
  • One embodiment provides a method for treating an HIV infection in a patient in need thereof (e.g., a human), comprising administering to the patient a therapeutically effective amount of a compound of formula L or a p!mrmaceutically acceptable salt thereof, in combination with, a therapeutically effective amount of an additional therapeutic agent, wherein the additional therapeutic agent is an HXV protease inhibiting compound, an HIV i?on - nucleoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, a gp4! inhibitor, a CXC 4 inhibitor, a g l20 inhibitor, a CCR5 inhibitor, a capsid polymerization inhibitor, or a non-catalytic site HIV integrase inhibitor and combinations thereof.
  • the additional therapeutic agent is an HXV protease inhibiting compound, an HIV i?on - nucleoside inhibitor of reverse transcript
  • One embodiment provides a compound of formula % or a pharmaceutically acceptable salt thereof for use in medical therapy (e.g.. for use in treating a Retroviridae viral infection (e.g., an HIV viral infection) or the proliferation of the HIV virus or AIDS in a patient (e.g., a human)),
  • a Retroviridae viral infection e.g., an HIV viral infection
  • a patient e.g., a human
  • One embodiment provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the therapeutic treatment of a Retroviridae viral infection, an HIV virus infection, or AIDS,
  • One embodiment provides a compound of formula I, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating a Reimvmdm viral infection (e.g., an HIV viral infection) or the proliferation of the HIV virus or AIDS in a patient (e.g., a human).
  • a Reimvmdm viral infection e.g., an HIV viral infection
  • a patient e.g., a human
  • a compound of formula I, or a pharmaceutically acceptable salt thereof for use as a research tool, e.g., for use in identifying a compound for treating an HIV Infection
  • a compound of formula I, or a pharmaceutically acceptable salt thereof is us d in a method of identifying a compound that inhibits HIV by a two-stage antiviral mechanism involving early-stage (nuclear import block) and late-stage (improper capsid assembly) effects on virus replication.
  • One embodiment provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in an in vitro method.
  • the in vitro method can comprise administering to a cell infected with HIV with a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the compound is used as a standard, e.g., in a method of elucidating the mechanism of action of a test compound.
  • One embodiment provides an in vitro method of detecting ami -HI activity of a test compound, comprising administering the test compound to a cell Infected with HIV and comparing the and -HIV activity of the test compound to the anti-HlV activity of a compound of formula L or a pharmaceutically acceptable salt thereof.
  • One embodiment provides processes and intermediates disclosed herein that are useful for preparing compounds of formul I or salts thereof.
  • Another embodiment provides processes and intermediates disclosed herein that are useful for preparing compound s of any one of formulas ⁇ and la, or pharmaceutically acceptable salts thereof.
  • the present disclosure relates to, inter alia, compounds useful tor treating viral infections, in particular an HIV infection, pharmaceutical compositions thereof, processes for making the compounds, and methods of use thereof In treating viral infections, in particular an HIV (human immunodeficiency virus) infection.
  • HIV human immunodeficiency virus
  • a prefix such as “C « - v " or (C u -C v ) indicates that the following group has from u to v carbon atoms, wherein u and v represent positive integers, For example, "C h alk ! Indicates that the alkyl group has from 1 to 6 carbon atoms,
  • treatment is an approach for obtaining beneficial or desired results.
  • beneficial or desired results include, but are not limited to, alleviation of a symptom and/or dl lnishment of the extent of a symptom and/or preventing a worsening of a symptom associated with disease or condition.
  • Treatment includes one or more of the following: a) Inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) relieving the disease or condition, e.g., causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, Increasing the quality of life, and/or prolonging survival.
  • Inhibiting the disease or condition e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition
  • slowing or arresting the development of one or more symptoms associated with the disease or condition e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition
  • relieving the disease or condition e.g., causing
  • delaying development of a disease or cond ition means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and or Individual being treated. As is evident to one skilled In the art. a sufficient or significant delay can, in effect, encompass prevention,, in thai the individual does not develop the disease or condition.
  • a method that "delays" development of AIDS is a method thai reduces the probability of disease development in a given time frame and/or reduces extent of the disease in a given time frame, when compared to not using the method.
  • Such comparisons may be based on clinical studies, using a statistically significant number of subjects.
  • the development of AIDS can be detected using known methods, such as confirming an individual's HIV* status and assessing the individual's T-cell count or other indication, of AIDS
  • development such as extreme fatigue, weight loss, persistent diarrhea, high fever, swollen lymph nodes in the neck, armpits or groin, or presence of an opportunistic condition that is known to be associated with AIDS ⁇ e.g., a condition that is generally not present in individuals with functioning immune systems but does occur in AIDS patients). Development may also refer to disease progression that may be initially undetectable and includes occurrence, recurrence and onset.
  • an "at risk” individual is an indi vidual who is at risk of developing a condition to be treated.
  • An individual “at risk” may or may not have detectable disease or condition, and may or may not have displayed detectable disease prior to the treatment of methods described herein,
  • At risk denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease or condition and are known in the art.
  • An individual having one or more of these risk factors has a higher probability of developing the disease or condition than an individual without these risk factor(s). For example, individuals at risk for AIDS are those having Hi V,
  • the term "effective amount” refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the effective amount will vary depending on the compound, the disease, and its severity and the age, weight, etc., of the subject to be treated, The effecti ve amount can include a range of amounts.
  • an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint
  • An effective amount may he considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
  • Suitable doses of any co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
  • the salt is a pharmaceutically acceptable salt.
  • compositions detailed herein may comprise a compound of Formula (I) in a race ink- or non-racemic mixture of stereoisomers or may comprise a compound of Formula (I) as a substantially pure isomer (e.g., as the (S)-isomer at one or more
  • the compound of Formula ( ⁇ ) or (la) may be prepared and/or formulated as
  • Pharmaceutically acceptable salts are non-toxic salts of a free base form of a compound that possesses the desired pharmacological activity of the fee bass, These salts may be derived from inorganic or organic acids or bases.
  • a compound that contains a basic nitrogen may be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid.
  • Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bi sulfates, sulfites, bisuifstes, phosphates, morjohydrogen-phosphates, dihydrogenphosphates, m.etaphosphates,
  • pyrophosphates chlorides, bromides, iodides, acetates, propionates, dacanoates, eapryiates, aery!ates, formates, isobutyrates, caproates, heptanoates, propionates, oxalates, malonates, succinates, suberafes, sebacat.es, furnarates, malea es, butyne- 1 ,4 dioates, hexyne- 1 ,6-dioates, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, hydroxybenzoates,
  • methoxybenzoates phihalates, sulfonates, methylsulicnatcs, propylsuiionat.es, bes lates, xylenesulfonates, naphthalene- 1 -sulfonates, naphtha!ene-2-sulfosiafes 5 phenylacetates, phenyl propionates, pheny!butyrates, citrates, lactates, ⁇ -hydroxylwtyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in
  • solvate refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent
  • the solvent may be water, in which case the solvate may be a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the present invention may ex st as a hydrate, including a monohydrate, dihydrate, he ihydrate, sesquihydrate, trihydratc, tetrahydrate and the like, as well as the corresponding solvated forms.
  • the compound of the invention may be true solvates, while in other cases, the compound of the invention m ay merely retain ad ventitious water or be a mixture of water plus some adventitious solvent,
  • this invention also includes any compound provided herein that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as. but mi limited to, deuterium. ( 2 H or D).
  • the compounds disclosed herein may contain cMral centers, which may be either of the (R) or (S) configuration, or which may comprise a mixture thereof. Accordingly, the present disclosure includes stereoisomers of the compounds described herein, where applicable, either Individually or admixed in any proportions. Stereoisomers may include, but are not limited to, enantlomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present disclosure,
  • the compounds of the present disclosure may be compounds according to Formula (I) or (la) wit one or more chiral centers, which may be either of the (R) or (S) configuration, or which may comprise a mixture thereof.
  • the carbon to which -CHa-CeHjFa is connected may he either of the R or S configurations.
  • the chiral center is S configuration,
  • the present disclosure includes both racemic mixtures of a compound of Formula ⁇ and isolated isomers of Formula I. Where more than one chiral center is present in a compound of the present disclosure, some, none, or all of the chiral centers may be enantlomerlcaily enriched. Thus, mixtures of a compound of Formula I may be racemic with respect to one or more chiral ce ters and/or enantioniericail enriched with respect to one or more chiral centers.
  • compositions include a solid oral dosage form.
  • pH of the formulations ranges from about 3 to about I I, but Is ordinarily about 7 to 10,
  • Such formulations comprise at least one acti ve ingredient, as above defined, together with one or more acceptable carriers and optionally other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
  • the formulations include those suitable for the foregoing administration routes.
  • the formulations may conveniently he presented in unit dosage form and may be prepared by any of 15 017822 the methods well known m the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Eastern, PA). Such methods include the step of bringing into association the active ingredient with inactive ingredients (e.g., a carrier, pharmaceutical exeipienis, etc) which constitutes one or more accessory ingredients.
  • inactive ingredients e.g., a carrier, pharmaceutical exeipienis, etc
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations described herein that are suitable for oral administration may be presented as discrete units including but not limited to capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions disclosed herein comprise one or more compounds disclosed herei together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • Pharmaceutical formulations containing the active ingredient may be in any form suitable for fee intended method of administration. When used .for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • compositions inimdsd tor oral use may be prepared according to any meihod known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufac ture of tablets are acceptable.
  • These exeipienis may be, for example, inert diluents , , such as calcium, or sodium carbonate, lactose, lactose monohydrate, croscarmeliose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, macrocrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic ac d or talc.
  • inert diluents such as calcium, or sodium carbonate, lactose, lactose monohydrate, croscarmeliose sodium, povidone, calcium or sodium phosphate
  • granulating and disintegrating agents such as maize starch, or alginic acid
  • binding agents such as cellulose, macrocrystalline cellulose, starch, gelatin or acacia
  • lubricating agents such as
  • Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and. thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl nionosiearate or glyceryl distearate alone or with a wax may be employed,
  • a dosage form for oral administration to humans contains approximately 1 to 1000 mg of active material formulated with an appropriate and convenient amount of carrier materia! (e.g., inactive ingredient or exeipient material).
  • a dosage form (e.g., for oral administration to humans) contains: from 10 mg to 1000 mg or from 50 mg to 1000 mg or from 100 mg to 1000 mg or from 200 mg to 1000 mg or from.
  • active maierial e.g., a compound of any of Formula (I) or (la)
  • a dosage form for oral administration to humans contains at least any of 1.0, 25, SO, 100, 150, 200, 2S0 or 300 mg and. no more than 500 or 800 or 1000 mg of active material (e.g., from at least 50 mg to no more than 500 mg)
  • a dosage form for oral administration to humans contains at least any of 10, 25, 50, 100. 150, 200, 250 or 300 mg or no more than 500 or 800 or 1000 mg of active material, in some embodiments, a.
  • dosage form for oral administration to humans contains any of 10, 25, 50, 1.00, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of active material
  • a dosage form in an amount provided herein may be administered to a patient (e.g., a human in need thereof) in accordanc with a dosing regimen provided herein, such as once, twice or thrice daily dosing, in one aspect, a dosing regimen, provides for administration of at least .10 mg and no more than 1,000 mg of active material (e.g., a compound of any of Formula (I) or (la)) daily, and it is understood that the amount may be provided in any suitable dosage form and amount (e.g., 500 mg twice daily or 1,000 mg once daily would provide the same amount of 1,000 mg/day dosing).
  • the invention embraces once daily dosing to an individual (e.g., a human in need thereof) of a dosage form of compound (e.g., a compound of any of Formula (I) or (la)) containing at least 50 mg and not more than 300 mg of compound.
  • the carrier material varies from about 5 to about 95% of the total compositions (weight:weight),
  • a formulation comprising an active ingredient provided herein (a compound of any one of Formula (I) or (la), or a pharmaceutical salt thereof) in one variation does not contain an agent thai affects the rate at which the active ingredient is metabolized.
  • compositions comprising a compound of any one of Formula (I) or (la) in one aspect do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound of any one of Formula (1) or (la) or any other active ingredient administered separately, sequentially or simultaneously with a compound of any one of Formula (I) or (la), It is also understood that any of the methods, kits, articles of manufacture and the like detailed herein In one aspect do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound of any one of Formula (I) or (la) or any other active ingredient administered separately, sequentially or simultaneously with a compound of any one of Formula (I) or (la),
  • a compound of any one of Formula (I ; or (la) is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HIV, in certain instances, the tablet can contain another active ingredient for treating HIV, such as an HIV protease inhibiting compound, an HIV non-nucleoside Inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, an HI V lntegra.se inhibitor, a gp41 Inhibitor, a CXCR4 inhibitor, a gp!20 inhibitor, a CC 5 Inhibitor, a eapsid polymerization inhibitor, or a non-catalytic site HIV integrase inhibitor, or combinations thereof.
  • such tablets are suitable for once daily dosing,
  • Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophyiacticany (lower doses), the method of deli very, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies.
  • Formulations comprising a compound of formula L or a pharmaceutically acceptable salt thereof, not intended for pharmaceutical use are also embraced by the Invention.
  • a formulation can comprise a compound of formula I, or a pharmaceutically acceptable salt thereof, in a solvent or carrier for use in an in vitro method.
  • the solvent is one that is suitable for in vitro use but not for pharmaceutical use.
  • a method of inhibiting the proliferation of the HIV virus in an individual in need thereof comprising administering a compound of any of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, to the individual. Also provided is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, for use in such a method. Also provided is the use of a compound of M of Formula (! or (la), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting the proliferation of the HIV virus In an individual in need thereof. In one aspect, the individual in need thereof is a human who has been infected with HiV.
  • the individual in need thereof is a human who has been infected with HIV but who has not developed AIDS. In one variation, the individual in need thereof is an individual at risk for developing AIDS, In another variation, the individual in need thereof Is a human who has been infected with HIV and who has developed AIDS.
  • a compound of any of Formula (I) or (la), or a pharmaceutically acceptable salt thereof is administered to the individual separately, sequentially or simultaneously with another active ingredient for treating HTV, such as an HIV protease inhibiting compound, an HIV non-nuckoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an.
  • HIV nucleotide Inhibitor of reverse transcriptase an HIV integrase inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a g i 20 inhibitor, a CCRS inhibitor, a eapsid polymerization inhibitor, or a non-catalytic site HIV Integrase inhibitor or combinations thereof.
  • One embodiment provides a method for treating a Reiroviridae viral infection (e.g., an HIV viral infection) in an Individual (e.g.. a human), comprising administering a compound of any of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, to the individual
  • a Reiroviridae viral infection e.g., an HIV viral infection
  • an Individual e.g.. a human
  • administering a compound of any of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, to the individual
  • One embodiment provides a method for inhibiting the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS in an individual (e.g., a human), comprising administering a compound of any of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, to the individual,
  • One embodiment provides a method for treating an HIV infection in an individual (e.g., a human), comprising administering a compound of any of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, to the individual.
  • One embodiment provides a method for treating an HIV infection in an individual (e.g., a human), comprising administering to the individual n need thereof a therapeutically effective amount of a compound of any of Formul (I) or (la), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of an additional therapeutic agent, wherein the therapeutic agent is an HIV protease inhibiting compound, art HIV non ⁇ nucleoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse
  • transcriptase an HIV nucleotide mhibitor of reverse transcriptase, an HIV irstegrase inhibitor, a gp41 inhibitor, a CXC 4 inhibitor, a gp!20 inhibitor, a CCR5 inhibitor, a capsid polymerization mhibitor, or a non-catalytic site HIV integrase inhibitor or combinations thereof.
  • a compound of Formula ( ⁇ ) or (la) or a pharmaceutically acceptable salt thereof for use in such a method .
  • One embodiment provides a compound of any of Formula (I) or (la), or a
  • a Reiroviridae viral infection e.g., m HIV viral infection
  • a Reiroviridae viral infection e.g., m HIV viral infection
  • the proliferation of the HIV virus or AIDS or delaying the onset of AIDS in an individual ⁇ e.g., a human
  • One embodiment provides a compound of any of Formula (I) or (la), or a
  • a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating & Reiroviridae viral infection ⁇ e.g., an H viral infection) or the proliferation of the HIV virus or AIDS or delaying the onset of AIDS in an individual (e.g., a human).
  • One embodiment provides the use of a compound of a y of Formula ( ⁇ ) or (la), or a phamiaceuticaliy acceptable salt thereof, for the manufacture of a medicament for a Reiroviridae virus infection (e.g., m HIV virus infection) in an individual ⁇ e.g., a human).
  • the administration is to an individual (e.g., a human) in need of the treatment in some embodiments, in the methods of use, the administration Is to an individual (e.g., a human) who is at risk of developing AIDS.
  • a method of identifying a compound for treating an HI infection comprising administering to a cell infected with an i-OV infection a test compound, and comparing the anti ⁇ HIV activity obtained with the test compound to the anti-HIV activity of a compound of formula I, or a pharmaceutically acceptable salt thereof, in one aspect, a method of identifying a compound that inhibits HIV by a two-stage antiviral mechanism involving early-stage (nuclear import block) and late- stage (improper capsld assembly) effects on virus replication is provided, comprising administering to a ceil infected with, an HiV infection a test compound, and comparing the mechanism of action of anti- HIV activity of the test compound to the mechanism of actio of anti-HIV activity of a compound of formula L or a pharmaceutically acceptable salt thereo
  • an in vitro method of detecting anti-HIV activity of a test compound comprises administering the test compound to a cell infected with HIV and comparing the anti-HIV activity of the test compound to the anti-HIV activ ty of a compound of formula I, or a pharmaceutically acceptable salt thereof
  • One or more compounds disclosed herein are administered by any route appropriate to the condition to be treated. Suitable routes include oral rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal s intrathecal and epidural), and the like, it will be appreciated that the preferred route may vary with for example the condition of the recipient.
  • An ad vantage of the compounds disclosed herein is that they are orally bioavailable and can be dosed orally.
  • the compound such as a compound of any of Formula (I) or (la) may be administered to an indivi dual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer.
  • the compound is administered on a daily or intermittent schedule for the duration of the individual's life.
  • the dosage or dosing frequency of a compound of any of Formula (I) or (fa) may be adjusted over the course of the treatment, e.g., based on the judgment of the administering physician,
  • the compound may be administered to an individual i an effective amount, In one aspect, the compound is administered once dally, in one aspect, the compound is administered twice a day. In one aspect, the compound is administered three times daily. It is understood that, the compound may he administered in any dosage amount provided herein, such as a dosage amount that would provide at least 10 mg day dosing and no more than 1,000 mg day dosing. Once daily oral dosing is embraced, such as by administering a dosage form containing from SO mg to 300 rag of compound.
  • the invention provides a method for treating an HIV infection, comprising administering to a patient in need thereof a therapeutically effecti ve amoun of a compound disclosed herein, or a pharmaceutically acceptable salt, thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HJ.V Infection, Also provided Is a compound disclosed herein, or a
  • a compound as disclosed herein e,g., a compound of any of Formula (I) or (la), or a pharmaceutically acceptable salt thereof
  • a method for treating or preventing an HIV infection in a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof la combination with a therapeutically effective amount of one or more additional therapeutic agents. Also provided is a compound disclosed herein, or a
  • the invention provides pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent, and a pharmaceutically acceptable carrier.
  • the therapeutic agent used In combination with the compound disclosed herein can be any anti- HIV agent.
  • combination pharmaceutical agents comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, In combination with one or more additional therapeutic agents are provided.
  • compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent and a pharmaceutically acceptable carrier.
  • the additional tlierapeutic agent may be an anti-HIV agent.
  • the additional therapeutic agent is selected from the group consisting of HIV protease inhibiting compounds (HIV protease inhibitors), HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrate inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, entry inhibitors (e.g., CCRS inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gp!20 Inhibitors, G6PD and NADH-oxidase inhibitors, capsid polymerization inhibitors or capsid disrupting compounds such as those disclosed in US 2013/0165489 (University of Pennsylvania), and WO 2013/006792 (Pharma Resources), pharmacokinetic enhancers, and other drags for treating HIV, or combinations thereof,
  • HIV protease inhibiting compounds HIV non-nu
  • One embodiment provides a pharmaceutical composition comprising a compound disclosed herein; and an additional therapeutic agent, wherein the additional therapeutic agent is an HIV protease inMbiiing compound, an HIV non-nucleoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HiV nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp!20 inhibitor, a. CCR5 inhibitor, a capsid polymerization inhibitor, or a non-catalytic site HIV integrase inhibitor, or combinations thereof,
  • the additional therapeutic agent is an HIV protease inMbiiing compound, an HIV non-nucleoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HiV nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, a gp41 inhibitor, a CXCR4
  • the additional therapeutic agent is selected from one or more of:
  • HIV protease inhibitors selected from the group consisting of amprenavir, atazanavir, fosamprenavir, Indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavk.
  • HIV non-nucieoside or non-nucleoiide I hibitors of reverse transcriptase selected from the group consisting of capravirme, em vin e, de!aviridine, efavirenz, ncvirapine, (+) calanoiide A, etravirine, GW5634, DFC-083, DPC-961, DPC-963, MIV-150, TMC-120, nipivirine, B1LR 355 BS, VRX 840773, lerslvirine (UK-453061), RDEA8G6. M023 and MK-
  • HIV nucleoside inhibitors of reverse transcriptase selected from the group consisting of zidovudine, erntrieltablne, didaraosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, e!vuehahine, alovudme, MfV-210, ⁇ FTC, D-d4FC, emtricitabine, phosphatide, fozivudine tidoxil, apricitlbine (AVX754), amdoxovir, KP ⁇ 1.461, GS-9131 (Gilead Sciences) and f salvudine tidoxil (formerly HDP 99.0003);
  • HiV nucleotide inhibitors of reverse transcriptase selected from the group consisting of tenofovir, tenofovir dlsoproxll fumarate, tenofovir dssoproxil hemifumarate, tenofovir disoproxii, tenofovir alafenamide fumaraie, tenofovir alafenamide heraifumamte, tenofovir alafenamide, GS-7340 (Gilead Sciences), GS- 148 (Gilead Sciences), adefovir, adefovir diplvoxil, CMX-001 (Chimerix) and C.MX-157 (Chimcrix);
  • HiV integrase inhibitors selected from the group consisting of curcumin, deri vatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquiiuc acid, aisrmtnearboxylic acid, derivatives of aurintriearboxyHc acid, eaf&ie acid phenethyi ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-1360, AR-177, L-8708.12, and L-870810, raltegravir, BMS-538158, GS.K364735C, BMS-707035, -2048, ⁇ 0 ⁇ , eivitegravir, dokstegravir and GSK-744;
  • NICKi integrase inhibitors mekding
  • BI-224436 CX0516, CX05045, CX14442, compounds disclosed in WO
  • gp 1 inhibitors selected from the group consisting of enfuviriide, sifuvirtide, albuvirtide, FB006M, and TRI-1144;
  • CC 5 inhibitors selected from the group consisting of aplaviroc, vicriviroc, maraviroc, cenietiviroc, PROI4Q, INCB1505G, FF-232798 (Pfizer), and CC 5mAb004;
  • CD4 attachment inhibitors selected from the gr u consisting of ibalizumab (TMB ⁇ 355) and B S-068 (B S-663068);
  • pharmacokinetic enhancers selected from the group consisting of eohieistat, ritonavir,, and SPI-452;
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with two. three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents, hi further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents, The two, three four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, or they can be selected from different classes of therapeutic age-its.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleotide inhibitor of reverse transcriptase and an HIV non- nuv!eoside inhibitor of reverse transcriptase
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleotide inhibi tor of reverse transcriptase, and an HIV protease inhibiting compound
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and an HIV protease inhibiting compound
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleotide inhibitor of reverse transcriptase, an HIV non-nucieoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with ienoiovir, tenofovir disoproxi! fumarate, tenofovir disoproxi! hemifumarate, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof Is combined with tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir alafenamide.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with emtricitabine, abacavir or lamivudine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with one of: tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and one of: emtricitabine, abacavir or lamivudine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with one of: tenofovir disoproxil fomarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide fumarate, or tenofovir alafenamide and one of: emtricitabine or abacavir.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifemarate, or tenofovir alafenamide and 200 mg emtricitabine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 5- 10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine, bi some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine.
  • a compound as disclosed herein may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 300 mg of compound) the same as if each combination of dosages were specifically and individually listed, [0073]
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 200-400 mg tenofovlr disoproxil fumarate, tenofovlr dlsoproxii hemifumarate s or tenofovlr disoproxi!
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 200- 250: 200-300; 200-350; 250-350; 250-400; 350-400; 300-400; or 250-400 mg tenofovlr disoproxil fu arate, tenoibvir dlsoproxii hemifurnarate, or tenofovlr disoproxil and 200 mg em rieitabke.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 300 mg tenofovir disoproxil fumarate, tenofovlr disoproxil hemifurnarate, or tenofovlr disoproxil and 200 mg emtrieitabine,
  • a compound as disclosed herein e.g., a compound of any of Formula (I) or (la), or a pharmaceutically acceptable salt thereof
  • the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 300 mg of compoimd) the same as if each combination of dosages were specifically and individually listed.
  • one or more of fee compounds disclosed herein are combined with one or more other active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient, in certain embodiments, a pharmaceutical composition including one or more of fee compounds disclosed herein combined with one or more other active therapeutic agents is provided. In certain embodiments, the compounds disclosed herein are combined with one or more other active therapeutic agents in a solid dosage form. The combination therapy may he administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administratio s, [0075] In some embodiments, one or more of the compounds disclosed herein are coadministered with one or more other active therapeutic agents.
  • Co-administration of a compound disclosed herein with one or more other active therapeutic agents generally refers to simultaneous or sequential adm inistration of a compound disclosed herein and one or more other active therapeutic agents, such that therapeutically effective amounts of disclosed herein and one or more other active therapeutic agents are both present in the body of the patient.
  • the present application provides a method for treating an HIV Infection comprising administering to a patient Irs need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents such as those disclosed above. Also provided is a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents such as those disclosed above, for use in treating an HIV infection. Also provided is a compound disclosed herein, or pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents such as those disclosed above, for use in treating an HIV infection.
  • the invention also provides a product comprising a compound disclosed herein, or a pharmaceutically acceptable salt or co-crystal thereof, and an add tional therapeutic agent such as those disclosed above as a combined preparation for simultaneous, separate or sequential use in therapy (e.g., in treating an HIV infection).
  • kits comprising a compound of any of Formula (I) or (la), or a pharmaceutically acceptable salt thereof.
  • the kit may further comprise instructions for use, e.g., for use in inhibiting an HTV protease, such as for use in treating an. HIV infection or AIDS.
  • the instructions for use are generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable.
  • kits comprising one or more containers comprising a compound of any of Formula (I) or (la), or a pharmaceutically acceptable salt, thereof.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice reflects approval by the agency for the manufacture, use or sale for human administration.
  • Each component if there is more than one component
  • the kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
  • [3 ⁇ 4 ⁇ )79 Also provided are articles of manufacture comprising a unit dosage of a, compound of any of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, in suitable packaging for use in the methods described herein.
  • suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like.
  • An article of manufacture may further be sterilized and/or sealed.
  • the embodiments are also directed to processes and intermediates useful for preparing the subject compounds or pharmaceutically acceptable salts thereof, which are shown in Example I, for example.
  • Compounds as described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically the disclosed compounds are purified via silica gel and/or alumina chromatography. See, e.g., Introduction to Modem Liquid Chromatography, 2nd ed., ed. L. R. Snyder and 1 J. Kirkland, John Wiley and Sons, 1979; and Thin Layer
  • any of the processes for preparation of the subject compounds i .may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups as described in standard works, such as T, W. Greene and P. G, M. Wuts, "Protective Groups in Organic Synthesis," 4 th ed,, Wiley, New York 2006.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art
  • the processes further involve the step of forming a salt of a compound of the present disclosure.
  • Embodiments are directed to the other processes described herein; and to the product prepared by any of the processes described herein,

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Abstract

La présente invention concerne des composés de formule (I); ou des sels de ceux-ci. L'invention concerne également des compositions pharmaceutiques comprenant un composé représenté par la formule (I), des procédés de préparation des composés représentés par la formule (I), des intermédiaires utiles pour préparer les composés représentés par la formule (I) et des méthodes thérapeutiques pour traiter une infection virale par Reirovirida , notamment une infection causée par le virus du VIH.
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WO2021064677A1 (fr) 2019-10-04 2021-04-08 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2021070054A1 (fr) 2019-10-08 2021-04-15 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
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